JPH08208602A - Indoylguanidine derivative - Google Patents

Abstract

(57) [Summary] [Purpose] It has a sodium / proton exchange transport system inhibitory action and is, for example, hypertension, arrhythmia, angina, cardiac hypertrophy, diabetes, ischemia or ischemia-reperfusion-induced organ damage, cerebral ischemia damage. A novel compound useful as a therapeutic or prophylactic agent for [Structure] An indoloylguanidine derivative represented by the following formula. Embedded image In the formula, R ₁ is a hydrogen atom, an alkyl group, a substituted alkyl group,
Alkenyl group, an alkynyl group, a cycloalkyl group, a halogen atom, a nitro group, an acyl group, a carboxyl group, an alkoxycarbonyl group, an aromatic group, or a group of the formula -OR _3,, -
_{NR 6 R 7, -SO 2 NR} 6 R 7 or -S (O) _n
R ₄₀ represents a group, and R ₂ represents a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a hydroxyl group, an alkoxy group, an aromatic group or a group represented by the formula —CH ₂ R ₂₀ .

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel indoloylguanidine derivative. The compound of the present invention has a sodium / proton (Na ⁺ / H ⁺ ) exchange transport system inhibitory action, and is a disease caused by enhancement of the sodium / proton (Na ⁺ / H ⁺ ) exchange transport system, for example, hypertension, arrhythmia, constriction. Organ damage due to cardiomyopathy, cardiac hypertrophy, diabetes, ischemia or ischemia-reperfusion (eg myocardial ischemia-reperfusion injury, acute renal failure, surgical treatment (eg organ transplant or PTCA (Percutaneous Transluminance)).
al Coronary Angioplasty)) caused by)),
Causes of cerebral ischemic disorders (eg, disorders associated with cerebral infarction, disorders that occur as sequelae after stroke, cerebral edema, etc.), and hyperproliferation of cells (eg, proliferation of fibroblasts, proliferation of smooth muscle cells, proliferation of mesangial cells, etc.) Diseases (eg, atherosclerosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, renal glomerulosclerosis, organ hypertrophy, prostatic hypertrophy, diabetic complications, PTC)
It is useful as a therapeutic or prophylactic drug for diseases such as restenosis after A) and diseases caused by endothelial cell damage.

[0002]

2. Description of the Related Art Certain polycyclic aroylguanidine derivatives, for example, naphthalene, 9,10-dihydroanthracene, benzofuran, 2,3-dihydrobenzofuran, benzothiophene, benzothiazole, methylenedioxybenzene as a polycycle, Pyridothiophene, pyrimidothiophene, quinoline, 1,6-naphthyridine, 1,8-
Naphthyridine, 3,4-dihydrobenzopyran, 3,4
-Dihydroquinazolin-4-one, 1,2,3,4-tetrahydroquinazolin-2-one, quinoxaline, 5,
6,7,8-tetrahydroquinoxaline, benzazepine, benzotriazepine, benzimidazolothiazine,
Polycyclic aroylguanidine derivatives having a benzopyranopyran or benzocarbazole ring are known, and as an aroylguanidine derivative having an indole ring, 1
-Guanidinocarbonyltryptophan (registered in Chemical Abstracts, but has no mention of literature name.
Registration number: 18322-34-4) is known.

On the other hand, certain monocyclic aroylguanidine derivatives such as pyrazinoylguanidine derivatives represented by amiloride are sodium / proton (Na ⁺ /
It is known to have an inhibitory action on the H ⁺ ) exchange transport system and an antiarrhythmic action (for example, J. Membrane Biol., V
ol. 105, 1 (1988); Circulation, Vol. 79, 1257 (19
89)). Further, it was recently reported that a benzoylguanidine derivative has a sodium / proton (Na ⁺ / H ⁺ ) exchange transport system inhibitory action and an antiarrhythmic action (for example, J. Mol. Cell. Cardiol. ., Vol.24, Sup
pl.I, S.92 (1992); J. Mol. Cell. Cardiol., Vol.24,
Suppl.I, S.117 (1992); JP-A-3-106858; JP-A-5-339228).

[0004]

DISCLOSURE OF THE INVENTION The present invention has a sodium / proton (Na ⁺ / H ⁺ ) exchange transport system inhibitory action and is caused by enhancement of the sodium / proton (Na ⁺ / H ⁺ ) exchange transport system. Diseases such as hypertension, arrhythmia, angina, cardiac hypertrophy, diabetes, ischemia or ischemia or ischemia-reperfusion-induced organ damage (eg myocardial ischemia-reperfusion injury, acute renal failure, surgical treatment (eg organ transplantation or PTCA ( Percutaneous Tran
sluminal Coronary Angioplasty))), cerebral ischemic disorder (eg, cerebral infarction, morbidity after stroke, cerebral edema, etc.), hyperproliferation of cells (eg, fibroblast proliferation, smooth muscle cells) Diseases caused by proliferation, mesangial cell proliferation, etc. (eg, atherosclerosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, renal glomerulosclerosis, organ hypertrophy, prostatic hypertrophy, diabetic complication, P
It is an object of the present invention to provide a novel indoloylguanidine derivative useful as a therapeutic or prophylactic agent for diseases such as restenosis after TCA) and diseases caused by endothelial cell damage.

[0005]

The present invention provides the following general formula (1):

[Chemical 10] (In the formula, R ₁ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group,
Halogen atom, nitro group, acyl group, carboxyl group,
Alkoxycarbonyl group, aromatic group, or formula-O
_{R 3, -NR 6 R 7,} -SO 2 NR 6 R 7 or -S
A group represented by (O) _n R ₄₀ (R ₄₀ represents an alkyl group, a substituted alkyl group or an aromatic group, and n represents 0, 1 or 2), or

[Chemical 11] Wherein, A represents an oxygen atom or the formula -S (O) _n - or -N (R ₅₀₎ - represents a group represented by (R ₅₀ represents a hydrogen atom or an alkyl group), R 'is a hydrogen atom, It represents an alkyl group or a substituted alkyl group, and the ring represents a saturated heterocycle containing one 3- to 8-membered nitrogen atom. ], Which may be substituted by one or the same or different, and R ₂ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a hydroxyl group, an alkoxy group, an aromatic group or a formula —CH ₂ R ₂₀ (R ₂₀ represents an alkenyl group or an alkynyl group). R ₃ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group,
An aromatic group or a group represented by the formula —CH ₂ R ₃₀ (R ₃₀ represents an alkenyl group or an alkynyl group), R ₆
And R ₇ are each independently a hydrogen atom, an alkyl group,
A substituted alkyl group, a cycloalkyl group, an acyl group, an aromatic group, or a group represented by the formula —CH ₂ R ₆₀ (R ₆₀ represents an alkenyl group or an alkynyl group), or R ₆ and R ₇ are mutually When combined, represents a saturated 5- to 7-membered cyclic amino group which may contain other heteroatoms in the ring. However, in the above general formula, the R ₁ group and the guanidinocarbonyl group may be bonded to either the 6-membered ring portion or the 5-membered ring portion of the indole ring. And an pharmaceutically acceptable acid addition salt thereof, and a sodium / proton exchange transport system inhibitor containing the above compound.

The compounds represented by the following general formulas (2) and (1 ') and the sodium / proton exchange transport system inhibitors containing them are each examples of the embodiments of the present invention.

[Chemical 12]

[Chemical 13] (In the formula, R ₁ and R ₂ are as described above. R _a is equivalent to the group represented by R ₁ , but in particular, one or more arylalkyl groups which are the same or different from each other. Or a heteroarylalkyl group, and the aryl moiety and the heteroaryl moiety are an alkyl group, a substituted alkyl group, an alkoxycarbonyl group, a carboxyl group, —CONR ₆ R ₇ , —SO ₂ NR ₆ R ₇ and —S (O ) _N R ₄₀ has a substituent selected from the group consisting of, or R _a is a formula —A—R _b [A is an oxygen atom or a formula —S (O) _n — or —N (R ₅₀ ) —. Represents a group (R ₅₀ is a hydrogen atom or an alkyl group) represented by R
_b represents an aryl group or a heteroaryl group, the aryl group and heteroaryl group, an alkyl group, a substituted alkyl group, a halogen atom, a nitro group, an alkoxycarbonyl group, a carboxyl _{group, -OR 3, -NR 6 R 7} , −
_{CONR 6 R 7, -SO 2 NR} 6 R 7 and -S (O)
_It may have a substituent selected from the group consisting of _n R ₄₀ . ] The group shown by

Embedded image Wherein, A represents an oxygen atom or the formula -S (O) _n - or -N (R ₅₀₎ - represents a group represented by (R ₅₀ represents a hydrogen atom or an alkyl group), R 'is a hydrogen atom, It represents an alkyl group or a substituted alkyl group, and the ring represents a saturated heterocycle containing one 3- to 8-membered nitrogen atom. ] Groups represented by or wherein _{-A-, (CH 2) m -R} c [A represents an oxygen atom or the formula -S (O) _n - or -N (R ₅₀₎ - group (R ₅₀ represented by hydrogen Represents an atom or an alkyl group),
R _c represents an aryl group or a heteroaryl group, and the aryl group and the heteroaryl group are an alkyl group, a substituted alkyl group, an alkoxycarbonyl group, a carboxyl group, —OR ₃₁ , —CONR ₆ R ₇ , —SO ₂ NR ₆ R ₇
And —S (O) _n R ₄₀ having a substituent selected from the group consisting of, m represents 1 to 8, R ₃₁ represents a substituted alkyl group,
It represents a cycloalkyl group or —CH ₂ R ₃₀ (R ₃₀ is an alkenyl group or an alkynyl group). ] Represents the group shown.
R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₂ are independently of each other,
It represents a group corresponding to R ₁ . ) In still another embodiment, in the above formula (2), R
_At least one of ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₂ is R
_The case where it is the group shown by a is mentioned.

Various groups in the present invention will be described below. As the alkyl group, for example, linear or branched carbon such as methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl, heptyl, octyl and the like. Examples thereof include alkyl groups having 8 or less atoms.

Examples of the alkenyl group include alkenyl groups having 6 or less carbon atoms such as vinyl, allyl, propenyl, 2-propenyl, butenyl, pentenyl and hexenyl. Examples of the alkynyl group include alkynyl groups having 2 to 6 carbon atoms such as ethynyl, propargyl, butynyl and pentynyl.

Examples of the cycloalkyl group include cycloalkyl groups having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Examples of the halogen atom include fluorine, chlorine and bromine atoms.

Examples of the acyl group include linear or branched alkanoyl groups having 8 or less carbon atoms such as acetyl, propanoyl and 2-methylpropanoyl, and 10 carbon atoms such as phenylacetyl and phenylpropanoyl. The following arylalkanoyl groups include, for example, benzoyl, 1-naphthoyl, 2-naphthoyl, and other aroyl groups having 11 or less carbon atoms.

Examples of the alkoxycarbonyl group include linear or branched alkoxycarbonyl groups having 6 or less carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and 2-propoxycarbonyl.

The aromatic group includes an aryl group which may have a substituent and a heteroaryl group which may have a substituent. Examples of the aryl group include phenyl and
Aryl groups having 10 or less carbon atoms such as naphthyl,
Examples of the heteroaryl group include 2-, 3-, 4-pyridyl, imidazolyl, triazolyl, tetrazolyl,
2-, 3-furyl, 2-, 3-thienyl, 1-, 3-,
A 5- to 6-membered heteroaryl group containing 1 to 4 nitrogen atoms such as 4-oxazolyl, 3-, 4-, 5-isoxazolyl and 1 to 2 nitrogen atoms and 1 oxygen atom or 1 sulfur atom. 5- to 6-membered heteroaryl groups including are mentioned. Substituents in the substituted aryl group and the substituted heteroaryl group include an alkyl group, a substituted alkyl group, a halogen atom, a nitro group, an alkoxycarbonyl group, a carboxyl group and a formula —OR ₃ , —NR ₆ R ₇ , —CONR ₆
R _7, include groups represented by -SO ₂ NR ₆ R ₇ or _{-S (O) n R 40,} .

R ₁ is a group represented by the formula —OR ₃ , and examples of typical —OR ₃ group in the case where R ₃ is an aromatic group are a phenoxy group and a substituted phenoxy group. Examples of the substituted phenoxy group include, for example, nitro group, -NR
₆ R ₇ group (as R ₆ and R ₇ , for example, a hydrogen atom,
Alkyl group, etc., substituted alkyl group (as a substituent,
Examples thereof include a phenoxy group substituted with a hydroxyl group, a —NR ₆ R ₇ group, etc.). More specific substituted phenoxy groups include, for example, o-, m- or p-nitrophenoxy, o-, m- or p-aminophenoxy, o.
-, M- or p- (dimethylamino) phenoxy, o
-, M- or p- (aminomethyl) phenoxy, o
-, M- or p- (dimethylaminomethyl) phenoxy and the like can be mentioned.

As the alkoxy group, for example, methoxy,
Examples thereof include linear or branched alkoxy groups having 6 or less carbon atoms such as ethoxy, isopropoxy and tert-butoxy.

The saturated 5- to 7-membered cyclic amino group which may have other heteroatoms in the ring and which is formed by R ₆ and R ₇ being bonded to each other is, for example, 1 to 1 nitrogen atom.
5- to 7-membered ring groups containing 3 or 5- to 7-membered ring groups containing 1 nitrogen atom and 1 oxygen atom, and more specifically 1-pyrrolidinyl, piperidino, 1-piperazinyl,
Examples thereof include morpholino and 4-methylpiperazinyl.

The substituent in the substituted alkyl group is a halogen atom, a hydroxyl group, an alkoxy group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an acyl group, an aromatic group,
And the formula —CONR ₄ R ₅ (R ₄ and R ₅ independently of each other represent a hydrogen atom or an alkyl group, or R ₄ and R ₅ are bonded to each other and may contain another heteroatom in the ring. Represents a saturated saturated 5- to 7-membered cyclic amino group), -NR ₆ R ₇ or

[Chemical 15] (E represents a nitrogen atom or a CH group, R ″ represents a hydrogen atom, an alkyl group or a substituted alkyl group, and the ring is a 3- to 8-membered saturated aliphatic ring or a saturated heterocycle containing one nitrogen atom. Represents a group).
When R ₁ , R ₂ and R ₃ are substituted alkyl groups, the substituents include a cycloalkyl group, a halogen atom, a hydroxyl group,
Examples include an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an acyl group, an aromatic group, and a group represented by the formula —CONR ₄ R ₅ or —NR ₆ R ₇ , and the like.
When R ₆ and R ₇ are substituted alkyl groups, examples of the substituent include a cycloalkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an acyl group, an aryl group, and a formula —CONR ₄ R ₅ or —NR. ₄ R ₅
And the like. Moreover, as the alkyl part of the substituted alkyl group, the same examples as the above-mentioned alkyl group can be given.

Examples of such a substituted alkyl group include an alkyl group having 1 to 5 carbon atoms substituted with a cycloalkyl having 3 to 6 carbon atoms, a polyhaloalkyl group having 1 to 5 carbon atoms, and a carbon atom number. A hydroxyalkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 2 to 6 carbon atoms, a cyanoalkyl group having 2 to 6 carbon atoms, a carboxyalkyl group having 2 to 6 carbon atoms, an alkoxycarbonyl having 3 to 8 carbon atoms An alkyl group, an alkanoylalkyl group having 3 to 8 carbon atoms, an aroylalkyl group having 16 or less carbon atoms, an optionally substituted phenyl or naphthyl-C ₁ -C ₅ alkyl group, a nitrogen atom being one one or two C ₁ -C ₃ alkyl substituted carbamoyl -C ₁ optionally -C ₃ alkyl group, one nitrogen atom or two C ₁ -C ₃ Al Le or C ₇ -C ₁₁ aralkyl substituted by amino -C ₁ optionally -C ₅ alkyl group, a saturated 5- to 7-membered cyclic amino -C ₁ -C ₃ alkyl group, and the like.

A typical example of the substituted alkyl group is R ₁
In, trifluoromethyl, trifluoroethyl,
A polyhaloalkyl group having 1 to 3 carbon atoms such as trichloromethyl, hydroxymethyl, hydroxyethyl, 1-
Examples thereof include a hydroxyalkyl group having 1 to 6 carbon atoms such as hydroxyethyl, and an aminoalkyl group having 1 to 5 carbon atoms such as aminomethyl, aminoethyl, 1-aminoethyl, etc., and R ₂ is hydroxyethyl or hydroxy. Propyl, hydroxybutyl, 2-hydroxypropyl, 3,4-dihydroxybutyl etc. have 1 carbon atom
~ 6 hydroxyalkyl group, C1-6 alkoxyalkyl group such as methoxyethyl, ethoxyethyl, methoxypropyl, etc., C2-6 carboxyalkyl group such as carboxyethyl, carboxypropyl, methoxycarbonylmethyl, 3 to 3 carbon atoms such as ethoxycarbonylmethyl and methoxycarbonylethyl
7 alkoxycarbonylalkyl group, benzyl, phenylethyl, phenylpropyl, phenylbutyl, 1-
Alternatively, phenyl or naphthyl-C ₁ -C ₅ alkyl group such as 2-naphthylmethyl (C ₁ -C ₃ alkyl group in phenyl or naphthyl moiety, halogen atom, nitro group, amino group, hydroxyl group, C ₁ -C ₃ alkoxy) Carbamoylmethyl, carbamoylmethyl, carbamoylethyl, dimethylcarbamoylmethyl, etc., in which the nitrogen atom may be substituted with one or two C ₁ -C ₃ alkyl. ₁ -C ₃ alkyl group, aminoethyl, aminopropyl, dimethylaminoethyl, dimethylaminopropyl, such as diethylaminoethyl, nitrogen atoms of one or two C ₁ -C ₃
Examples thereof include an amino-C ₁ -C ₅ alkyl group which may be substituted with alkyl, and in R ₃ and R ₄₀ , hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, hydroxybutyl, 2,3-dihydroxypropyl and the like. C1-C6 hydroxyalkyl groups, carboxymethyl, carboxyethyl and other C2-C6 carboxyalkyl groups, benzyl, phenylethyl, phenylpropyl and other phenyl-C ₁ -C
₅ alkyl groups, carbamoyl-C ₁ -C ₃ alkyl groups such as carbamoylmethyl, carbamoylethyl, aminoethyl, aminopropyl, dimethylaminoethyl, dimethylaminopropyl, benzylmethylaminoethyl and the like having one or two nitrogen atoms. C ₁ -C ₃ alkyl or C ₇ -C ₁₁ aralkyl substituted by amino -C ₁ optionally -C ₅ alkyl group, 1-pyrrolidinylethyl, saturated 5- to 7-membered cyclic amino -C ₁ such piperidinoethyl To C ₃ alkyl groups, R ₆ and R
_{In 7} , phenyl-C ₁ -C such as phenylethyl
₅ examples include an alkyl group.

The saturated 5- to 7-membered cyclic amino group which may have other heteroatoms in the ring and which is formed by R ₄ and R ₅ being bonded to each other is the above-mentioned R ₆ and R ₇
The same examples as in the case of the cyclic amino group formed by can be mentioned.

Examples of the group represented by the formula -S (0) _n R ₄₀ include a methylsulfonyl group, an ethylsulfonyl group,
Examples thereof include an alkylsulfonyl group having 8 or less carbon atoms such as a propylsulfonyl group and an isopropylsulfonyl group, and a corresponding alkylsulfinyl group and an alkylthio group. formula

Embedded image Examples of the group represented by

[Chemical 17] And a group represented by, preferably (piperidine-
3-yl) oxy, (piperidin-4-yl) oxy,
(1-Methylpiperidin-3-yl) oxy, (1-methylpiperidin-4-yl) oxy, (pyrrolidin-3
-Yl) oxy, (1-methylpyrrolidin-3-yl)
Oxy, (piperidin-3-yl) thio, (piperidin-4-yl) thio, (1-methylpiperidin-3-yl) thio, (1-methylpiperidin-4-yl) thio,
(Pyrrolidin-3-yl) thio, (1-methylpyrrolidin-2-yl) thio, (piperidin-3-yl) amino, (piperidin-4-yl) amino, (1-methylpiperidin-3-yl) amino , (1-Methylpiperidin-4-yl) amino, (pyrrolidin-3-yl) amino, (1-methylpyrrolidin-3-yl) amino.

The compound of the present invention represented by the general formula (1) can be produced, for example, by the following method. (A) The compound (1) of the present invention can be obtained by reacting a reactive derivative of indolecarboxylic acid represented by the general formula (3) with guanidine in an inert solvent.

Embedded image (In the formula, X represents a leaving group which can be easily displaced by a nucleophile, and R ₁ and R ₂ have the same meaning as described above.)

In this reaction, when the indolecarboxylic acid derivative (3) has a group active in the reaction such as a hydroxyl group or an amino group, these groups are protected in advance by a protecting group, and this reaction is carried out. The target indoloylguanidine derivative (1) can be produced by removing the protecting group after carrying out.

Examples of the reactive derivative of carboxylic acid include acid halides, acid anhydrides (including mixed acid anhydrides) and ester derivatives. Specific examples of the acid halides include acid chlorides or acid bromides. As the mixed acid anhydride, ethyloxycarbonyl chloride, an alkyloxy chloride type such as isobutyloxycarbonyl chloride, and a mixed acid anhydride with an α-polyalkyl-substituted carboxylic acid chloride type compound such as diethylacetyl chloride and trimethylacetyl chloride, As the ester derivative, p-
Mention may be made of active esters such as nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenyl ester and common esters such as methyl ester and ethyl ester. Such a reactive derivative of a carboxylic acid is prepared according to a general method which is usually carried out.
It can be easily obtained from the corresponding carboxylic acid.

When reacting with an acid halide or acid anhydride (including mixed acid anhydride), it can be carried out in the presence of a base or an excess of guanidine in a solvent under cooling to room temperature. Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and the like, and organic bases such as triethylamine and pyridine are used as the base, and aromatic hydrocarbons such as benzene, toluene and xylene are used as the solvent. solvent,
Tetrahydrofuran, ether solvent such as 1,4-dioxane, halogenated hydrocarbon solvent such as dichloromethane, chloroform, 1,2-dichloroethane, amide solvent such as dimethylformamide and dimethylacetamide, basic solvent such as pyridine, or These mixed solvents are mentioned.

The reaction with the ester derivative is carried out in the presence of equimolar or excess guanidine in a solvent while cooling or heating. In the case of an active ester, for example, tetrahydrofuran, 1,2-dimethoxyethane, an ether solvent such as dioxane, an ester solvent such as ethyl acetate, dimethylformamide or a mixed solvent thereof, in the case of another ester, For example,
It is preferable to carry out the reaction in an alcohol solvent such as methanol, ethanol or isopropanol, an ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane, dimethylformamide or a mixed solvent thereof. In some cases, it is also possible to heat at around 130 ° C. for a short time after distilling off the solvent.

(B) The compound (1) of the present invention is obtained by reacting the indolecarboxylic acid represented by the general formula (4) with guanidine, preferably in the presence of a condensing agent, in an inert solvent at room temperature or under heating. Can be obtained by

[Chemical 19] (In the formula, R ₁ and R ₂ have the same meanings as described above.) In this reaction, when the indolecarboxylic acid (4) has a reactive group such as a carboxyl group, a hydroxyl group or an amino group, Protects these groups with a protecting group in advance, and after carrying out this reaction, the protecting group is removed to give the desired indoloylguanidine derivative (1).
Can be manufactured.

The reaction is carried out, for example, by dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (WSC), benzotriazol-1-yl-tris (dimethylamino). ) Phosphonium hexafluorophosphide salt (BOP), diphenylphosphonyl azide (DPPA), N, N-carbonyldiimidazole (Angew.Chem.Int.Ed.Engl., Vol. 1, 35
1 (1962)) in the presence of a condensing agent, such as N-hydroxysuccinimide (HONSu),
1-hydroxybenzotriazole (HOBt), 3-
Hydroxy-4-oxo-3,4-dihydro-1,2,
Addition of additives such as 3-benzotriazine (HOObt), for example, aromatic hydrocarbon solvents such as benzene, toluene, xylene, tetrahydrofuran, 1,4-
In an ether solvent such as dioxane, a halogenated hydrocarbon solvent such as dichloromethane, chloroform and 1,2-dichloroethane, an amide solvent such as dimethylformamide and dimethylacetamide, a basic solvent such as pyridine, or a mixed solvent thereof. It is preferable to carry out.

(C) The compound (1a) of the present invention can be obtained by debenzylating the benzyloxyindoloylguanidine derivative represented by the general formula (5).

Embedded image (In the formula, R ₂ has the same meaning as described above.) The debenzylation reaction is a catalytic reduction reaction using a palladium / carbon catalyst (J. Chem. Soc., 1953, 4058) or hydrochloric acid / acetic acid (J Amer. Chem. Soc., Vol.73, 5765 (1951)).
It can be carried out according to the method described in the literature such as decomposition reaction under acidic conditions such as.

(D) The compound (1b) of the present invention can be obtained by reducing the nitroindoloylguanidine derivative represented by the general formula (6).

[Chemical 21] (In the formula, R ₂ has the same meaning as described above.) As reducing conditions, zinc, iron, tin or tin chloride (I
I) etc. under acidic conditions (Ann., 641, 81 (19
61), J. Amer. Chem. Soc., Vol.66, 1781 (1944), etc.), sodium dithionite (Na ₂ S ₂ O ₄ ) (J.
Amer. Chem. Soc., Vol.72, 1361 (1950), etc., reduction with sulfides, palladium / carbon (Synth. Commu.
n., 1, 47 (1971)), Raney Nickel (Org. Synth., IV,
A catalytic reduction reaction using a catalyst such as 226 (1963)) can be applied.

As the protective group for protecting the hydroxyl group, amino group, carboxyl group and the like active in the reaction of the above-mentioned production method (a) or (b), a general protective group used in the field of synthetic organic chemistry may be used. The introduction and removal of such protecting groups can be carried out according to conventional methods (eg Pr
otective Groups in Organic Synthesys, JOHN WILLEY
& SONS, 1991). For example, as a hydroxyl-protecting group,
Examples thereof include a methoxymethyl group and a tetrahydropyranyl group, and examples of the amino group-protecting group include a tert-butyloxycarbonyl group. Such a hydroxyl-protecting group can be removed by reacting in a solvent such as hydrous methanol, hydrous ethanol, or hydrous tetrahydrofuran in the presence of an acid such as hydrochloric acid, sulfuric acid, or acetic acid to protect the amino group. The group can be removed by reacting in a solvent such as hydrous tetrahydrofuran, methylene chloride, chloroform or hydrous methanol in the presence of an acid such as hydrochloric acid or trifluoroacetic acid.

In the case of protecting the carboxyl group, examples of the form of protection include tert-butyl ester, orthoester, acid amide and the like. In the case of tert-butyl ester, removal of such a protecting group is carried out, for example, by reacting in a water-containing solvent in the presence of hydrochloric acid,
In the case of orthoester, for example, it is carried out by treating with an acid in a solvent such as water-containing methanol, water-containing tetrahydrofuran, and water-containing 1,2-dimethoxyethane, and subsequently by treating with an alkali such as sodium hydroxide to obtain the acid amide. In the case, for example, in the presence of an acid such as hydrochloric acid or sulfuric acid,
It can be carried out by reacting in a solvent such as water, hydrous methanol, hydrous tetrahydrofuran.

The indolecarboxylic acids used as the raw material compounds in the above-mentioned production methods (a) and (b) are, for example, indole-5-carboxylic acid, 5-chloro-2-indolecarboxylic acid, indole-3-carboxylic acid and indole-carboxylic acid. 2-
Commercially available products such as carboxylic acid, indole-4-carboxylic acid and 5-methoxy-2-indolecarboxylic acid can be obtained or can be synthesized by a known method.

For example, according to Reissert's method (Reissert's indole synthesis method), 4-chloro-2-indolecarboxylic acid (J. Chem. Soc., 1955, 3490), 6-n
-Amyl-2-indolecarboxylic acid (J. Amer. Chem.
Soc., Vol.75, 4921 (1953)), 7-indolecarboxylic acid (J. Amer. Chem. Soc., Vol.77, 5700 (1955)),
5-Cyano-2-indolecarboxylic acid (J. Org. Che
m., Vol. 18, 354 (1953)), 6-cyano-2-indolecarboxylic acid (J. Chem. Soc., 1924, 2285), 6-benzyloxy-2-indolecarboxylic acid (J. Chem. So
c., 1937, 1726) etc. can be synthesized.

According to Fischer's method (Fischer's indole synthesis method), nitro-2-indolecarboxylic acid (J. Amer. Chem. Soc., Vol. 80, 4621 (1958)), 7-
Chloro-2-indolecarboxylic acid (J. Chem. Soc., 19
55, 3499), 4-trifluoromethyl-2-indolecarboxylic acid (J. Amer. Chem. Soc., Vol. 79, 1745 (195
7)) etc. can be synthesized. In addition, 2-indolecarboxylic acids can be obtained by a known method using a benzaldehyde derivative as a raw material (eg, Tetrahedron, Vol. 42, 3259 (1986); Monats
h. Chem., 101, 161, (1970), etc.).

Furthermore, 4-indolecarboxylic acids, 5
-For indolecarboxylic acids and 6-indolecarboxylic acids, see the literature (J. Chem. Tech. Biotechnol.,
Vol.36, 562 (1986); Tetrahedron Letters, Vol.27, 1
653 (1986)). 1
-Hydroxyindolecarboxylic acids are described in the literature (Chem.
Ber., Vol.56, 1024 (1923)). Aryl oxindole carboxylic acids are obtained by catalyzing alkali metal salts of hydroxy indole carboxylic acids (eg sodium salt, potassium salt etc.) and aryl halides in an inert solvent (eg dimethylformamide, tetrahydrofuran etc.) (eg copper, iodide). (Copper, etc.) or the reaction can be carried out without a catalyst. In addition, when the aryl halide used at this time has a reactive group such as a carboxyl group, a hydroxyl group, or an amino group, these groups are protected in advance with an appropriate protecting group, and the coupling reaction is performed. Is carried out, and then the reaction with guanidine is carried out, and then the protecting group is removed, whereby the desired indoloylguanidine derivative (1) can be produced.
As the other indolecarboxylic acids, commercially available ones can be obtained, or the following review (a) to
It can be produced by referring to the synthesis method described in (c). (A) WAremers, RKBrown, ^ Indoles "(ed. By WJHou
lihan), Part I, Part II and Part III, Wiley-Interscie
nce, New York, 1972. (b) RJ Sundberg, ^ The Chemistry of Indoles ", Aca
demic Press, New York, 1970. (c) ARKatritzky, CWRees, "Comprehensive Hetero
cyclic Chemistry "(ed. by CWBird, GWHCheeseman),
Volume 4, Pergamon Press, Oxford, 1984.

General formula (1) produced as described above
Examples of the compound represented by are the following compounds. 1-methyl-2-indoloylguanidine 1-methyl-3-indoloylguanidine 1-methyl-4-indoloylguanidine 1-methyl-5-indoloylguanidine 1-methyl-6-indoloylguanidine 4-chloro-1 -Methyl-2-indoloylguanidine 5-chloro-1-methyl-2-indoloylguanidine 6-chloro-1-methyl-2-indoloylguanidine 7-chloro-1-methyl-2-indoloylguanidine 5-chloro -2-Indoylguanidine

1,4-Dimethyl-2-indoloylguanidine 1,5-Dimethyl-2-indoloylguanidine 1,6-Dimethyl-2-indoloylguanidine 1,7-Dimethyl-2-indoloylguanidine 4-methoxy -1-Methyl-2-indoloylguanidine 5-methoxy-1-methyl-2-indoloylguanidine 6-methoxy-1-methyl-2-indoloylguanidine 7-methoxy-1-methyl-2-indoloylguanidine 1 -Methyl-4-nitro-2-indoloylguanidine 1-methyl-5-nitro-2-indoloylguanidine 1-methyl-6-nitro-2-indoloylguanidine

1-Methyl-7-nitro-2-indoloylguanidine 4-amino-1-methyl-2-indoloylguanidine 5-amino-1-methyl-2-indoloylguanidine 6-amino-1-methyl- 2-Indoloylguanidine 7-Amino-1-methyl-2-indoloylguanidine 1-benzyl-2-indoloylguanidine 1-benzyl-3-indoloylguanidine 1-benzyl-5-indoloylguanidine 1-isopropyl-2 -Indoloylguanidine 1-isopropyl-3-indoloylguanidine

1-isopropyl-5-indoloylguanidine 2-indoloylguanidine 3-indoloylguanidine 5-indoloylguanidine 4-hydroxy-1-methyl-2-indoloylguanidine 5-hydroxy-1-methyl-2- Indoloylguanidine 6-hydroxy-1-methyl-2-indoloylguanidine 7-hydroxy-1-methyl-2-indoloylguanidine 1- (3-dimethylaminopropyl) -4-trifluoromethyl-2-indoloylguanidine 1- (3-diethylaminopropyl) -4-trifluoromethyl-2-indoloylguanidine

1- [3- (N-pyrrolidinyl) propyl] -4-trifluoromethyl-2-indoloylguanidine 6- (3-aminopropoxy) -1-methyl-4-trifluoromethyl-2-indoloyl Guanidine 6- (3-dimethylaminopropoxy) -1-methyl-
4-Trifluoromethyl-2-indoloylguanidine 6- (3-diethylaminopropoxy) -1-methyl-
4-Trifluoromethyl-2-indoloylguanidine 6- (2-aminoethoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6- (2-dimethylaminoethoxy) -1-methyl-4
-Trifluoromethyl-2-indoloylguanidine 6- (2-diethylaminoethoxy) -1-methyl-4
-Trifluoromethyl-2-indoloylguanidine 1-methyl-6- [3- (N-pyrrolidinyl) propoxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-6- [2- (N- Pyrrolidinyl) ethoxy] -4-trifluoromethyl-2-indoloylguanidine 1- (3-dimethylaminopropyl) -4-methoxy-
2-indoloylguanidine

1- (3-diethylaminopropyl) -4
-Methoxy-2-indoloylguanidine 1- (3-aminopropyl) -4-methoxy-2-indoloylguanidine 4-methoxy-1- [3- (N-pyrrolidinyl) propyl] -2-indoloylguanidine 6- (3-Aminopropoxy) -4-methoxy-1-methyl-2-indoloylguanidine 6- (3-Dimethylaminopropoxy) -4-methoxy-1-methyl-2-indoloylguanidine 6- (3-diethylaminopropoxy ) -4-Methoxy-1-methyl-2-indoloylguanidine 6- (2-aminoethoxy) -4-methoxy-1-methyl-2-indoloylguanidine 6- (2-dimethylaminoethoxy) -4-methoxy −
1-Methyl-2-indoloylguanidine 6- (2-diethylaminoethoxy) -4-methoxy-
1-Methyl-2-indoloylguanidine 4-methoxy-1-methyl-6- [3- (N-pyrrolidinyl) propoxy] -2-indoloylguanidine

4-methoxy-1-methyl-6- [2-
(N-Pyrrolidinyl) ethoxy] -2-indoloylguanidine 7- (3-aminopropoxy) -4-methoxy-1-methyl-2-indoloylguanidine 7- (3-dimethylaminopropoxy) -4-methoxy-1 -Methyl-2-indoloylguanidine 7- (3-diethylaminopropoxy) -4-methoxy-1-methyl-2-indoloylguanidine 4-methoxy-1-methyl-7- [3- (N-pyrrolidinyl) propoxy] -2-Indoloylguanidine 1- (3-dimethylaminopropyl) -4-isopropoxy-2-indoloylguanidine 1- (3-diethylaminopropyl) -4-isopropoxy-2-indoloylguanidine 1- (3- Aminopropyl) -4-isopropoxy-2
-Indoloylguanidine 4-isopropoxy-1- [3- (N-pyrrolidinyl)
Propyl] -2-indoloylguanidine 6- (3-aminopropoxy) -4-isopropoxy-
1-methyl-2-indoloylguanidine

6- (3-dimethylaminopropoxy)-
4-Isopropoxy-1-methyl-2-indoloylguanidine 6- (3-diethylaminopropoxy) -4-isopropoxy-1-methyl-2-indoloylguanidine 6- (2-aminoethoxy) -4-isopropoxy -1
-Methyl-2-indoloylguanidine 6- (2-dimethylaminoethoxy) -4-isopropoxy-1-methyl-2-indoloylguanidine 6- (2-diethylaminoethoxy) -4-isopropoxy-1-methyl- 2-indoloylguanidine 4-isopropoxy-1-methyl-6- [3- (N-pyrrolidinyl) propoxy] -2-indoloylguanidine 4-isopropoxy-1-methyl-6- [2- (N-pyrrolidinyl ) Ethoxy] -2-indoloylguanidine 7- (3-aminopropoxy) -4-isopropoxy-
1-Methyl-2-indoloylguanidine 7- (3-dimethylaminopropoxy) -4-isopropoxy-1-methyl-2-indoloylguanidine 7- (3-diethylaminopropoxy) -4-isopropoxy-1-methyl -2-Indoyl guanidine

4-isopropoxy-1-methyl-7-
[3- (N-pyrrolidinyl) propoxy] -2-indoloylguanidine 1- (3-aminopropyl) -4-methyl-2-indoloylguanidine 1- (3-dimethylaminopropyl) -4-methyl-2
-Indoyl guanidine 1- (3-diethylaminopropyl) -4-methyl-2
-Indoloylguanidine 4-methyl-1- [3- (N-pyrrolidinyl) propyl] -2-indoloylguanidine 6- (3-aminopropoxy) -1,4-dimethyl-2
-Indoloylguanidine 1,4-dimethyl-6- (3-dimethylaminopropoxy) -2-indoloylguanidine 6- (3-diethylaminopropoxy) -1,4-dimethyl-2-indoloylguanidine 1,4-dimethyl -6- (2-Dimethylaminoethoxy) -2-indoloylguanidine 6- (2-Diethylaminoethoxy) -1,4-dimethyl-2-indoloylguanidine

6- (2-Aminoethoxy) -1,4-dimethyl-2-indoloylguanidine 1,4-dimethyl-6- [3- (N-pyrrolidinyl) propoxy] -2-indoloylguanidine 1,4 -Dimethyl-6- [2- (N-pyrrolidinyl) ethoxy] -2-indoloylguanidine 7- (3-aminopropoxy) -1,4-dimethyl-2
-Indoloylguanidine 1,4-dimethyl-7- (3-dimethylaminopropoxy) -2-indoloylguanidine 7- (3-diethylaminopropoxy) -1,4-dimethyl-2-indoloylguanidine 1,4-dimethyl -7- [3- (N-pyrrolidinyl) propoxy] -2-indoloylguanidine 4-tert-butyl-1-methyl-2-indoloylguanidine 1- (3-aminopropyl) -4-tert-butyl-2 −
Indoroylguanidine 4-tert-butyl-1- (3-dimethylaminopropyl) -2-indoloylguanidine

4-tert-Butyl-1- (3-diethylaminopropyl) -2-indoloylguanidine 4-tert-butyl-1- [3- (N-pyrrolidinyl) propyl] -2-indoloylguanidine 6- ( 3-dimethylaminopropoxy) -1-methyl-
2-indoloylguanidine 6- (3-diethylaminopropoxy) -1-methyl-
2-indoloylguanidine 6- (2-aminoethoxy) -1-methyl-2-indoloylguanidine 6- (2-dimethylaminoethoxy) -1-methyl-2
-Indoylguanidine 6- (2-diethylaminoethoxy) -1-methyl-2
-Indoloylguanidine 1-methyl-6- [3- (N-pyrrolidinyl) propoxy] -2-indoloylguanidine 1-methyl-6- [2- (N-pyrrolidinyl) ethoxy] -2-indoloylguanidine 7- (3-Dimethylaminopropoxy) -1-methyl-
2-indoloylguanidine

7- (3-diethylaminopropoxy)-
1-Methyl-2-indoloylguanidine 1-methyl-7- [3- (N-pyrrolidinyl) propoxy] -2-indoloylguanidine 1-methyl-6-phenoxy-2-indoloylguanidine 1-methyl-7- Phenoxy-2-indoloylguanidine 1-methyl-6- (2-nitrophenoxy) -2-indoloylguanidine 1-methyl-7- (2-nitrophenoxy) -2-indoloylguanidine 1-methyl-6- ( 3-Nitrophenoxy) -2-indoloylguanidine 1-methyl-7- (3-nitrophenoxy) -2-indoloylguanidine 1-methyl-6- (4-nitrophenoxy) -2-indoloylguanidine 1-methyl -7- (4-Nitrophenoxy) -2-indoloylguanidine

6- (2-aminophenoxy) -1-methyl-2-indoloylguanidine 7- (2-aminophenoxy) -1-methyl-2-indoloylguanidine 6- (3-aminophenoxy) -1- Methyl-2-indoloylguanidine 7- (3-aminophenoxy) -1-methyl-2-indoloylguanidine 6- (4-aminophenoxy) -1-methyl-2-indoloylguanidine 7- (4-aminophenoxy) ) -1-Methyl-2-indoloylguanidine 6- [2- (aminomethyl) phenoxy] -1-methyl-2-indoloylguanidine 7- [2- (aminomethyl) phenoxy] -1-methyl-2- Indoloylguanidine 6- [3- (aminomethyl) phenoxy] -1-methyl-2-indoloylguanidine 7- [ - (aminomethyl) phenoxy] -1-methyl-2-India acryloyl guanidine

6- [4- (aminomethyl) phenoxy]
-1-Methyl-2-indoloylguanidine 7- [4- (aminomethyl) phenoxy] -1-methyl-2-indoloylguanidine 6- [2- (dimethylaminomethyl) phenoxy] -1
-Methyl-2-indoloylguanidine 7- [2- (dimethylaminomethyl) phenoxy] -1
-Methyl-2-indoloylguanidine 6- [3- (dimethylaminomethyl) phenoxy] -1
-Methyl-2-indoloylguanidine 7- [3- (dimethylaminomethyl) phenoxy] -1
-Methyl-2-indoloylguanidine 6- [4- (dimethylaminomethyl) phenoxy] -1
-Methyl-2-indoloylguanidine 7- [4- (dimethylaminomethyl) phenoxy] -1
-Methyl-2-indoloylguanidine 4-chloro-1-methyl-6-phenoxy-2-indoloylguanidine 4-chloro-1-methyl-7-phenoxy-2-indoloylguanidine 4-chloro-1-methyl- 6- (2-nitrophenoxy) -2-indoloylguanidine

4-chloro-1-methyl-7- (2-nitrophenoxy) -2-indoloylguanidine 4-chloro-1-methyl-6- (3-nitrophenoxy) -2-indoloylguanidine 4-chloro -1-Methyl-7- (3-nitrophenoxy) -2-indoloylguanidine 4-chloro-1-methyl-6- (4-nitrophenoxy) -2-indoloylguanidine 4-chloro-1-methyl-7 -(4-Nitrophenoxy) -2-indoloylguanidine 6- (2-aminophenoxy) -4-chloro-1-methyl-2-indoloylguanidine 7- (2-aminophenoxy) -4-chloro-1- Methyl-2-indoloylguanidine 6- (3-aminophenoxy) -4-chloro-1-methyl-2-indoloylguanidine 7- (3 Aminophenoxy) -4-chloro-1-methyl-2-India acryloyl guanidine 6- (4-aminophenoxy) -4-chloro-1-methyl-2-India acryloyl guanidine

7- (4-aminophenoxy) -4-chloro-1-methyl-2-indoloylguanidine 6- [2- (aminomethyl) phenoxy] -4-chloro-1-methyl-2-indoloylguanidine 7- [2- (aminomethyl) phenoxy] -4-chloro-1-methyl-2-indoloylguanidine 6- [3- (aminomethyl) phenoxy] -4-chloro-1-methyl-2-indoloylguanidine 7- [3- (aminomethyl) phenoxy] -4-chloro-1-methyl-2-indoloylguanidine 6- [4- (aminomethyl) phenoxy] -4-chloro-1-methyl-2-indoloylguanidine 7- [4- (Aminomethyl) phenoxy] -4-chloro-1-methyl-2-indoloylguanidine 4-chloro-6- [2- (dimethyl) Luminomethyl) phenoxy] -1-methyl-2-indoloylguanidine 4-chloro-7- [2- (dimethylaminomethyl) phenoxy] -1-methyl-2-indoloylguanidine 4-chloro-6- [3- ( Dimethylaminomethyl) phenoxy] -1-methyl-2-indoloylguanidine

4-chloro-7- [3- (dimethylaminomethyl) phenoxy] -1-methyl-2-indoloylguanidine 4-chloro-6- [4- (dimethylaminomethyl) phenoxy] -1-methyl- 2-Indoloylguanidine 4-chloro-7- [4- (dimethylaminomethyl) phenoxy] -1-methyl-2-indoloylguanidine 1-methyl-6-phenoxy-4-trifluoromethyl-2-indoloylguanidine 1-Methyl-7-phenoxy-4-trifluoromethyl-2-indoloylguanidine 1-methyl-6- (2-nitrophenoxy) -4-trifluoromethyl-2-indoloylguanidine 1-methyl-7- ( 2-Nitrophenoxy) -4-trifluoromethyl-2-indoloylguanidine 1-methyl-6- (3-Nitrophenoxy) -4-trifluoromethyl-2-indoloylguanidine 1-methyl-7- (3-nitrophenoxy) -4-trifluoromethyl-2-indoloylguanidine 1-methyl-6- (4 -Nitrophenoxy) -4-trifluoromethyl-2-indoloylguanidine

1-Methyl-7- (4-nitrophenoxy) -4-trifluoromethyl-2-indoloylguanidine 6- (2-aminophenoxy) -1-methyl-4-trifluoromethyl-2-indoloyl Guanidine 7- (2-aminophenoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6- (3-Aminophenoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7 -(3-aminophenoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6- (4-aminophenoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7- ( 4-Aminophenoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6- [ 2- (Aminomethyl) phenoxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7- [2- (aminomethyl) phenoxy] -1-methyl-4-trifluoromethyl-2-indoloyl Guanidine 6- [3- (aminomethyl) phenoxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine

7- [3- (aminomethyl) phenoxy]
-1-Methyl-4-trifluoromethyl-2-indoloylguanidine 6- [4- (aminomethyl) phenoxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7- [4- (amino Methyl) phenoxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6- [2- (dimethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 7- [2- (dimethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 6- [3- (dimethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 7- [3- (dimethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 6- [4- (dimethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 7- [4- (dimethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 6- [2- (diethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine

7- [2- (diethylaminomethyl) phenoxy] -1-methyl-4-trifluoromethyl-2-
Indoyl guanidine 6- [3- (diethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 7- [3- (diethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 6- [4- (diethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 7- [4- (diethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 1-methyl-6- [2- (N-pyrrolidinylmethyl) phenoxy] -2-indoloylguanidine 1-methyl-7- [2- (N -Pyrrolidinylmethyl) phenoxy] -2-indoloylguanidine 1-methyl-6- [3- (N-pyrrolidinylmethyl) phenoxy] -2-indoloylguanidine 1-methyl-7- [3- (N -Pyrrolidinylmethyl) phenoxy] -2-indoloylguanidine 1-Methyl-6- [4- (N-pyrrolidinylmethyl) phenoxy] -2-indoloylguanidine

1-Methyl-7- [4- (N-pyrrolidinylmethyl) phenoxy] -2-indoloylguanidine 1-methyl-6- [2- (N-piperidinylmethyl) phenoxy] -2- Indoloylguanidine 1-methyl-7- [2- (N-piperidinylmethyl) phenoxy] -2-indoylguanidine 1-methyl-6- [3- (N-piperidinylmethyl) phenoxy] -2- Indoloylguanidine 1-methyl-7- [3- (N-piperidinylmethyl) phenoxy] -2-indoylguanidine 1-methyl-6- [4- (N-piperidinylmethyl) phenoxy] -2- Indoloylguanidine 1-methyl-7- [4- (N-piperidinylmethyl) phenoxy] -2-indoloylguanidine 6- [2- (aminomethyl) benzyl Oxy] -1-methyl-2-indoloylguanidine 7- [2- (aminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 6- [3- (aminomethyl) benzyloxy] -1-methyl -2-Indoyl guanidine

7- [3- (Aminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 6- [4- (aminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 7- [ 4- (aminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 6- [2- (dimethylaminomethyl) benzyloxy]
-1-Methyl-2-indoloylguanidine 7- [2- (dimethylaminomethyl) benzyloxy]
-1-Methyl-2-indoloylguanidine 6- [3- (dimethylaminomethyl) benzyloxy]
-1-Methyl-2-indoloylguanidine 7- [3- (dimethylaminomethyl) benzyloxy]
-1-Methyl-2-indoloylguanidine 6- [4- (dimethylaminomethyl) benzyloxy]
-1-Methyl-2-indoloylguanidine 7- [4- (dimethylaminomethyl) benzyloxy]
-1-Methyl-2-indoloylguanidine 4-chloro-6- [2- (diethylaminomethyl) phenoxy] -1-methyl-2-indoloylguanidine

4-chloro-7- [2- (diethylaminomethyl) phenoxy] -1-methyl-2-indoloylguanidine 4-chloro-6- [3- (diethylaminomethyl) phenoxy] -1-methyl-2- Indoylylguanidine 4-chloro-7- [3- (diethylaminomethyl) phenoxy] -1-methyl-2-Indoylguanidine 4-chloro-6- [4- (diethylaminomethyl) phenoxy] -1-methyl-2- Indoloylguanidine 4-chloro-7- [4- (diethylaminomethyl) phenoxy] -1-methyl-2-indoloylguanidine 4-chloro-1-methyl-6- [2- (N-pyrrolidinylmethyl) phenoxy ] -2-Indoloylguanidine 4-chloro-1-methyl-7- [2- (N-pyrrolidinylmethyl) Enoxy] -2-indoloylguanidine 4-chloro-1-methyl-6- [3- (N-pyrrolidinylmethyl) phenoxy] -2-indoloylguanidine 4-chloro-1-methyl-7- [3- (N-pyrrolidinylmethyl) phenoxy] -2-indoloylguanidine 4-chloro-1-methyl-6- [4- (N-pyrrolidinylmethyl) phenoxy] -2-indoloylguanidine

4-chloro-1-methyl-7- [4- (N
-Pyrrolidinylmethyl) phenoxy] -2-indoloylguanidine 4-chloro-1-methyl-6- [2- (N-piperidinylmethyl) phenoxy] -2-indoloylguanidine 4-chloro-1-methyl -7- [2- (N-Piperidinylmethyl) phenoxy] -2-indoloylguanidine 4-chloro-1-methyl-6- [3- (N-piperidinylmethyl) phenoxy] -2-indoloyl Guanidine 4-chloro-1-methyl-7- [3- (N-piperidinylmethyl) phenoxy] -2-indoloylguanidine 4-chloro-1-methyl-6- [4- (N-piperidinylmethyl) ) Phenoxy] -2-indoloylguanidine 4-chloro-1-methyl-7- [4- (N-piperidinylmethyl) phenoxy] -2-indoloylguanidine 4-chloro-6- [2- (aminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 4-chloro-7- [2- (aminomethyl) benzyloxy] -1-methyl-2-indo Roylguanidine 4-chloro-6- [3- (aminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine

4-chloro-7- [3- (aminomethyl)
Benzyloxy] -1-methyl-2-indoloylguanidine 4-chloro-6- [4- (aminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 4-chloro-7- [4- (amino Methyl) benzyloxy] -1-methyl-2-indoloylguanidine 4-chloro-6- [2- (dimethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 4-chloro-7- [2 -(Dimethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 4-chloro-6- [3- (dimethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 4-chloro- 7- [3- (dimethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 4-chloro -6- [4- (Dimethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 4-chloro-7- [4- (dimethylaminomethyl) benzyloxy] -1-methyl-2-indoloyl Guanidine 6- [2- (diethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine

7- [2- (diethylaminomethyl) phenoxy] -1-methyl-4-trifluoromethyl-2-
Indoyl guanidine 6- [3- (diethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 7- [3- (diethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 6- [4- (diethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 7- [4- (diethylaminomethyl) phenoxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 1-methyl-6- [2- (N-pyrrolidinylmethyl) phenoxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-7 -[2- (N-Pyrrolidinylmethyl) phenoxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-6- [3- (N-pyrrolidinylmethyl) phenoxy] -4-trifluoro Methyl-2-indoloylguanidine 1-methyl-7- [3- (N-pyrrolidinylmethyl) phenoxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-6- [4- (N- Pyrrolidinylmethyl) phenoxy] -4-trifluoromethyl-2-indoloylguanidine

1-Methyl-7- [4- (N-pyrrolidinylmethyl) phenoxy] -4-trifluoromethyl-2
-Indoloylguanidine 1-methyl-6- [2- (N-piperidinylmethyl) phenoxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-7- [2- (N-piperidinyl Methyl) phenoxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-6- [3- (N-piperidinylmethyl) phenoxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl -7- [3- (N-Piperidinylmethyl) phenoxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-6- [4- (N-piperidinylmethyl) phenoxy] -4- Trifluoromethyl-2-indoloylguanidine 1-methyl-7- [4- (N-piperidinylmethyl) phenoxy] -4-trifluoro Cyl-2-indoloylguanidine 6- [2- (aminomethyl) benzyloxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7- [2- (aminomethyl) benzyloxy] -1- Methyl-4-trifluoromethyl-2-indoloylguanidine 6- [3- (aminomethyl) benzyloxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine

7- [3- (Aminomethyl) benzyloxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6- [4- (aminomethyl) benzyloxy] -1-methyl-4- Trifluoromethyl-2-indoloylguanidine 7- [4- (aminomethyl) benzyloxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6- [2- (dimethylaminomethyl) benzyloxy]
-1-Methyl-4-trifluoromethyl-2-indoloylguanidine 7- [2- (dimethylaminomethyl) benzyloxy]
-1-Methyl-4-trifluoromethyl-2-indoloylguanidine 6- [3- (dimethylaminomethyl) benzyloxy]
-1-Methyl-4-trifluoromethyl-2-indoloylguanidine 7- [3- (dimethylaminomethyl) benzyloxy]
-1-Methyl-4-trifluoromethyl-2-indoloylguanidine 6- [4- (dimethylaminomethyl) benzyloxy]
-1-Methyl-4-trifluoromethyl-2-indoloylguanidine 7- [4- (dimethylaminomethyl) benzyloxy]
-1-Methyl-4-trifluoromethyl-2-indoloylguanidine 6- [2- (diethylaminomethyl) benzyloxy]
-1-Methyl-2-indoloylguanidine

7- [2- (diethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 6- [3- (diethylaminomethyl) benzyloxy]
-1-Methyl-2-indoloylguanidine 7- [3- (diethylaminomethyl) benzyloxy]
-1-Methyl-2-indoloylguanidine 6- [4- (diethylaminomethyl) benzyloxy]
-1-Methyl-2-indoloylguanidine 7- [4- (diethylaminomethyl) benzyloxy]
-1-Methyl-2-indoloylguanidine 1-methyl-6-[(pyridin-2-yl) oxy]-
2-indoloylguanidine 1-methyl-7-[(pyridin-2-yl) oxy]-
2-indoloylguanidine 1-methyl-6-[(4-nitropyridin-2-yl)
Oxy] -2-indoloylguanidine 1-methyl-7-[(4-nitropyridin-2-yl)
Oxy] -2-indoloylguanidine 6-[(4-aminopyridin-2-yl) oxy] -1
-Methyl-2-indoloylguanidine

7-[(4-aminopyridin-2-yl)
Oxy] -1-methyl-2-indoloylguanidine 6-[[4- (aminomethyl) pyridin-2-yl] oxy] -1-methyl-2-indoloylguanidine 7-[[4- (aminomethyl) Pyridin-2-yl] oxy] -1-methyl-2-indoloylguanidine 6-[[4- (dimethylaminomethyl) pyridin-2-
Iyl] oxy] -1-methyl-2-indoloylguanidine 7-[[4- (dimethylaminomethyl) pyridine-2-
Iyl] oxy] -1-methyl-2-indoloylguanidine 6-[[4- (diethylaminomethyl) pyridine-2-
Iyl] oxy] -1-methyl-2-indoloylguanidine 7-[[4- (diethylaminomethyl) pyridine-2-
Iyl] oxy] -1-methyl-2-indoloylguanidine 1-methyl-6-[[4- (N-pyrrolidinylmethyl)
Pyridin-2-yl] oxy] -2-indoloylguanidine 1-methyl-7-[[4- (N-pyrrolidinylmethyl)
Pyridin-2-yl] oxy] -2-indoloylguanidine 1-methyl-6-[(pyridin-3-yl) oxy]-
2-indoloylguanidine

1-Methyl-7-[(pyridin-3-yl) oxy] -2-indoloylguanidine 1-methyl-6-[(5-nitropyridin-3-yl)
Oxy] -2-indoloylguanidine 1-methyl-7-[(5-nitropyridin-3-yl)
Oxy] -2-indoloylguanidine 6-[(5-aminopyridin-3-yl) oxy] -1
-Methyl-2-indoloylguanidine 7-[(5-aminopyridin-3-yl) oxy] -1
-Methyl-2-indoloylguanidine 6-[[5- (aminomethyl) pyridin-3-yl] oxy] -1-methyl-2-indoloylguanidine 7-[[5- (aminomethyl) pyridine-3- Iyl] oxy] -1-methyl-2-indoloylguanidine 6-[[5- (dimethylaminomethyl) pyridine-3-
Iyl] oxy] -1-methyl-2-indoloylguanidine 7-[[5- (dimethylaminomethyl) pyridine-3-
Iyl] oxy] -1-methyl-2-indoloylguanidine 4-chloro-6- [2- (diethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine

4-chloro-7- [2- (diethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 4-chloro-6- [3- (diethylaminomethyl) benzyloxy] -1-methyl- 2-Indoloylguanidine 4-chloro-7- [3- (diethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 4-chloro-6- [4- (diethylaminomethyl) benzyloxy] -1- Methyl-2-indoloylguanidine 4-chloro-7- [4- (diethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 4-chloro-1-methyl-6-[(pyridin-2-yl ) Oxy] -2-indoloylguanidine 4-chloro-1-methyl-7-[(pyridin-2-yl) Xy] -2-indoloylguanidine 4-chloro-1-methyl-6-[(4-nitropyridin-2-yl) oxy] -2-indoloylguanidine 4-chloro-1-methyl-7-[(4 -Nitropyridin-2-yl) oxy] -2-indoloylguanidine 6-[(4-aminopyridin-2-yl) oxy] -4
-Chloro-1-methyl-2-indoloylguanidine

7-[(4-aminopyridin-2-yl)
Oxy] -4-chloro-1-methyl-2-indoloylguanidine 6-[[4- (aminomethyl) pyridin-2-yl] oxy] -4-chloro-1-methyl-2-indoloylguanidine 7- [[4- (Aminomethyl) pyridin-2-yl] oxy] -4-chloro-1-methyl-2-indoloylguanidine 4-chloro-6-[[4- (dimethylaminomethyl) pyridin-2-yl ] Oxy] -1-methyl-2-indoloylguanidine 4-chloro-7-[[4- (dimethylaminomethyl) pyridin-2-yl] oxy] -1-methyl-2-indoloylguanidine 4-chloro- 6-[[4- (diethylaminomethyl) pyridin-2-yl] oxy] -1-methyl-2-indoloylguanidine 4-chloro-7-[[4- (diethylamido Methyl) pyridin-2-yl] oxy] -1-methyl-2-indoloylguanidine 4-chloro-1-methyl-6-[[4- (N-pyrrolidinylmethyl) pyridin-2-yl] oxy] 2-Indoloylguanidine 4-chloro-1-methyl-7-[[4- (N-pyrrolidinylmethyl) pyridin-2-yl] oxy] -2-indoloylguanidine 4-chloro-1-methyl- 6-[(pyridin-3-yl) oxy] -2-indoloylguanidine

4-chloro-1-methyl-7-[(pyridin-3-yl) oxy] -2-indoloylguanidine 4-chloro-1-methyl-6-[(5-nitropyridin-3-yl) Oxy] -2-indoloylguanidine 4-chloro-1-methyl-7-[(5-nitropyridin-3-yl) oxy] -2-indoloylguanidine 6-[(5-aminopyridin-3-yl) Oxy] -4
-Chloro-1-methyl-2-indoloylguanidine 7-[(5-aminopyridin-3-yl) oxy] -4
-Chloro-1-methyl-2-indoloylguanidine 6-[[5- (aminomethyl) pyridin-3-yl] oxy] -4-chloro-1-methyl-2-indoloylguanidine 7-[[5- (Aminomethyl) pyridin-3-yl] oxy] -4-chloro-1-methyl-2-indoloylguanidine 4-chloro-6-[[5- (dimethylaminomethyl) pyridin-3-yl] oxy]- 1-Methyl-2-indoloylguanidine 4-chloro-7-[[5- (dimethylaminomethyl) pyridin-3-yl] oxy] -1-methyl-2-indoloylguanidine 6- [2- (diethylaminomethyl) ) Benzyloxy]
-1-Methyl-4-trifluoromethyl-2-indoloylguanidine

7- [2- (diethylaminomethyl) benzyloxy] -1-methyl-4-trifluoromethyl-
2-indoloylguanidine 6- [3- (diethylaminomethyl) benzyloxy]
-1-Methyl-4-trifluoromethyl-2-indoloylguanidine 7- [3- (diethylaminomethyl) benzyloxy]
-1-Methyl-4-trifluoromethyl-2-indoloylguanidine 6- [4- (diethylaminomethyl) benzyloxy]
-1-Methyl-4-trifluoromethyl-2-indoloylguanidine 7- [4- (diethylaminomethyl) benzyloxy]
-1-Methyl-4-trifluoromethyl-2-indoloylguanidine 1-methyl-6-[(pyridin-2-yl) oxy]-
4-Trifluoromethyl-2-indoloylguanidine 1-methyl-7-[(pyridin-2-yl) oxy]-
4-Trifluoromethyl-2-indoloylguanidine 1-methyl-6-[(4-nitropyridin-2-yl)
Oxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-7-[(4-nitropyridin-2-yl)
Oxy] -4-trifluoromethyl-2-indoloylguanidine 6-[(4-aminopyridin-2-yl) oxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine

7-[(4-aminopyridin-2-yl)
Oxy] -1-methyl-4-trifluoromethyl-2-
Indoloylguanidine 6-[[(4-aminomethyl) pyridin-2-yl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7-[[(4-aminomethyl) pyridine-2 -Yl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6-[[4- (dimethylaminomethyl) pyridine-2-
Ill] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7-[[4- (dimethylaminomethyl) pyridine-2-
Iyl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6-[[4- (diethylaminomethyl) pyridine-2-
Iyl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7-[[4- (diethylaminomethyl) pyridine-2-
Iyl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 1-methyl-6-[[4- (N-pyrrolidinylmethyl)
Pyridin-2-yl] oxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-7-[[4- (N-pyrrolidinylmethyl)
Pyridin-2-yl] oxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-6-[(pyridin-3-yl) oxy]-
4-trifluoromethyl-2-indoloylguanidine

1-Methyl-7-[(pyridin-3-yl) oxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-6-[(5-nitropyridin-3-yl)
Oxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-7-[(5-nitropyridin-3-yl)
Oxy] -4-trifluoromethyl-2-indoloylguanidine 6-[(5-aminopyridin-3-yl) oxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 7-[(5-aminopyridin-3-yl) oxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 6-[[[5- (aminomethyl) pyridin-3-yl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7- [[5- (Aminomethyl) pyridin-3-yl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6-[[5- (dimethylaminomethyl) pyridin-3-
Iyl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7-[[5- (dimethylaminomethyl) pyridine-3-
Iyl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6-[[5- (diethylaminomethyl) pyridine-3-
Yl] oxy] -1-methyl-2-indoloylguanidine

7-[[5- (diethylaminomethyl) pyridin-3-yl] oxy] -1-methyl-2-indoloylguanidine 1-methyl-6-[[5- (N-pyrrolidinylmethyl)
Pyridin-3-yl] oxy] -2-indoloylguanidine 1-methyl-7-[[5- (N-pyrrolidinylmethyl)
Pyridin-3-yl] oxy] -2-indoloylguanidine 1-methyl-6-[(pyridin-4-yl) oxy]-
2-indoloylguanidine 1-methyl-7-[(pyridin-4-yl) oxy]-
2-indoloylguanidine 1-methyl-6-[(2-nitropyridin-4-yl)
Oxy] -2-indoloylguanidine 1-methyl-7-[(2-nitropyridin-4-yl)
Oxy] -2-indoloylguanidine 6-[(2-aminopyridin-4-yl) oxy] -1
-Methyl-2-indoloylguanidine 7-[(2-aminopyridin-4-yl) oxy] -1
-Methyl-2-indoloylguanidine 6-[[2- (dimethylaminomethyl) pyridine-4-
Yl] oxy] -1-methyl-2-indoloylguanidine

7-[[2- (Dimethylaminomethyl) pyridin-4-yl] oxy] -1-methyl-2-indoloylguanidine 6-[[2- (diethylaminomethyl) pyridin-4-
Iyl] oxy] -1-methyl-2-indoloylguanidine 7-[[2- (diethylaminomethyl) pyridine-4-
Iyl] oxy] -1-methyl-2-indoloylguanidine 1-methyl-6-[[2- (N-pyrrolidinylmethyl)
Pyridin-4-yl] oxy] -2-indoloylguanidine 1-methyl-7-[[2- (N-pyrrolidinylmethyl)
Pyridin-4-yl] oxy] -2-indoloylguanidine 1-methyl-6-[(thiophen-2-yl) oxy]
-2-indoloylguanidine 1-methyl-7-[(thiophen-2-yl) oxy]
-2-Indoyl guanidine 1-methyl-6-[(5-nitrothiophen-2-yl) oxy] -2-indoyl guanidine 1-methyl-7-[(5-nitrothiophen-2-yl) oxy] -2-Indoyl guanidine 6-[(5-aminothiophen-2-yl) oxy]-
1-methyl-2-indoloylguanidine

7-[(5-Aminothiophen-2-yl) oxy] -1-methyl-2-indoloylguanidine 6-[[5- (dimethylaminomethyl) thiophene-2
-Yl] oxy] -1-methyl-2-indoloylguanidine 7-[[5- (dimethylaminomethyl) thiophene-2
-Yl] oxy] -1-methyl-2-indoloylguanidine 6-[[5- (diethylaminomethyl) thiophene-2
-Yl] oxy] -1-methyl-2-indoloylguanidine 7-[[5- (diethylaminomethyl) thiophene-2
-Yl] oxy] -1-methyl-2-indoloylguanidine 6-[[5- (aminomethyl) thiophen-2-yl]
Oxy] -1-methyl-2-indoloylguanidine 7-[[5- (aminomethyl) thiophen-2-yl]
Oxy] -1-methyl-2-indoloylguanidine 1-methyl-6-[[5- (N-pyrrolidinylmethyl)
Thiophen-2-yl] oxy] -2-indoloylguanidine 1-methyl-7-[[5- (N-pyrrolidinylmethyl)
Thiophene-2-yl] oxy] -2-indoloylguanidine 4-chloro-6-[[5- (diethylaminomethyl) pyridin-3-yl] oxy] -1-methyl-2-indoloylguanidine

4-chloro-7-[[5- (diethylaminomethyl) pyridin-3-yl] oxy] -1-methyl-2-indoloylguanidine 4-chloro-1-methyl-6-[[5- ( N-pyrrolidinylmethyl) pyridin-3-yl] oxy] -2-indoloylguanidine 4-chloro-1-methyl-7-[[5- (N-pyrrolidinylmethyl) pyridin-3-yl] oxy ] -2-Indoloylguanidine 4-chloro-1-methyl-6-[(pyridin-4-yl) oxy] -2-indoloylguanidine 4-chloro-1-methyl-7-[(pyridin-4-yl ) Oxy] -2-indoloylguanidine 4-chloro-1-methyl-6-[(2-nitropyridin-4-yl) oxy] -2-indoloylguanidine 4-chloro-1-methyl- - [(2-nitropyridin-yl) oxy] -2-India acryloyl guanidine 6 - [(2-Amino-4-yl) oxy] -4
-Chloro-1-methyl-2-indoloylguanidine 7-[(2-aminopyridin-4-yl) oxy] -4
-Chloro-1-methyl-2-indoloylguanidine 4-chloro-6-[[2- (dimethylaminomethyl) pyridin-4-yl] oxy] -1-methyl-2-indoloylguanidine

4-chloro-7-[[2- (dimethylaminomethyl) pyridin-4-yl] oxy] -1-methyl-2-indoloylguanidine 4-chloro-6-[[2- (diethylaminomethyl) Pyridin-4-yl] oxy] -1-methyl-2-indoloylguanidine 4-chloro-7-[[2- (diethylaminomethyl) pyridin-4-yl] oxy] -1-methyl-2-indoloylguanidine 4-Chloro-1-methyl-6-[[2- (N-pyrrolidinylmethyl) pyridin-4-yl] oxy] -2-indoloylguanidine 4-chloro-1-methyl-7-[[2- (N-Pyrrolidinylmethyl) pyridin-4-yl] oxy] -2-indoloylguanidine 4-chloro-1-methyl-6-[(thiophen-2-yl) oxy] -2 Indoloylguanidine 4-chloro-1-methyl-7-[(thiophen-2-yl) oxy] -2-indoloylguanidine 4-chloro-1-methyl-6-[(5-nitrothiophen-2-yl) Oxy] -2-indoloylguanidine 4-chloro-1-methyl-7-[(5-nitrothiophen-2-yl) oxy] -2-indoloylguanidine 6-[(5-aminothiophen-2-yl) Oxy]-
4-chloro-1-methyl-2-indoloylguanidine

7-[(5-Aminothiophen-2-yl) oxy] -4-chloro-1-methyl-2-indoloylguanidine 6-[[5- (aminomethyl) thiophen-2-yl]
Oxy] -4-chloro-1-methyl-2-indoloylguanidine 7-[[5- (aminomethyl) thiophen-2-yl]
Oxy] -4-chloro-1-methyl-2-indoloylguanidine 4-chloro-6-[[5- (dimethylaminomethyl) thiophen-2-yl] oxy] -1-methyl-2-indoloylguanidine 4 -Chloro-7-[[5- (dimethylaminomethyl) thiophen-2-yl] oxy] -1-methyl-2-indoloylguanidine 4-chloro-6-[[5- (diethylaminomethyl) thiophene-2- Iyl] oxy] -1-methyl-2-indoloylguanidine 4-chloro-7-[[5- (diethylaminomethyl) thiophen-2-yl] oxy] -1-methyl-2-indoloylguanidine 4-chloro- 1-Methyl-6-[[5- (N-pyrrolidinylmethyl) thiophen-2-yl] oxy] -2-indoloylguanidine 4-chloro 1-methyl-7 - [[5- (N-pyrrolidinylmethyl) thiophen-2-yl] oxy] -2-India acryloyl guanidine 6 - [[5- (diethylaminomethyl) pyridin-3
Yl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine

7-[[5- (diethylaminomethyl) pyridin-3-yl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 1-methyl-6-[[5- (N- Pyrrolidinylmethyl)
Pyridin-3-yl] oxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-7-[[5- (N-pyrrolidinylmethyl)
Pyridin-3-yl] oxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-6-[(pyridin-4-yl) oxy]-
4-Trifluoromethyl-2-indoloylguanidine 1-methyl-7-[(pyridin-4-yl) oxy]-
4-Trifluoromethyl-2-indoloylguanidine 1-methyl-6-[(2-nitropyridin-4-yl)
Oxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-7-[(2-nitropyridin-4-yl)
Oxy] -4-trifluoromethyl-2-indoloylguanidine 6-[(2-aminopyridin-4-yl) oxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 7-[(2-aminopyridin-4-yl) oxy] -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine 6-[[2- (dimethylaminomethyl) pyridine-4-
Yl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine

7-[[2- (dimethylaminomethyl) pyridin-4-yl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6-[[2- (dimethylaminomethyl) pyridine -4-
Iyl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7-[[2- (dimethylaminomethyl) pyridine-4-
Iyl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 1-methyl-6-[[2- (N-pyrrolidinylmethyl)
Pyridin-4-yl] oxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-7-[[2- (N-pyrrolidinylmethyl)
Pyridin-4-yl] oxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-6-[(thiophen-2-yl) oxy]
-4-Trifluoromethyl-2-indoloylguanidine 1-methyl-7-[(thiophen-2-yl) oxy]
-4-Trifluoromethyl-2-indoloylguanidine 1-methyl-6-[(5-nitrothiophen-2-yl) oxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-7- [ (5-Nitrothiophen-2-yl) oxy] -4-trifluoromethyl-2-indoloylguanidine 6-[(5-aminothiophen-2-yl) oxy]-
1-methyl-4-trifluoromethyl-2-indoloylguanidine

7-[(5-aminothiophen-2-yl) oxy] -1-methyl-4-trifluoromethyl-
2-indoloylguanidine 6-[[5- (aminomethyl) thiophen-2-yl]
Oxy] -1-methyl-4-trifluoromethyl-2-
Indoylguanidine 7-[[5- (aminomethyl) thiophen-2-yl]
Oxy] -1-methyl-4-trifluoromethyl-2-
Indoylguanidine 6-[[5- (dimethylaminomethyl) thiophene-2
-Yl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7-[[5- (dimethylaminomethyl) thiophene-2
-Yl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6-[[5- (diethylaminomethyl) thiophene-2
-Yl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7-[[5- (diethylaminomethyl) thiophene-2
-Yl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 1-methyl-6-[[5- (N-pyrrolidinylmethyl)
Thiophen-2-yl] oxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-7-[[5- (N-pyrrolidinylmethyl)
Thiophen-2-yl] oxy] -4-trifluoromethyl-2-indoloylguanidine 6-[[5- (aminomethyl) thiophen-2-yl]
Methoxy] -1-methyl-2-indoloylguanidine

7-[[5- (aminomethyl) thiophen-2-yl] methoxy] -1-methyl-2-indoloylguanidine 6-[[5- (aminomethyl) furan-2-yl] methoxy]- 1-Methyl-2-indoloylguanidine 7-[[5- (aminomethyl) furan-2-yl] methoxy] -1-methyl-2-indoloylguanidine 6-[[5- (aminomethyl) thiophene-2 -Ill]
Methoxy] -4-chloro-1-methyl-2-indoloylguanidine 7-[[5- (aminomethyl) thiophen-2-yl]
Methoxy] -4-chloro-1-methyl-2-indoloylguanidine 6-[[5- (aminomethyl) furan-2-yl] methoxy] -4-chloro-1-methyl-2-indoloylguanidine 7- [[5- (Aminomethyl) furan-2-yl] methoxy] -4-chloro-1-methyl-2-indoloylguanidine 4-chloro-6-[[5- (dimethylaminomethyl) thiophen-2-yl ] Methoxy] -1-methyl-2-indoloylguanidine 4-chloro-7-[[5- (dimethylaminomethyl) thiophen-2-yl] methoxy] -1-methyl-2-indoloylguanidine 4-chloro- 6-[[5- (dimethylaminomethyl) furan-2-yl] methoxy] -1-methyl-2-indoloylguanidine

4-chloro-7-[[5- (dimethylaminomethyl) furan-2-yl] methoxy] -1-methyl-2-indoloylguanidine 6-[[5- (aminomethyl) thiophene-2- Ill]
Methoxy] -1-methyl-4-trifluoromethyl-2
-Indoloylguanidine 7-[[5- (aminomethyl) thiophen-2-yl]
Methoxy] -1-methyl-4-trifluoromethyl-2
-Indoloylguanidine 6-[[5- (aminomethyl) furan-2-yl] methoxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7-[[5- (aminomethyl) furan- 2-yl] methoxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6-[[5- (dimethylaminomethyl) thiophene-2
-Yl] methoxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7-[[5- (dimethylaminomethyl) thiophene-2
-Yl] methoxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6-[[5- (dimethylaminomethyl) furan-2-yl] methoxy] -1-methyl-4-trifluoromethyl 2-Indoloylguanidine 7-[[5- (dimethylaminomethyl) furan-2-yl] methoxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6-[[5- (aminomethyl ) Furan-2-yl] oxy] -1-methyl-2-indoloylguanidine

7-[[5- (aminomethyl) furan-2
-Yl] oxy] -1-methyl-2-indoloylguanidine 6-[[5- (dimethylaminomethyl) furan-2-yl] oxy] -1-methyl-2-indoloylguanidine 7-[[5- (Dimethylaminomethyl) furan-2-yl] oxy] -1-methyl-2-indoloylguanidine 6-[[5- (diethylaminomethyl) furan-2-yl] oxy] -1-methyl-2-indoloyl Guanidine 7-[[5- (diethylaminomethyl) furan-2-yl] oxy] -1-methyl-2-indoloylguanidine 6-[[5- (N-pyrrolidinylmethyl) furan-2-
Iyl] oxy] -1-methyl-2-indoloylguanidine 7-[[5- (N-pyrrolidinylmethyl) furan-2-
Yl] oxy] -1-methyl-2-indoloylguanidine 6-[[5- (aminomethyl) furan-2-yl] oxy] -4-chloro-1-methyl-2-indoloylguanidine 7-[[ 5- (Aminomethyl) furan-2-yl] oxy] -4-chloro-1-methyl-2-indoloylguanidine 4-chloro-6-[[5- (dimethylaminomethyl) furan-2-yl] oxy ] -1-Methyl-2-indoloylguanidine

4-chloro-7-[[5- (dimethylaminomethyl) furan-2-yl] oxy] -1-methyl-
2-Indoloylguanidine 4-chloro-6-[[5- (diethylaminomethyl) furan-2-yl] oxy] -1-methyl-2-indoloylguanidine 4-chloro-7-[[(5-diethylaminomethyl ) Furan-2-yl] oxy] -1-methyl-2-indoloylguanidine 4-chloro-1-methyl-6-[[5- (N-pyrrolidinylmethyl) furan-2-yl] oxy]- 2-indoloylguanidine 4-chloro-1-methyl-7-[[5- (N-pyrrolidinylmethyl) furan-2-yl] oxy] -2-indoloylguanidine 6-[[5- (aminomethyl ) Furan-2-yl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 7-[[5- (aminomethyl) furan-2-yl] oxy] -1 Methyl-4-trifluoromethyl-2-India acryloyl guanidine 6 - [[5- (dimethylaminomethyl) furan-2-yl] oxy] -1-methyl-4-trifluoromethyl -
2-indoloylguanidine 7-[[5- (dimethylaminomethyl) furan-2-yl] oxy] -1-methyl-4-trifluoromethyl-
2-indoloylguanidine 6-[[5- (diethylaminomethyl) furan-2-yl] oxy] -1-methyl-4-trifluoromethyl-
2-indoloylguanidine

7-[[5- (diethylaminomethyl) furan-2-yl] oxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine 1-methyl-6-[[5- (N- Pyrrolidinylmethyl)
Furan-2-yl] oxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-7-[[5- (N-pyrrolidinylmethyl)
Furan-2-yl] oxy] -4-trifluoromethyl-2-indoloylguanidine 6-[[5- (dimethylaminomethyl) thiophene-2
-Yl] methoxy] -1-methyl-2-indoloylguanidine 7-[[5- (dimethylaminomethyl) thiophene-2
-Yl] methoxy] -1-methyl-2-indoloylguanidine 6-[[5- (dimethylaminomethyl) furan-2-yl] methoxy] -1-methyl-2-indoloylguanidine 7-[[5- (Dimethylaminomethyl) furan-2-yl] methoxy] -1-methyl-2-indoloylguanidine

The compound represented by the general formula (1) can be made into an acid addition salt with a pharmaceutically acceptable inorganic acid or organic acid, if necessary. Examples of such acid addition salts include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; formic acid, acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, malic acid, tartaric acid, Salts with organic carboxylic acids such as aspartic acid and glutamic acid; methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
Examples thereof include salts with sulfonic acids such as hydroxybenzene sulfonic acid and dihydroxybenzene sulfonic acid. Further, the compound represented by the general formula (1) and the acid addition salt thereof may be an anhydride, hydrate or solvate thereof.

The compounds of the present invention have a sodium / proton (Na ⁺ / H ⁺ ) exchange transport system inhibitory action, and are caused by abnormalities in the sodium / proton (Na ⁺ / H ⁺ ) exchange transport system, such as hypertension. , As an agent for the treatment and prevention of organ damage caused by ischemia or ischemia-reperfusion, arrhythmia, angina, diabetes, cardiac hypertrophy, cerebral ischemic injury, diseases caused by hyperproliferation of cells or diseases caused by endothelial cell damage It is useful.

The compounds of the present invention can be administered orally or parenterally when they are used as medicines. That is, it can be orally administered in a commonly used dosage form such as powder, granules, tablets, capsules, syrups, suspensions, or the like, or, for example, as a solution, emulsion or suspension thereof. The dosage form can be parenterally administered in the form of injection. It may also be administered rectally in the form of suppositories. The above suitable dosage forms can be produced, for example, by incorporating the active compound into an acceptable conventional carrier, excipient, binder, stabilizer and diluent. When used in an injection form, for example, an acceptable buffer,
A solubilizing agent and an isotonicity agent can also be added. The dose and frequency of administration will vary depending on, for example, the target disease, symptoms, age, body weight, and administration form, but usually 0.1 to 2000 mg / day, preferably 1 to 200 mg / day for adults are divided into one or several divided doses. It can be administered.

The present invention will be described more specifically below with reference to Reference Examples, Examples and Experimental Examples, but the present invention is not limited to these. Reference Example 1 Synthesis of 7-chloro-2-indolecarboxylic acid (Fisher's indole synthesis method) a) Synthesis of ethyl 2- (2-chlorophenyl) hydrazonopropionate Ethyl 2-methylacetoacetate (14.4 g, 0.10 mo
50% aqueous potassium hydroxide solution (50 g) was added dropwise to a solution of l) in ethanol (100 ml) at 0 ° C. Add ice (7
0 g) and then o-chloroaniline (12.8 g, 0.10
mol), sodium nitrite (13.6 g, 0.20 mol) and concentrated hydrochloric acid (60 g) were added at once in a diazonium salt solution. The reaction solution was stirred at 0 ° C. for 30 minutes, and the precipitate was collected by filtration and dried under reduced pressure to give the target ethyl 2- (2
-Chlorophenyl) hydrazono propionate (9.10 g,
37.7%). b) Synthesis of ethyl 7-chloro-2-indolecarboxylate Ethyl 2- (2-chlorophenyl) hydrazonopropionate (8.00 g, 33.2 mmol) obtained above was added to polyphosphoric acid.
(20 g), and gradually heat to 190 ℃, 1
Hold at 90 ° C. for 5 minutes. The reaction solution was cooled to 60 ° C., water was added, the mixture was extracted with ethyl acetate (three times), the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. By separating and purifying by silica gel column chromatography, the target ethyl 7
-Chloro-2-indolecarboxylate (3.40 g, 4
5.7%). ¹ Hnmr (CDCl ₃ ) δ; 1.40-1.46 (3H, m), 4.43
(2H, dd, J = 7.3, 14.2Hz), 7.09 (1H, t, J = 7.9Hz), 7.2
5 (1H, d, J = 2.3Hz), 7.32 (1H, dd, J = 1.0, 7.6Hz), 7.5
8-7.61 (1H, m), 9.02 (1H, br-s).

Reactions were carried out according to the method of Reference Example 1 to synthesize the compounds shown below. (1) Ethyl 5-nitro-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.42-1.47 (3H, m), 4.45
(2H, dd, J = 7.3, 14.2Hz), 7.38 (1H, dd, J = 0.7, 2.0
Hz), 7.50 (1H, d, J = 9.3Hz), 8.21-8.25 (1H, m), 8.69
(1H, d, J = 2.0Hz), 9.3 (1H, br-s). (2) Ethyl 7-nitro-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.42-1.48 (3H, m), Four.
43-4.51 (2H, m), 7.25-7.28 (1H, m), 7.37 (1H, d, J = 2.
3Hz), 8.04-8.08 (1H, m), 8.31 (1H, dd, J = 1.0,7.9Hz),
10.4 (1H, br-s). (3) Ethyl 4-methoxy-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.38-1.43 (3H, m), 3.
96 (3H, s), 4.36-4.44 (2H, m), 6.51 (1H, d, J = 7.9Hz),
7.01 (1H, d, J = 8.3Hz), 7.22 (1H, d, J = 7.9Hz), 7.34-
7.35 (1H, m), 8.9 (1H, br-s). (4) Ethyl 6-methoxy-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.38-1.43 (3H, m), 3.
85 (3H, s), 4.39 (2H, dd, J = 7.3, 14.2Hz), 6.80-6.84
(2H, m), 7.16-7.17 (1H, m), 7.52-7.56 (1H, m), 8.9 (1
H, br-s). (5) Ethyl 4-nitro-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.44-1.49 (3H, m), 4.
43-4.51 (2H, m), 7.41-7.47 (1H, m), 7.77-7.80 (1H,
m), 7.92 (1H, dd, J = 1.0, 2.3Hz), 8.20 (1H, dd, J = 0.
7, 7.9Hz), 9.4 (1H, br-s).

(6) Ethyl 6-nitro-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.46 (3H, t, J = 7.3H
z), 4.48 (2H, dd, J = 7.3, 14.2Hz), 7.29-7.30 (1H, m),
7.78 (1H, d, J = 8.9Hz), 8.05 (1H, dd, J = 2.0, 8.9Hz),
8.42 (1H, t, J = 1.0Hz), 9.6 (1H, br-s). (7) Ethyl 4-trifluoromethyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.42-1.47 (3H,
m), 4.45 (2H, dd, J = 6.9, 14.2Hz), 7.35
-7.41 (2H, m), 7.46-7.49 (1H, m), 7.62
(1H, d, J = 8.3Hz), 9.32 (1H, br-
s). (8) Ethyl 6-trifluoromethyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.41-1.47 (3H,
m), 4.41-4.49 (2H, m), 7.26-7.27 (1H,
m), 7.36-7.40 (1H, m), 7.73-7.81 (2H,
m), 9.26 (1H, br-s). (9) Ethyl 7-phenyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.28-1.43 (3H,
m), 4.41 (2H, dd, J = 6.9, 14.2Hz), 7.20
-7.26 (1H, m), 7.35-7.57 (6H, m), 7.66-
7.70 (2H, m), 9.11 (1H, br-s). (10) Ethyl 4-acetyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.41-1.47 (3H,
m), 2.72 (3H, s), 4.40-4.48 (2H, m), 7.
38 (1H, dd, J = 7.3, 8.2Hz), 7.66 (1H,
dd, J = 1.0, 8.3 Hz), 7.78 (1H, dd, J =
1.0, 7.3 Hz), 7.99-8.00 (1 H, m), 9.42 (1
H, br-s).

Reference Example 2 Synthesis of 4-methyl-2-indolecarboxylic acid (Lysert's indole synthesis method) a) Synthesis of (6-methyl-2-nitrophenyl) pyruvic acid Potassium tert.-butoxide (11.2 g, 0.10) 2-Methyl-3-nitrotoluene (15.1 g, 0.10 mol) and diethyl oxalate (14.
A solution of 6 g, 0.10 mol) in ethanol (10 ml) was added. The reaction solution was stirred at room temperature for 1.5 hours and then heated under reflux for 1.5 hours. Further, water (60 ml) was added to the reaction solution, and the mixture was heated under reflux for 1 hour. After cooling the reaction solution, ice water was added, and the mixture was washed with ethyl acetate (twice), the aqueous layer was acidified with concentrated hydrochloric acid, extracted with chloroform (three times), and the extract was washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure to obtain the desired 6-methyl-2-nitrophenylpyruvic acid.
(10.4 g, 46.6%) was obtained. b) Synthesis of 4-methyl-2-indolecarboxylic acid 6-methyl-2-nitrophenylpyruvic acid obtained above
A 5% aqueous solution of ammonia (10.4 g, 46.6 mmol) was suspended in water (324 ml) containing iron (II) sulfate heptahydrate (96.4 g, 0.33 mol) and 28% aqueous ammonia (37 ml). It was added to the suspension and heated under reflux for 10 minutes. After removing the insoluble matter by filtration, the filtrate was acidified with concentrated hydrochloric acid, extracted with ethyl acetate (3 times), the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. , The desired 4-methyl-2-indolecarboxylic acid (4.30 g, 24.5% (2-
Yield from methyl-3-nitrotoluene)) was obtained. ¹ H nmr (DMSO-d6) δ; 2.49 (3H, s), 6.83 (1H, d, J =
6.3Hz), 7.08-7.14 (2H, m), 7.25 (1H, d, J = 8.3Hz), 11.
7 (1H, br-s), 12.8 (1H, br-s).

Reactions were carried out according to the method of Reference Example 2 to synthesize the compounds shown below. (1) 4-Chloro-2-indolecarboxylic acid ¹ H nmr (DMSO-d6) δ; 7.06 (1H, d, J = 2.0Hz), 7.16
(1H, d, J = 7.6Hz), 7.22-7.28 (1H, m), 7.42 (1H, d, J =
7.9Hz), 12.2 (1H, br-s), 13.2 (1H, br-s). (2) 6-chloro-2-indolecarboxylic acid ¹ H nmr (DMSO-d6) δ; 7.04-7.10 (2H, m), 7.43 (1H,
d, J = 0.7Hz), 7.65 (1H, d, J = 8.6Hz), 11.9 (1H, br-s),
13.0 (1H, br-s). (3) 5-Methyl-2-indolecarboxylic acid ¹ H nmr (DMSO-d6) δ; 2.36 (3H, s), 6.98 (1H, dd, J =
1.0, 2.0Hz), 7.04-7.08 (1H, m), 7.30-7.33 (1H, m),
7.40 (1H, s), 11.6 (1H, br-s), 12.9 (1H, br-s). (4) 6-Methyl-2-indolecarboxylic acid ¹ H nmr (DMSO-d6) δ; 2.40 (3H , s), 6.87-6.90 (1H,
m), 7.00-7.01 (1H, m), 7.21 (1H, s), 7.50 (1H, d, J = 8.
(3Hz), 11.6 (1H, br-s), 12.7 (1H, br-s). (5) 7-methyl-2-indolecarboxylic acid ¹ H nmr (DMSO-d6) δ; 2.52 (3H, s), 6.93-7.02 (2H,
m), 7.09 (1H, d, J = 2.0Hz), 11.5 (1H, br-s), 12.8 (1H,
br-s). (6) 7-benzyloxy-2-indolecarboxylic acid ¹ Hnmr (DMSO-d ₆ ) δ; 5.27 (2H, s),
6.86 (1H, d, J = 7.3Hz), 6.94-7.00 (1H,
m), 7.07 (1H, dd, J = 2.0, 7.3Hz), 7.17
-7.23 (1H, m), 7.31-7.43 (3H, m), 7.65
(2H, d, J = 6.9Hz), 11.82 (1H, br-
s), 12.81 (1H, br-s). (7) 4-benzyloxy-2-indolecarboxylic acid ¹ Hnmr (DMSO-d ₆ ) δ; 5.24 (2H, s),
6.62 (1H, d, J = 6.9Hz), 7.00-7.17 (3
H, m), 7.31-7.44 (3H, m), 7.50-7.53 (2
H, m), 11.78 (1H, br-s), 12.85 (1H,
br-s).

Reference Example 3 Synthesis of methyl 6-indole carboxylate a) Synthesis of methyl 4-chloro-3-nitrobenzoate 4-chloro-3-nitrobenzoic acid (10.0 g, 49.6 mmol)
In methanol (100 ml) at 0 ° C with thionyl chloride
(11.8 g, 99.2 mmol) was added dropwise. The reaction mixture was heated under reflux for 2 hours, the solvent was evaporated under reduced pressure, ice water was added to the obtained residue to make it alkaline with aqueous ammonia, and the mixture was extracted with ethyl acetate (three times), and the extract was washed with water and anhydrous sulfuric acid. After drying over magnesium, the solvent was distilled off under reduced pressure to give methyl 4
-Chloro-3-nitrobenzoate (10.9 g,> 99%)
I got b) Synthesis of methyl 3-nitro-4-trimethylsilylethynylbenzoate Methyl 4-chloro-3-nitrobenzoate (10.7 g, 49.6 mmol) obtained above, trimethylsilylacetylene
A mixture of (8.77 g, 89.3 mmol), dichloro-bis (triphenylphosphine) palladium (0.4 g) and triethylamine (120 ml) was heated with stirring at 75 ° C. for 3 hours. The reaction solution was cooled, the insoluble material was filtered off, the solvent was distilled off from the filtrate under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give methyl 3-nitro-4-trimethylsilylethynylbenzoate ( 8.40 g, 61.0%) was obtained.

C) Synthesis of methyl 4- (2,2-dimethoxyethyl) -3-nitrobenzoate The methyl 3-nitro-4-trimethylsilylethynylbenzoate (3.00 g, 10.8 mmol) obtained above was added to sodium methoxide. (2.92 g, 54.1 mmol) was added to a methanol solution, and the mixture was heated under reflux for 30 minutes. After cooling the reaction solution to 0 ° C,
Acetic acid (5.52 g, 54.1 mmol) was added, and then the solvent was evaporated under reduced pressure. Ice water was added to the obtained residue, which was extracted with dichloromethane (3 times), the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography. By this, methyl 4
-(2,2-Dimethoxyethyl) -3-nitrobenzoate (2.40 g, 82.4%) was obtained. d) Synthesis of methyl 3-amino-4- (2,2-dimethoxyethyl) benzoate Methyl 4- (2,2-dimethoxyethyl) obtained above
5% palladium-carbon (0.50 g) was added to a mixed solvent of 3-nitrobenzoate (4.40 g, 16.3 mmol) in methanol (200 ml) and acetic acid (2 ml), and catalytic reduction was performed at room temperature and atmospheric pressure. , Methyl 3 by post-treatment according to a conventional method
-Amino-4- (2,2-dimethoxyethyl) benzoate (4.16 g) was obtained. e) Synthesis of methyl 6-indole carboxylate The methyl 3-amino-4- (2,2-dimethoxyethyl) benzoate (4.00 g, 16.7 mmol) obtained above was treated with 1N.
Add to the hydrochloric acid (15 ml) / ethanol (15 ml) solution and add 60
The mixture was heated and stirred at 0 ° C for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate (three times), the extract solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
Methyl 6-indole carboxylate (3.00 g,>
99%). ¹ Hnmr (CDCl ₃ ) δ; 3.95 (3H, s), 7.13-7.
45 (4H, m), 7.68-7.72 (1H, m), 8.94 (1H, br-s).

Reference Example 4 Synthesis of methyl 1-methyl-2-indolecarboxylate 2-indolecarboxylic acid (2.00 g, 12.4 mmol) was added to 6
It was added to a suspension of 0% sodium hydride (0.99 g, 24.8 mmol) and dimethylformamide (40 ml) and stirred at room temperature to form a transparent solution, and then methyl iodide (7.05 g, 7.05 g, at room temperature). 49.6 mmol) of dimethylformamide (10 m
l) The solution was added dropwise and stirred at room temperature for 5 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (three times), the extract solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to recrystallize the residue obtained by recrystallization with n-hexane. Thus, methyl 1-methyl-2-indole carboxylate (1.70 g, 72.4%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 3.91 (3H, s), 4.08 (3
H, s), 7.12-7.18 (1H, m), 7.30 (1H, s), 7.32-7.41 (2
H, m), 7.66-7.70 (1H, m).

Reactions were carried out according to the method of Reference Example 4 to synthesize the compounds shown below. (1) Methyl 1-methyl-5-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.82 (3H, s), 3.93 (3
H, s), 6.58 (1H, dd, J = 1.0, 3.3Hz), 7.11 (1H, d, J =
3.3Hz), 7.32 (1H, d, J = 8.6Hz), 7.91-7.95 (1H, m), 8.
39-8.40 (1H, m). (2) Methyl 1-methyl-3-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.82 (3H, s), 3.91 (3
H, s), 7.24-7.37 (3H, m), 7.77 (1H, s), 8.14-8.20 (1
H, m). (3) Methyl 1-methyl-4-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.84 (3H, s), 3.98 (3
H, s), 7.10-7.11 (1H, m), 7.20 (1H, d, J = 3.0Hz), 7.2
4-7.29 (1H, m), 7.53 (1H, d, J = 8.2Hz), 7.91 (1H, dd,
J = 1.0, 7.6 Hz). (4) Methyl 4-chloro-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.60 (3H, s), 3.75 (3
H, s), 6.80-6.83 (1H, m), 6.89-6.95 (2H, m), 7.05 (1
(5) Methyl 5-chloro-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.64 (3H, s), 3.78 (3
H, s), 6.93 (1H, s), 6.97-7.02 (2H, m), 7.36 (1H, t,
J = 1.3Hz). (6) Methyl 6-chloro-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.91 (3H, s), 4.04 (3
H, s), 7.09-7.13 (1H, m), 7.25-7.26 (1H, m), 7.38-7.
39 (1H, m), 7.56-7.59 (1H, m). (7) Methyl 7-chloro-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.91 (3H, s), 4.47 ( 3
H, s), 6.99 (1H, m), 7.26-7.30 (2H, m), 7.52-7.56 (1
H, m).

(8) Methyl 1,4-dimethyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 2.56 (3H, s), 3.92 (3
H, s), 4.07 (3H, s), 6.93-6.96 (1H, m), 7.17-7.29 (2
(H, m), 7.33 (1H, d, J = 0.7Hz). (9) Methyl 1,5-dimethyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 2.44 (3H, s), 3.90 (3
H, s), 4.05 (3H, s), 7.16-7.29 (3H, m), 7.42-7.45 (1
H, m). (10) Methyl 1,6-dimethyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 2.51 (3H, s), 3.90 (3
H, s), 4.05 (3H, s), 6.99 (1H, dd, J = 1.0, 8.3Hz), 7.
12-7.16 (1H, m), 7.24-7.26 (1H, m), 7.55 (1H, d, J = 8.
(2Hz), 7.42-7.45 (1H, m). (11) Methyl 1,7-dimethyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 2.80 (3H, s), 3.89 (3
H, s), 4.35 (3H, s), 6.97 (2H, m), 7.25-7.27 (1H, m),
7.26 (1H, s), 7.48 (1H, d, J = 7.3Hz). (12) Methyl 1-methyl-5-methoxy-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.85 (3H, s) , 3.90 (3
H, s), 4.05 (3H, s), 7.00-7.09 (2H, m), 7.19-7.30 (2H,
m). (13) benzyl 1-benzyl-5-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 5.33 (2H, s), 5.38 (2
H, s), 6.64 (1H, d, J = 3.3Hz), 7.06-7.49 (12H, m), 7.
92 (1H, dd, J = 1.7, 8.9Hz), 8.45-8.46 (1H, m). (14) Isopropyl 1-isopropyl-5-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.38 (6H, d, J = 6.3H
z), 1.53 (6H, d, J = 6.6Hz), 4.62-4.75 (1H, m), 5.21-
5.35 (1H, m), 6.60 (1H, d, J = 3.3Hz), 7.27 (1H, d, J = 3.
3Hz), 7.36 (1H, d, J = 8.6Hz), 7.90 (1H, dd, J = 1.7, 8.
6Hz), 8.38 (1H, d, J = 1.7Hz).

Reference Example 5 Synthesis of methyl 1-methyl-6-indole carboxylate Methyl 6-indole carboxylate (3.00 g, 1
7.1 mmol), 60% sodium hydride (0.68 g, 17.1 m)
mol), methyl iodide (4.86 g, 34.4 mmol) and dimethylformamide (60 ml) according to the method of Reference Example 4, methyl 1-methyl-6-indolecarboxylate (2.75 g, 86.9%). ) Got. ¹ Hnmr (CDCl ₃ ) δ; 3.86 (3H, s), 3.95 (3
H, s), 6.51-6.53 (1H, m), 7.21 (1H, d, J = 3.3Hz), 7.6
3 (1H, d, J = 8.6Hz), 7.78-7.82 (1H, m), 8.10 (1H, s).

Reactions were carried out according to the method of Reference Example 5 to synthesize the compounds shown below. (1) Ethyl 4-methoxy-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.39 (3H, t, J = 7.3H
z), 3.96 (3H, s), 4.06 (3H, s), 4.35 (2H, dd, J = 7.3,
14.2Hz), 6.50 (1H, d, J = 7.6Hz), 6.98 (1H, d, J = 8.6H
z), 7.24-7.30 (1H, m), 7.42 (1H, d, J = 0.7Hz). (2) Ethyl 6-methoxy-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.37 -1.42 (3H, m), 3.8
9 (3H, s), 4.03 (3H, s), 4.31-4.39 (2H, m), 6.75 (1H,
s), 6.80-6.84 (1H, m), 7.25 (1H, s), 7.53 (1H, d, J = 8.
9Hz). (3) Ethyl 1-methyl-4-nitro-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.45 (3H, t, J = 7.3H
z), 4.17 (3H, s), 4.39-4.47 (2H, m), 7.41-7.48 (1H,
m), 7.74-7.77 (1H, m), 7.96 (1H, d, J = 1.0Hz), 8.18-
8.21 (1H, m). (4) Ethyl 1-methyl-6-nitro-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.41-1.46 (3H, m), 4.
17 (3H, s), 4.38-4.46 (2H, m), 7.34 (1H, d, J = 1.0Hz),
7.75 (1H, dd, J = 0.7, 8.9Hz), 8.03 (1H, dd, J = 2.0,
(8.9Hz), 8.39 (1H, d, J = 2.0Hz). (5) Ethyl 1-methyl-5-nitro-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.41-1.46 (3H, m), Four.
14 (3H, s), 4.41 (2H, dd, J = 7.3, 14.2Hz), 7.42-7.46
(2H, m), 8.22-8.26 (1H, m), 8.66 (1H, d, J = 2.0Hz). (6) Ethyl 1-methyl-7-nitro-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.43 (3H, t, J = 7.3H
z), 4.00 (3H, s), 4.37-4.45 (2H, m), 7.20 (1H, t, J =
7.9Hz), 7.43 (1H, s), 7.85-7.93 (2H, m).

(7) Methyl 1-benzyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.86 (3H, s), 5.84 (2
H, s), 7.02-7.06 (2H, m), 7.13-7.44 (7H, m), 7.70-7.
73 (1H, m). (8) Methyl 1-benzyl-3-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.91 (3H, s), 5.34 (2
H, s), 7.13-7.17 (2H, m), 7.20-7.36 (6H, m), 7.85 (1
H, s), 8.17-8.21 (1H, m). (9) Methyl 1-isopropyl-3-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.56 (6H, d, J = 6.9H
z), 3.92 (3H, s), 4.64-4.74 (1H, m), 7.24-7.31 (2H,
m), 7.39-7.42 (2H, m), 7.96 (1H, s), 8.15-8.20 (1H,
m). (10) Ethyl 1,3-dimethyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.42-1.47 (3H,
m), 2.59 (3H, s), 4.01 (3H, s), 4.37-4.
45 (2H, m), 7.10-7.18 (1H, m), 7.31-7.38
(2H, m), 7.64-7.67 (1H, m). (11) Ethyl 1-methyl-4-methylsulfonyl-
2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.41-1.46 (3H,
m), 3.14 (3H, s), 4.16 (3H, s), 4.41 (2)
H, dd, J = 7.3, 14.2Hz), 7.48 (1H, dd,
J = 7.3, 8.3 Hz), 7.68-7.71 (2H, m), 7.81
-7.84 (1H, m). (12) Ethyl 1-methyl-6-methylsulfonyl-
2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.41-1.46 (3H,
m), 3.11 (3H, s), 4.16 (3H, s), 4.37-4.
45 (2H, m), 7.34 (1H, d, J = 0.7Hz), 7.
62-7.70 (2H, m), 7.83 (1H, dd, J = 0.7,
8.6 Hz), 8.07 (1H, d, J = 0.7 Hz).

(13) Methyl 4-fluoro-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.92 (3H, s), 4.09
(3H, s), 6.77-6.83 (1H, m), 7.16 (1H,
d, J = 8.3 Hz), 7.23-7.31 (1H, m), 7.36
(1H, s). (14) Methyl 4-bromo-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.93 (3H, s), 4.08
(3H, s), 7.16-7.26 (1H, m), 7.31-7.35
(3H, m). (15) Methyl 1- (2-naphthylmethyl) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.86 (3H, s), 6.00
(2H, s), 7.14-7.32 (3H, m), 7.37-7.43
(5H, m), 7.66-7.78 (4H, m). (16) Methyl 1- (2-phenylethyl) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.06 (2H, t, J = 7.
9Hz), 3.90 (3H, s), 4.74-4.80 (2H,
m), 7.11-7.33 (9H, m), 7.66-7.69 (1H,
m). (17) Methyl 1- (4-bromobenzyl) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.87 (3H, s), 5.79
(2H, s), 6.92 (2H, dd, J = 2.0, 6.6H
z), 7.15-7.23 (1H, m), 7.31-7.38 (5H,
m), 7.70-7.74 (1H, m). (18) Methyl 1- (4-nitrobenzyl) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.87 (3H, s), 5.93
(2H, s), 7.14-7.41 (5H, m), 7.42 (1H,
d, J = 0.7 Hz), 7.73-7.77 (1H, m), 8.09-
8.14 (2H, m).

(19) Methyl 1- (3-phenylpropyl) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 2.06-2.22 (2H,
m), 2.69 (2H, d, J = 8.0Hz), 3.90 (3H,
s), 4.60 (2H, t, J = 8.0Hz), 7.05-7.40
(9H, m), 7.66 (1H, d, J = 8.0Hz). (20) Methyl 1- (2-methoxyethyl) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.28 (3H, s), 3.73
(2H, t, J = 5.9Hz), 3.91 (3H, s), 4.74
(2H, t, J = 5.9Hz), 7.14 (1H, ddd, J
= 1.0, 6.9, 7.4 Hz), 7.31 (1H, d, J = 0.7)
Hz), 7.36 (1H, dd, J = 1.3, 6.9Hz), 7.
48 (1H, dd, J = 0.7, 8.6Hz), 7.66 (1H,
dd, J = 1.1, 8.3 Hz). (21) Methyl 1- (2-diethylaminoethyl)-
2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.03 (6H, t, J = 7.
3Hz), 2.61 (4H, q, J = 7.3Hz), 2.70-2.
82 (2H, m), 3.91 (3H, s), 4.58-4.70 (2
H, m), 7.14 (1H, ddd, J = 1.3, 6.7, 8.6
Hz), 7.27 (1H, d, J = 1.0Hz), 7.34 (1
H, ddd, J = 1.0, 6.7, 7.1 Hz), 7.43 (1
H, dd, J = 1.0, 8.6 Hz), 7.61-7.71 (1H,
m). (22) Ethyl 4-chloro-1- (2-diethylaminoethyl) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.00 (6H, t, J = 7.
3Hz), 1.42 (3H, t, J = 7.3Hz), 2.59 (4
H, q, J = 7.3 Hz), 2.69-2.80 (2H, m), 4.
38 (2H, q, J = 7.3Hz), 4.56-4.68 (2H,
m), 7.14 (1H, dd, J = 1.0, 7.3Hz), 7.18
-7.28 (1H, m), 7.29-7.35 (1H, m), 7.37
(1H, d, J = 0.7Hz).

(23) Synthesis of methyl 1- [2- (2-tetrahydropyranyl) oxyethyl] -2-indolecarboxylate Methyl 2-indolecarboxylate (2.0 g, 1
1.4 mmol), 60% sodium hydride (0.55 g, 13.7 mmol)
, 2- (2-iodoethoxy) tetrahydropyran (prepared from 2-iodoethanol and 3,4-dihydro-2H-pyran; 3.63 g, 13.7 mmol) and dimethylformamide (50 ml) according to the method of Reference Example 5. The reaction was carried out to obtain methyl 1- [2- (2-tetrahydropyranyl) oxyethyl] -2-indolecarboxylate (2.87 g, 83.0%). ¹ Hnmr (CDCl ₃ ) δ; 1.27-1.75 (6H,
m), 3.26-3.54 (2H, m), 3.75 (1H, dt, J
= 4.6, 10.2Hz), 4.03 (1H, dt, J = 4.6, 1)
0.2Hz), 4.47 (1H, t, J = 3.0Hz), 4.80
(2H, t, J = 3.7Hz), 7.13 (1H, t, J = 7.
0Hz), 7.22-7.38 (2H, m), 7.53 (1H, d,
J = 8.0 Hz), 7.65 (1H, d, J = 8.0 Hz). (24) Methyl 1- [3- (2-tetrahydropyranyl) oxypropyl] -2-indolecarboxylate 2- (2-iodopropoxy) tetrahydropyran instead of 2- (2-iodoethoxy) tetrahydropyran The reaction was performed according to the method of Reference Example 5 (23) except for using it to obtain the title compound. ¹ Hnmr (CDCl ₃ ) δ; 1.42-1.97 (6H,
m), 2.11 (2H, dt, J = 5.9, 11.2Hz), 3.33
(1H, dt, J = 7.9, 8.3Hz), 3.40-3.55 (1
H, m), 3.72-3.88 (2H, m), 3.94 (3H,
s), 4.52 (1H, dd, J = 3.0, 4.3Hz), 4.69
(2H, dt, J = 0.9, 1.7Hz), 7.14 (1H, d
dd, J = 1.0, 7.0, 7.9 Hz), 7.27-7.37 (2
H, m), 7.48 (1H, dd, J = 0.9,8.5Hz),
7.66 (1H, dt, J = 1.0, 7.9Hz).

(25) Synthesis of methyl 1- (3-tert-butoxycarbonylaminopropyl) -2-indolecarboxylate Methyl-2-indolecarboxylate (5.00 g, 2
8.5mmol), 60% sodium hydride (1.26g, 31.4mmo)
l), tert-butyl N- (3-iodopropyl) carbamate (3-iodopropylamine and di-tert dioxide
-Prepared from butyl; 12.3 g, 43.2 mmol) and dimethylformamide (60 ml) were reacted according to the method of Reference Example 5 to give methyl 1- (3-tert-butoxycarbonylaminopropyl) -2-indolecarboxylate. (2.54 g, 27%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.45 (9H, s), 1.90
-2.10 (2H, m), 3.00-3.20 (2H, m), 3.91
(3H, s), 4.62 (2H, t, J = 6.9Hz), 4.98
(1H, br-s), 7.06-7.20 (1H, m), 7.28-
7.44 (3H, m), 7.68 (1H, d, J = 7.3Hz). (26) Methyl 1- (2-tert-butoxycarbonylaminoethyl) -2-indolecarboxylate tert-butyl N- (2-iodopropyl) carbamate instead of tert-butyl N- (3-iodopropyl) carbamate The reaction was carried out according to the method of Reference Example 5 (25) except for using it to obtain the title compound. ¹ Hnmr (CDCl ₃ ) δ; 1.41 (9H, s), 3.53
(2H, t, J = 5.9Hz), 3.90 (3H, s), 4.68
(2H, t, J = 6.3Hz), 4.60-4.80 (1H,
m), 7.15 (1H, ddd, 1H, J = 1.0, 6.9, 7.
4Hz), 7.27-7.38 (2H, m), 7.48 (1H, d,
J = 8.3 Hz), 7.66 (1H, d, J = 7.9 Hz).

(27) Ethyl 1-methyl-4- (2-
Tetrahydropyranyl) oxyethyl-2-indolecarboxylate The title compound was obtained in the same manner as in Reference Example 5. ¹ Hnmr (CDCl ₃ ) δ; 1.39-1.44 (3H,
m), 1.53-1.91 (6H, m), 3.50-3.61 (1H,
m), 3.84-4.03 (1H, m), 4.09 (3H, s), 4.
34-4.42 (2H, m), 4.75 (1H, t, J = 3.6H
z), 4.83 (1H, d, J = 12.2Hz), 5.08 (1H,
d, J = 12.2Hz), 7.18 (1H, t, J = 4.0H
z), 7.32-7.33 (2H, m), 7.42 (1H, s). (28) Ethyl 4-chloro-1- [4- (2-tetrahydropyranyl) oxybutyl] -2-indolecarboxylate 2- (2-iodoethoxy) tetrahydropyran and methyl 2-indolecarboxylate instead of 2
The reaction was performed according to the method of Reference Example 5 (23) except that-(4-iodobutoxy) tetrahydropyran and ethyl 4-chloro-2-indolecarboxylate were used to obtain the title compound. ¹ Hnmr (CDCl ₃ ) δ; 1.42 (3H, t, J = 7.
3Hz), 1.41-2.00 (10H, m), 3.32-3.56 (2
H, m), 3.68-3.90 (2H, m), 4.38 (2H, q,
J = 7.3 Hz), 4.55 (1 H, t, J = 4.0 Hz), 4.
60 (2H, t, J = 7.6Hz), 7.13 (1H, dd, J
= 1.0, 7.6Hz), 7.22 (1H, d, J = 8.2H
z), 7.32 (1H, d, J = 8.3Hz), 7.39 (1H,
s).

(29) Methyl 1- (3: 4-isopropylidenedioxybutyl) -2-indolecarboxylate Reference example 5 except that iodide 3: 4-isopropylidenedioxybutyl was used instead of methyl iodide. The reaction was performed according to the method of 1. to give the title compound. ¹ Hnmr (CDCl ₃ ) δ; 1.34 (3H, s), 1.46
(3H, s), 1.90-2.18 (2H, m), 3.52 (1H,
dd, J = 6.9, 7.9 Hz), 3.91 (3H, s), 3.97
(1H, dd, J = 5.9, 7.9Hz), 4.01-4.17 (1
H, m), 4.58-4.80 (2H, m), 7.15 (1H, dd
d, J = 1.0, 6.9, 7.4 Hz), 7.31 (1H, d, J
= 0.7 Hz), 7.35 (1H, ddd, J = 1.3, 6.9,
7.6 Hz), 7.47-7.55 (1 H, m), 7.63-7.70 (1
H, m). (30) Methyl 1- [2- [1- (4-methyl-2,
6,7-Trioxabicyclo [2.2.2] octyl)] ethyl] -2-indolecarboxylate Iodide 2- [1- (4-methyl-2,6,7-trio) instead of methyl iodide The reaction was conducted according to the method of Reference Example 5 except that xabicyclo [2.2.2] octyl)] ethyl was used to obtain the title compound. ¹ Hnmr (CDCl ₃ ) δ; 0.79 (3H, s), 2.17
(2H, ddd, J = 2.6, 5.3, 7.9Hz), 3.89
(6H, s), 3.90 (3H, s), 5.87 (2H, dd
d, J = 2.3, 5.6, 7.9 Hz), 7.12 (1H, dd
d, J = 1.0, 6.9, 7.4 Hz), 7.27 (1H, d, J
= 0.7 Hz), 7.32 (1H, ddd, J = 1.3, 6.9,
7.6Hz), 7.48 (1H, dd, J = 0.7, 8.6H
z), 7.65 (1H, ddd, J = 1.0, 1.5, 8.3H
z).

The following compounds were synthesized in the same manner as in Reference Example 5. (31) Methyl 4-benzyloxy-1-methyl-2
- indole carboxymethyl acrylate _{^{1 Hnmr (CDCl 3) δ;}} 3.89 (3H, s), 4.06
(3H, s), 5.22 (2H, s), 6.57 (1H, d, J
= 7.6Hz), 6.99 (1H, d, J = 8.6Hz), 7.22
-7.28 (1H, m), 7.30-7.51 (6H, m). (32) Methyl 6-benzyloxy-1-methyl-2
- indole carboxylate _{^{1 Hnmr (CDCl 3) δ;}} 3.89 (3H, s), 4.02
(3H, s), 5.15 (2H, s), 6.85 (1H, d, J
= 2.31Hz), 6.91 (1H, dd, J = 2.3, 8.6H
z), 7.24 (1H, d, J = 1.0Hz), 7.34-7.44
(3H, m), 7.47-7.52 (2H, m), 7.53-7.57
(1H, m). (33) Methyl 7-benzyloxy-1-methyl-2
- indole carboxylate _{^{1 Hnmr (CDCl 3) δ;}} 3.89 (3H, s), 4.38
(3H, s), 5.19 (2H, s), 6.78 (1H, d, J
= 8.6 Hz), 6.97-7.03 (1H, m), 7.24-7.27
(2H, m), 7.33-7.51 (5H, m).

Reference Example 6 Synthesis of methyl 2-indolecarboxylate In a solution of 2-indolecarboxylic acid (30.0 g, 186.2 mmol) in methanol (300 ml), thionyl chloride (4
4.3 g, 372.3 mmol) was added dropwise. The reaction solution was heated under reflux for 2 hours, the solvent was distilled off under reduced pressure, and ice water was poured into the obtained residue. The mixture was made alkaline with aqueous ammonia, extracted with ethyl acetate (three times), the extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
Methyl 2-indolecarboxylate (32.34 g, 9
9.2%). ¹ Hnmr (CDCl ₃ ) δ; 3.95 (3H, s), 7.13-7.
45 (4H, m), 7.69 (1H, dd, J = 1.0, 7.9Hz), 8.91 (1H, br
-s).

Reactions were carried out according to the method of Reference Example 6 to synthesize the compounds shown below. (1) Methyl 3-indole carboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.93 (3H, s), 7.24-7.
31 (2H, m), 7.38-7.45 (1H, m), 7.93 (1H, d, J = 3.0Hz),
8.17-8.22 (1H, m), 8.63 (1H, br-s) (2) Methyl 4-fluoro-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.96 (3H, s), 6.78
-6.85 (1H, m), 7.18-7.30 (3H, m), 8.99
(1H, br-s). (3) Methyl 4-bromo-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.97 (3H, s), 7.17
(1H, dd, J = 7.6, 8.3Hz), 7.28 (1H, d
d, J = 1.0, 2.3 Hz), 7.32-7.39 (2H, m),
9.05 (1H, br-s). (4) Methyl 7-benzyloxy-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.93 (3H, s), 5.21
(2H, s), 6.80 (1H, d, J = 6.9Hz), 7.01
-7.08 (1H, m), 7.19 (1H, dd, J = 2.3, 4.
3Hz), 7.24-7.31 (1H, m), 7.35-7.51 (5
H, m), 9.07 (1H, br-s). (5) Methyl 4-benzyloxy-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.93 (3H, s), 5.22
(2H, s), 6.58 (1H, d, J = 7.6Hz), 7.03
(1H, d, J = 8.3Hz), 7.19-7.26 (1H,
m), 7.31-7.44 (4H, m), 7.50 (2H, d, J =
7.3 Hz), 8.84 (1H, br-s).

Reference Example 7 Synthesis of methyl 5-indole carboxylate A mixture of 5-indolecarboxylic acid (1.00 g, 6.21 mmol) and 10% hydrogen chloride / methanol (50 ml) was added to 2 parts.
After heating under reflux for an hour, the reaction solution was poured into ice water and neutralized with sodium bicarbonate. Then, the mixture was extracted with ethyl acetate (three times), the extract was washed with sodium bicarbonate water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give methyl 5-indolecarboxylate (0.42 g, 38.6%). Got ¹ Hnmr (CDCl ₃ ) δ; 3.93 (3H, s), 6.64-6.
66 (1H, m), 7.26-7.29 (1H, m), 7.40 (1H, dd, J = 0.7,
8.6Hz), 7.91 (1H, dd, J = 1.7, 8.6Hz), 8.3-8.6 (2H,
m). Reference Example 8 Synthesis of methyl 1-isopropyl-5-indolecarboxylate Isopropyl 1-isopropyl-5-indolecarboxylate (2.20 g, 8.97 mmol), 2N aqueous caustic soda solution (100 ml) and ethanol (100 ml) The mixture was heated under reflux for 1 hr, and the solvent was evaporated under reduced pressure. Then
Water was added to the residue, which was then acidified with concentrated hydrochloric acid, and the precipitated solid was collected by filtration and dried under reduced pressure to give crude 1-isopropyl-5-indolecarboxylic acid (2.00 g). This crude 1-isopropyl-5-indolecarboxylic acid (2.00 g) and 60% sodium hydride (0.44 g, 1
1.1 mmol), methyl iodide (2.87 g, 20.2 mmol) and dimethylformamide (50 ml) were reacted according to the method of Reference Example 4 to give methyl 1-isopropyl-5-indolecarboxylate (1.64 g, isopropyl). Yield from 1-isopropyl-5-indolecarboxylate: 84.2%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.54 (6H, d, J = 6.9H
z), 3.93 (3H, s), 4.65-4.75 (1H, m), 6.61 (1H, d, J =
3.3Hz), 7.28 (1H, d, J = 3.3Hz), 7.37 (1H, d, J = 8.6H
z), 7.9 (1H, dd, J = 1.7, 8.6Hz), 8.39 (1H, d, J = 1.7H
z).

Reference Example 9 Synthesis of 7-chloro-2-indolecarboxylic acid Ethyl 7-chloro-2-indolecarboxylate (3.40 g, 15.2 mmol), 2N aqueous caustic soda solution (100 m
The mixture of l) and ethanol (100 ml) was heated under reflux for 1 hour, and then the solvent was distilled off under reduced pressure. Next, ice water was added to the residue, which was then acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3
The mixture was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 7-chloro-2-indolecarboxylic acid (2.85 g, 95.8%). ¹ H nmr (DMSO-d6) δ; 7.04-7.09 (1H, m), 7.19 (1H,
d, J = 2.0Hz), 7.30 (1H, dd, J = 1.0, 7.6Hz), 7.62 (1H,
d, J = 8.3Hz), 11.9 (1H, br-s), 13.1 (1H, br-s). Reference Example 10 Synthesis of 1-isopropyl-2-indolecarboxylic acid Methyl 2-indolecarboxylate (6.00 g, 3
4.2 mmol), 60% sodium hydride (1.36 g, 34.2
mmol), isopropyl iodide (6.40 g, 37.7 mmol)
And dimethylformamide (100 ml), Reference Example 4
The reaction is carried out according to the method described in 1., and methyl 1-isopropyl-2-indolecarboxylate and isopropyl
A mixture of 1-isopropyl-2-indolecarboxylate was obtained. This mixture and 2N caustic soda solution (15
0 ml) and ethanol (150 ml) were reacted according to the method of Reference Example 9 to obtain 1-isopropyl-2-indolecarboxylic acid (3.71 g, 53.3%). ¹ H nmr (DMSO-d6) δ; 1.58 (6H, d, J = 6.9Hz), 5.74-
5.85 (1H, m), 7.05-7.11 (1H, m), 7.19-7.28 (2H, m),
7.64-7.72 (2H, m), 12.9 (1H, br-s).

Reference Example 11 Synthesis of methyl 1-methyl-7-indolecarboxylate a) Ethyl 7-carbomethoxy-1-methyl-2-
Synthesis of Indole Carboxylate Ethyl-7-carbomethoxy-2-indolecarboxylate (5.00 g, 20.2 mmol) obtained by performing the reaction according to the method of Reference Example 1 was treated with 60% sodium hydride (0.81 g, 20.2mmol) and dimethylformamide (8
0 ml) and stirred at room temperature to form a transparent solution, and then methyl iodide (5.74 g, 40.4 mmol) was added at room temperature.
Was added dropwise, followed by stirring at 50 ° C. for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate (three times), the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue, which was separated by silica gel column chromatography. Purification yielded ethyl 7-carbomethoxy-1-methyl-2-indolecarboxylate (5.20 g, 98.5%). b) Synthesis of 1-methylindole-2,7-dicarboxylic acid Ethyl 7-carbomethoxy-1-methyl-2-indolecarboxylate (5.20 g, 19.9 mmol), 2N aqueous sodium hydroxide solution (90 ml) and ethanol (150).
ml) was heated to reflux for 3 hours. Ice water was added to the residue obtained by concentrating the reaction solution under reduced pressure, and 2N hydrochloric acid was added dropwise to make the reaction solution acidic. The precipitated solid is collected by filtration,
1-methylindole-by drying under reduced pressure
2,7-dicarboxylic acid (4.70 g,> 99%) was obtained.

C) Synthesis of 1-methyl-7-indolecarboxylic acid 1-methylindole-2,7-dicarboxylic acid (4.60
g, 21.0 mmol), copper (II) oxide (0.5 g) and quinoline (50 ml) were heated and stirred at 180 ° C. for 1 hour. After cooling the reaction mixture, it was poured into 2N hydrochloric acid (200 ml),
Extraction with ethyl acetate (3 times), washing with saturated brine, drying over anhydrous magnesium sulfate, evaporation of the solvent under reduced pressure and separation and purification of the residue by silica gel column chromatography gave 1-methyl. -7-Indolecarboxylic acid (1.82 g, 49.0%) was obtained. d) Synthesis of methyl 1-methyl-7-indolecarboxylate 1-Methyl-7-indolecarboxylic acid (1.82 g, 10.4)
Thionyl chloride (3.09 g, 26.0 mmol) was added dropwise to a methanol solution (70 ml) of (mmol) at 0 ° C. The reaction solution was heated under reflux for 2 hours, the solvent was distilled off under reduced pressure, and ice water was poured into the obtained residue. The mixture was made alkaline with aqueous ammonia, extracted with ethyl acetate (3 times), the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was separated and purified by silica gel column chromatography. By doing so, methyl 1-methyl-7-indolecarboxylate (1.16 g, 59.0%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 3.88 (3H, s), 3.96
(3H, s), 6.54 (1H, d, J = 3.3Hz), 7.10
(1H, t, J = 7.6Hz), 7.67 (1H, d, J = 7.
3Hz), 7.75 to 7.78 (1H, m).

Reference Example 12 Synthesis of ethyl-7-benzyloxy-4-chloro-2-indolecarboxylate a) Synthesis of 3-benzyloxy-6-chloro-2-nitrotoluene 4-chloro-3-methyl-2- Nitrophenol (1.50
g, 8.00 mmol), benzyl bromide (1.50 g, 8.80 mmol),
Potassium carbonate (2.43 g, 17.6 mmol) and acetone (70
The mixture was heated to reflux for 2 hours. Then, the insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue obtained was separated and purified by silica gel column chromatography to give 3-benzyloxy-6-chloro-2-nitrotoluene (2.22
g,> 99%). b) Synthesis of ethyl (3-benzyloxy-6-chloro-2-nitrophenyl) pyruvate Diethyl oxalate at room temperature in a suspension of potassium ethoxide (0.67 g, 7.92 mmol) in diethyl ether (50 ml). (1.20 g, 7.92 mmol) was added dropwise. Then 3-benzyloxy-6-chloro-2-nitrotoluene (2.00
g, 7.20 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into 1N hydrochloric acid and extracted with diethyl ether (2
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was separated and purified by silica gel column chromatography to give (3-benzyloxy). Ethyl-6-chloro-2-nitrophenyl) pyruvate (1.60 g, 53.5%) was obtained.

C) Ethyl 7-benzyloxy-4-
Synthesis of chloro-2-indolecarboxylate Ethyl (3-benzyloxy-6-chloro-2-nitrophenyl) pyruvate (1.60 g, 4.24 mmol), 20% titanium trichloride aqueous solution (22.9 g, 29.7 mmol) and acetone The mixture (60 ml) was stirred at room temperature for 3 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (three times), the extract solution was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue on a silica gel column. By separating and purifying by chromatography, ethyl 7-benzyloxy-4-chloro-2
-Indole carboxylate (0.50 g, 35.8%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.39 to 1.44 (3H,
m), 4.40 (2H, dd, J = 6.9, 14.2Hz), 5.18
(2H, s), 6.69 (1H, d, J = 8.3Hz), 7.01
(1H, d, J = 8.3Hz), 7.26 to 7.27 (1H,
m), 7.35 to 7.48 (5H, m), 9.15 (1H, br-
s).

Reference Example 13 Synthesis of ethyl-6-benzyloxy-4-chloro-2-indolecarboxylate a) Synthesis of ethyl-3- (4-benzyloxy-2-chlorophenyl) -2-azidopropenoate 4 -Benzyloxy-2-chlorobenzaldehyde (5.
40 g, 21.9 mmol) and ethyl azide acetate (11.3
g, 87.6 mmol) in ethanol solution (70 ml)
It was slowly added dropwise at 70 ° C. to an ethanol solution (70 ml) of sodium ethoxide (5.95 g, 87.6 mmol). After further stirring at -10 ° C for 5 hours, the reaction temperature was gradually raised to room temperature. The reaction mixture was poured into saturated ammonium chloride aqueous solution (200 ml) and extracted with ethyl acetate (3 times).
The extract was washed with a saturated aqueous solution of ammonium chloride, followed by washing with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography. , Ethyl 3- (4-benzyloxy-2-chlorophenyl) -2-azitopropenoate (4.50 g, 57.5%) was obtained. b) Ethyl-6-benzyloxy-4-chloro-2-
Synthesis of indole carboxylate A solution of ethyl 3- (4-benzyloxy-2-chlorophenyl-2-azidopropenoate (4.50 g, 12.6 mmol) in toluene (100 ml) was heated under reflux for 3 hours, and the reaction solution was concentrated under reduced pressure. The residue thus obtained was separated and purified by silica gel column chromatography to obtain ethyl-
6-Benzyloxy-4-chloro-2-indolecarboxylate (3.73 g, 89.9%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.38-1.43 (3H,
m), 4.35 to 4.43 (2H, m), 5.09 (2H, s), 6.
79 (1H, dd, J = 0.7, 2.0Hz), 6.95 (1H,
d, J = 2.0 Hz), 7.23 to 7.24 (1H, m), 7.31 to
7.45 (5H, m), 8.94 (1H, br-s).

Reference Example 14 Synthesis of methyl 1- (2-carbamoylethyl) -2-indolecarboxylate a) Synthesis of methyl 1- (2-cyanoethyl) -2-indolecarboxylate Methyl 2-indolecarboxylate (10.0 g) ,Five
7.1 mmol) in 1,4-dioxane (150 ml) in acrylonitrile (3.63 g, 68.4 mmol) and N-
Benzyltrimethylammonium hydroxide (40%
Methanol solution (2.2 ml) was added, and the mixture was stirred at 55 ° C for 1 hr. The residue obtained by concentrating the reaction solution under reduced pressure was added to a mixed solution of acetic acid (5 ml) and water (500 ml), the aqueous layer was extracted with methylene chloride (twice), and the extract was washed with water. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography to give methyl 1- (2-cyanoethyl) -2-indolecarboxylate (13.0
g) was obtained.

B) Synthesis of methyl 1- (2-carbamoylethyl) -2-indolecarboxylate Methyl 1- (2-cyanoethyl) -2-indolecarboxylate (3.12 g, 13.7 mmol), 10% aqueous sodium carbonate solution ( 30 ml), 30% hydrogen peroxide water (30 m
A mixture of l) and acetone (100 ml) was stirred at room temperature for 4 hours. Then, cool the reaction mixture to 0 ° C. and then
Excess peroxide was decomposed by dropping a 0% sodium sulfite aqueous solution. Next, most of the acetone in the reaction solution was distilled off under reduced pressure, and the concentrated solution was extracted with ethyl acetate (3
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was separated and purified by silica gel column chromatography to give methyl 1- (2 -Carbamoylethyl)-
2-Indole carboxylate (2.30 g, 68%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 2.75 (2H, ddd, J
= 1.7, 5.9, 7.6 Hz), 3.92 (3H, s), 4.85
(2H, ddd, J = 1.7, 5.9, 7.6Hz), 5.37
(1H, br-s), 5.72 (1H, br-s), 7.16
(1H, ddd, J = 1.0, 6.9, 7.4 Hz), 7.32
(1H, d, J = 1.0Hz), 7.37 (1H, ddd, J
= 1.0, 7.3, 7.8 Hz), 7.53 (1H, dd, J = 0.
8,8.4Hz), 7.67 (1H, dt, J = 1.0, 7.9H
z).

The reaction was carried out according to the method of Reference Example 14,
The compounds shown below were synthesized. (1) Ethyl 1- (2-carbamoylethyl) -4
-Chloro-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.43 (3H, t, J = 7.
3Hz), 2.65-2.82 (1H, m), 4.39 (2H, q,
J = 7.3 Hz), 4.84 (2H, ddd, J = 1.0, 6.
3,7.3 Hz), 5.45 (1H, br-s), 5.68 (1
H, br-s), 7.14 (1H, d, J = 7.9 Hz), 7.
26 (1H, dd, J = 7.6, 8.2Hz), 7.41 (1H,
d, J = 1.0Hz), 7.45 (1H, d, J = 8.6H)
z).

Reference Example 15 Methyl 7-carbamoylmethoxy-1-methyl-2-
Synthesis of indole carboxylate a) Synthesis of methyl 7-hydroxy-1-methyl-2-indolecarboxylate Methyl 7-benzyloxy-1-methyl-2-indolecarboxylate (2.31 g, 7.82 mmol) was added to tetrahydrofuran (50 ml). ) And methanol (50 ml) in a mixed solvent, and then 10% palladium / carbon (0.
After the addition of 5 g), the catalytic reduction was usually carried out at normal pressure. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography to give methyl 7-hydroxy-1-methyl-.
2-indole carboxylate (1.63g,> 99%)
I got b) Synthesis of methyl 7-carbamoylmethoxy-1-methyl-2-indolecarboxylate Methyl 7-hydroxy-1-methyl-2-indolecarboxylate (0.50 g, 2.44 mmol) was added to 60% sodium hydride (0.01 g, 2.44 mmol) and dimethylformamide (25 ml) were added to the suspension, and the mixture was stirred at room temperature to become a transparent liquid, and then 2-chloroacetamide (0.25 g, 2.68 mmol) was added at room temperature, and then 50 The mixture was stirred at 0 ° C for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate (3 times).
Then, the extract is washed with water and dried over anhydrous magnesium sulfate,
The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography to give methyl 7-carbamoylmethoxy-1-methyl-2-indolecarboxylate (0.54 g, 84.4%). ¹ Hnmr (CDCl ₃ ) δ; 3.91 (3H, s), 4.41
(3H, s), 4.67 (2H, s), 5.70 (1H, br-
s), 6.41 (1H, br-s), 6.70-6.73 (1H,
m), 7.03 (1H, t, J = 7.9Hz), 7.62 (1H,
s), 7.31-7.34 (1H, m).

Reactions were carried out according to the method of Reference Example 15 to synthesize the compounds shown below. (1) Methyl 1-methyl-7- (2-phenylethoxy) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.17-3.22 (2H,
m), 3.87 (3H, s), 4.24 (3H, s), 4.31-4.
36 (2H, m), 6.68 (1H, d, J = 7.6Hz), 6.
94-7.00 (1H, m), 7.18-7.35 (7H, m). (2) Methyl 1-methyl-7- (3-phenylpropoxy) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 2.16-2.26 (2H,
m), 2.84-2.90 (2H, m), 3.89 (3H, s), 4.
07-4.12 (2H, m), 4.43 (3H, s), 6.64 (1
H, d, J = 6.9Hz), 6.97 (1H, t, J = 7.9H
z), 7.18-7.23 (5H, m), 7.25-7.33 (2H,
m). (3) Ethyl 7-carbamoylmethoxy-4-chloro-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.33-1.36 (3H,
m), 4.29-4.37 (5H, m), 4.60 (2H, s), 6.
69 (1H, d, J = 8.3Hz), 7.06 (1H, dd, J
= 0.7, 8.2 Hz), 7.15 (1H, d, J = 0.7H
z), 7.38 (1H, br-s), 7.54 (1H, br-
s). (4) Ethyl 4-chloro-7- (2-dimethylaminoethoxy) -1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.39-1.44 (3H,
m), 2.36 (6H, s), 2.82 (2H, t, J = 5.9H)
z), 4.17 (2H, t, J = 5.9Hz), 4.33-4.40
(5H, m), 6.59 (1H, d, J = 8.3Hz), 6.96
(1H, d, J = 7.9Hz), 7.30 (1H, s). (5) Ethyl 6-carbamoylmethoxy-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.38-1.43 (3H,
m), 4.03 (3H, s), 4.32-4.40 (2H, m), 4.
60 (2H, s), 5.61 (1H, br-s), 6.59 (1
H, br-s), 6.79 (1H, d, J = 2.3 Hz), 6.
84 (1H, dd, J = 2.3, 8.6Hz), 7.26-7.27
(1H, m), 7.57-7.60 (1H, m).

(6) Ethyl-4-chloro-1-methyl-7- [2- (N-pyrrolidinyl) ethoxy] -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.39-1.44 (3H,
m), 1.79-1.84 (4H, m), 2.63-2.68 (4H,
m), 2.97-3.02 (2H, m), 4.20-4.24 (2H,
m), 4.33-4.41 (5H, m), 6.60 (1H, d, J =
8.6Hz), 6.97 (1H, d, J = 8.3Hz), 7.31
(1H, s). (7) Methyl 7- (3-tert-butoxycarbonylaminopropoxy) -1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.43 (9H, s), 2.09
(2H, t, J = 6.3Hz), 3.35-3.42 (2H,
m), 3.89 (3H, s,), 4.13-4.18 (2H, m),
4.39 (3H, s), 4.73 (1H, br-s), 6.69 (1
H, d, J = 7.9 Hz), 6.96-7.02 (1H, m), 7.
21-7.26 (2H, m). (8) Ethyl 7- (3-tert-butoxycarbonylaminopropoxy) -4-chloro-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.38-1.44 (12H,
m), 2.03-2.13 (2H, m), 3.33-3.40 (2H,
m), 4.12 (2H, t, J = 5.9Hz), 4.33-4.41
(5H, m), 4.70 (1H, br-s), 6.58 (1H,
d, J = 8.3Hz), 6.96 (1H, d, J = 8.3H)
z), 7.31 (1H, s). (9) Ethyl 6- (3-tert-butoxycarbonylaminopropoxy) -1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.37-1.42 (3H,
m), 1.45 (9H, s), 2.02 (2H, dd, J = 6.
3,12.5Hz), 3.33-3.40 (2H, m), 4.02 (3
H, s), 4.10 (2H, t, J = 5.9Hz), 4.35 (2
H, dd, J = 6.9, 14.2Hz), 4.78 (1H, br-
s), 6.76 (1H, s), 6.78-6.83 (1H, m), 7.
24-7.26 (1H, m), 7.53 (1H, d, J = 8.6H
z).

(10) Ethyl 7- (2-tert-butoxycarbonylaminoethoxy) -4-chloro-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.39-1.44 (3H,
m), 1.45 (9H, s), 3.63 (2H, dd, J = 5.
3,10.6Hz), 4.13 (2H, t, J = 5.3Hz), 4.
30-4.41 (5H, m), 4.63-4.89 (1H, m), 6.58
(1H, d, J = 8.3Hz), 6.97 (1H, d, J = 8.3.
3Hz), 7.31 (1H, s). (11) Methyl 1-methyl-7- [2- (2-tetrahydropyranyl) oxyethoxy] -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.52-1.85 (6H,
m), 3.50-3.58 (1H, m), 3.83-3.90 (5H,
m), 4.11-4.19 (1H, m), 4.26-4.30 (2H,
m), 4.42 (3H, s), 4.73-4.75 (1H, m), 6.
70-6.73 (1H, m), 7.01 (1H, t, J = 7.9H
z), 7.22-7.26 (2H, m). (12) Ethyl 4-chloro-1-methyl-7- [2-
(2-Tetrahydropyranyl) oxyethoxy] -2-
Indole carboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.42 (3H, t, J = 7.
3Hz), 1.52-1.85 (6H, m), 3.51-3.56 (1
H, m), 3.81-3.91 (2H, m), 4.10-4.17 (1
H, m), 4.23-4.27 (2H, m), 4.33-4.40 (5
H, m), 4.72-4.73 (1H, m), 6.61 (1H, d,
J = 8.2Hz), 6.96 (1H, d, J = 8.3Hz), 7.
30 (1H, s).

(13) Ethyl 4-chloro-7- (2:
3-isopropylidenedioxypropoxy) -1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.39-1.47 (9H,
m), 3.91-3.99 (1H, m), 4.06-4.23 (3H,
m), 4.33-4.41 (5H, m), 4.51-4.63 (1H,
m), 6.60 (1H, d, J = 8.3Hz), 6.97 (1H,
d, J = 8.3 Hz), 7.31 (1 H, s). (14) Ethyl 4-chloro-1-methyl-7- [4-
(2-Tetrahydropyranyl) oxybutoxy] -2-
Indole carboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.39-1.44 (3H,
m), 1.52-1.85 (8H, m), 1.87-2.04 (2H,
m), 3.44-3.55 (2H, m), 3.79-3.91 (2H,
m), 4.10 (2H, t, J = 6.3Hz), 4.33-4.41
(5H, m), 4.58-4.61 (1H, m), 6.56 (1H,
d, J = 8.3Hz), 6.96 (1H, d, J = 8.3H)
z), 7.30 (1H, s).

Reference Example 16 Synthesis of ethyl-4-carboxy-1-methyl-2-indolecarboxylate a) Ethyl 4-hydroxymethyl-1-methyl-2
-Synthesis of indolecarboxylate Ethyl 1-methyl-4- (2-tetrahydropyranyl) oxymethyl-2-indolecarboxylate (4.00 g, 12.6 mmol) in a mixed solvent of 2N hydrochloric acid (20 ml) / tetrahydrofuran (60 ml). It was melted and stirred at 50 ° C. for 1 hour. The reaction mixture was poured into ice water, the aqueous layer was extracted with ethyl acetate (three times), the extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl 4 was obtained by separating and purifying the residue by silica gel column chromatography.
-Hydroxymethyl-1-methyl-indole carboxylate (2.90 g, 99%) was obtained. b) Synthesis of ethyl 4-carboxy-1-methyl-2-indolecarboxylate Ethyl 4-hydroxymethyl-1-methyl-indolecarboxylate (0.70 g, 3.00 mmol) was dissolved in acetone (30 ml) and added to this solution. Jones reagent (chromium (VI) oxide (26.7 g) in concentrated sulfuric acid (23 ml) at room temperature
3.3 ml of a reagent prepared by dissolving in water (40 ml) and diluting the whole with 100 ml of water) was added dropwise, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was poured into ice water, the aqueous layer was extracted with chloroform (three times), the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. By separating and purifying by silica gel column chromatography, ethyl 4-carboxy-1-
Methyl-2-indolecarboxylate (0.38g, 5
1.2%) was obtained. ¹ Hnmr (DMSO-d ₆ ) δ; 1.34-1.40 (3H,
m), 4.08 (3H, s), 4.35 (2H, dd, J = 7.
3, 14.2Hz), 7.41-7.47 (1H, m), 7.72 (1
H, s), 7.82-7.89 (2H, m), 12.7 (0.5H, b)
r-s).

Reference Example 17 Synthesis of ethyl 6-benzyloxy-4-methyl-2-indolecarboxylate a) Synthesis of 4-benzyloxy-2-methylbenzoic acid 5-Benzyloxy-2-bromotoluene (5.00 g, 18.
A mixture of 9 mmol), magnesium metal (0.46 g, 18.9 mmol), a catalytic amount of iodine and tetrahydrofuran (20 ml) was heated under reflux for 2 hours. Next, the reaction solution was cooled to −50 ° C., and then carbon dioxide was bubbled for 30 minutes. The reaction temperature was raised to room temperature and further stirred at room temperature for 2 hours. Then, the reaction solution was poured into IN hydrochloric acid water, extracted with ethyl acetate (twice), the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue on silica gel. By separating and purifying by column chromatography, 4-benzyloxy-2-methylbenzoic acid (1.40
g) got. b) Synthesis of methyl 4-benzyloxy-2-methylbenzoate 4-benzyloxy-2-methylbenzoic acid (1.40 g, 5.78
mmol), thionyl chloride (1.37 g, 11.6 mmol) and methanol (50 ml) were used and the reaction was carried out according to Reference Example 6 to give methyl 4-benzyloxy-2-methylbenzoate (0.7).
7g) was obtained. c) Synthesis of 4-benzyloxy-2-methylbenzyl alcohol A suspension of lithium aluminum hydride (0.11g, 2.93mmol) in tetrahydrofuran (20ml) was cooled to 0 ° C and methyl 4-benzyl was added to the suspension. A solution of oxy-2-methylbenzoate (0.75g, 2.93mmol) in THF (20ml) was added dropwise at 0 ° C. The reaction solution was stirred at 0 ° C. for 2 hours and then post-treated by a conventional method to give 4-benzyloxy-2-methylbenzyl alcohol (0.66 g).

D) Synthesis of 4-benzyloxy-2-methylbenzaldehyde 4-benzyloxy-2-methylbenzyl alcohol
(0.70g, 3.07mmol), manganese dioxide (2.67g, 30.7mmo
A mixture of l), methanol (0.5 ml) and chloroform (20 ml) was stirred at room temperature for 11 hours. Next, insoluble matter is filtered off, the obtained filtrate is concentrated under reduced pressure, and the obtained residue is separated and purified by silica gel column chromatography to give 4-benzyloxy-2-methylbenzaldehyde.
(0.60g) was obtained. e) Synthesis of ethyl 3- (4-benzyloxy-2-methylphenyl) -2-azidopropenoate 4-benzyloxy-2-methylbenzaldehyde (2.8
0g, 12.4mmol), ethyl azide acetate (6.39g, 49.5
mmol), sodium ethoxide (3.37 g, 49.5 mmol) and ethanol (50 ml) were used and the reaction was carried out according to a) of Reference Example 13 to obtain ethyl 3- (4-benzyloxy-2-methylphenyl) -2. -Azidopropenoate (3.24g) was obtained. f) Synthesis of ethyl 6-benzyloxy-4-methyl-2-indolecarboxylate Ethyl 3- (4-benzyloxy-2-methylphenyl) -2-azidopropenoate (3.22 g) and toluene
(100 ml) was used and the reaction was carried out according to b) of Reference Example 13 to obtain ethyl 6-benzyloxy-4-methyl-2-indolecarboxylate (2.66 g). ¹ Hnmr (CDCl ₃ ) δ; 1.38 to 1.43 (3H, m), 2.51 (3H, s),
4.38 (2H, dd, J = 6.9,14.2Hz), 5.09 (2H, s), 6.72 (2H, s),
7.19 (1H, d, J = 2.3Hz), 7.29 to 7.46 (5H, m), 8.71 (1H, br-
s).

The reaction was carried out according to the method of Reference Example 17,
The compounds shown below were synthesized. (1) Ethyl 6-benzyloxy-4-trifluoromethyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.39 to 1.44 (3H, m), 4.37 to 4.45 (2
H, m), 5.14 (2H, s), 7.05 (1H, s), 7.23 to 7.24 (1H.m), 7.
30 (1H, s), 7.35 to 7.47 (5H, m), 8.92 (1H, br-s).

Reference Example 18 Ethyl 4-chloro-6-hydroxy-1-methyl-2
-Synthesis of indolecarboxylate a) Synthesis of ethyl 6-benzyloxy-4-chloro-1-methyl-2-indolecarboxylate Ethyl 6-benzyloxy-4-chloro-2-indolecarboxylate (3.70 g, 11.2 mmol) ) Was added to a suspension of 60% sodium hydride (0.45 g, 11.2 mmol) and dimethylformamide (70 ml), and the mixture was stirred at room temperature,
After becoming a nearly transparent solution, at room temperature, methyl iodide (3.
A solution of 18 g, 22.4 mmol) in dimethylformamide (10 ml) was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (3 times), and the extract solution was washed with water,
After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography to give ethyl 6-benzyloxy-4-chloro-1-methyl-2-indolecarboxy. A latte (3.72 g, 96.4%) was obtained. b) Synthesis of ethyl 4-chloro-6-hydroxy-1-methyl-2-indolecarboxylate Ethyl 6-benzyloxy-4-chloro-1-methyl-2-indolecarboxylate (2.20 g, 6.40 mmo
l) was dissolved in tetrahydrofuran (60 ml), 10% palladium / carbon (0.3 g) was added thereto, and the mixture was catalytically reduced at room temperature and atmospheric pressure. After completion of the reaction, the catalyst was removed by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was separated and purified by silica gel column chromatography to give ethyl 4-.
Chloro-6-hydroxy-1-methyl-2-indolecarboxylate (1.50 g, 92.4%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.38 to 1.44 (3H, m), 3.98 (3H, s),
4.33 to 4.40 (2H, m), 5.07 (1H, s), 6.67 (1H, t, J = 0.99Hz)
, 6.78 (1H, d, J = 1.98Hz), 7.30 (1H, d, J = 0.99Hz)

Reference Example 19 Ethyl 4-chloro-7-hydroxy-1-methyl-2
-Synthesis of indolecarboxylate a) Synthesis of ethyl 7-benzyloxy-4-chloro-1-methyl-2-indolecarboxylate Ethyl 7-benzyloxy-4-chloro-2-indolecarboxylate (8.00 g, 24.3 mmol ), 60% sodium hydride (0.97 g, 24.3 mmol), methyl iodide (10.3 g, 72.8 mmol) and dimethylformamide (20
0 ml) and the reaction is carried out according to the method of Reference Example 18a) to give ethyl 7-benzyloxy-4-chloro-1-methyl-2-indolecarboxylate (7.
71 g, 92.4%) was obtained. b) Synthesis of ethyl 4-chloro-7-hydroxy-1-methyl-2-indolecarboxylate Ethyl 7-benzyloxy-4-chloro-1-methyl-2-indolecarboxylate (7.71 g, 22.4 mmo
l) 10% Palladium on carbon (0.50 g) and tetrahydrofuran (150 ml) were reacted according to the method of Reference Example 18b) to give ethyl 4-chloro-
7-Hydroxy-1-methyl-2-indolecarboxylate (4.70 g, 82.6%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.40 to 1.45 (3H, m), 4.34 to 4.42 (5
H, m), 5.20 (1H, s), 6.50 (1H, d, J = 7.92Hz), 6.88 (1H, d,
J = 7.92Hz), 7.31 (1H, s)

Reference Example 20 Synthesis of ethyl 7-hydroxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate a) Synthesis of 4-bromo-3-methyl-2-nitrophenol 4-Bromo-3- Methylphenol (10.0g, 53.5mmo
l), acetic acid (50 ml) and water (10 ml) mixture 0-
Stir under cooling to 5 ° C, and add 70% nitric acid (3.71
g, 58.8 mmol) was added dropwise. About 1 at room temperature after dropping
After stirring for an hour, the reaction solution was poured into ice water, extracted with diethyl ether (three times), the extract solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue on a silica gel column. 4-Bromo-3-methyl-2-nitrophenol (1.70 g, 13.7%) was obtained by separation and purification by chromatography. b) Synthesis of 3-benzyloxy-6-bromo-2-nitrotoluene 4-Bromo-3-methyl-2-nitrophenol (6.30
g, 27.2 mmol), benzyl bromide (5.11 g, 29.9 mmol),
Potassium carbonate (8.26 g, 59.7 mmol) and acetone (15
0 ml) to carry out the reaction according to the method of Reference Example 12 a) to give 3-benzyloxy-6-bromo-2-
Nitrotoluene (5.10 g, 58.3%) was obtained. c) 3-benzyloxy-6-trifluoromethyl-2
-Synthesis of nitrotoluene 3-benzyloxy-6-bromo-2-nitrotoluene (1.50 g, 4.66 mmol), sodium trifluoroacetate (6.33 g, 46.6 mmol), copper (I) iodide (4.43 g, 23.3 mm)
ol) and N-methylpyrrolidone (80 ml) in a mixture of 1
The mixture was heated and stirred at 60 ° C for 7 hours. Next, the reaction solvent was distilled off under reduced pressure, ethyl acetate was added to the obtained residue, and then the insoluble matter was filtered off. The filtrate was washed with water (twice), dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography to give 3-benzyloxy-6-trifluoromethyl-. 2-Nitrotoluene (0.70 g, 48.3%) was obtained.

D) Synthesis of ethyl (3-benzyloxy-6-trifluoromethyl-2-nitrophenyl) pyruvate 3-Benzyloxy-6-trifluoromethyl-2-nitrotoluene (14.6 g, 46.9 mmol), Shu Diethyl acid (13.7g, 93.8mmol), potassium ethoxide (7.90g,
93.8 mmol) and diethyl ether (300 ml),
By carrying out the reaction according to the method of Reference Example 12 b),
(3-benzyloxy-6-trifluoromethyl-2-
Nitrophenyl) ethyl pyruvate (10.9g, 56.9%)
I got e) Synthesis of ethyl 7-benzyloxy-4-trifluoromethyl-2-indolecarboxylate (3-benzyloxy-6-trifluoromethyl-2-
Nitrophenyl) ethyl pyruvate (10.9g, 26.7mmo
l), 20% titanium trichloride aqueous solution (165g, 213mmo
l) and ethanol (100 ml) and used in Reference Example 12 c).
By carrying out the reaction according to the method of 7-
Benzyloxy-4-trifluoromethyl-2-indolecarboxylate (8.00 g, 82.6%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.40 to 1.45 (3H, m), 4.38 to 4.46 (2
H, m), 5.26 (2H, s), 6.79 (1H, d, J = 7.59Hz), 7.32 ~ 7.49
(7H, m), 9.25 (1H, br-s) f) Synthesis of ethyl 7-benzyloxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate Ethyl 7-benzyloxy-4-trifluoromethyl -2-Indole carboxylate (8.00g, 22.0mmo
l), 60% sodium hydride (0.88 g, 22.0 mmol),
Ethyl 7-benzyloxy-1-methyl-4-trifluoromethyl was obtained by using methyl iodide (6.25 g, 44.0 mmol) and dimethylformamide (150 ml) according to the method of Reference Example 18a). 2-Indole carboxylate (7.40 g, 89.1%) was obtained.

G) Synthesis of ethyl 7-hydroxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate Ethyl 7-benzyloxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate (6.50
g, 17.2 mmol), 10% palladium / carbon (1.0 g), ethanol (150 ml), and ethyl acetate (50 ml) were reacted according to the method of Reference Example 18b) to give ethyl 7-hydroxy- 1-methyl-4-trifluoromethyl-2-indolecarboxylate (4.95
g, 97.0%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.39 to 1.45 (3H, m), 4.33 to 4.41 (2
H, m), 4.43 (3H, s), 6.69 (1H, dd, J = 0.66, 7.92Hz), 7.20
(1H, dd, J = 0.99, 7.92Hz), 7.31 ~ 7.33 (1H, m), 9.69 (1H,
br-s)

Reference Example 21 Synthesis of ethyl 1,4-dimethyl-7-hydroxy-2-indolecarboxylate a) Synthesis of 3,4-dimethyl-2-nitrophenol 3,4-Dimethylphenol (15.7 g, 129 mmol) ,
Acetic acid (130 ml), water (8 ml) and 70% nitric acid (12.2
g, 135 mmol) and according to the method of Reference Example 20 a) to obtain 3,4-dimethyl-2-nitrophenol (7.01 g, 26.0%). b) Synthesis of ethyl 7-benzyloxy-4-methyl-2-indolecarboxylate 3,4-Dimethyl-2-nitrophenol (7.01 g, 4
1.9 mmol) was used as the starting material and the reaction was carried out according to the method of Reference Example 12 a) to c) to obtain ethyl 7-benzyloxy-4-methyl-2-indolecarboxylate (3.68 g). . ¹ Hnmr (CDCl ₃ ) δ; 1.39 to 1.44 (3H, m), 2.49 (3H, s),
4.40 (2H, dd, J = 7.26, 14.19Hz), 5.18 (2H, s), 6.69 (1H,
d, J = 7.92Hz), 6.78 to 6.82 (1H, m), 7.22 (1H, J = 2.31Hz)
, 7.33 to 7.50 (5H, m), 9.05 (1H, br-s) c) ethyl 1,4-dimethyl-7-hydroxy-2-
Synthesis of Indole Carboxylate Using ethyl 7-benzyloxy-4-methyl-2-indolecarboxylate (4.30 g, 13.9 mmol) as a starting material and performing the reaction according to the method of Reference Example 19 a) to b). This gave ethyl 1,4-dimethyl-7-hydroxy-2-indolecarboxylate (2.95 g). ¹ Hnmr (CDCl ₃ ) δ; 1.39 to 1.44 (3H, m), 2.45 (3H, m),
4.33 to 4.41 (5H, m), 4.76 (1H, s), 6.49 (1H, d, J = 7.59Hz)
, 6.65 ~ 6.69 (1H, m), 7.26 (1H, s)

Reference Example 22 Synthesis of 4- (tert-butoxycarbonylaminomethyl) benzyl chloride a) Synthesis of 4- (tert-butoxycarbonylaminomethyl) benzoic acid Sodium hydroxide (2.65 g, 66.2 mmol), 1, 4-in a mixture of 4-dioxane (50 ml) and water (50 ml)
(Aminomethyl) benzoic acid (5.00g, 33.1
mmol), followed by di-tert-butyl dicarbonate (10.8 g, 49.6 mmol) in 1,4-dioxane (10 m
l) The solution was added dropwise. The reaction solution was stirred at room temperature for 2 hours, poured into ice water, and weakly acidified with 10% hydrochloric acid (pH = 5 to 5).
6). The precipitated crystals were collected by filtration and dried under reduced pressure to give 4- (tert-butoxycarbonylaminomethyl) benzoic acid (7.90 g, 95.1%). b) Synthesis of methyl 4- (tert-butoxycarbonylaminomethyl) benzoate 4- (tert-butoxycarbonylaminomethyl) benzoic acid (16.2 g, 64.5 mmol), 1-ethyl-3
A mixture of-(3-dimethylaminopropyl) carbodiimide hydrochloride (13.6 g, 70.9 mmol), 4-dimethylaminopyridine (1.00 g) and methanol (200 ml) was stirred at room temperature for 4 hours. Methanol was distilled off under reduced pressure, ice water was added to the resulting residue, and the mixture was extracted with ethyl acetate (2
The extract was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution.
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain methyl 4- (tert-butoxycarbonylaminomethyl) benzoate (14.3 g, 83.6%).

C) Synthesis of 4- (tert-butoxycarbonylaminomethyl) benzyl alcohol A suspension of lithium aluminum hydride (1.40 g, 36.8 mmol) in tetrahydrofuran (150 ml) was stirred at 0 ° C. In this suspension, methyl 4- (tert-butoxycarbonylaminomethyl) benzoate (13.0 g, 49.0 mm
ol) in tetrahydrofuran (50 ml) was slowly added dropwise. After completion of the dropping, the reaction solution was heated under reflux for 2 hours, then cooled to 0 ° C., 50% aqueous tetrahydrofuran solution (20 ml) was added dropwise, and then ethyl acetate (100 ml) was added.
ml) was added. The filtrate obtained by removing the insoluble matter by filtration was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography to give 4- (tert-butoxycarbonylaminomethyl) benzyl alcohol (8.80
g, 75.7%) was obtained. d) Synthesis of 4- (tert-butoxycarbonylaminomethyl) benzyl chloride 4- (tert-butoxycarbonylaminomethyl) benzyl alcohol (8.80 g, 37.1 mmol), carbon tetrachloride (12
A mixture of 0 ml) and dimethylformamide (50 ml) was stirred at room temperature. Triphenylphosphine (12.2 g, 44.5 mmol) was added little by little to this solution, and the mixture was stirred at room temperature for 2 hours. Ice water was added to the residue obtained by concentrating the reaction solution under reduced pressure, and the mixture was extracted with ethyl acetate (twice). The extract was washed with saturated aqueous sodium hydrogen carbonate solution, saturated brine, and dried over anhydrous magnesium sulfate. After that, the solvent was distilled off under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography to give 4- (tert-
Butoxycarbonylaminomethyl) benzyl alcohol (7.50 g, 79.1%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.46 (9H, s), 4.31 (2H, d, J = 5.94Hz)
, 4.57 (2H, s), 4.85 (1H, br-s), 7.27 (2H, d, J = 7.26Hz)
, 7.35 (2H, d, J = 7.25)

[0140]

【Example】

Example 1 Synthesis of 1-methyl-2-indoloylguanidine-hydrochloride In a methanol solution (70 ml) of sodium methoxide (4.85 g, 89.8 mmol), guanidine-hydrochloride (8.58) was added.
g, 89.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes, and then the precipitated sodium chloride was filtered off to give a solution of methyl 1-methyl-2-indolecarboxylate (1.70 g, 8.97).
mmol) was added, and then methanol was distilled off under reduced pressure. The obtained residue was heated at 130 ° C for 5 minutes and allowed to stand at room temperature for 1 hour, then water was poured into the reaction solution and extracted with ethyl acetate (3 times). The extract solution was washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography to obtain 1-methyl-2-indoloylguanidine of interest. This was dissolved in chloroform and hydrochloric acid was salified with hydrogen chloride / ether to give 1-methyl-2-indoloylguanidine hydrochloride (0.70 g, 30.8%). mp 250 ° C or higher. ¹ H nmr (DMSO-d6) δ;
4.04 (3H, s), 7.12-7.21 (1H, m), 7.31-7.44 (1H, m),
7.61 (1H, d, J = 8.6Hz), 7.73 (1H, d, J = 7.9Hz), 7,89 (1
H, s), 8.5 (2H, br-s), 8.7 (2H, br-s), 11.9 (1H, br-
s).

Example 2 Synthesis of 1-methyl-5-indoloylguanidine hydrochloride hydrochloride Methyl 1-methyl-5-indolecarboxylate (1.00 g, 5.29 mmol) guanidine hydrochloride (5.05 g,
52.9 mmol) and sodium methoxide (2.85 g, 5
(2.9 mmol) in methanol (50 ml) was reacted according to the method of Example 1 to obtain 1-methyl-5-indoloylguanidine hydrochloride (0.92 g, 68.9%). mp 260 ℃ or more. ¹ Hnmr (DMSO-d6) δ;
3.86 (3H, s), 6.62-6.64 (1H, m), 7.50 (1H, d, J = 3.3H
z), 7.61 (1H, d, J = 8.9Hz), 7.91-7.95 (1H, m), 8.44 (2
H, br-s), 8.47 (1H, d, J = 1.3Hz), 8.7 (2H, br-s), 11.
7 (1H, br-s). Example 3 Synthesis of 1-methyl-3-indoloylguanidine hydrochloride Methyl 1-methyl-3-indolecarboxylate (1.00 g, 5.29 mmol), guanidine hydrochloride (5.05
g, 52.9 mmol) and sodium methoxide (2.85 g,
The reaction was performed according to the method of Example 1 from a methanol solution (50 ml) of 52.9 mmol) to obtain 1-methyl-3-indoloylguanidine hydrochloride (0.48 g, 35.9%). mp 252-253 ° C. ¹ Hnmr (DMSO-d6) δ;
3.91 (3H, s), 7.25-7.37 (2H, m), 7.58-7.61 (1H, m),
8.15 (1H, dd, J = 1.3, 6.6Hz), 8.3 (2H, br-s), 8.6 (2H,
br-s), 8.78 (1H, s), 11.8 (1H, br-s).

Example 4 Synthesis of 1-methyl-4-indoloylguanidine hydrochloride hydrochloride Methyl 1-methyl-4-indolecarboxylate (0.85 g, 4.49 mmol), guanidine hydrochloride hydrochloride (4.29 g,
44.9 mmol) and sodium methoxide (2.43 g, 44.
Example 1 from a methanol solution (50 ml) of 9 mmol).
The reaction was carried out according to the method of 1) to give 1-methyl-4-indoloylguanidine hydrochloride (0.75 g, 66.1%). mp 186-187 ° C. ¹ Hnmr (DMSO-d6) δ;
3.88 (3H, s), 6.97 (1H, d, J = 3.0Hz), 7.92-7.35 (1H,
m), 7.56 (1H, d, J = 3.0Hz), 7.84 (1H, d, J = 7.9Hz), 7.
98 (1H, d, J = 7.6Hz), 8.5 (2H, br-s), 8.7 (2H, br-s),
11.7 (1H, br-s). Example 5 Synthesis of 4-chloro-1-methyl-2-indoloylguanidine hydrochloride Methyl 4-chloro-1-methyl-2-indolecarboxylate (2.00 g, 8.94 mmol) ), Guanidine hydrochloride (8.54 g, 89.4 mmol) and sodium methoxide (4.83 g, 89.4 mmol) in methanol (50 ml) were reacted according to the method of Example 1 to give 4-chloro-1. -Methyl-2-indoloylguanidine hydrochloride (1.06g, 41.3%) was obtained. mp 288-290 ° C. ¹ Hnmr (DMSO-d6) δ;
4.05 (3H, s), 7.24 (1H, d, J = 7.6Hz), 7.35-7.41 (1H,
m), 7.62 (1H, d, J = 8.6Hz), 7.98 (1H, s), 8.56 (2H, br
-s), 8.63 (2H, br-s), 12.0 (1H, br-s).

The reaction was carried out according to the method of Example 1 to synthesize the compounds of Examples 6 to 81 below. Example 6 5-Chloro-1-methyl-2-indoloylguanidine-hydrochloride Yield: 43.6% .mp 281-282 ° C. ¹ Hnmr (DMSO
-D6) δ; 4.03 (3H, s), 7.39 (1H, dd, J = 2.0, 8.
9Hz), 7.67 (1H, d, J = 8.9Hz), 7.77 (1H, s), 7.81 (1H,
d, J = 1.7Hz), 8.5 (2H, br-s), 8.6 (2H, br-s), 11.9 (1
H, br-s). Example 7 6-Chloro-1-methyl-2-indoloylguanidine hydrochloride yield: 59.6%. Mp 290-294 ° C. ¹ Hnmr (DMSO
-D6) δ; 4.02 (3H, s), 7.17 (1H, dd, J = 2.0, 8.
6Hz), 7.74-7.77 (2H, m), 7.84 (1H, s), 8.5 (2H, br-s),
8.6 (2H, br-s) , 11.9 (1H, br-s) Example 8 7-Chloro-1-methyl-2-India acryloyl guanidine hydrochloride Yield:... 56.5% mp 243-244 ℃ 1 Hnmr (DMSO
-D6) δ; 4.33 (3H, s), 7.11-7.17 (1H, m), 7.41
(1H, d, J = 7.6Hz), 7.71 (1H, d, J = 7.9Hz), 7.81 (1H,
s), 8.5 (2H, br-s), 8.6 (2H, br-s), 12.0 (1H, br-s). Example 9 1,4-Dimethyl-2-indoloylguanidine / hydrochloride Yield: 32.5% .mp 279-280 ℃. ¹ Hnmr (DMSO
-D6) δ; 2.53 (3H, s), 4.02 (3H, s), 6.96 (1H,
d, J = 6.9Hz), 7.26-7.32 (1H, m), 7.41 (1H, d, J = 8.3H
z), 7.99 (1H, s), 8.5 (2H, br-s), 8.7 (2H, br-s), 11.
9 (1H, br-s).

Example 10 1,5-Dimethyl-2-indoloylguanidine / hydrochloride Yield: 30.5% .mp 281-282 ° C. ¹ Hnmr (DMSO
-D6) δ; 2.41 (3H, s), 4.00 (3H, s), 7.23 (1H,
d, J = 8.9Hz), 7.48-7.51 (2H, m), 7.79 (1H, s), 8.5 (2H,
br-s), 8.7 (2H, br-s), 11.9 (1H, br-s). Example 11 1,6-Dimethyl-2-indoloylguanidine-hydrochloride Yield: 63.1%. mp 267-269 ° C. ¹ Hnmr (DMSO
-D6) δ; 2.47 (3H, s), 3.99 (3H, s), 7.02 (1H,
d, J = 8.3Hz), 7.41 (1H, s), 7.61-8.00 (2H, m), 8.4 (2H,
br-s), 8.5 (2H, br-s), 11.6 (1H, br-s). Example 12 1,7-Dimethyl-2-indoloylguanidine-hydrochloride Yield: 27.3%. mp 271-273 ° C. ¹ Hnmr (DMSO
-D6) δ; 2.78 (3H, s), 4.25 (3H, s), 6.99-7.11
(2H, m), 7.53 (1H, d, J = 7.6Hz), 7.70 (1H, s), 8.4 (2H,
br-s), 8.6 (2H, br-s), 11.8 (1H, br-s). Example 13 5-methoxy-1-methyl-2-indoloylguanidine hydrochloride salt yield: 50.1%. mp 235 -236 ℃. ¹ Hnmr (DMSO
-D6) δ; 3.80 (3H, s), 4.01 (3H, s), 7.03-7.07
(1H, m), 7.16 (1H, d, J = 2.3Hz), 7.52 (1H, d, J = 8.9H
z), 7.75 (1H, s), 8.4 (2H, br-s), 8.7 (2H, br-s), 11.
8 (1H, br-s).

Example 14 1-Methyl-6-indoloylguanidine-hydrochloride Yield: 62.1% .mp 297-298 ° C. ¹ Hnmr (DMSO
-D6) δ; 3.94 (3H, s), 6.55 (1H, dd, J = 0.7, 3.
0Hz), 7.61 (1H, d, J = 3.0Hz), 7.67-7.78 (2H, m), 8.4
(2H, br-s), 8.6 (1H, s), 8.9 (2H, br-s), 12.0 (1H, br
-s). Example 15 1-Benzyl-2-indoloylguanidine-hydrochloride Yield: 54.9%. mp 228-229 ° C. ¹ Hnmr (DMSO
-D6) δ; 5.86 (2H, s), 7.03 (2H, d, J = 6.6Hz),
7.17-7.39 (4H, m), 7.57 (1H, d, J = 8.3Hz), 7.78 (1H,
d, J = 7.9Hz), 7.98 (1H, s), 8.4 (2H, br-s), 8.6 (2H, b
rs), 11.9 (1H, br-s). Example 16 1-benzyl-3-indoloylguanidine / hydrochloride Yield: 66.2% .mp 252-253 ° C. ¹ Hnmr (DMSO
-D6) δ; 5.53 (2H, s), 7.23-7.37 (7H, m), 7.62
-7.66 (1H, m), 8.15-8.18 (1H, m), 8.3 (2H, br-s), 8.6
(2H, br-s), 8.95 (1H, s), 11.8 (1H, br-s). Example 17 1-Isopropyl-3-indoloylguanidine / hydrochloride Yield: 49.7% .mp 221-223 ° C . ¹ Hnmr (DMSO
-D6) δ; 1.51 (6H, d, J = 6.6Hz), 4.85-4.90 (1H,
m), 7.24-7.34 (2H, m), 7.67 (1H, d, J = 7.6Hz), 8.14-
8.17 (1H, m), 8.3 (2H, br-s), 8.6 (2H, br-s), 9.12 (1
H, s), 11.9 (1H, br-s). Example 18 2-Indoylylguanidine hydrochloride: Yield: 61.9% .mp 192-194 ° C. ¹ Hnmr (DMSO
-D6) δ; 7.09-7.14 (1H, m), 7.28-7.34 (1H, m),
7.49 (1H, d, J = 8.3Hz), 7.71 (1H, d, J = 8.3Hz), 8.5 (2
H, br-s), 8.7 (2H, br-s), 12.06 (1H, br-s), 12.13 (1
H, br-s) ..

Example 19 3-Indoylguanidine hydrochloride: Yield: 42.2% .mp 287 ° C. ¹ Hnmr (DMSO-d
6) δ; 7.20-7.29 (2H, m), 7.53 (1H, dd, J = 1.7,
6.6Hz), 8.12-8.16 (1H, m), 8.3 (2H, br-s), 8.7 (2H, b
rs), 8.83 (1H, d, J = 3.3Hz), 11.8 (1H, br-s), 12.2 (1
H, br-s). Example 20 5-Indoloylguanidine-hydrochloride Yield: 55.9% .mp 219-222 ° C. ¹ Hnmr (DMSO
-D6) δ; 6.61-6.63 (1H, m), 7.50-7.56 (2H, m),
7.85-7.89 (1H, m), 8.45 (2H, br-s), 8.49 (1H, d, J = 1.
7Hz), 8.75 (2H, br-s), 11.6 (1H, br-s), 11.7 (1H, br-
s). Example 21 1-isopropyl-5-indoloylguanidine-hydrochloride Yield: 72.5% .mp 219 ° C. ¹ Hnmr (DMSO-d
6) δ; 1.48 (6H, d, J = 6.6Hz), 4.81-4.88 (1H, m),
6.67 (1H, d, J = 3.3Hz), 7.68-7.71 (2H, m), 7.89-7.93
(1H, m), 8.3-8.6 (3H, m), 8.7 (2H, br-s), 11.7 (1H, br
-s). Example 22 4-Methoxy-1-methyl-2-indoloylguanidine-hydrochloride Yield: 54.5%. mp 281-282 ° C. ¹ Hnmr (DMSO
-D6) δ; 3.93 (3H, s), 4.01 (3H, s), 6.62 (1H,
d, J = 7.9Hz), 7.16 (1H, d, J = 8.6Hz), 7.30-7.36 (1H,
m), 7.83 (1H, s), 8.5 (2H, br-s), 8.6 (2H, br-s), 11.
7 (1H, br-s).

Example 23 6-Methoxy-1-methyl-2-indoloylguanidine-hydrochloride Yield: 75.5% .mp 272 ° C. ¹ Hnmr (DMSO-d
6) δ; 3.87 (3H, s), 4.00 (3H, s), 6.81 (1H, dd,
J = 2.0, 8.9Hz), 7.05 (1H, d, J = 2.0Hz), 7.59 (1H, d, J
= 8.9Hz), 7.84 (1H, s), 8.4 (2H, br-s), 8.7 (2H, br-
. s), 11.8 (1H, br-s) Example 24 1-methyl-4-nitro-2-India acryloyl guanidine hydrochloride Yield:.. 97.7% mp 292-293 ℃ 1 Hnmr (DMSO
-D6) δ; 4.14 (3H, s), 7.59-7.65 (1H, m), 8.16
(1H, m), 8.20-8.28 (2H, m), 8.5 (4H, br-s), 11.8 (1H,
br-s). Example 25 1-Methyl-6-nitro-2-indoloylguanidine-hydrochloride Yield: 68.4%. mp 279-283 ° C. ¹ Hnmr (DMSO
-D6) δ; 4.15 (3H, s), 7.89 (1H, s), 7.95-8.03
(2H, m), 8.51-8.66 (5H, m), 12.1 (1H, br-s). Example 26 1-Methyl-7-nitro-2-indoloylguanidine / hydrochloride Yield: 66.8% .mp 268-270 ℃. ¹ Hnmr (DMSO
-D6) δ; 3.83 (3H, s), 7.36 (1H, t, J = 7.9Hz),
7.98 (1H, s), 8.06 (1H, dd, J = 1.0, 7.9Hz), 8.19 (1H,
dd, J = 1.0, 7.9Hz), 8.44-8.74 (4H, m), 12.2 (1H, br-
s).

Example 27 1-Methyl-5-nitro-2-indoloylguanidine hydrochloride Yield: 73.6% .mp 294-295 ° C. ¹ Hnmr (DMSO
-D6) δ; 4.09 (3H, s), 7.86-7.91 (2H, m), 8.23
(1H, dd, J = 2.3, 9.2Hz), 8.49 (4H, br-s), 8.83 (1H,
. d, J = 2.3Hz), 11.9 (1H, br-s) Example 28 1-Methyl-7-India acryloyl guanidine hydrochloride ^{Yield: 37.4% mp203-204 ℃ 1 Hnmr (} D
MSO-d ₆ ) δ; 3.78 (3H, s), 6.60 (1H,
d, J = 3.3Hz), 7.16 (1H, t, J = 7.6H
z), 7.44 (1H, d, J = 3.0Hz), 7.53 (1H,
d, J = 7.6 Hz), 7.85 (1H, d, J = 7.9H
z), 8.44 (2H, br-s), 8.52 (2H, br-
s), 11.90 (1H, br-s). Example 29 1-Methyl-4-trifluoromethyl-2-indoloylguanidine-hydrochloride Yield: 57.8% mp 283-285 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 4.10 (3H, s), 7.52-7.58 (2
H, m), 7.91 (1H, s), 7.98-8.01 (1H,
m), 8.4-8.8 (4H, m), 11.99 (1H, br-
s). Example 30 5-Fluoro-1-methyl-2-indoloylguanidine-hydrochloride Yield: 60.8% mp278-281 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 4.03 (3H, s), 7.25-7.33 (1
H, m), 7.54 (1H, dd, J = 2.3, 9.6Hz),
7.69 (1H, dd, J = 4.6, 9.2Hz), 7.82 (1
H, s), 8.51 (2H, br-s), 8.69 (2H, br)
-S), 11.98 (1H, br-s).

Example 31 5-Ethoxy-1-methyl-2-indoloylguanidine · hydrochloride Yield: 30.9% mp234-236 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 1.35 (3H, t, J = 6.9Hz),
3.99 (3H, s), 4.05 (2H, dd, J = 6.9, 14.2
Hz), 7.05 (1H, dd, J = 2.3, 9.2Hz), 7.
16 (1H, d, J = 2.3Hz), 7.54 (1H, d, J =
8.9Hz), 7.73 (1H, s), 8.42 (2H, br-
s), 8.65 (2H, br-s), 11.81 (1H, br-
s). Example 32 5-Benzyloxy-1-methyl-2-indoloylguanidine-hydrochloride Yield: 45.2% mp 249-251 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 3.99 (3H, s), 5.14 (2H,
s), 7.12-7.16 (1H, m), 7.28-7.58 (7H,
m), 7.67 (1H, s), 8.28-8.68 (4H, m), 1
1.71 (1H, brs). Example 33 1-Methyl-6-trifluoromethyl-2-indoloylguanidine · hydrochloride Yield: 44.4% mp 255-257 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.11 (3H, s), 7.44 (1H, d
d, J = 1.3, 8.6 Hz), 7.97 (1H, d, J = 8.6
Hz), 8.10 (1H, s), 8.48 (2H, br-s),
8.63 (2H, br-s), 12.03 (1H, br-s). Example 34 7-Benzyloxy-1-methyl-2-indoloylguanidine-hydrochloride Yield: 53.5% mp221-222 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 4.27 (3H, s), 5.26 (2H,
s), 6.97-7.08 (2H, m), 7.27-7.56 (5H,
m), 7.72 (1H, s), 8.43 (2H, br-s), 8.
60 (2H, br-s), 11.80 (1H, br-s).

Example 35 1- (2-naphthylmethyl) -2-indoloylguanidine hydrochloride Yield: 56.4% mp 254-255 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 6.02 (2H, s), 7.17-7.27 (2
H, m), 7.32-7.38 (1H, m), 7.43-7.48 (3
H, m), 7.60 (1H, d, J = 7.9 Hz), 7.73-7.
86 (4H, m), 8.07 (1H, s), 8.43 (2H, br
-S), 8.67 (2H, br-s), 12.04 (1H, br)
-S). Example 36 1- (2-phenylethyl) -2-indoloylguanidine-hydrochloride Yield: 55.1% mp262-264 ° C ¹ Hnmr (D
_{MSO-d 6) δ; 2.97-3.03} (2H, m), 4.73-4.
79 (2H, m), 7.13-7.24 (6H, m), 7.32-7.38
(1H, m), 7.59 (1H, d, J = 7.9Hz), 7.73
(1H, d, J = 7.9Hz), 7.84 (1H, s), 8.43
(2H, br-s), 8.62 (2H, br-s), 11.78
(1H, br-s). Example 37 1- (4-Bromobenzyl) -2-indoloylguanidine · hydrochloride Yield: 53.3% mp 260-263 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 5.82 (2H, s), 6.99 (2H,
d, J = 8.3 Hz), 7.17-7.23 (1H, m), 7.35-
7.40 (1H, m), 7.47 (2H, d, J = 8.3Hz),
7.57 (1H, d, J = 8.3Hz), 7.79 (1H, d, J
= 7.9 Hz), 8.06 (1H, s), 8.47 (2H, br-
s), 8.69 (2H, br-s), 12.07 (1H, br-
s).

Example 38 1- (4-Nitrobenzyl) -2-indoloylguanidine hydrochloride Yield: 42.7% mp 245-247 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 5.98 (2H, s), 7.20-7.27 (3
H, m), 7.39 (1H, t, J = 7.3Hz), 7.56 (1
H, d, J = 8.3Hz), 7.82 (1H, d, J = 7.9H)
z), 8.05 (1H, s), 8.16 (2H, d, J = 8.6H
z), 8.41 (2H, br-s), 8.61 (2H, br-
s), 12.02 (1H, br-s). Example 39 1- (4-Methoxybenzyl) -2-indoleguanidine-hydrochloride Yield: 54.8% mp239-240 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 3.68 (3H, s), 5.78 (2H,
s), 6.82 (2H, d, J = 8.6Hz), 7.18 (1H,
t, J = 7.3 Hz), 7.34-7.40 (1H, m), 7.61
(1H, d, J = 8.6Hz), 7.77 (1H, d, J = 7.6.
9Hz), 7.92 (1H, s), 8.43 (2H, br-
s), 8.60 (2H, br-s), 11.89 (1H, br-
s). Example 40 1- (3-Phenylpropyl) -2-indoloylguanidine · hydrochloride Yield: 39.0% mp 147-148 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 1.97-2.13 (2H, m), 5.62 (2
H, t, J = 8.0Hz), 4.59 (2H, t, J = 7.0H
z), 7.11-7.34 (6H, m), 7.40 (1H, dt, J
= 1.0, 8.0 Hz), 7.57 (1H, d, J = 8.0H
z), 7.76 (1H, d, J = 8.0Hz), 7.81 (1H,
s), 8.25-8.70 (4H, m), 11.75 (1H, br-
s).

Example 41 1- (4-Phenylbutyl) -2-indoloylguanidine · hydrochloride Yield: 51.0% mp 154-155 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 1.43-1.65 (2H, m), 1.65-1.
68 (2H, m), 2.57 (2H, t, J = 8.0Hz), 4.
58 (1H, t, J = 7.0Hz), 7.03-7.32 (6H,
m), 7.39 (1H, dt, J = 1.0, 8.0Hz), 7.63
(1H, d, J = 8.0Hz), 7.73 (1H, d, J = 8.
0Hz), 7.92 (1H, s), 8.20-9.00 (4H,
m), 11.95 (1H, br-s). Example 42 1-Isopropyl-6-indoloylguanidine hydrochloride Yield: 37.7% mp218-220 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 1.51 (6H, d, J = 6.6Hz),
4.92-5.02 (1H, m), 6.59 (1H, d, J = 3.0H
z), 7.66-7.81 (3H, m), 8.41 (2H, br-
s), 8.66 (1H, s), 8.86 (2H, br-s), 1
2.04 (1H, br-s). Example 43 1-Benzyl-6-indoloylguanidine-hydrochloride Yield: 44.5% mp227-228 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 5.57 (2H, s), 6.62 (1H,
d, J = 3.0 Hz), 7.24-7.32 (5H, m), 7.69-
7.79 (2H, m), 7.81 (1H, d, J = 3.0Hz),
8.43 (2H, br-s), 8.71 (1H, s), 8.86 (2
H, br-s), 12.06 (1H, br-s).

Example 44 1-Isopropyl-4-indoloylguanidine · hydrochloride Yield: 49.0% mp 95-97 ° C. ¹ Hnmr (DMS
O-d ₆ ) δ; 1.48 (6H, d, J = 6.6Hz), 4.87
(1H, m), 7.01 (1H, d, J = 3.0Hz), 7.26
-7.31 (1H, m), 7.72 (1H, d, J = 3.3H
z), 7.91 (1H, d, J = 8.3Hz), 8.02 (1H,
d, J = 7.6 Hz), 8.54 (2H, br-s), 8.83
(2H, br-s), 11.85 (1H, br-s). Example 45 1-Benzyl-4-indoloylguanidine-hydrochloride Yield: 42.6% mp203-205 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 5.52 (2H, s), 7.03 (1H,
d, J = 3.0 Hz), 7.17-7.32 (6H, m), 7.74
(1H, t, J = 1.7Hz), 7.84 (1H, d, J = 7.
9Hz), 7.98 (1H, d, J = 7.6Hz), 8.48 (2
H, br-s), 8.77 (2H, br-s), 11.79 (1
H, br-s). Example 46 4-Benzyloxy-1-methyl-2-indoloylguanidine / hydrochloride Yield: 57.6% mp 260 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 4.01 (3H, s), 5.26 (2H, s), 6.75
(1H, d, J = 7.6Hz), 7.20 (1H, d, J = 8.
6Hz), 7.30-7.54 (6H, m), 7.75 (1H,
s), 8.40 (4H, br-s), 11.41 (1H, br-
s). Example 47 1,3-Dimethyl-2-indoloylguanidine / hydrochloride Yield: 55.5% mp 228-229 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 2.56 (3H, s), 3.84 (3H,
s), 7.12-7.18 (1H, m), 7.34-7.40 (1H,
m), 7.53 (1H, d, J = 8.3Hz), 7.69 (1H,
d, J = 7.9 Hz), 8.61-8.68 (4H, m), 11.67
(1H, br-s).

Example 48 1-Methyl-7-phenyl-2-indoloylguanidine hydrochloride Yield: 58.9% mp265-267 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.07 (3H, s), 7.27 (1H,
d, J = 7.3 Hz), 7.41-7.75 (7H, m), 7.89
(1H, s), 8.50 (4H, br-s), 11.77 (1
H, br-s). Example 49 4-Acetyl-1-methyl-2-indoloylguanidine hydrochloride yield: 45.4% mp 288-289 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 2.71 (3H, s), 4.07 (3H,
s), 7.50-7.56 (1H, m), 7.91-7.97 (2H,
m), 8.25 (1H, s), 8.53 (4H, br-s), 1
1.71 (1H, br-s). Example 50 6-Benzyloxy-1-methyl-2-indoloylguanidine · hydrochloride Yield: 42.7% mp 269-270 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 3.99 (3H, s), 5.20 (2H,
s), 6.89 (1H, d, J = 10.6Hz), 7.22 (1H,
s), 7.35-7.58 (6H, m), 7.62-7.67 (1H,
m), 8.4 (4H, br-s), 11.35 (1H, br-
s). Example 51 4-Ethoxy-1-methyl-2-indoloylguanidine-hydrochloride Yield: 69.8% mp262-263 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 1.42 (3H, t, J = 6.9Hz),
3.99 (3H, s), 4.19 (2H, q, J = 6.9Hz),
6.62 (1H, d, J = 7.6Hz), 7.16 (1H, d, J
= 8.6Hz), 7.28-7.34 (1H, m), 7.77 (1H,
s), 8.51 (4H, br-s), 11.60 (1H, br-
s).

Example 52 1- (2-carbamoylethyl) -2-indoloylguanidine · hydrochloride Yield: 30.0% mp 285-286 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 2.55 (2H, t, J = 7.3Hz),
4.74 (2H, t, J = 7.3Hz), 6.85 (1H, br-
s), 7.17 (1H, t, J = 6.9Hz), 7.33 (1H,
br-s), 7.39 (1H, ddd, J = 1.0, 7.3, 7.
8 Hz), 7.70 (2H, dd, J = 8.4, 17.7Hz),
7.82 (1H, s), 8.46 (2H, br-s), 8.64 (2
H, br-s), 11.85 (1H, br-s). Example 53 1-Propyl-2-indoloylguanidine-hydrochloride Yield: 53.2% mp218-219 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 0.85 (3H, t, J = 7.6Hz),
1.66-1.77 (2H, m), 4.51 (2H, dd, J = 6.
9,7.6Hz), 7.10-7.23 (1H, m), 7.32-7.45
(1H, m), 7.65 (1H, d, J = 8.6Hz), 7.73
(1H, d, J = 7.9Hz), 7.97 (1H, s), 8.52
(2H, br-s), 8.77 (2H, br-s), 12.01
(1H, br-s). Example 54 1- (2-Methoxyethyl) -2-indoloylguanidine-hydrochloride Yield: 15.0% mp174-176 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 3.16 (3H, s), 3.63 (2H,
t, J = 5.3Hz), 4.72 (2H, t, J = 5.3H)
z), 7.11-7.22 (1H, m), 7.31-7.44 (1H,
m), 7.66 (1H, d, J = 8.6Hz), 7.72 (1H,
d, J = 7.9 Hz), 7.89 (1H, s), 8.49 (2H,
br-s), 8.70 (2H, br-s), 11.96 (1H,
br-s).

Example 55 4-Fluoro-1-methyl-2-indoloylguanidine · hydrochloride Yield: 53.1% mp 281-282 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.04 (3H, s), 6.97 (1H, d
d, J = 7.6, 10.2 Hz), 7.35-7.43 (1H, m),
7.50 (1H, d, J = 8.3Hz), 7.89 (1H, s),
8.48-8.60 (4H, m), 11.92 (1H, br-s). Example 56 4-Bromo-1-methyl-2-indoloylguanidine hydrochloride yield: 58.2% mp 306-307 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.04 (3H, s), 7.30-7.36 (1
H, m), 7.42 (1H, d, J = 7.6Hz), 7.69 (1
H, d, J = 8.6Hz), 7.78 (1H, s), 8.56 (4
H, br-s), 11.91 (1H, br-s). Example 57 4-isobutyroxy-1-methyl-2-indoloylguanidine-hydrochloride Yield: 58.1% mp 245-247 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 1.05 (6H, d, J = 6.9Hz),
2.06-2.16 (1H, m), 3.90 (2H, d, J = 6.3H
z), 3.99 (3H, s), 6.61 (1H, d, J = 7.9H
z), 7.16 (1H, d, J = 8.6Hz), 7.28-7.34
(1H, m), 7.84 (1H, s), 8.51 (4H, br-
s), 11.65 (1H, br-s). Example 58 4-Isopropoxy-1-methyl-2-indoloylguanidine-hydrochloride Yield: 62.3% mp 269-270 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 1.35 (6H, d, J = 5.9Hz),
3.99 (3H, s), 4.75-4.84 (1H, m), 6.65 (1
H, d, J = 7.6Hz), 7.14 (1H, d, J = 8.6H)
z), 7.28-7.34 (1H, m), 7.75 (1H, s), 8.
53 (4H, br-s), 11.59 (1H, br-s).

Example 59 1-Methyl-7- (2-phenylethoxy) -2-indoloylguanidine hydrochloride Yield: 24.3% mp155-156 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 3.21 (2H, t, J = 6.3Hz),
4.13 (3H, s), 4.43 (2H, t, J = 6.3Hz),
6.95 (1H, d, J = 7.9Hz), 7.08 (1H, t, J
= 7.9 Hz), 7.25-7.44 (6H, m), 7.60 (1H,
s,) 8.44 (4H, br-s), 11.62 (1H, br-
s). Example 60 1-Methyl-7- (3-phenylpropoxy) -2-indoloylguanidine hydrochloride Yield: 46.1% mp165-166 ° C ¹ Hnmr (D
_{MSO-d 6) δ; 2.12-2.17} (2H, m), 2.79-2.
85 (2H, m), 4.09-4.13 (2H, m), 4.31 (3
H, s), 6.83 (1H, m), 7.00-7.05 (1H,
m), 7.19-7.32 (6H, m), 7.69 (1H, s), 8.
56 (4H, br-s), 11.75 (1H, br-s). Example 61 7-Benzyloxy-4-chloro-1-methyl-2-indoloylguanidine hydrochloride Yield: 54.4% mp 264 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 4.27 (3H, s), 5.26 (2H, s), 6.96
(1H, d, J = 8.6Hz), 7.11 (1H, d, J = 8.6Hz)
3Hz), 7.32-7.54 (5H, m), 7.78 (1H,
s), 8.5-8.6 (4H, m), 11.94 (1H, br-
s).

Example 62 4-Carboxy-1-methyl-2-indoloylguanidine hydrochloride Yield: 40.5% mp 302-303 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.07 (3H, s), 7.48-7.54 (1
H, m), 7.86-7.95 (2H, m), 8.10 (1H,
s), 8.3-8.7 (4H, m), 11.58 (1H, br-
s), 13.0 (0.7H, br-s). Example 63 7-carbamoylmethoxy-1-methyl-2-indoloylguanidine · hydrochloride Yield: 56.7% mp 268-269 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.32 (3H, s), 4.61 (2H,
s), 6.76 (1H, d, J = 7.9Hz), 7.03 (1H,
t, J = 7.9Hz), 7.30 (1H, d, J = 7.6H)
z), 7.40 (1H, br-s), 7.58 (1H, br-
s), 7.68 (1H, s), 8.54 (4H, m), 11.74
(1H, br-s). Example 64 7-carbamoylmethoxy-4-chloro-1-methyl-
2-Indoloylguanidine / hydrochloride Yield: 29.7% mp270-271 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 4.33 (3H, s), 4.61 (2H,
s), 6.73 (1H, d, J = 8.3Hz), 7.10 (1H,
d, J = 8.3 Hz), 7.39 (1H, br-s), 7.58
(1H, br-s), 7.74 (1H, s), 8.57 (4H,
br-s), 11.93 (1H, br-s).

Example 65 4-Chloro-7- (2-dimethylaminoethoxy) -1
-Methyl-2-indoloylguanidine dihydrochloride Yield: 50.8% mp287-288 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 2.86 (6H, d, J = 5.0Hz),
3.62-3.64 (2H, m), 4.29 (3H, s), 4.51-4.
55 (2H, m), 6.92 (1H, d, J = 8.2Hz), 7.
14 (1H, d, J = 8.3Hz), 7.88 (1H, s), 8.
6-8.9 (4H, m), 11.01 (1H, br-s), 1
2.13 (1H, br-s). Example 66 6-carbamoylmethoxy-1-methyl-2-indoloylguanidine hydrochloride yield: 26.8% mp 275 ° C ¹ Hnmr (DMSO-
d ₆ ) δ; 3.98 (3H, s), 4.53 (2H, s), 6.90
-6.95 (1H, m), 7.11 (1H, d, J = 2.0H
z), 7.45 (1H, br-s), 7.58 (1H, br-
s), 7.65 (1H, d, J = 8.9Hz), 7.77 (1H,
s), 8.38-8.58 (4H, m), 11.72 (1H, br-
s). Example 67 1-Methyl-6- (2-phenylethoxy) -2-indoloylguanidine-hydrochloride Yield: 48.6% mp219-221 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 3.07-3.12 (2H, m), 3.97 (3
H, s), 4.29 (2H, t, J = 6.9Hz), 6.79-6.
83 (1H, m), 7.11 (1H, d, J = 2.0Hz), 7.
23-7.39 (5H, m), 7.60 (1H, d, J = 8.6H
z), 7.74 (1H, s), 8.36-8.56 (4H, m), 1
1.67 (1H, br-s).

Example 68 1-Methyl-6- (3-phenylpropoxy) -2-indoloylguanidine · hydrochloride Yield: 72.4% mp232−233 ° C. ¹ Hnmr (D
_{MSO-d 6) δ; 2.02-2.13} (2H, m), 2.75-2.
81 (2H, m), 3.97 (3H, s), 4.07 (2H, t,
J = 6.3 Hz), 6.82-6.86 (1 H, m), 7.06 (1
H, d, J = 1.7 Hz), 7.16-7.33 (5H, m), 7.
61 (1H, d, J = 8.9Hz), 7.75 (1H, s), 8.
36-8.58 (4H, m), 11.69 (1H, br-s). Example 69 1-Methyl-6-methylsulfonyl-2-indoloylguanidine-hydrochloride Yield: 30.7% mp303-304 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 3.25 (3H, s), 4.12 (3H,
s), 7.65 (1H, dd, J = 1.3, 8.6Hz), 7.97
-8.00 (2H, m), 8.24 (1H, s), 8.57 (2H,
br-s), 8.74 (2H, br-s), 12.23 (1H, b
r-s). Example 70 1-Methyl-4-methylsulfonyl-2-indoloylguanidine-hydrochloride Yield: 19.4% mp313-314 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 3.30 (3H, s), 4.10 (3H,
s), 7.60 (1H, dd, J = 7.6, 8.3Hz), 7.72
-7.75 (1H, m), 8.04-8.07 (2H, m), 8.63
(4H, br-s), 12.29 (1H, br-s).

Example 71 4-Chloro-1- (2-methoxyethyl) -2-indoloylguanidine hydrochloride Yield: 27.0% mp 147-150 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 3.15 (3H, s), 3.63 (2H,
t, J = 5.3Hz), 4.73 (2H, t, J = 5.3H)
z), 7.26 (1H, d, J = 6.9Hz), 7.31-7.44
(1H, m), 7.66 (1H, d, J = 8.6Hz), 7.94
(1H, s), 8.60 (2H, br-s), 8.67 (2H,
br-s), 12.05 (1H, br-s). Example 72 1- (2-carbamoylethyl) -4-chloro-2-indoloylguanidine hydrochloride yield: 11.0% mp 295 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 2.56 (2H, t, J = 6.9Hz), 4.76 (2
H, t, J = 6.9 Hz), 6.84 (1H, br-s), 7.
26 (1H, d, J = 7.7Hz), 7.30-7.46 (2H,
m), 7.68 (1H, d, J = 8.2Hz), 7.89 (1H,
s), 8.56 (2H, br-s), 8.62 (2H, br-
s), 11.95 (1H, br-s). Example 73 4-Chloro-1-methyl-7- [2- (N-pyrrolidinyl) ethoxy] -2-indoloylguanidine dihydrochloride Yield: 53.8% mp 250 ° C ¹ Hnmr (DMSO-
_{d 6) δ; 1.93-2.03 (4H} , m), 3.0-3.2 (2
H, m), 3.61-3.71 (4H, m), 4.30 (3H,
s), 4.51-4.54 (2H, m), 6.92 (1H, d, J =
8.2Hz), 7.14 (1H, d, J = 8.3Hz), 7.85
(1H, s), 8.6-8.7 (4H, m), 11.20 (1
H, br-s), 12.07 (1H, br-s).

Example 74 4-Chloro-7- (3-dimethylaminopropoxy)-
1-Methyl-2-indoloylguanidine dihydrochloride Yield: 35.4% mp 250 ° C. ¹ Hnmr (DMSO-
_{d 6) δ; 2.24-2.30 (2H} , m), 2.78 (6H,
s), 3.2-3.3 (2H, m), 4.20 (2H, t, J =
5.9Hz), 4.29 (3H, s), 6.85 (1H, d, J =
8.3Hz), 7.11 (1H, d, J = 8.3Hz), 7.82
(1H, s), 8.5-8.7 (4H, m), 10.74 (1
H, brs), 12.04 (1H, br-s). Example 75 7- [2- (N-benzyl-N-methylamino) ethoxy] -4-chloro-1-methyl-2-indoloylguanidine dihydrochloride Yield: 43.5% mp230 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 2.80 (3H, s), 3.61 (2H, br-
s), 4.20 (3H, s), 4.40-4.57 (4H, m), 6.
89 (1H, d, J = 8.3Hz), 7.13 (1H, d, J =
8.3 Hz), 7.45-7.47 (3 H, m), 7.6-7.7 (2
H, m), 7.82 (1H, s), 8.5-8.7 (4H,
m), 11.10 (1H, br-s), 12.04 (1H, br
-S). Example 76 4-Isopropenyl-1-methyl-2-indoloylguanidine-hydrochloride Yield: 41.5% mp 235 [deg.] C ¹ Hnmr (DMSO-
d ₆ ) δ; 2.24 (3H, s), 4.03 (3H, s), 5.35
-5.36 (1H, m), 5.48 (1H, d, J = 1.0H
z), 7.15 (1H, dd, J = 0.7, 7.3Hz), 7.38
(1H, dd, J = 7.3, 8.6Hz), 7.56 (1H,
d, J = 8.6 Hz), 8.07 (1H, s), 8.45-8.70
(4H, m), 12.03 (1H, br-s).

Example 77 4-Isopropyl-1-methyl-2-indoloylguanidine hydrochloride Yield: 75.6% mp 255 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 1.35 (6H, d, J = 6.9 Hz), 3.27-3.
37 (1H, m), 4.02 (3H, s), 7.03 (1H, d,
J = 6.9 Hz), 7.31-7.37 (1 H, m), 7.44 (1
H, d, J = 8.6 Hz), 8.08 (1 H, s), 8.42-8.
70 (4H, m), 11.97 (1H, br-s). Example 78 1- (2-Diethylaminoethyl) -2-indoloylguanidine dihydrochloride Yield: 19.3% mp 250 ° C ¹ Hnmr (DMSO-
d ₆ ) δ; 1.28 (6H, t, J = 7.3Hz), 3.10-3.
43 (6H, m), 4.88-5.10 (2H, m), 7.23 (1
H, t, J = 7.6 Hz), 7.46 (1H, ddd, J = 1.
0, 8.3, 8.7Hz), 7.76 (1H, d, J = 7.6H)
z), 7.94 (1H, d, J = 8.7Hz), 8.09 (1H,
br-s), 8.61 (2H, br-s), 8.79 (2H, b
r-s), 11.27 (1H, br-s), 12.3 (1H, b
r-s). Example 79 4-chloro-1- (2-diethylaminoethyl) -2-
Indoyl guanidine dihydrochloride Yield: 36.0% mp 260-261 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 1.28 (6H, t, J = 7.3Hz),
3.10-3.48 (6H, m), 4.90-5.15 (2H, m), 7.
31 (1H, d, J = 7.7Hz), 7.45 (1H, dd, J
= 7.7, 8.3Hz), 7.98 (1H, d, J = 8.3H)
z), 8.14 (1H, br-s), 8.72 (2H, br-
s), 8.75 (2H, br-s), 11.38 (1H, br-
s), 12.33 (1H, br-s).

Example 80 1- (2-Dimethylaminoethyl) -2-indoloylguanidine dihydrochloride Yield: 27.0% mp239-242 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 2.84 (6H, s), 3.23-3.53 (2
H, m), 4.85-5.08 (2H, m), 7.23 (1H, d
d, J = 7.3, 7.9 Hz), 7.41-7.43 (1H, m),
7.77 (1H, d, J = 7.9Hz), 7.88 (1H, d, J
= 8.3 Hz), 8.11 (1H, s), 8.64 (2H, br-
s), 8.81 (2H, br-s), 11.09 (1H, br-
s), 12.26 (1H, br-s). Example 81 4-chloro-1- (2-dimethylaminoethyl) -2-
Indroylguanidine dihydrochloride Yield: 26.0% mp245-248 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 2.84 (6H, s), 3.31-3.52 (2
H, m), 4.88-5.08 (2H, m), 7.32 (1H, d,
J = 7.6Hz), 7.46 (1H, dd, J = 7.6, 8.3H
z), 7.91 (1H, d, J = 8.3Hz), 8.16 (1H,
s), 8.71 (2H, br-s), 8.77 (2H, br-
s), 11.19 (1H, m), 12.32 (1H, br-
s).

Example 82 Synthesis of 1-benzyl-5-indoloylguanidine hydrochloride The guanidine hydrochloride (2.24) was added to a solution of sodium methoxide (1.26 g, 23.4 mmol) in methanol (50 ml).
g, 23.4 mmol) and dissolved, then benzyl 1
-Benzyl-5-indolecarboxylate (0.80
g, 2.34 mmol) was added, and the mixture was heated with stirring at 50 to 60 ° C. for 30 hours. Methanol was distilled off under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography to obtain 1-benzyl-5-indoloylguanidine of interest. This was subjected to hydrochloric acid salification with a 2N hydrochloric acid aqueous solution to obtain 1-benzyl-5-indoloylguanidine hydrochloride (0.08 g, 10.4%). mp 216-222 ° C. ¹ Hnmr (DMSO-d6) δ;
5.51 (2H, s), 6.69 (1H, d, J = 2.6Hz), 7.20-7.34 (5H,
m), 7.62-7.68 (2H, m), 7.88 (1H, dd, J = 1.7, 8.9Hz),
8.43-8.48 (3H, m), 8.72 (2H, br-s), 11.7 (1H, br-s).

Example 83 Synthesis of 7-methoxy-1-methyl-2-indoloylguanidine hydrochloride a) 2-methoxyaniline (24.6 g, 0.20 mmol), sodium nitrite (15.2 g, 0.22 mmol), concentrated Hydrochloric acid (84 ml),
Ethyl 2-methylacetoacetate (28.8 g, 0.20 mmo
l) and ethanol (20 ml), referential example 1-a)
The reaction was carried out according to the method of 1. to obtain crude ethyl 2- (2-methoxyphenylhydrazono) propionate (23.0 g). b) The crude ethyl 2- (2-methoxyphenylhydrazono) propionate (23.0 g) obtained above was added to 10% hydrogen chloride / ethanol (150 ml), and the mixture was heated under reflux for 30 minutes.
After cooling, the reaction solution was poured into ice water and extracted by ether extraction (three times), the extract solution was washed with water, washed with sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. Was crudely purified by silica gel column chromatography to obtain crude ethyl 7-methoxy-2-indolecarboxylate (8.00 g). c) Crude ethyl 7-methoxy-2-indolecarboxylate (8.00 g, 36.5 mmol) obtained above, 60% sodium hydride (1.44 g, 36 mmol), methyl iodide (7.76 g, 54.7 mmol) and dimethyl. The reaction was carried out from formamide (50 ml) according to the method of Reference Example 5 to obtain crude ethyl 7-methoxy-1-methyl-2-indolecarboxylate (4.4 g). d) Crude ethyl 7-methoxy-1-methyl-obtained above
2-indolecarboxylate (4.40 g, 18.9 mmol)
, Guanidine hydrochloride (18.0 g, 189 mmol) and sodium methoxide (10.2 g, 189 mmol) in methanol
(150 ml), the reaction was carried out according to the method of Example 1,
7-Methoxy-1-methyl-2-indoloylguanidine hydrochloride (1.58 g, yield from 2-methoxyaniline: 5.6%) was obtained. mp 252-253 ° C. ¹ Hnmr (DMSO-d6) δ;
3.93 (3H, s), 4.28 (3H, s), 6.86 (1H, d, J = 7.6Hz), 7.
05 (1H, t, J = 7.9Hz), 7.26 (1H, d, J = 7.6Hz), 7.74 (1H,
s), 8.5 (2H, br-s), 8.6 (2H, br-s), 11.8 (1H, br-s).

Example 84 Synthesis of 1-isopropyl-2-indoloylguanidine · hydrochloride 1-isopropyl-2-indolecarboxylic acid (2.00
g, 9.84 mmol) and carbonyldiimidazole (2.3
9 g, 14.8 mmol) in tetrahydrofuran (60 ml
Was stirred at room temperature for 2 hours and then at 45-50 ° C. for 1 hour. After returning this to room temperature, guanidine hydrochloride (5.
64 g, 59.0 mmol) and triethylamine (5.97 g,
59.0 mmol) in dimethylformamide (30 ml) was added, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure,
Water was added to the obtained residue and pH = 5-6 with 2N hydrochloric acid aqueous solution.
After adjusting to, extraction with ethyl acetate (three times), drying over anhydrous magnesium sulfate, filtration of the crystals precipitated by acidification with hydrogen chloride / ether and drying, the desired 1-
Isopropyl-2-indoloylguanidine hydrochloride (1.31 g, 47.4%) was obtained. mp 150-151 ° C. ¹ Hnmr (DMSO-d6) δ;
1.61 (6H, d, J = 7.3Hz), 5.46-5.57 (1H, m), 7.15 (1H,
t, J = 7.9Hz), 7.32-7.38 (1H, m), 7.68-7.78 (3H, m),
8.5 (2H, br-s), 8.7 (2H, br-s), 11.8-11.9 (1H, m).

The reaction is carried out according to the method of Example 84,
The compound of Example 85 below was synthesized. Example 85 1-carbamoylmethyl-2-indoloylguanidine · hydrochloride Yield: 2.1% mp 261-262 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 5.17 (2H, s), 7.10-7.28 (2
H, m), 7.32-7.45 (1H, m), 7.56 (1H, d,
J = 8.6Hz), 7.59 (1H, br-s), 7.75 (1
H, dd, J = 0.7, 7.0 Hz), 7.81 (1H, s),
8.45 (2H, br-s), 8.61 (2H, br-s), 1
1.90 (1H, br-s). Example 86 Synthesis of 5-chloro-2-indoloylguanidine hydrochloride 5-chloro-2-indolecarboxylic acid (2.00 g, 10.2
mmol), carbonyldiimidazole (1.82 g, 11.3 m
mol), guanidine / hydrochloride (5.86 g, 61.3 mmol),
Triethylamine (6.20 g, 61.3 mmol), tetrahydrofuran (50 ml) and dimethylformamide (50 ml)
), The reaction was carried out according to the method of Example 84, and
-Chloro-2-indoloylguanidine hydrochloride (1.85
g, 66.2%) was obtained. mp 250 ° C or higher. ¹ Hnmr (DMSO-d6) δ;
7.32 (1H, dd, J = 2.0, 8.9Hz), 7.51 (1H, d, J = 8.9Hz),
7.82 (2H, s), 8.53 (2H, br-s), 8.68 (2H, br-s), 12.2 (1
H, br-s), 12.3 (1H, br-s).

Example 87 Synthesis of 6-amino-1-methyl-2-indoloylguanidine hydrochloride 1-methyl-6-nitro-2-indoloylguanidine
(1.10 g, 4.21 mmol) was dissolved in a mixed solvent of tetrahydrofuran (100 ml) and methanol (100 ml), and then,
10% palladium / carbon (0.5
After adding 0 g), catalytic reduction was carried out at room temperature and atmospheric pressure. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and hydrogen chloride / methanol was added to the obtained residual liquid to perform hydrochloric acid salification to give 6-amino-1-methyl-2-indoloylguanidine / hydrochloric acid. Obtained salt (0.73 g, 64.7%). mp 282-283 ° C. ¹ Hnmr (DMSO-d6) δ;
4.00 (3H, s), 7.06 (1H, dd, J = 1.7, 8.6Hz), 7.39 (1H,
s), 7.76 (1H, d, J = 8.6Hz), 7.93 (1H, s), 8.5 (2H, br-
s), 8.7 (2H, br-s), 9.0-10.3 (2H, br), 12.0 (1H, br-
s).

The reaction was carried out according to the method of Example 87,
The following compounds of Examples 88 to 90 were synthesized. Example 88 4-Amino-1-methyl-2-indoloylguanidine-hydrochloride Yield:> 99%. Mp 279-283 ° C. ¹ Hnmr (DMSO-
d6) δ; 4.00 (3H, s), 6.80 (1H, d, J = 7.6Hz), 7.2
0-7.31 (2H, m), 7.84 (1H, s), 8.5 (2H, br-s), 8.6 (2H,
br-s), 11.9 (1H, br-s). Example 89 5-Amino-1-methyl-2-indoloylguanidine-hydrochloride Yield: 89.8% .mp 301-302 ° C. ¹ Hnmr (DMSO
-D6) δ; 4.04 (3H, s), 7.35-7.39 (1H, m), 7.72
-7.79 (2H, m), 7.93 (1H, s), 8.5 (2H, br-s), 8.7 (2H,
br-s), 10.1 (2H, br-s), 12.1 (1H, br). Example 90 7-amino-1-methyl-2-indoloylguanidine hydrochloride salt yield: 66.7%. mp 299-300 ° C. ¹ Hnmr (DMSO
-D6) δ; 4.28 (3H, s), 7.08-7.14 (1H, m), 7.24
(1H, d, J = 7.3Hz), 7.55 (1H, d, J = 7.9Hz), 7.76 (1H,
s), 8.5 (2H, br-s), 8.6 (2H, br-s), 12.0 (1H, br-s).

Example 91 Synthesis of 5-hydroxy-1-methyl-2-indoloylguanidine hydrochloride The 5-benzyloxy-1-methyl-2-indoloylguanidine obtained in Example 32 (0.83 g, 2.58) mmol) in methanol (50 ml) and then in a nitrogen stream,
After 10% palladium / carbon (0.30 g) was added with stirring at room temperature, catalytic reduction was performed at room temperature and atmospheric pressure. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography to obtain 5-hydroxy-1-methyl-2-indoloylguanidine. Furthermore, this 5-hydroxy-1-methyl-2-indoloylguanidine was treated with hydrogen chloride / methanol to give 5-hydroxy-1-methyl-2-indoloylguanidine hydrochloride (0.37 g, 68.6 g).
%) Was obtained. mp288-289 ° C. ¹ Hnmr (DMSO-d ₆ ).
δ: 3.96 (3H, s), 6.93-6.98 (2H, m), 7.43
-7.47 (1H, m), 7.65 (1H, s), 8.43 (2H,
br-s), 8.65 (2H, br-s), 9.18 (1H,
s), 11.76 (1H, br-s).

The reaction is carried out according to the method of Example 91,
The following compounds of Examples 92-96 were synthesized. Example 92 7-Hydroxy-1-methyl-2-indoloylguanidine · hydrochloride Yield 53.0% mp244-246 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.29 (3H, s), 6.71 (1H,
d, J = 7.6 Hz), 6.88-6.94 (1H, m), 7.12
(1H, d, J = 7.9Hz), 7.65 (1H, s), 8.42
-8.56 (4H, m), 10.08 (1H, s), 11.70 (1
H, br-s). Example 93 4-Hydroxy-1-methyl-2-indoloylguanidine-hydrochloride yield 27.4% mp 267-268 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 3.96 (3H, s), 6.50 (1H,
d, J = 7.6Hz), 7.00 (1H, d, J = 8.3H)
z), 7.16-7.22 (1H, m), 7.71 (1H, s), 8.
42 (4H, br-s), 10.14 (1H, br-s), 1
1.51 (1H, br-s). Example 94 6-Hydroxy-1-methyl-2-indoloylguanidine · hydrochloride Yield 73.4% mp270-271 ° C. ¹ Hnmr (DM
SO-d ₆ ) δ; 3.90 (3H, s), 6.72-6.76 (1
H, m), 6.81 (1H, s), 7.53-7.61 (2H,
m), 8.4 (4H, br-s), 9.76 (1H, br-
s), 11.39 (1H, br-s).

Example 95 4-Chloro-7-hydroxy-1-methyl-2-indoloylguanidine · hydrochloride Yield 23.9% mp 280 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 4.30 (3H, s), 6.70 (1H, d, J = 7.
9Hz), 6.96 (1H, d, J = 8.3Hz), 7.68 (1
H, s), 8.54 (4H, br-s), 10.37 (1H,
s), 11.79 (1H, br-s). Example 96 4-Chloro-6-hydroxy-1-methyl-2-indoloylguanidine hydrochloride Yield 40.1% mp 270 ° C ¹ Hnmr (DMSO-d
₆ ) δ; 3.91 (3H, s), 6.83-6.84 (2H, m),
7.77 (1H, s), 8.3-8.7 (4H, m), 10.14
(1H, s), 11.72 (1H, br-s).

Example 97 Synthesis of 4-acetamido-1-methyl-2-indoloylguanidine hydrochloride a) Synthesis of ethyl 4-amino-1-methyl-2-indolecarboxylate Ethyl 1-methyl-4-nitro 2-Indolecarboxylate (1.37 g, 5.52 mmol) was dissolved in a mixed solvent of tetrahydrofuran (50 ml) and methanol (50 ml) and then 10% palladium / carbon (0.30 g).
After the addition of, was catalytically reduced at room temperature and atmospheric pressure. After the reaction,
The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography to give ethyl 4-amino-1-methyl-2-indolecarboxylate (1.2 g,> 99). %) Was obtained. b) Synthesis of ethyl 4-acetamido-1-methyl-2-indolecarboxylate Ethyl 4-amino-1-methyl-2-indolecarboxylate (1.2 g, 5.52 mmol) was added to pyridine (20 m).
l), and acetic anhydride (10 ml) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours, poured into ice water, extracted with ethyl acetate (three times), the extract was washed with 1N hydrochloric acid, followed by washing with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. After that, the solvent was distilled off under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography to obtain ethyl 4-acetamide-
1-methyl-2-indolecarboxylate (1.40
g, 97.9%) was obtained. c) Synthesis of 4-acetamido-1-methyl-2-indoloylguanidine ・ hydrochloride Ethyl 4-acetamido-1-methyl-2-indolecarboxylate (1.40 g, 5.38 mmol), guanidine ・ hydrochloride (5.14 g, 53.8 mmol) and sodium methoxide (2.91 g, 53.8 mmol) in methanol (50 ml)
The reaction was carried out according to the method of Example 1 to give 4-acetamido-1-methyl-2-indoloylguanidine.
The hydrochloride salt (1.15 g, 69.0%) was obtained. mp 277-279 ° C. ¹ Hnmr (DMSO-d ₆ ).
δ: 2.15 (3H, s), 3.99 (3H, s), 7.30-7.35
(2H, m), 7.5-7.6 (1H, m), 7.79 (1H,
s), 8.4-8.7 (4H, m), 10.00 (1H, br-
s), 11.68 (1H, br-s).

The reaction is carried out according to the method of Example 97,
The following compounds of Examples 98-100 were synthesized. Example 98 5-acetamido-1-methyl-2-indoloylguanidine · hydrochloride Yield 49.2% mp 260-261 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 2.06 (3H, s), 3.99 (3H,
s), 7.46 (1H, dd, J = 2.0, 8.9Hz), 7.56
(1H, d, J = 8.9Hz), 7.83 (1H, s), 8.09
(1H, d, J = 1.7Hz), 8.47 (2H, br-
s), 8.71 (2H, br-s), 9.97 (1H, br-
s), 11.92 (1H, br-s). Example 99 7-acetamido-1-methyl-2-indoloylguanidine hydrochloride yield 17.1% mp 285 ° C. ¹ Hnmr (DMSO-d
₆ ) δ; 2.10 (3H, s), 4.07 (3H, s), 7.07-
7.15 (2H, m), 7.61-7.64 (1H, m), 7.76 (1
H, s), 8.45 (2H, br-s), 8.60 (2H, br)
-S), 9.90 (1H, br-s), 11.86 (1H, br)
-S). Example 100 6-acetamido-1-methyl-2-indoloylguanidine-hydrochloride Yield 63.8% mp 280-281 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 2.09 (3H, s), 3.95 (3H,
s), 7.18 (1H, dd, J = 1.7, 8.6Hz), 7.64
(1H, d, J = 8.9Hz), 7.72 (1H, s), 8.09
(1H, s), 8.2-8.8 (4H, m), 10.17 (1
H, br-s), 11.75 (1H, br-s).

Example 101 Synthesis of 1-hydroxy-2-indoloylguanidine hydrochloride a) Synthesis of methyl 1-hydroxy-2-indolecarboxylate 1-Hydroxy-2-indolecarboxylic acid (3.99 g,
22.5 mmol), thionyl chloride (5.36 g, 45.0 mmol) and methanol (100 ml) were carried out according to the method of Reference Example 6 to give methyl 1-hydroxy-
2-Indole carboxylate (2.56 g, 59.5%) was obtained. b) 1-hydroxy-2-indoloylguanidine
Synthesis of Hydrochloride Methyl 1-hydroxy-2-indolecarboxylate (1.00 g, 5.23 mmol), guanidine hydrochloride (5.00
g, 52.3 mmol) and sodium methoxide (2.82 g,
Example 1 from a methanol solution (50 ml) of 52.3 mmol)
The reaction was carried out according to the method of 1 to obtain 1-hydroxy-2-indoloylguanidine hydrochloride (0.56 g, 42.0%). mp 217 ° C. ¹ Hnmr (DMSO-d ₆ ) δ;
7.13-7.19 (1H, m), 7.37-7.52 (2H, m), 7.
69-7.73 (1H, m), 8.45 (2H, br-s), 8.70
(2H, br-s), 11.4-11.8 (2H, m).

Example 102 Synthesis of 1-methoxy-2-indoloylguanidine-hydrochloride a) Synthesis of methyl 1-methoxy-2-indolecarboxylate Methyl 1-hydroxy-2-indolecarboxylate (0.56 g, 2.93 mmol) ) In a nitrogen stream at room temperature,
60% Sodium hydride (0.12g, 2.93mmol) was added to a suspension of tetrahydrofuran (20ml). After confirming that the reaction solution became transparent, methyl iodide (0.83 g,
5.86 mmol) was added and the mixture was heated under reflux for 2 hours. The reaction solution was cooled to room temperature, poured into ice water, and extracted with ethyl acetate (3
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was separated and purified by silica gel column chromatography to give methyl 1-methoxy-2-. Indole carboxylate (0.46 g, 76.5%) was obtained. b) Synthesis of 1-methoxy-2-indoloylguanidine hydrochloride Methyl 1-methoxy-2-indolecarboxylate (0.46 g, 2.24 mmol), guanidine hydrochloride (2.14)
g, 22.4 mmol) and sodium methoxide (1.21 g,
22.4 mmol) in a methanol solution (15 ml) was used in Example 1.
The reaction was performed according to the method described in (1) to give 1-methoxy-2-indoloylguanidine hydrochloride (0.15 g, 24.9%). mp 214 ° C. ¹ Hnmr (DMSO-d ₆ ) δ;
4.16 (3H, s), 7.21-7.26 (1H, m), 7.44-7.
50 (1H, m), 7.62 (1H, d, J = 8.6Hz), 7.
74-7.79 (2H, m), 8.48 (2H, br-s), 8.66
(2H, br-s), 11.93 (1H, br-s).

Example 103 Synthesis of 5-benzamido-1-methyl-2-indoloylguanidine hydrochloride a) Synthesis of ethyl 5-benzamido-1-methyl-2-indolecarboxylate Ethyl 5-amino-1-methyl 2-Indole carboxylate (0.80 g, 3.67 mmol) was added to pyridine (20 m
l) and benzoyl chloride (0.57
g, 4.03 mmol) was added, and the mixture was stirred at 70 ° C. for 2 hours. The reaction solution was cooled to room temperature, poured into ice water, extracted with ethyl acetate (three times), the extract was washed with 1N hydrochloric acid, followed by washing with a saturated sodium hydrogen carbonate aqueous solution, dried over anhydrous magnesium sulfate, and then the solvent. Was distilled off under reduced pressure, and the residue obtained was separated and purified by silica gel column chromatography to give ethyl 5-benzamide-1-methyl-2.
-Indole carboxylate (0.62 g, 52.5%) was obtained. b) Synthesis of 5-benzamido-1-methyl-2-indoloylguanidine hydrochloride hydrochloride Ethyl 5-benzamido-1-methyl-2-indolecarboxylate (0.62 g, 1.92 mmol), guanidine hydrochloride (3.68 g, 38.4 mmol) and sodium methoxide (2.08 g, 38.4 mmol) in methanol (50 ml)
Then, the reaction was carried out according to the method of Example 1 to give 5-benzamido-1-methyl-2-indoloylguanidine.
The hydrochloride salt (0.38 g, 53.1%) was obtained. mp 185-190 ° C. ¹ Hnmr (DMSO-
_{d 6) δ; 4.03 (3H} , s), 7.50-7.60 (4H,
m), 7.63-7.74 (1H, m), 7.81 (1H, s), 7.
96-8.00 (2H, m), 8.25 (1H, d, J = 1.7H
z), 8.44 (2H, br-s), 8.62 (2H, br-
s), 10.26 (1H, br-s), 11.82 (1H, br)
-S).

The reaction was carried out according to the method of Example 103 to synthesize the compounds of the following Examples 104-106. Example 104 4-benzamido-1-methyl-2-indoloylguanidine-hydrochloride Yield 54.7% mp 302-303 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 4.04 (3H, s), 7.37-7.64 (6
H, m), 7.87 (1H, s), 8.05-8.09 (2H,
m), 8.52 (4H, br-s), 10.35 (1H, br-
s), 11.70 (1H, br-s). Example 105 7-benzamido-1-methyl-2-indoloylguanidine-hydrochloride Yield 45.7% mp318-319 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 4.07 (3H, s), 7.16-7.24 (2
H, m), 7.53-7.72 (4H, m), 7.80 (1H,
m), 8.04-8.06 (2H, m), 8.45 (2H, br-
s), 8.61 (2H, br-s), 10.44 (1H, br-
s), 11.88 (1H, br-s).

Example 106 6-benzamido-1-methyl-2-indoloylguanidine · hydrochloride Yield 40.1% mp 309 ° C. ¹ Hnmr (DMSO-
_{d 6) δ; 4.00 (3H} , s), 7.48-7.62 (4H,
m), 7.70-7.75 (2H, m), 7.98-8.01 (2H,
m), 8.27 (1H, s), 8.2-8.8 (4H, m), 1
0.45 (1H, br-s), 11.73 (1H, br-
s). Example 107 Synthesis of 1- (4-aminobenzyl) -2-indoloylguanidine-hydrochloride 1- (4-Nitrobenzyl) -2-indoloylguanidine (0.45 g, 1.20 mmol), 10% palladium / carbon ( 0.50 g), tetrahydrofuran (25 ml) and methanol (25 ml) were reacted according to the method of Example 87 to give 1- (4-aminobenzyl) -2-indoloylguanidine hydrochloride (0.33 g, 79.7 g). %) Was obtained. mp 226-228 ° C. ¹ Hnmr (DMSO-d
₆ ) δ; 5.83 (2H, s), 7.00-7.13 (4H, m),
7.17-7.23 (1H, m), 7.34-7.40 (1H, m), 7.
58 (1H, d, J = 8.3Hz), 7.79 (1H, d, J =
7.9Hz), 8.02 (1H, s), 8.50 (2H, br-
s), 8.66 (2H, br-s), 9.0-9.8 (2H,
m), 12.01 (1H, br-s).

Example 108 Synthesis of 1- (2-hydroxyethyl) -2-indoloylguanidine hydrochloride hydrochloride Methyl 1- [2- (2-tetrahydropyranyl) oxyethyl] -2-indolecarboxylate (1.00
g, 3.30mmol), guanidine hydrochloride (3.15g, 33.0mm)
ol) and sodium methoxide (1.78g, 33.0mmol)
Was reacted according to the method of Example 1 to give 1- [2- (2-tetrahydropyranyl) oxyethyl] -2-indoloylguanidine (0.85 g). Subsequently, this compound (0.69 g) was dissolved in hydrochloric acid / methanol and stirred at room temperature for 5.5 hours. The reaction solution was concentrated under reduced pressure, a mixed solvent of methanol / diethyl ether was added to the residue, the precipitate was collected by filtration, and the product on the filter was dried under reduced pressure to give 1- (2-hydroxyethyl). ) -2-Indoloylguanidine hydrochloride (0.49 g,
65%). mp 190-193 ° C ¹ Hnmr (DMSO-
_{d 6) δ; 3.60-3.82 (2H} , m), 4.60 (2H, t,
J = 5.0 Hz), 4.74-4.97 (1H, brs), 7.17
(1H, dt, J = 7.0, 7.8Hz), 7.38 (1H, d
t, J = 7.0, 7.8 Hz), 7.66 (1H, d, J = 8.0)
Hz), 7.72 (1H, d, J = 8.0Hz), 7.84 (1
H, s), 8.20-8.90 (4H, m), 11.87 (1H, b
r-s).

The reaction was carried out according to the method of Example 108 to obtain the compounds of Examples 109-110 below. Example 109 1- (3-Hydroxypropyl) -2-indoloylguanidine · hydrochloride Yield 81.0% mp 206-207 ° C. ¹ Hnmr
(DMSO-d ₆ ) δ; 1.90 (2H, dt, J = 6.9,
7.3Hz), 3.39 (2H, t, J = 6.3Hz), 4.60
(2H, t, J = 6.9Hz), 7.18 (1H, dd, J =
7.0, 7.8Hz), 7.41 (1H, dd, J = 7.1, 8.5
Hz), 7.65 (1H, d, J = 8.2Hz), 7.74 (1
H, d, J = 7.8 Hz), 7.88 (1 H, s), 8.28-8.
85 (4H, m), 11.87 (1H, br-s). Example 110 1- (4-hydroxybutyl) -2-indoloylguanidine / hydrochloride Yield 84.0% mp 226 ° C. ¹ Hnmr (DMS
O-d ₆ ) δ; 1.30-1.50 (2H, m), 1.62-1.86
(2H, m), 3.38 (2H, t, J = 6.4Hz), 4.43
(1H, br-s), 4.56 (2H, t, J = 7.3H
z), 7.17 (1H, t, J = 7.4Hz), 7.40 (1H,
ddd, J = 1.0, 6.9, 7.4 Hz), 7.65 (1H,
d, J = 8.3Hz), 7.73 (1H, d, J = 7.9H)
z), 7.96 (1H, s), 8.52 (2H, br-s), 8.
76 (2H, br-s), 12.00 (1H, s).

Example 111 Synthesis of 3-methyl-2-indoloylguanidine-hydrochloride a) Synthesis of ethyl 2-phenylhydrazonobutyronate Aniline instead of o-chloroaniline, and ethyl 2-methylacetoacetate. Ethyl instead of tart 2
-Ethyl 2-phenylhydrazonobutyronate was obtained according to the method described in Reference Example 1-a), except that ethyl acetoacetate was used. b) Synthesis of ethyl 3-methyl-2-indolecarboxylate Ethyl 2-phenylhydrazonobutyronate (25.0
g) was dissolved in hydrochloric acid / ethanol (80 ml) and heated under reflux for 1 hour. The reaction solution was cooled to room temperature, poured into ice water, extracted with diethyl ether (3 times), the extract solution was washed with water, then with a saturated sodium hydrogen carbonate aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography to obtain ethyl 3-methyl-2-indolecarboxylate (14.0 g, 69.0%).
I got c) Synthesis of 3-methyl-2-indoloylguanidine / hydrochloride Ethyl 3-methyl-2-indolecarboxylate (1.50 g, 7.38 mmol), guanidine / hydrochloride (7.05 g,
73.8 mmol) and sodium methoxide (3.99 g, 73.8
(Methanol) (50 ml) in methanol according to the method of Example 1 to give 3-methyl-2-indoloylguanidine hydrochloride (1.61 g, 86.3%). mp285-286 ° C ¹ Hnmr (DMSO-
d ₆ ) δ; 2.60 (3H, s), 7.12 (1H, t, J = 7.
9Hz), 7.31-7.44 (2H, m), 7.70 (1H, d,
J = 7.9 Hz), 8.46 (4H, br-s), 11.78 (1
H, br-s), 11.94 (1H, br-s).

Example 112 1-Methyl-7- (3-phenylpropionamide)-
Synthesis of 2-indoloylguanidine-hydrochloride a) Synthesis of ethyl 1-methyl-7- (3-phenylpropionamido) -2-indolecarboxylate Ethyl 7-amino-1-methyl-2-indolecarboxylate (0.20 g, 0.92 mmol), 3-phenylpropionic acid (0.14 g, 0.94 mmol), 4-dimethylaminopyridine (0.11 g, 0.94 mmol), and dicyclohexylcarbodiimide (0.19 g, 0.94 mmol) suspended in methylene chloride (5 ml). The liquid was stirred at room temperature for 24 hours. The reaction solution was poured into ice water and extracted with ethyl acetate (three times), the extract solution was washed with 1N hydrochloric acid, 5% aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue thus obtained was separated and purified by silica gel column chromatography to obtain ethyl 1-methyl-7- (3-phenylpropionamido) -2-indolecarboxylate.

B) Synthesis of 1-methyl-7- (3-phenylpropionamide) -2-indoloylguanidine hydrochloride hydrochloride Ethyl 1-methyl-7- (3-phenylpropionamide) -2-indolecarboxylate ( 0.42 g, 1.
21 mmol), guanidine hydrochloride (2.31 g, 24.2 mmol) and sodium methoxide (1.31 g, 24.2 mmol) in methanol (30 ml) were reacted according to the method of Example 1 to give 1-methyl-7. -(3-phenylpropionamide) -2-indoloylguanidine hydrochloride (0.
16 g, 34.9%) was obtained. mp279-280 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 2.72 (2H, t, J = 7.6Hz), 2.96 (2
H, t, J = 7.6 Hz), 3.34 (3H, s), 7.03-7.
14 (2H, m), 7.20-7.24 (1H, m), 7.29-7.31
(4H, m), 7.62 (1H, d, J = 6.9Hz), 7.69
(1H, s), 8.53 (4H, m), 9.89 (1H, s),
11.76 (1H, br-s).

Reaction was carried out according to the method of Example 112 to synthesize the compound of Example 113 below. Example 113 1-Methyl-6- (3-phenylpropionamide)-
2-Indoylguanidine hydrochloride yield 34.6% mp 245-247 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 2.66-2.71 (2H, m), 2.91
-2.97 (2H, m), 3.95 (3H, s), 7.16-7.30
(6H, m), 7.63-7.71 (2H, m), 8.13 (1H,
s), 8.36-8.52 (4H, m), 10.16 (1H, br-
s), 11.67 (1H, br-s). Example 114 Synthesis of 1- (3-aminopropyl) -2-indoloylguanidine dihydrochloride Methyl 1- (3-tert-butoxycarbonylaminopropyl) -2-indolecarboxylate (1.50 g,
4.51mmol), guanidine hydrochloride (4.31g, 45.1mmol)
And a solution of sodium methoxide (2.44 g, 45.1 mmol) in methanol (60 ml) were reacted according to the method of Example 1 to give 1- (3-tert-butoxycarbonylaminopropyl) -2-indoloylguanidine ( 1.57
g) was obtained. This compound (1.55 g) was dissolved in hydrochloric acid / methanol and stirred at 70 ° C. for 3.5 hours. By recrystallizing the residue obtained by concentrating the reaction solution under reduced pressure from water,
1- (3-aminopropyl) -2-indoloylguanidine dihydrochloride (0.65 g, 46.0%) was obtained. mp296-297 ° C ¹ Hnmr (DMSO-
d ₆ ) δ; 2.05 (2H, ddd, J = 7.6, 11.4, 14.5)
Hz), 2.63-2.86 (2H, m), 4.65 (2H, t, J
= 7.3Hz), 7.19 (1H, t, J = 7.9Hz), 7.42
(1H, t, J = 7.6Hz), 7.74 (2H, d, J = 8.
6Hz), 7.83-8.16 (4H, m), 8.27-9.03 (4
H, m), 12.00-12.30 (1H, br-s).

The reaction was carried out according to the method of Example 114 to synthesize the compound of the following Example 115. Example 115 1- (2-aminoethyl) -2-indoloylguanidine dihydrochloride Yield 54.0% mp 240 ° C. ¹ Hnmr (DMS
O-d ₆ ) δ; 3.14-3.30 (2H, m), 4.77 (2H,
t, J = 6.3 Hz), 7.22 (1H, dd, J = 7.3, 7.
6Hz), 7.45 (1H, dd, J = 7.3, 7.6Hz),
7.77 (1H, d, J = 7.6Hz), 7.83 (1H, d, J
= 7.6 Hz), 8.03 (1H, br-s), 8.20 (3H,
br-s), 8.58 (2H, br-s), 8.74 (2H, b
r-s), 12.14 (1H, br-s).

Example 116 Synthesis of 4-aminomethyl-1-methyl-2-indoloylguanidine dihydrochloride Ethyl 1-methyl-4-tert-butyloxycarbonylaminomethyl-2-indolecarboxylate (1.
40g, 4.21mmol), guanidine hydrochloride (4.02g, 42.1)
mmol) and sodium methoxide (2.27 g, 42.1 mmol)
The reaction was performed according to the method of Example 1 from the methanol solution (60 ml) to give 1-methyl-4-tert-butyloxycarbonylaminomethyl-2-indoloylguanidine (1.50 g). This compound was dissolved in a mixed solution of trifluoroacetic acid (35 ml) / methylene chloride (70 ml) and stirred at room temperature for 2 hours. Ice water was poured into the residue obtained by concentrating the reaction solution under reduced pressure, the aqueous layer was made alkaline with 28% ammonia water, and then extracted with ethyl acetate (three times).
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue obtained was hydrochloric acid-chlorinated with hydrogen chloride / ether to give 4-aminomethyl-1-. Methyl-2-indoloylguanidine
The dihydrochloride (0.58 g, 43.2%) was obtained. mp283-284 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 4.06 (3H, s), 4.28 (2H, d, J = 6.
6Hz), 7.32 (1H, d, J = 6.9Hz), 7.43-7.
49 (1H, m), 7.66 (1H, d, J = 8.3Hz), 8.
28 (1H, s), 8.5-8.7 (5H, m), 8.79 (2
H, br-s), 12.28 (1H, br-s).

The reaction was carried out according to the method of Example 116 to synthesize the compounds of the following Examples 117-122. Example 117 7- (3-aminopropoxy) -1-methyl-2-indoloylguanidine dihydrochloride Yield 51.8% mp 287-288 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 2.09-2.17 (2H, m), 3.32 (2
H, br-s), 4.21 (2H, t, J = 5.9Hz), 4.
28 (3H, s), 6.86 (1H, d, J = 6.9Hz), 7.
05 (1H, t, J = 7.9Hz), 7.28 (1H, d, J =
7.9 Hz), 7.76 (1 H, s), 7.98 (3 H, br-
s), 8.47-8.67 (4H, m), 11.92 (1H, br-
s). Example 118 7- (3-aminopropoxy) -4-chloro-1-methyl-2-indoloylguanidine dihydrochloride Yield 41.7% mp299-300 ° C. ¹ Hnmr
(DMSO-d ₆ ) δ; 2.14-2.19 (2H, m), 3.00
-3.02 (2H, m), 4.21-4.26 (2H, m), 4.28
(3H, s), 6.83 (1H, d, J = 8.3Hz), 7.10
(1H, d, J = 8.3Hz), 7.88 (1H, s), 8.18
(3H, br-s), 8.6-8.7 (4H, m), 12.12
(1H, br-s).

Example 119 6- (3-Aminopropoxy) -1-methyl-2-indoloylguanidine dihydrochloride Yield 61.3% mp 280-281 ° C. ¹ Hnmr
(DMSO-d ₆ ) δ; 2.09-2.16 (2H, m), 3.01
(2H, d, J = 6.3Hz), 4.02 (3H, s), 4.19
-4.24 (2H, m), 6.87 (1H, dd, J = 2.0, 8.
9Hz), 7.15 (1H, s), 7.75 (1H, d, J = 8.
9Hz), 7.95 (1H, s), 8.07 (3H, br-
s), 8.51-8.80 (4H, m), 12.00 (1H, br-
s). Example 120 1- (3-aminopropyl) -4-chloro-2-indoloylguanidine dihydrochloride Yield 46.0% mp 280-282 ° C. ¹ Hnmr
(DMSO-d ₆ ) δ; 1.95-2.16 (2H, m), 2.65
-2.88 (2H, m), 4.66 (2H, t, J = 6.6H
z), 7.29 (1H, d, J = 7.6Hz), 7.42 (1H,
dd, J = 7.6, 8.3 Hz), 7.79 (1H, d, J = 3.
0Hz), 8.02 (3H, br-s), 8.11 (1H,
s), 8.68 (2H, br-s), 8.78 (2H, br-
s), 12.2 (1H, br-s).

Example 121 7- (2-aminoethoxy) -4-chloro-1-methyl-2-indoloylguanidine dihydrochloride Yield 31.9% mp 285 ° C. ¹ Hnmr (DMS
O-d ₆ ) δ; 3.2-3.4 (2H, m), 4.30 (3H,
s), 4.33-4.37 (2H, m), 6.89 (1H, d, J =
8.3Hz), 7.13 (1H, d, J = 8.3Hz), 7.83
(1H, s), 8.33 (3H, br-s), 8.6-8.7
(4H, m), 12.06 (1H, br-s). Example 122 6- (3-aminopropoxy) -4-chloro-1-methyl-2-indoloylguanidine dihydrochloride Yield 38.7% mp 230 ° C. ¹ Hnmr (DMS
O-d ₆ ) δ; 2.06-2.11 (2H, m), 2.97-2.99
(2H, m), 4.00 (3H, s), 4.18-4.23 (2H,
m), 6.96 (1H, d, J = 1.7Hz), 7.14 (1H,
s), 7.95 (1H, s), 8.09 (3H, br-s), 8.
5-8.7 (4H, m), 12.03 (1H, br-s).

Example 123 Synthesis of 4-hydroxymethyl-1-methyl-2-indoloylguanidine hydrochloride hydrochloride Ethyl 1-methyl-4- (2-tetrahydropyranyl) oxymethyl-2-indolecarboxylate (1.50 g , 4.73mmol), guanidine hydrochloride (6.02g, 6
3.0 mmol) and sodium methoxide (3.40 g, 63.0 m)
mol) solution in methanol (60 ml) according to the method of Example 1 to obtain 1-methyl-4- (2-tetrahydropyranyl) oxymethyl-2-indoloylguanidine. This compound was then added to 2N hydrochloric acid (30 ml)
/ Dissolve in a mixed solvent of tetrahydrofuran (60 ml),
The mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, the aqueous layer was made alkaline with 28% ammonia water and then extracted with ethyl acetate (three times), the extract solution was washed with saturated saline solution and dried with anhydrous magnesium sulfate, and then the solvent was added. The residue obtained by evaporation under reduced pressure was separated and purified by silica gel column chromatography to give 4-hydroxymethyl-1.
-Methyl-2-indoloylguanidine was obtained. Next, this compound was subjected to hydrochloric acid salification with hydrogen chloride / methanol to obtain 4-hydroxymethyl-1-methyl-2-indoloylguanidine hydrochloride (0.58 g, 44.2%). mp226-229 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 4.03 (3H, s), 4.80 (2H, s), 5.26
(1H, brs), 7.17 (1H, d, J = 6.9Hz),
7.34-7.39 (1H, m), 7.48 (1H, d, J = 8.3H
z), 7.93 (1H, s), 8.48-8.60 (4H, m), 1
1.81 (1H, br-s). The reaction was carried out according to the method of Example 123 to synthesize the compounds of the following Examples 124-133.

Example 124 7- (2-Hydroxyethoxy) -1-methyl-2-indoloylguanidine · hydrochloride Yield 62.5% mp 243-244 ° C. ¹ Hnmr
(DMSO-d ₆ ) δ; 3.82 (2H, br-s), 4.12
-4.15 (2H, m), 4.31 (3H, s), 4.94 (1H,
br-s), 6.86 (1H, d, J = 7.3Hz), 7.03
(1H, t, J = 7.9Hz), 7.26 (1H, d, J = 7.9.
3Hz), 7.73 (1H, s), 8.45-8.63 (4H,
m), 11.82 (1H, br-s). Example 125 4-chloro-7- (2-hydroxyethoxy) -1-methyl-2-indoloylguanidine hydrochloride salt yield 17.7% mp 277-279 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 3.79-3.83 (2H, m), 4.12
-4.15 (2H, m), 4.31 (3H, s), 4.9 (1H,
br-s), 6.85 (1H, d, J = 8.3Hz), 7.10
(1H, d, J = 8.3Hz), 7.75 (1H, s), 8.58
(4H, br-s), 11.88 (1H, br-s).

Example 126 6- (2-Hydroxyethoxy) -1-methyl-2-indoloylguanidine · hydrochloride Yield 59.8% mp265-268 ° C. ¹ Hnmr
(DMSO-d ₆ ) δ; 3.32-3.77 (2H, m), 3.98
(3H, s), 4.08-4.11 (2H, m), 4.91 (1H,
br-s), 6.81-6.85 (1H, m), 7.08 (1H,
s), 7.61 (1H, d, J = 8.9Hz), 7.81 (1H,
s), 8.39-8.64 (4H, m), 11.77 (1H, br-
s). Example 127 4-chloro-7- (2,3-dihydroxypropoxy)
-1-Methyl-2-indoloylguanidine / hydrochloride Yield 40.2% mp237-238 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 3.50 (2H, d, J = 5.9H
z), 3.88-3.91 (1H, m), 4.03 (1H, dd, J
= 5.6,9.9 Hz), 4.15 (1H, dd, J = 4.0, 9.
9Hz), 4.30 (3H, s), 6.85 (1H, d, J = 8.
3Hz), 7.11 (1H, d, J = 8.3Hz), 7.68 (1
H, s), 8.50 (4H, br-s), 11.76 (1H, b
r-s).

Example 128 4-Chloro-7- (3-hydroxypropoxy) -1-
Methyl-2-indoloylguanidine / hydrochloride yield 53.2% mp210-212 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 1.93-2.02 (2H, m), 3.60
-3.64 (2H, m), 4.15-4.20 (2H, m), 4.28
(3H, s), 6.84 (1H, d, J = 8.6Hz), 7.09
(1H, d, J = 8.3Hz), 7.77 (1H, s), 8.5
-8.6 (4H, m), 11.92 (1H, br-s). Example 129 4-chloro-7- (4-hydroxybutoxy) -1-methyl-2-indoloylguanidine hydrochloride salt yield 69.5% mp 220-222 ° C. ¹ Hnmr
(DMSO-d ₆ ) δ; 1.59-1.67 (2H, m), 1.84
-1.89 (2H, m), 3.45-3.50 (2H, m), 4.10-
4.15 (2H, m), 4.29 (3H, s), 6.84 (1H,
d, J = 8.3Hz), 7.10 (1H, d, J = 8.3H)
z), 7.71 (1H, s), 8.52 (4H, br-s), 1
1.80 (1H, br-s). Example 130 4-chloro-1- (3-hydroxypropyl) -2-indoloylguanidine-hydrochloride Yield 60.0% mp213-215 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 1.78-1.98 (2H, m), 3.30
-3.45 (2H, m), 4.61 (2H, t, J = 7.3H
z), 4.68 (1H, br-s), 7.27 (1H, d, J =
7.6Hz), 7.39 (1H, dd, J = 7.3, 8.6H
z), 7.66 (1H, d, J = 8.6Hz), 7.93 (1H,
s), 8.55 (2H, br-s), 8.64 (2H, br-)
s), 11.96 (1H, br-s).

Example 131 4-chloro-1- (4-hydroxybutyl) -2-indoloylguanidine hydrochloride Yield 48.0% mp 226-227 ° C. ¹ Hnmr
(DMSO-d ₆ ) δ; 1.28-1.51 (2H, m), 1.60
-1.84 (2H, m), 3.37 (2H, t, J = 6.6H
z), 4.44 (1H, br-s), 4.58 (1H, t, J =
7.3Hz), 7.28 (1H, d, J = 7.6Hz), 7.39
(1H, dd, J = 7.6, 8.6Hz), 7.68 (1H,
d, J = 8.6Hz), 7.92 (1H, s), 8.53 (2H,
br-s), 8.63 (2H, br-s), 11.92 (1H,
br-s). Example 132 4-Chloro-6- (2-hydroxyethoxy) -1-methyl-2-indoloylguanidine-hydrochloride Yield 51.9% mp 250-252 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 3.74-3.77 (2H, m), 3.99
(3H, s), 4.11 (2H, t, J = 5.0Hz), 6.94
(1H, d, J = 2.0Hz), 7.13 (1H, s), 7.80
(1H, s), 8.3-8.7 (4H, m), 11.76 (1
H, br-s). Example 133 1- (3,4-dihydroxybutyl) -2-indoloylguanidine-hydrochloride Yield 73.0% mp219-222 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 1.53-1.73 (1H, m), 1.85
-2.04 (1H, m), 3.12-3.55 (3H, m), 4.37-
4.88 (4H, m), 7.18 (1H, t, J = 7.3Hz),
7.40 (1H, ddd, J = 1.0, 7.3, 7.8Hz), 7.
65 (1H, d, J = 8.3Hz), 7.74 (1H, d, J =
7.9Hz), 7.86 (1H, s), 8.21 (2H, br-
s), 8.67 (2H, br-s), 11.87 (1H, br-
s).

Example 134 Synthesis of 1- (2-carboxyethyl) -2-indoloylguanidine · hydrochloride 1- [2- [1- (4-methyl-2,6,7-trioxabicyclo [2. 2.2] Octyl)] ethyl] -2-
Indoyl guanidine (0.80g, 2.23mmol) 1,2
-Suspended in dimethoxyethane (80 ml), 1N hydrochloric acid (8 ml) was added thereto, and the mixture was stirred at room temperature for 20 minutes. Subsequently, 1N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred at room temperature for 40 minutes. Subsequently, 4N hydrochloric acid (10 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the resulting residue was washed with water, and then the water was filtered off. The product on the filter was recrystallized from 0.5N hydrochloric acid to obtain 1- (2-carboxyethyl) -2-indoloylguanidine hydrochloride (0.44 g, 64.0%). mp 254 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 2.
72 (2H, t, J = 7.3Hz), 4.76 (2H, t, J =
7.4Hz), 7.17 (1H, t, J = 7.9Hz), 7.40
(1H, ddd, J = 1.0, 6.9, 7.4Hz), 7.68
(1H, d, J = 8.6Hz), 7.73 (1H, d, J = 7.
9Hz), 7.91 (1H, s), 8.50 (2H, br-
s), 8.72 (2H, br-s), 12.22 (1.5H, br)
-S).

Example 135 7-Carboxymethoxy-4-chloro-1-methyl-2
-Synthesis of Indoylylguanidine Hydrochloride 7-carbamoylmethoxy-4-obtained in Example 64
A suspension of chloro-1-methyl-2-indoloylguanidine hydrochloride (0.40 g, 1.11 mmol) in 2N hydrochloric acid (100 ml) was heated under reflux for 1 hour. The reaction solution was gradually cooled, and the precipitated crystals were collected by filtration and dried under reduced pressure to give 7
-Carboxymethoxy-4-chloro-1-methyl-2-
Indoylguanidine hydrochloride (0.39 g, 97.2%) was obtained. mp283-284 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 4.34 (3H, s), 4.84 (2H, s), 6.82
(1H, d, J = 8.3Hz), 7.09 (1H, d, J = 8.3.
3Hz), 7.69 (1H, s), 8.48 (4H, br-
s), 11.5-13.5 (1.3H, br-s).

The reaction was carried out according to the method of Example 135 to synthesize the compounds of the following Examples 136-137. Example 136 7-Carboxymethoxy-1-methyl-2-indoloylguanidine · hydrochloride Yield 41.5% mp 264 ° C. ¹ Hnmr (DMS
O-d ₆ ) δ; 4.34 (3H, s), 4.84 (2H, s),
6.83 (1H, d, J = 7.6Hz), 7.03 (1H, t, J
= 7.9 Hz), 7.30 (1H, d, J = 7.9 Hz), 7.74
(1H, s), 8.47-8.63 (4H, m), 11.71 -12.0
7 (1H, m), 12.6-13.3 (1H, m). Example 137 6-Carboxymethoxy-1-methyl-2-indoloylguanidine-hydrochloride Yield 53.0% mp 298 ° C ¹ Hnmr (DMS
O-d ₆ ) δ; 3.97 (3H, s), 4.79 (2H, s),
6.85 (1H, dd, J = 2.0, 8.9Hz), 7.09 (1
H, s), 7.63 (1H, d, J = 8.9Hz), 7.72 (1
H, s), 8.34-8.51 (4H, m), 10-13 (2
H, m).

Example 138 1-Methyl-7- (2-phenylethylamino) -2-
Synthesis of indoylguanidine hydrochloride: a) Synthesis of ethyl 1-methyl-7- (2-phenylethylamino) -2-indolecarboxylate Ethyl 7-amino-1-methyl-2-indolecarboxylate (0.10 g, 0.46mmol), phenylacetaldehyde (50% isopropanol solution; 0.12g, 0.50)
mmol), sodium cyanoborohydride (0.043 g, 0.
69 mmol) and acetic acid (0.1 ml) in acetonitrile (5 m
l) The solution was stirred at room temperature for 15 minutes and then acetic acid (0.2 m
l) was added and left at room temperature for 15 hours. 1 in the reaction mixture
It was obtained by adding N sodium hydroxide aqueous solution and then extracting with diethyl ether (three times), washing the extract with 1N potassium hydroxide aqueous solution, and drying over anhydrous magnesium sulfate, and then distilling off the solvent under reduced pressure. The residue was separated and purified by silica gel column chromatography to give ethyl acetate.
1-methyl-7- (2-phenylethylamino) -2-
Indole carboxylate (0.045 g, 30.5%) was obtained.

B) Synthesis of 1-methyl-7- (2-phenylethylamino) -2-indoloylguanidine hydrochloride hydrochloride Ethyl 1-methyl-7- (2-phenylethylamino) -2-indolecarboxylate ( 0.16 g, 0.51
mmol), guanidine hydrochloride (0.49 g, 5.09 mmol) and sodium methoxide (0.28 g, 5.09 mmol) in methanol (10 ml) to carry out the reaction according to the method of Example 1 to give 1-methyl-7. -(2-Phenylethylamino) -2-indoloylguanidine hydrochloride (0.075
g, 39.5%) was obtained. mp220-223 ° C ¹ Hnmr (DMSO-
d ₆ ) δ; 2.96-3.02 (2H, m), 3.29-3.35 (2
H, m), 4.18 (3H, s), 6.60-6.95 (1H,
m), 6.99 (1H, d, J = 7.3Hz), 7.06 (1H,
d, J = 7.3 Hz), 7.20-7.25 (1H, m), 7.31-
7.33 (4H, m), 7.64 (1H, s), 8.42-8.59 (4
H, m), 11.73 (1H, br-s).

Reaction was carried out according to the method of Example 138 to synthesize the compound of Example 139 below. Example 139 1-Methyl-6- (2-phenylethylamino) -2-
Indoyl guanidine / hydrochloride yield 26.6% mp243-246 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 2.91-2.97 (2H, m), 3.38
-3.51 (2H, m), 3.92 (3H, s), 6.70 (1H,
s), 6.79 (1H, d, J = 7.9Hz), 7.20-7.29
(1H, m), 7.31 (4H, m), 7.49 (1H, d, J
= 8.6 Hz), 7.76 (1 H, s), 8.35-8.63 (4 H,
m), 11.64 (1H, br-s).

Example 140 Synthesis of 1- (3-aminopropyl) -4-trifluoromethyl-2-indoloylguanidine dihydrochloride a) Ethyl-1- (3-tert-butoxycarbonylaminopropyl) -4 -Synthesis of trifluoromethyl-2-indolecarboxylate Ethyl 4-trifluoromethyl-2-indolecarboxylate (2.60 g, 10.11 mmol), 60% sodium hydride (0.445 g, 11.12 mmol), tert-butyl N-
(3-Iodopropyl) carbamate (4.32 g, 15.17
mmol) and dimethylformamide (100 ml),
The reaction was performed according to the method of Reference Example 5 (25) to obtain ethyl 1- (3-tert-butoxycarbonylaminopropyl) -4-trifluoromethyl-2-indolecarboxylate (2.81 g, 67.1%). .

B) 1- (3-aminopropyl) -4-
Trifluoromethyl-2-indoloylguanidine ・ 2
Synthesis of Hydrochloride Ethyl 1- (3-tert-butoxycarbonylaminopropyl) -4-trifluoromethyl-2-indolecarboxylate (2.81 g, 6.78 mmol), guanidine hydrochloride (6.48 g, 67.8 mmol) and sodium The reaction was carried out from a methanol solution (100 ml) of methoxide (3.66 g, 67.8 mmol) according to the method of Example 1 to give 1- (3-
tert-Butoxycarbonylaminopropyl) -4-trifluoromethyl-2-indoloylguanidine (2.83
g) was obtained. This compound (2.72 g) was reacted according to the method of Example 114 to give 1- (3-aminopropyl) -4-trifluoromethyl-2-indoloylguanidine dihydrochloride (1.45 g, 57.0 g). %) Was obtained. mp 245 ° C (decomposition) ¹ Hnmr (DMSO-
d ₆ ) δ; 1.99-2.20 (m, 2H), 2.70-2.89 (2
H, m), 4.72 (2H, t, J = 6.9Hz), 7.51-7.
68 (2H, m), 8.06 (3H, br-s), 8.06-8.27
(2H, m), 8.71 (2H, br-s), 8.80 (2H,
br-s), 12.30 (1H, br-s).

Example 141 Synthesis of 1- (3-dimethylaminopropyl) -4-trifluoromethyl-2-indoloylguanidine dihydrochloride (1) Ethyl 1- (3-dimethylaminopropyl)-
Synthesis of 4-trifluoromethyl-2-indolecarboxylate Ethyl 4-trifluoromethyl-2-indolecarboxylate (2.07 g, 4.84 mmol), 60% sodium hydride (0.43 g, 10.7 mmol), 3-chloropropyl Ethyl 1- (3-dimethylaminopropyl) -4-trifluoro was obtained by using dimethylamine / hydrochloride (1.15 g, 7.26 mmol) and dimethylformamide (80 ml) according to the method of Reference Example 5. Methyl-2-indolecarboxylate (1.77 g, 74%) was obtained. (2) Synthesis of 1- (3-dimethylaminopropyl) -4-trifluoromethyl-2-indoloylguanidine dihydrochloride Ethyl 1- (3-dimethylaminopropyl) -4-trifluoromethyl-2-indole Carboxylate (1.77 g, 3.45 mmol), guanidine hydrochloride (3.30 g,
34.5 mmol) and sodium methoxide (1.87 g, 34.5
(1 mmol) in a methanol solution (100 ml) according to the method of Example 1, 1- (3-dimethylaminopropyl) -4-trifluoromethyl-2-indoloylguanidine dihydrochloride (0.42 g, 28%). mp 252-255 ℃ ¹ Hnmr (DMSO-d ₆ ) δ; 2.07-2.30 (2H, m)
, 2.58-2.60 (6H, m), 3.00-3.19 (2H, m), 4.59-4.81 (2
H, m), 7.49-8.67 (2H, m), 8.04-8.26 (2H, m), 8.71 (2
H, br-s), 8.79 (2H, br-s), 10.69 (1H, br-s), 12.29 (1
H, br-s) By carrying out the reaction according to the method of Example 141,
The following compounds of Examples 142-147 were synthesized.

Example 142 1- (3-Dimethylaminopropyl) -2-indoloylguanidine dihydrochloride Yield 12.3% mp 240 ° C. ¹ Hnmr (DMSO-d ₆ ).
δ; 2.04-2.27 (2H, m), 2.60-2.78 (6H, m), 2.98-3.17
(2H, m), 4.51-4.72 (2H, m), 7.12-7.28 (1H, m), 7.37-
7.49 (1H, m), 7.75 (1H, d, J = 8.3Hz), 8.07 (1H, s), 8.60
(2H, br-s), 8.81 (2H, br-s), 10.50 (1H, br-s), 12.15
(1H, br-s) Example 143 4-chloro-1- (3-dimethylaminopropyl) -2
-Indoylguanidine dihydrochloride Yield 47.6% mp 237-240 ℃ ¹ Hnmr (DMSO-d ₆ ).
δ; 2.07-2.27 (2H, m), 2.70 (6H, d, J = 1.3Hz), 3.02-3.14
(2H, m), 4.55-4.72 (2H, m), 7.30 (1H, d, J = 7.3Hz), 7.3
8-7.48 (1H, m), 7.77 (1H, d, J = 8.6Hz), 8.06 (1H, s), 8.6
1 (2H, br-s), 8.68 (2H, br-s), 10.36 (1H, br-s), 12.11
(1H, br-s)

Example 144 1- [2- (N-pyrrolidinyl) ethyl] -2-indoloylguanidine dihydrochloride Yield 23.8% mp 236-239 ° C. ¹ Hnmr (DMSO-d ₆ ).
δ; 1.75-2.11 (4H, m), 2.88-3.13 (2H, m), 3.40-3.68 (4
H, m), 4.85-5.04 (2H, m), 7.16-7.29 (1H, m), 7.40-7.5
4 (1H, m), 7.78 (1H, d, J = 7.9Hz), 7.87 (1H, d, J = 8.3Hz),
8.10 (1H, s), 8.62 (2H, br-s), 8.81 (2H, br-s), 11.17
(1H, br-s), 12.24 (1H, br-s) Example 145 4-chloro-1- [2- (N-pyrrolidinyl) ethyl]
-2-Indoloylguanidine dihydrochloride Yield 6.1% mp 220 ° C ¹ Hnmr (DMSO-d ₆ ) δ;
1.72-2.10 (4H, m), 2.83-3.13 (2H, m), 3.41-3.69 (4H, m
m), 4.86-5.05 (2H, m), 7.32 (1H, d, J = 7.7Hz), 7.45 (1
H, dd, J = 8.3, 7.7Hz), 7.89 (1H, d, J = 8.3Hz), 8.14 (1H, br
-s), 8.67 (2H, br-s), 8.74 (2H, br-s), 11.35 (1H, br-
s), 12.28 (1H, br-s) Example 146 1- (3-diethylaminopropyl) -4-trifluoromethyl-2-indoloylguanidine dihydrochloride Yield 30.8% mp 222-225 ° C ¹ Hnmr ( DMSO-d ₆ )
δ; 1.18 (6H, t, J = 6.9Hz), 2.08-2.30 (2H, m), 2.92-3.2
0 (6H, m), 4.57-4.80 (2H, m), 7.50-7.65 (2H, m), 8.07
-8.24 (2H, m), 8.66 (2H, br-s), 8.78 (2H, br-s), 10.5
8 (1H, br-s), 12.30 (1H, br-s)

Example 147 1- [2- (N-morpholinyl) ethyl] -2-indoloylguanidine dihydrochloride Yield 20.5% mp 180 ° C. ¹ Hnmr (DMSO-d ₆ ) δ;
3.00-3.27 (2H, m), 3.27-3.70 (4H, m), 3.70-4.10 (4H, m
m), 4.88-5.14 (2H, m), 7.15-7.30 (1H, m), 7.39-7.52
(1H, m), 7.78 (1H, d, J = 7.9Hz), 7.90 (1H, d, J = 8.9Hz),
8.10 (1H, s), 8.65 (2H, br-s), 8.81 (2H, br-s), 11.85
(1H, br-s), 12.26 (1H, br-s)

Example 148 Synthesis of 6- (3-aminopropoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine dihydrochloride a) Ethyl 6-benzyloxy-1-methyl-4- Synthesis of trifluoromethyl-2-indolecarboxylate Ethyl 6-benzyloxy-4-trifluoromethyl-2-indolecarboxylate (2.20 g, 6.06 mmol),
Using 60% sodium hydride (0.24 g, 6.06 mmol), methyl iodide (1.72 g, 12.1 mmol) and dimethylformamide (50 ml), the reaction was carried out according to the method of Reference Example 5, ethyl 6-benzyloxy. -1-Methyl-4-trifluoromethyl-2-indolecarboxylate (2.25 g) was obtained. b) Synthesis of ethyl 6-hydroxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate Ethyl 6-benzyloxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate (2.23
g, 5.91 mmol), 10% palladium / carbon (0.3 g) and tetrahydrofuran (50 ml) were reacted according to the method of Reference example 15, a) to obtain ethyl 6-hydroxy-1-methyl-4-tri Fluoromethyl-2-indole caboxylate (1.70 g) was obtained. c) Synthesis of ethyl 6- (3-tert-butoxycarbonylaminopropoxy) -1-methyl-4-trifluoromethyl-2-indolecarboxylate Ethyl 6-hydroxy-1-methyl-4-trifluoromethyl-2- Indole carboxylate (1.00g, 3.4
8 mmol), 60% sodium hydride (0.14 g, 3.48 mmol), te
rt-Butyl N- (3-iodopropyl) carbamate
(0.99 g, 3.48 mmol) and dimethylformamide (40 ml) were reacted according to the method of Reference Example 5 to obtain ethyl 6
-(3-tert-butoxycarbonylaminopropoxy)
-1-Methyl-4-trifluoromethyl-2-indolecarboxylate (1.28 g) was obtained.

D) 6- (3-aminopropoxy) -1-
Synthesis of methyl-4-trifluoromethyl-2-indoloylguanidine dihydrochloride Ethyl 6- (3-tert-butoxycarbonylaminopropoxy) -1-methyl-4-trifluoromethyl-2
-Indole carboxylate (1.28 g, 2.88 mmol), guanidine hydrochloride (5.50 g, 57.6 mmol) and sodium methoxide (3.11 g, 57.6 mmol) in methanol (60 ml) according to the method of Example 1 6- (3-tert-butoxycarbonylaminopropoxy) -1-methyl-4-
Trifluoromethyl-2-indoloylguanidine (0.4
1g) was obtained. This compound (0.41 g) was reacted according to the method of Example 114 to give 6- (3-aminopropoxy) -1-methyl-4-trifluoromethyl-2.
-Indoylguanidine dihydrochloride (0.27g, 21.8%)
I got mp 272-274 ℃, ¹ Hnmr (DMSO-d ₆ ) δ; 2.08〜2.13 (2
H, m), 2.99 to 3.01 (2H, m), 4.05 (3H, s), 4.24 to 4.28 (2H.
m), 7.21 (1H, s), 7.48 (1H, s), 7.97 (1H, s), 8.07 (3H, br
-s), 8.56 to 8.70 (4H, m), 12.06 (1H, br-s). By carrying out the reaction according to the method of Example 148,
The following compound of Example 149 was synthesized. Example 149 6- (3-aminopropoxy) -1,4-dimethyl-2-
Indoloylguanidine dihydrochloride mp 265-267 ℃, ¹ Hnmr (DMSO-d ₆ ) δ; 2.04 to 2.09 (2
H, m), 2.46 (3H, s), 2.96 to 2.99 (2H, m), 3.98 (3H, s), 4.
13 ~ 4.18 (2H.m), 6.65 (1H, s), 6.91 (1H, s), 8.00 ~ 8.04
(4H, m), 8.44 (2H, br-s), 8.73 (2H, br-s), 11.92 (1H, b
rs).

Example 150 6- (3-Dimethylaminopropoxy) -1-methyl-
Synthesis of 4-trifluoromethyl-2-indoloylguanidine dihydrochloride a) Ethyl 6- (3-dimethylaminopropoxy)-
Synthesis of 1-methyl-4-trifluoromethyl-2-indolecarboxylate Ethyl 6-hydroxy-obtained in Example 148 b)
1-Methyl-4-trifluoromethyl-2-indolecarboxylate (1.00 g, 3.48 mmol), 60% sodium hydride (0.35 g, 8.70 mmol), 3-chloropropyldimethylamine hydrochloride (0.82 g, 5.22) mmol) and dimethylformamide (40 ml) according to the method of Reference Example 4 to give ethyl 6- (3-dimethylaminopropoxy) -1-methyl-4-trifluoromethyl-2-.
Indole carboxylate (0.72 g) was obtained. b) Synthesis of 6- (3-dimethylaminopropoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine dihydrochloride Ethyl 6- (3-dimethylaminopropoxy) -1-
Methyl-4-trifluoromethyl-2-indole caboxylate (0.72 g, 1.93 mmol), guanidine hydrochloride (3.6
9g, 38.7mmol) and sodium methoxide (2.09g, 38.7mmo
l) in methanol solution (50 ml) was reacted according to the method of Example 1 to give 6- (3-dimethylaminopropoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine.2. The hydrochloride salt (0.31 g, 35.0%) was obtained. mp 264-265 ℃, ¹ Hnmr (DMSO-d ₆ ) δ; 2.17〜2.23 (2
H, m), 2.80 (6H, s), 3.2 to 3.4 (2H, m), 4.06 (3H, s), 4.2
3 to 4.27 (2H.m), 7.20 (1H, s), 7.50 (1H, s), 7.88 (1H, s)
s), 8.5 to 8.7 (4H, m), 10.27 (1H, br-s), 11.90 (1H, br-
s).

The compound of the following Example 151 was synthesized by performing the reaction according to the method of Example 150. Example 151 1,4-Dimethyl-6- (3-dimethylaminopropoxy) -2-indoloylguanidine dihydrochloride mp 282-284 ° C., ¹ Hnmr (DMSO-d ₆ ) δ; 2.14 to 2.20 (2
H, m), 2.46 (3H, s), 2.79 ~ 2.80 (6H, m), 3.1 ~ 3.3 (2H.
m), 3.98 (3H, s), 4.13 to 4.17 (2H, m), 6.66 (1H, s), 6.9
3 (1H, s), 7.99 (1H, s), 8.42-8.74 (4H, m), 10.26 (1H, br
-s), 11.85 (1H, br-s).

Example 152 7-[(3-aminopropyl) amino] -1-methyl-
Synthesis of 2-indoloylguanidine dihydrochloride a) Ethyl 7-[(3-aminopropyl) amino]-
Synthesis of 1-methyl-2-indolecarboxylate Ethyl 7-amino-1-methyl-2-indolecarboxylate (4.00 g, 18.3 mmol), 3- (benzyloxycarbonylamino) propionaldehyde (7.60
g, 36.7 mmol), sodium cyanoborohydride (2.43
g, 38.6 mmol), acetic acid (2.1 ml), molecular sieves (3A, 5.0 g) and methanol (200 ml) were stirred at room temperature for 4.5 hours. 28% ammonia water was added to the reaction solution to make it alkaline, which was then extracted with ethyl acetate (three times). The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was suspended in ethanol (100 ml), and ammonium formate (6.40 g, 101 mmol) and 10
% Palladium / carbon (0.91 g) was added, and the mixture was heated under reflux for 8 hours. The insoluble material was filtered off, the obtained filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography to obtain ethyl 7-[(3-
Aminopropyl) amino] -1-methyl-2-indolecarboxylate (1.04 g, 24.6%) was obtained.

B) Ethyl 7-[(3-tert-butoxycarbonylaminopropyl) amino] -1-methyl-2
-Synthesis of indolecarboxylate Ethyl 7-[(3-aminopropyl) amino] -1-
Methyl-2-indolecarboxylate (0.20 g, 0.
71 mmol), di-tert-butyl dicarbonate (0.17 g,
A mixture of 0.79 mmol) and dichloromethane (3 ml) was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography to give ethyl 7-[(3-tert-butoxycarbonylaminopropyl) amino] -1-methyl-2-.
Indole carboxylate (0.25 g, 91.6%) was obtained.

C) Synthesis of 7-[(3-tert-butoxycarbonylaminopropyl) amino] -1-methyl-2-indolecarboxylic acid Ethyl 7-[(3-tert-butoxycarbonylaminopropyl) amino] -1 A mixture of -methyl-2-indolecarboxylate (0.12 g, 0.31 mmol), 5N aqueous potassium hydroxide solution (2 ml) and ethanol (5 ml) was stirred at room temperature for 2.5 hours. The pH of the reaction solution was adjusted to 6 by adding 2N hydrochloric acid, and the reaction solution was concentrated under reduced pressure. The resulting residue was extracted with chloroform (3 times), the extract was dried over anhydrous sodium sulfate, and the solvent was depressurized. The residue obtained by evaporation was separated and purified by silica gel column chromatography to give 7-[(3-tert-butoxycarbonylaminopropyl) amino] -1-methyl-2-indolecarboxylic acid (0.079 g, 72.4%).

D) Synthesis of 7-[(3-tert-butoxycarbonylaminopropyl) amino] -1-methyl-2-indoloylguanidine 7-[(3-tert-butoxycarbonylaminopropyl) amino] -1- Methyl-2-indolecarboxylic acid
(0.068g, 0.18mmol) and carbonyldiimidazole
A solution of (0.088g, 0.54mmol) in tetrahydrofuran (5ml) was stirred at room temperature for 2 hours and then at 45-50 ° C for 1 hour. After returning this to room temperature, guanidine hydrochloride (0.10
g, 1.08mmol) and triethylamine (0.16ml, 1.15mm
ol) in dimethylformamide (5 ml) was added, and the mixture was stirred at room temperature for 7 hours. The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography to give 7-[(3-tert-butoxycarbonylaminopropyl) amino] -1-methyl-2-indoloylguanidine ( 0.043 g, 61.2%) was obtained.

E) Synthesis of 7-[(3-aminopropyl) amino] -1-methyl-2-indoloylguanididihydrochloride 7-[(3-tert-butoxycarbonylaminopropyl) amino]- 1-Methyl-2-indoloylguanidine (0.04 g, 0.10 mmol) was dissolved in hydrochloric acid / methanol (2 ml), and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, 2N aqueous sodium hydroxide solution was added to the obtained residue, followed by extraction with chloroform (three times), the extract was dried over anhydrous potassium carbonate, and the solvent was distilled off under reduced pressure. By separating and purifying the obtained residue by silica gel column chromatography, 7-[(3-aminopropyl) amino] -1-methyl-2-indoloylguanidine (0.023
g, 80.0%) was obtained. This was subjected to hydrochloric acid salification with hydrochloric acid / methanol and then recrystallized from methanol to give 7-
[(3-Aminopropyl) amino] -1-methyl-2-
Indroylguanidine dihydrochloride was obtained. mp 282-284 ° C. (decomposition) ¹ Hnmr (DMSO-d ₆ ) δ; 1.96 (2H, m), 2.96 (2H, m), 3.18
(2H, m), 4.27 (3H, s), 6.59 (1H, d, J = 6.9Hz), 6.96 ~ 7.09
(2H, m), 7.72 (1H, s), 8.49 (2H, m), 8.69 (2H, m)

By reacting according to the method of Example 150, the compounds of the following Examples 153-169 were synthesized. Example 153 1,4-Dimethyl-7- (3-dimethylaminopropoxy) -2-indoloylguanidine dihydrochloride mp 276-278 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 2.20-2.26 (2H, m ), 2.42 (3H,
s), 2.80 (6H, d, J = 4.62Hz), 3.21 to 3.29 (2H, m), 4.13 to
4.18 (2H, m), 4.28 (3H, s), 6.75 ~ 6.89 (2H, m), 7.87 (1H,
s), 8.46 (2H, brs), 8.64 (2H, br-s), 10.24 (1H, br-s),
11.88 (1H, s) Example 154 7- (3-Diethylaminopropoxy) -1,4-dimethyl-2-indoloylguanidine dihydrochloride mp 235-236 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 1.24 ( 6H, t, J = 7.26Hz), 2.20 ~
2.30 (2H, m), 2.41 (3H, s), 3.14 to 3.28 (6H, m), 4.17 (2H, m)
t, J = 5.94Hz), 4.29 (3H, s), 6.80 (2H, dd, J = 7.92,18.2H
z), 7.91 (1H, s), 8.49 (2H, br-s), 8.69 (2H, br-s), 1
0.27 (1H, br-s), 11.94 (1H, br-s)

Example 155 1,4-Dimethyl-7- [2- (N-pyrrolidinyl) ethoxy] -2-indoloylguanidine dihydrochloride mp 287-288 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 1.91 ~ 2.04 (4H, m), 2.42 (3H,
s), 3.10 to 3.20 (2H, m), 3.62 to 3.70 (4H, m), 4.29 (3H, m)
s), 4.46 (2H, t, J = 4.95Hz), 6.85 (2H, s), 7.94 (1H, s),
8.50 (2H, br-s), 8.70 (2H, br-s), 10.81 (1H, br-s), 1
1.97 (1H, br-s) Example 156 1,4-Dimethyl-7- (2-dimethylaminoethoxy) -2-indoloylguanidine dihydrochloride mp 245 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 2.42 (3H, s), 2.88 (6H, s), 3.60
~ 3.70 (2H, m), 4.28 (3H, s), 4.45 ~ 4.48 (2H, m), 6.84 (2
H, s), 7.93 (1H, s), 8.49 (2H, br-s), 8.70 (2H, br-s),
10.51 (1H, br-s), 11.98 (1H, br-s)

Example 157 6- (3-dimethylaminopropoxy) -4-methoxy-1-methyl-2-indoloylguanidine dihydrochloride mp 225 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 2.10-2.28 ( 2H, m), 2.80 (6H,
s), 3.12 to 3.37 (2H, m), 3.89 (3H, s), 3.95 (3H, s), 4.16
(1H, t, J = 5.9Hz), 6.27 (1H, d, J = 1.7Hz), 6.67 ~ 6.73 (1H,
m), 7.77 (1H, br-s), 8.36 (2H, br-s), 8.50 (2H, br-s)
, 10.10 to 10.28 (1H, m), 11.57 (1H, br-s) Example 158 6- (3-Dimethylaminopropoxy) -4-isopropoxy-1-methyl-2-indoloylguanidine-2
Hydrochloride mp 255 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 1.33 (6H, d, J = 5.9Hz), 2.10 to 2.2
8 (2H, m), 2.78 (6H, d, J = 4.0Hz), 3.14 to 3.30 (2H, m), 3.9
4 (3H, s), 4.15 (2H, t, J = 5.9Hz), 4.76 (1H, sept, J = 5.9Hz)
, 6.28 (1H, d, J = 1.1Hz), 6.68 (1H, d, J = 1.1Hz), 7.70 (1
H, s), 8.48 (4H, br-s), 10.44 ~ 10.65 (1H, m), 11.46
(1H, br-s)

Example 159 7- (3-Dimethylaminopropoxy) -4-methoxy-1-methyl-2-indoloylguanidine dihydrochloride mp 243 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 2.13 to 2.31 ( 2H, m), 2.79 (6H, d, J
= 4.6Hz), 3.13 to 3.38 (2H, m), 3.85 (3H, s), 4.13 (2H, t, J
= 5.9Hz), 4.26 (3H, s), 6.46 (1H, d, J = 8.2Hz), 6.79 (1H,
d, J = 8.2Hz), 7.75 (1H, s), 8.51 (2H, br-s), 8.56 (2H, br
-s), 10.33 to 10.55 (1H, m), 11.73 (1H, br-s) Example 160 7- (2-Dimethylaminoethoxy) -1-methyl-4
-Trifluoromethyl-2-indoloylguanidine
Dihydrochloride mp 278-280 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 2.88 (6H, s), 3.67 (2H, br-s),
4.32 (3H, s), 4.59 to 4.63 (2H, m), 7.04 (1H, d, J = 7.92Hz)
, 7.49 (1H, d, J = 8.25Hz), 7.79 (1H, d, J = 1.65Hz), 8.60
(4H, br-s), 10.71 (1H, br-s), 12.00 (1H, br-s)

Example 161 6- (2-Dimethylaminoethoxy) -1-methyl-4
-Trifluoromethyl-2-indoloylguanidine
Dihydrochloride mp 286-288 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 2.86 (6H, s), 3.58 (2H, m), 4.07
(3H, s), 4.58 (2H, t, J = 5.3Hz), 7.28 (1H, d, J = 1.0Hz), 7.
60 (1H, s), 8.07 (1H, d, J = 1.0Hz), 8.70-8.81 (4H, m), 1
0.95 (1H, br-s), 12.20 (1H, br-s) Example 162 6- (2-diethylaminoethoxy) -1-methyl-4
-Trifluoromethyl-2-indoloylguanidine
Dihydrochloride mp 287-289 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 1.29 (6H, t, J = 7.5Hz), 3.24 (4H, 4H,
m), 3.56 (2H, m), 4.07 (3H, s), 4.58 (2H, t, J = 4.8Hz), 7.
25 (1H, s), 7.59 (1H, s), 8.03 (1H, s), 8.63-8.76 (4H, s)
m), 10.73 (1H, br-s), 12.16 (1H, br-s)

Example 163 4-chloro-6- (2-dimethylaminoethoxy) -1
-Methyl-2-indoloylguanidine dihydrochloride mp 261-262 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 2.86 (6H, s), 3.48-3.59 (2H,
m), 4.02 (3H, s), 4.45 ~ 4.49 (2H, m), 7.04 (1H, d, J = 1.98
Hz), 7.26 (1H, s), 7.82 (1H, s), 8.39-8.63 (4H, br-s)
, 10.14 to 10.32 (1H, m), 11.82 (1H, br-s) Example 164 4-chloro-6- (3-dimethylaminopropoxy)-
1-methyl-2-indoloylguanidine dihydrochloride mp 277-278 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 2.16-2.21 (2H, m), 2.79 (6H,
s), 3.23 to 3.26 (2H, m), 4.00 (3H, s), 4.19 (2H, t, J = 5.94
Hz), 6.97 (1H, d, J = 1.98Hz), 7.17 (1H, s), 7.88 (1H,
s), 8.50 (2H, br-s), 8.63 (2H, br-s), 10.36 (1H, br-
s), 11.92 (1H, br-s)

Example 165 4-chloro-6- (2-diethylaminoethoxy) -1
-Methyl-2-indoloylguanidine dihydrochloride mp 268 to 270 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 1.24 to 1.30 (6H, m), 3.20 to 3.26
(4H, m), 3.45 ~ 3.55 (2H, m), 4.02 (3H, s), 4.48 ~ 4.51 (2
H, m), 7.04 (1H, d, J = 1.98Hz), 7.25 (1H, br-s), 7.90 (1
H, s), 8.50 (2H, br-s), 8.63 (2H, br-s), 10.27 (1H, br-
s), 11.93 (1H, br-s) Example 166 4-chloro-1-methyl-6- [2- (N-pyrrolidinyl) ethoxy] -2-indoloylguanidine dihydrochloride mp 272-274 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 1.91 (2H, br-s), 2.03 (2H, br-s)
, 3.12 to 3.26 (2H, m), 3.62 (4H, br-s), 4.02 (3H, s),
4.45 ~ 4.49 (2H, m), 7.56 (1H, d, J = 1.98Hz), 7.25 (1H, br
-s), 7.85 (1H, s), 8.50 (2H, br-s), 8.58 (2H, br-s),
10.60 (1H, br-s), 11.86 (1H, br-s)

Example 167 4-chloro-7- (3-diethylaminopropoxy)-
1-methyl-2-indoloylguanidine dihydrochloride mp 254-255 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 1.24 (6H, t, J = 7.26Hz), 2.20〜
2.40 (2H, m), 3.11 to 3.28 (6H, m), 4.19 to 4.24 (2H, m), 4.
29 (3H, s), 6.87 (1H, d, J = 8.58Hz), 7.14 (1H, d, J = 8.25H
z), 7.75 (1H, s), 8.56 (4H, br-s), 10.26 (1H, br-s), 1
1.90 (1H, br-s) Example 168 1-Methyl-6- [2- (N-pyrrolidinyl) ethoxy] -4-trifluoromethyl-2-indoloylguanidine dihydrochloride mp 320 ° C. ¹ Hnmr (DMSO -d ₆ ) δ; 1.94 to 2.03 (4H, m), 3.15 (2H,
m), 3.64 (4H, m), 4.07 (3H, s), 4.56 (1H, m), 7.27 (1H,
s), 7.59 (1H, s), 8.05 (1H, s), 8.68 to 8.79 (4H, m), 11.2
1 (1H, br-s), 12.16 (1H, br-s) Example 169 7- (3-Dimethylaminopropoxy) -1-methyl-
4-Trifluoromethyl-2-indoloylguanidine dihydrochloride mp 250 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 2.2 to 2.4 (2H, m), 2.79 (6H, d, J
= 4.62Hz), 3.1 to 3.3 (2H, m), 4.28 to 4.32 (5H, m), 6.9
7 (1H, d, J = 8.25Hz), 7.47 (1H, d, J = 8.25Hz), 7.78 (1H,
d, J = 1.32Hz), 8.61 (4H, br-s), 10.63 (1H, br-s), 12.0
0 (1H, br-s)

The compounds of Examples 170 to 178 below were synthesized by carrying out the reaction according to the method of Example 148. Example 170 6- (3-aminopropoxy) -4-methoxy-1-methyl-2-indoloylguanidine dihydrochloride mp 245 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 2.00 to 2.15 (2H, m) , 2.90 ~ 3.07
(2H, m), 3.89 (3H, s), 3.95 (3H, s), 4.17 (2H, t, J = 6.3H
z), 6.30 (1H, d, J = 1.3Hz), 6.65 ~ 6.73 (1H, m), 7.83 (1H,
s), 7.98 (3H, br-s), 8.42 (2H, br-s), 8.60 (2H, br-s)
, 11.68 (1H, br-s) Example 171 6- (3-aminopropoxy) -4-isopropoxy-
1-Methyl-2-indoloylguanidine dihydrochloride mp 230 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 1.33 (6H, d, J = 5.9Hz), 2.00-2.1
3 (2H, m), 2.90 to 3.07 (2H, m), 3.94 (3H, s), 4.15 (2H, t, J
= 5.9Hz), 4.77 (1H, sept, J = 5.9Hz), 6.30 (1H, d, J = 1.3H)
z), 6.63 to 6.70 (1H, m), 7.65 (1H, s), 7.98 (3H, br-s),
8.42 (4H, br-s), 11.37 (1H, br-s)

Example 172 7- (3-aminopropoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine dihydrochloride mp 284-286 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 2.16 ~ 2.18 (2H, m), 3.02 ~ 3.04
(2H, m), 4.28 to 4.31 (5H, m), 6.97 (1H, d, J = 8.92Hz), 7.
48 (1H, d, J = 8.25Hz), 7.81 (1H, s), 8.07 (3H, br-s), 8.
63 (4H, br-s), 12.03 (1H, br-s) Example 173 7- (2-aminoethoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine dihydrochloride mp 291 ~ 292 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 3.2 ~ 3.5 (2H, m), 4.32 (3H,
s), 4.44 (2H, t, J = 4.95Hz), 7.01 (1H, d, J = 8.25Hz), 7.4
7 (1H, d, J = 8.25Hz), 7.79 (1H, s), 8.30 (3H, br-s), 8.62
(4H, br-s), 12.02 (1H, br-s)

Example 174 7- (2-aminoethoxy) -1,4-dimethyl-2-
Indoylguanidine dihydrochloride mp 305-306 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 2.49 (3H, s), 3.3-3.5 (2H, m)
, 4.29 (5H, m), 6.81 ~ 6.83 (2H, m), 7.89 (1H, s), 8.19
(3H, br-s), 8.50 (2H, br-s), 8.67 (2H, br-s), 11.92
(1H, br-s) Example 175 6- (2-aminoethoxy) -4-chloro-1-methyl-2-indoloylguanidine dihydrochloride mp 308-309 ° C. ¹ Hnmr (DMSO-d ₆ ) δ ; 3.1 to 3.3 (2H, m), 4.02 (3H, m
s), 4.32 (2H, t, J = 4.95Hz), 7.00 (1H, d, J = 1.65Hz), 7.2
3 (1H, br-s), 7.90 (1H, s), 8.19 (3H, br-s), 8.51 (2H, b
rs), 8.65 (2H, br-s), 11.95 (1H, br-s)

Example 176 7- (3-aminopropoxy) -4-isopropoxy-
1-Methyl-2-indoloylguanidine dihydrochloride mp 220 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 1.31 (6H, d, J = 6.3Hz), 2.00-2.2
0 (2H, m), 2.90 to 3.10 (2H, m), 4.13 (2H, t, J = 5.9Hz), 4.2
4 (1H, s), 4.67 (1H, sept, J = 6.3Hz), 6.50 (1H, d, J = 8.6H
z), 6.77 (1H, d, J = 8.6Hz), 7.55 to 7.64 (1H, m), 7.83 to 8.
08 (3H, m), 8.32-8.56 (4H, m), 11.64 (1H, br-s) Example 177 6- (2-aminoethoxy) -1-methyl-4-trifluoromethyl-2-indoloyl Guanidine dihydrochloride mp 289 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 3.2 to 3.3 (2H, m), 4.07 (3H,
s), 4.36 to 4.40 (2H, m), 7.23 (1H, s), 7.55 (1H, s), 7.99
(1H, s), 8.30 (3H, br-s), 8.57 ~ 8.72 (4H, m), 12.10 (1
H, br-s)

Example 178 7- (3-aminopropoxy) -1,4-dimethyl-2
-Indoylguanidine dihydrochloride mp 318 to 320 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 2.09 to 2.18 (2H, m), 2.41 (3H,
s), 3.00 (2H, t, J = 6.93Hz), 4.16 (2H, t, J = 5.94Hz), 4.2
8 (3H, s), 6.75 ~ 6.87 (2H, m), 7.95 (1H, s), 8.01 ~ 8.05
(3H, br-s), 8.51 (2H, br-s), 8.72 (2H, br-s), 11.98
(1H, br-s) By reacting according to the method of Example 141, the compounds of the following Examples 179 to 180 were synthesized. Example 179 1- [3- (N-pyrrolidinyl) propyl] -4-trifluoromethyl-2-indoloylguanidine dihydrochloride mp 180 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 1.74 to 2.07 (4H, m), 2.08 to 2.32
(2H, m), 2.82 ~ 3.03 (2H, m), 3.08 ~ 3.25 (2H, m), 3.42 ~
3.61 (2H, m), 4.72 (2H, t, J = 5.3Hz), 7.51 to 7.66 (2H, m),
8.04 ~ 8.13 (2H, m), 8.68 (2H, br-s), 8.75 (2H, br-s),
10.90 (1H, br-s), 12.23 (1H, br-s)

Example 180 1- (3-Dimethylaminopropyl) -4-fluoro-
2-Indoylguanidine dihydrochloride mp 259-261 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 2.14-2.25 (2H, m), 2.72 (6H,
s), 3.10 to 3.12 (2H, m), 4.61 to 4.66 (2H, m), 7.00 (1H, d
d, J = 7.59, 10.23Hz), 7.38 to 7.46 (1H, m), 7.61 (1H, d, J
= 8.58Hz), 8.11 (1H, s), 8.58 (2H, br-s), 8.73 (2H, br-
s), 10.34 (1H, br-s), 12.17 (1H, br-s)

By reacting according to the method of Example 114, the compound of the following Example 181 was synthesized. Example 181 1- (3-aminopropyl) -4-fluoro-2-indoloylguanidine dihydrochloride mp 277-278 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 2.04-2.09 (2H, m), 2.74 ~ 2.80
(2H, m), 4.63 ~ 4.68 (2H, m), 6.96 ~ 7.03 (1H, m), 7.38 ~
7.46 (1H, m), 7.63 (1H, d, J = 8.25Hz), 7.98 (3H, br-s),
8.15 (1H, s), 8.63 (2H, br-s), 8.79 (2H, br-s), 12.25
(1H, br-s)

The compounds of Examples 182 to 183 below were synthesized by carrying out the reaction according to the method of Example 1. Example 182 6-benzyloxy-1-methyl-4-trifluoromethyl-2-indoloylguanidine hydrochloride mp 253 to 255 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 4.05 (3H, s), 5.27 ( 2H, s), 7.26
(1H, s), 7.35 ~ 7.59 (6H, m), 7.80 (1H, s), 8.49 (4H, br-
s), 11.74 (1H, br-s) Example 183 7-benzyloxy-1-methyl-4-trifluoromethyl-2-indoloylguanidine hydrochloride, mp 255-257 ° C. ¹ Hnmr (DMSO-d ₆ ). δ; 4.30 (3H, s), 5.36 (2H, s), 7.10
(1H, d, J = 8.25Hz), 7.37 to 7.57 (6H, m), 7.74 (1H, s), 8.
54 (4H, br-s), 11.87 (2H, br-s)

By reacting according to the method of Example 91, the compounds of the following Examples 184-185 were synthesized. Example 184 6-Hydroxy-1-methyl-4-trifluoromethyl-2-indoloylguanidine hydrochloride mp 268 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 3.96 (3H, s), 7.12 (1H, s) ), 7.16
(1H, s), 7.74 (1H, s), 8.46 (4H, br-s), 10.33 (1H, s),
11.64 (1H, br-s) Example 185 1,4-Dimethyl-7-hydroxy-2-indoloylguanidine hydrochloride mp 267 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 2.37 (3H, s), 4.29 (3H, s), 6.61
(1H, d, J = 7.58Hz), 6.69 (1H, d, J = 7.59Hz), 7.77 (1H,
s), 8.44 (2H, br-s), 8.58 (2H, br-s), 9.84 (1H, s), 1
1.72 (1H, br-s)

Example 186 Synthesis of 6- (2-aminophenoxy) -4-chloro-1-methyl-2-indoloylguanidine.hydrochloride salt a) Ethyl 4-chloro-1-methyl-6- (2-nitro) Synthesis of phenoxy) -2-indolecarboxylate Ethyl 4-chloro-6-hydroxy-1-methyl-2
-Indole carboxylate (0.42g, 1.64mmol) was added to a suspension of 60% sodium hydride (0.066g, 1.64mmol) and dimethylformamide (5ml) and stirred at room temperature to give a nearly clear solution. Then at room temperature 1-fluoro-
2-Nitrobenzene (0.35 g, 2.49 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (three times), the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue, which was separated by silica gel column chromatography. By purification, ethyl 4-chloro-1-methyl-6- (2
-Nitrophenoxy) -2-indolecarboxylate (0.53 g, 94.3%) was obtained.

B) 4-chloro-1-methyl-6- (2-
Synthesis of (nitrophenoxy) -2-indoloylguanidine Guanidine hydrochloride (2.87 g, 3) in sodium methoxide (1.62 g, 30.0 mmol) in methanol (25 ml)
0.0 mmol) was added and the mixture was stirred at room temperature for 30 minutes, and then the precipitated salt was filtered off, and ethyl 4-chloro- was added to the resulting solution.
1-Methyl-6- (2-nitrophenoxy) -2-indolecarboxylate (0.51 g, 1.50 mmol) was added,
Subsequently, methanol was distilled off under reduced pressure. The residue obtained is 13
After heating at 0 ° C for 5 minutes and standing at room temperature for 1 hour, water was poured into the reaction solution, extracted with ethyl acetate (3 times), the extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent Was distilled off under reduced pressure, and the residue obtained was separated and purified by silica gel column chromatography to give 4-chloro-1.
-Methyl-6- (2-nitrophenoxy) -2-indoloylguanidine (0.23 g, 40.1%) was obtained.

C) 6- (2-aminophenoxy) -4-
Synthesis of chloro-1-methyl-2-indoloylguanidine hydrochloride 4-chloro-1-methyl-6- (2-nitrophenoxy) -2-indoloylguanidine (0.23 g, 0.60 mmo
l), tin (II) chloride dihydrate (0.72 g, 3.20 mmol)
A mixture of ethanol and ethanol (15 ml) was heated to reflux for 3 hours. After cooling the reaction solution, 28% aqueous ammonia was added, ethanol was distilled off under reduced pressure, the obtained residue was extracted with ethyl acetate (three times), and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After drying, the solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography to give 6- (2-aminophenoxy) -4.
-Chloro-1-methyl-2-indoloylguanidine (0.11 g, 51.6%) was obtained. This was subjected to hydrochloric acid salification with hydrogen chloride / methanol to obtain 6- (2-aminophenoxy) -4-chloro-1-methyl-2-indoloylguanidine hydrochloride (0.097 g). mp 302 ° C (decomposition) ¹ Hnmr (DMSO-d ₆ ) δ; 3.97 (3H, s), 7.04 (1H, d, J = 2.0H
z), 7.11 to 7.17 (2H, m), 7.32 to 7.35 (3H, m), 7.94 (1H, m)
s), 8.53 to 8.65 (4H, m)

Example 187 Synthesis of 7- (2-aminophenoxy) -1-methyl-2-indoloylguanidine-hydrochloride Performed using ethyl 7-hydroxy-1-methyl-2-indolecarboxylate as starting material. Reaction was carried out according to the method of Example 186 to give 7- (2-aminophenoxy)
-1-Methyl-2-indoloylguanidine hydrochloride was obtained. mp 255-257 ° C. (decomposition) ¹ Hnmr (DMSO-d ₆ ) δ; 4.21 (3H, s), 6.75-6.80 (2H,
m), 6.91 to 6.97 (1H, m), 7.05 to 7.12 (2H, m), 7.23 (1H, d,
J = 7.25Hz), 7.52 (1H, d, J = 7.25Hz), 7.85 (1H, s), 8.50
(2H, br-s), 8.67 (2H, br-s), 11.99 (1H, br-s)

Example 188 Synthesis of 7- (2-aminophenoxy) -4-chloro-1-methyl-2-indoloylguanidine hydrochloride salt Ethyl 4-chloro-7-hydroxy-1-methyl-2
-Using indolecarboxylate as a starting material, the reaction was carried out according to the method of Example 186 to obtain 7- (2-aminophenoxy) -4-chloro-1-methyl-2-indoloylguanidine hydrochloride. . mp 286 to 288 ° C. (decomposition) ¹ Hnmr (DMSO-d ₆ ) δ; 4.23 (3H, s), 6.73 (1H, d, J = 8.25H
z), 6.86 (1H, dd, J = 1.32, 7.92Hz), 6.95 ~ 7.01 (1H,
m), 7.08 to 7.14 (1H, m), 7.18 (1H, d, J = 8.25Hz), 7.25 to
7.28 (1H, m), 7.89 (1H, s), 8.59 (2H, br-s), 8.65 (2H, br
-s), 12.08 (1H, br-s)

Example 189 Synthesis of 7- (3-aminophenoxy) -4-chloro-1-methyl-2-indoloylguanidine-hydrochloride a) Ethyl 4-chloro-1-methyl-7- (3-nitro Synthesis of phenoxy) -2-indolecarboxylate Ethyl 4-chloro-7-hydroxy-1-methyl-2
-Indole carboxylate (0.50 g, 1.97 mmol) was added to a suspension of 60% sodium hydride (0.16 g, 3.94 mmol) and dimethylformamide (10 ml), and the mixture was stirred at room temperature for 30 minutes and then at room temperature for 1 minute. -Fluoro-3-nitrobenzene (0.28g, 1.97mmol) was added, followed by 150 ° C.
The mixture was heated and stirred for 3 hours. After cooling the reaction solution, it was poured into ice water, extracted with ethyl acetate (3 times), the extract solution was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. By separating and purifying by silica gel column chromatography, ethyl 4-chloro-1-methyl-7- (3-nitrophenoxy) -2-
Indole carboxylate (0.18 g, 24.3%) was obtained.

B) 4-chloro-1-methyl-7- (3-
Synthesis of nitrophenoxy) -2-indoloylguanidine Ethyl 4-chloro-1-methyl-7- (3-nitrophenoxy) -2-indolecarboxylate (0.17
g, 0.45mmol), guanidine hydrochloride (1.30g, 13.6mm
ol), sodium methoxide (0.74 g, 13.6 mmol) and methanol (30 ml) according to the method of Example 186 b) to give 4-chloro-1-methyl-7- (3- Nitrophenoxy) -2-indoloylguanidine (0.06 g, 34.3%) was obtained.

C) 7- (3-aminophenoxy) -4-
Synthesis of chloro-1-methyl-2-indoloylguanidine hydrochloride 4-chloro-1-methyl-7- (3-nitrophenoxy) -2-indoloylguanidine (0.055 g, 0.14 mmo
l), tin (II) chloride dihydrate (0.16g, 0.71mmol)
And ethanol (5 ml) and ethyl acetate (5 ml),
By performing the reaction according to the method of Example 186 c), 7- (3-aminophenoxy) -4-chloro-1-
Methyl-2-indoloylguanidine ・ hydrochloride (0.036
g, 59.0%) was obtained. mp 245 ° C. (decomposition) ¹ Hnmr (DMSO-d ₆ ) δ; 4.12 (3H, s), 6.27 to 6.59 (3H,
m), 6.93 (1H, d, J = 8.3Hz), 7.08-7.20 (1H, m), 7.23 (1H,
d, J = 8.3Hz), 7.71 (1H, s), 8.44 (4H, br-s), 11.75 (1H,
m)

Example 190 Synthesis of 6- (3-aminophenoxy) -4-chloro-1-methyl-2-indoloylguanidine hydrochloride salt Starting material was ethyl 6-hydroxy-1-methyl-2-indolecarboxylate. Was used according to the method of Example 189 to give 6- (3-aminophenoxy) -4-chloro-1-methyl-2-indoloylguanidine hydrochloride. mp 272 ° C. (decomposition) ¹ Hnmr (DMSO-d ₆ ) δ; 3.97 (3H, s), 6.62 (1H, s), 6.66
(1H, d, J = 7.92Hz), 6.76 (1H, d, J = 8.57Hz), 7.04 (1H, d,
J = 1.98Hz), 7.25 to 7.31 (1H, m), 7.37 (1H, s), 7.87 (1H, m)
s), 8.52 (4H, m), 11.88 (1H, br-s)

Example 191 Synthesis of 6- (4-aminophenoxy) -4-chloro-1-methyl-2-indoloylguanidine dihydrochloride a) Ethyl 4-chloro-1-methyl-6- (4- Synthesis of nitrophenoxy) -2-indolecarboxylate Ethyl 4-chloro-6-hydroxy-1-methyl-2
-Indole carboxylate (0.41 g, 1.62 mmol),
Example 186 using 60% sodium hydride (0.09g, 2.23mmol), 1-fluoro-4-nitrobenzene (0.34g, 2.40mmol) and dimethylformamide (5ml).
By performing the reaction according to the method in a), ethyl 4
-Chloro-1-methyl-6- (4-nitrophenoxy)
-2-Indole carboxylate (0.51g, 92.0%)
I got

B) 4-chloro-1-methyl-6- (4-
Synthesis of nitrophenoxy) -2-indoloylguanidine Ethyl 4-chloro-1-methyl-6- (4-nitrophenoxy) -2-indolecarboxylate (0.45
g, 1.32mmol), guanidine hydrochloride (2.52g, 26.4mm)
ol), sodium methoxide (1.42 g, 26.4 mmol) and methanol (25 ml) according to the method of Example 186 b) to give 4-chloro-1-methyl-6- (4- Nitrophenoxy) -2-indoloylguanidine (0.24 g, 47.0%) was obtained.

C) 6- (4-aminophenoxy) -4-
Chloro-1-methyl-2-indoloylguanidine-2
Synthesis of Hydrochloride 4-Chloro-1-methyl-6- (4-nitrophenoxy) -2-indoloylguanidine (0.24g, 0.62mmo
l), tin (II) chloride dihydrate (0.72g, 3.20mmol)
And ethanol (15 ml) according to the method of Example 186 c) to give 6- (4-aminophenoxy) -4-chloro-1-methyl-2-indoloylguanidine dihydrochloride. (0.089 g) was obtained. mp 265-267 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 3.97 (3H, s), 6.97 (1H, m), 7.06
~ 7.19 (3H, m), 7.36 (1H, m), 8.01 (1H, d, J = 0.7Hz), 8.59
~ 8.72 (4H, m), 12.13 (2H, br-s)

Example 192 Synthesis of 7- (4-aminophenoxy) -1-methyl-2-indoloylguanidine-hydrochloride Performed using ethyl 7-hydroxy-1-methyl-2-indolecarboxylate as starting material. The reaction was performed according to the method of Example 191 to obtain 7- (4-aminophenoxy) -1-methyl-2-indoloylguanidine · hydrochloride. mp 286 to 288 ° C. (decomposition) ¹ Hnmr (DMSO-d ₆ ) δ; 4.12 (3H, s), 6.89 to 6.92 (1H,
m), 7.07 to 7.17 (3H, m), 7.30 to 7.33 (2H, m), 7.56 to 7.59
(1H, m), 7.87 (1H, s), 8.50 (2H, br-s), 8.66 (2H, br-s)
, 9.50 ~ 10.20 (2H, m), 11.80 ~ 12.20 (1H, m)

Example 193 Synthesis of 7- (4-aminophenoxy) -4-chloro-1-methyl-2-indoloylguanidine hydrochloride salt Ethyl 4-chloro-7-hydroxy-1-methyl-2
-Using indolecarboxylate as a starting material and performing a reaction according to the method of Example 191, 7- (4-aminophenoxy) -4-chloro-1-methyl-2-indoloylguanidine hydrochloride was obtained. . mp 276 to 278 ° C. (decomposition) ¹ Hnmr (DMSO-d ₆ ) δ; 4.14 (3H, s), 6.87 (1H, d, J = 7.92H
z), 7.11 (2H, d, J = 8.91Hz), 7.21 (1H, d, J = 8.25Hz),
7.31 (2H, d, J = 8.91Hz), 7.88 (1H, s), 8.60 (4H, br-s),
9.40 to 10.00 (2H, m), 11.80 to 12.20 (1H, m)

Example 194 Synthesis of 7- (4-aminophenoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine hydrochloride salt Ethyl 7-hydroxy-1-methyl-4-trifluoromethyl- Using 2-indolecarboxylate as a starting material, the reaction was carried out according to the method of Example 191.
-(4-Aminophenoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine hydrochloride was obtained. mp 264 to 266 ° C. (decomposition) ¹ Hnmr (DMSO-d ₆ ) δ; 4.27 (3H, s), 6.81 (1H, d, J = 7.59H
z), 7.19 to 7.31 (4H, m), 7.49 (1H, d, J = 8.91Hz), 7.83
(1H, d, J = 1.64Hz), 8.56 (4H, br-s)

Example 195 7- (4-aminophenoxy) -1,4-dimethyl-2
-Synthesis of indoloylguanidine hydrochloride hydrochloride Example 19 using ethyl 1,4-dimethyl-7-hydroxy-2-indolecarboxylate as starting material
The reaction was performed according to the method of 1 to obtain 7- (4-aminophenoxy) -1,4-dimethyl-2-indoloylguanidine · hydrochloride. mp 285 ° C. (decomposition) ¹ Hnmr (DMSO-d ₆ ) δ; 4.08 (3H, s), 6.86 (1H, d, J = 7.59H
z), 6.95 (1H, d, J = 8.57Hz), 7.05 (2H, d, J = 8.91Hz),
7.33 (2H, d, J = 8.91Hz), 8.03 (1H, s), 8.50 (2H, br-s),
8.68 (2H, br-s), 10.0 (2H, br-s), 12.0 (1H, br-s)

Example 196 Synthesis of 6- [4- (aminomethyl) phenoxy] -4-chloro-1-methyl-2-indoloylguanidine dihydrochloride a) Ethyl 4-chloro-6- (4-formyl) Synthesis of phenoxy) -1-methyl-2-indolecarboxylate Ethyl 4-chloro-6-hydroxy-1-methyl-2
-Indole carboxylate (1.00 g, 3.94 mmol) was added to a suspension of 60% sodium hydride (0.16 g, 3.94 mmol) and dimethylformamide (30 ml) and stirred at room temperature to give a nearly transparent solution. After that, 4-fluorobenzaldehyde (0.54 g, 4.34 mmol) was added at room temperature, followed by stirring at 70 ° C. for 10 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (three times), the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue, which was separated by silica gel column chromatography. By purification, ethyl 4-chloro-6- (4
-Formylphenoxy) -1-methyl-2-indolecarboxylate (0.91 g, 64.5%) was obtained.

B) Synthesis of ethyl 4-chloro-6- [4- (hydroxymethyl) phenoxy] -1-methyl-2-indolecarboxylate Ethyl 4-chloro-6- (4-formylphenoxy)
-1-Methyl-2-indolecarboxylate (0.90
g, 2.52 mmol), sodium borohydride (0.10 g, 2.
A mixture of 52 mmol) and ethanol (20 ml) was stirred at 0 ° C for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate (three times), the extract solution was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give ethyl 4-chloro-6. -[4- (Hydroxymethyl) phenoxy] -1-methyl-2-indolecarboxylate (0.91 g,> 99%) was obtained.

C) Synthesis of ethyl 4-chloro-6- [4- (chloromethyl) phenoxy] -1-methyl-2-indolecarboxylate Ethyl 4-chloro-6- [4- (hydroxymethyl)
Phenoxy] -1-methyl-2-indolecarboxylate (0.91 g, 2.52 mmol), triethylamine (0.56
g, 5.53 mmol) and dichloromethane (30 ml) were stirred under cooling to 0 ° C., and methanesulfonyl chloride (0.35 g, 3.02 mmol) was added dropwise to this mixture. Next, the reaction temperature was raised from 0 ° C. to 20 ° C., and the mixture was further stirred at 20 ° C. for 5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate (three times), and the extract solution was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium hydrogen carbonate, a saturated saline solution and dried over anhydrous magnesium sulfate, and then the solvent. Was distilled off under reduced pressure and the resulting residue was separated and purified by silica gel column chromatography to give ethyl 4-chloro-6- [4- (chloromethyl) phenoxy] -1-.
Methyl-2-indolecarboxylate (0.70g, 7
3.6%).

D) Ethyl 4-chloro-6- [4- (te
rt-Butoxycarbonylaminomethyl) phenoxy]-
Synthesis of 1-methyl-2-indolecarboxylate Ethyl 4-chloro-6- [4- (chloromethyl) phenoxy] -1-methyl-2-indolecarboxylate (0.67 g, 1.77 mmol), sodium azide (0.17 g,
A mixture of 2.66 mmol) and dimethylformamide (30 ml) was stirred at room temperature for 3 hours. Pour the reaction solution into ice water,
The mixture was extracted with ethyl acetate (twice), the extract was washed with saturated aqueous ammonium chloride solution, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 50 ml), 10% palladium / carbon (0.10 g) and di-tert-butyl dicarbonate (0.77)
g, 3.54 mmol) was added and the mixture was catalytically reduced at room temperature and atmospheric pressure. After completion of the reaction, the catalyst was removed by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was separated and purified by silica gel column chromatography to give ethyl 4-.
Chloro-6- [4- (tert-butoxycarbonylaminomethyl) phenoxy] -1-methyl-2-indolecarboxylate (0.57 g, 70.1%) was obtained.

E) Synthesis of 6- [4- (aminomethyl) phenoxy] -4-chloro-1-methyl-2-indoloylguanidine dihydrochloride Ethyl 4-chloro-6- [4- (tert-butoxy] Carbonylaminomethyl) phenoxy] -1-methyl-2-
Indole carboxylate (0.55g, 1.20mmol), guanidine hydrochloride (2.29g, 24.0mmol), sodium methoxide (1.29g, 24.0mmol) and methanol (50m
l) was used according to the method of Example 186 b) to give ethyl 4-chloro-6- [4- (tert-butoxycarbonylaminomethyl) phenoxy] -1-methyl-
2-Indoylguanidine (0.70 g) was obtained. This was mixed with dichloromethane (30 ml) containing trifluoroacetic acid (5 ml).
ml) and stirred at room temperature for 2 hours. Ice water was added to the residue obtained by concentrating the reaction mixture under reduced pressure, and then the mixture was made alkaline with 28% ammonia water and extracted with ethyl acetate (three times). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After drying with, the solvent was distilled off under reduced pressure, and the resulting residue was treated with hydrogen chloride / methanol.
6- [4- (aminomethyl) phenoxy] -4-chloro-1-methyl-2-indoloylguanidine dihydrochloride (0.28 g, 52.5%) was obtained. mp 287 ° C (decomposition) ¹ Hnmr (DMSO-d ₆ ) δ; 3.97 (3H, s), 4.01 (2H, d, J = 5.61H
z), 6.96 (1H, d, J = 1.65Hz), 7.11 (2H, d, J = 8.58Hz),
7.35 (1H, s), 7.52 (2H, d, J = 8.57Hz), 7.95 (1H, s), 8.31
(3H, br-s), 8.54 to 8.65 (4H, m), 12.04 (1H, br-s)

Example 197 Synthesis of 7- [4- (aminomethyl) phenoxy] -4-chloro-1-methyl-2-indoloylguanidine dihydrochloride Ethyl 4-chloro-7-hydroxy-1-methyl- Two
-By reacting indolecarboxylate as a starting material according to the method of Example 196, 7-
[4- (aminomethyl) phenoxy] -4-chloro-1
-Methyl-2-indoloylguanidine dihydrochloride was obtained. mp 290 to 291 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 4.00 to 4.02 (2H, m), 4.12 (3H,
s), 6.87 (1H, d, J = 8.25Hz), 7.07 to 7.10 (2H, m), 7.23 (1
H, d, J = 8.24Hz), 7.49 to 7.52 (2H, m), 7.85 (1H, s), 8.25
(3H, br-s), 8.54 (4H, br-s), 11.98 (1H, br-s)

Example 198 4-Chloro-6- [4- (dimethylaminomethyl) phenoxy] -1-methyl-2-indoloylguanidine.
Synthesis of dihydrochloride a) Synthesis of ethyl 4-chloro-6- [4- (dimethylaminomethyl) phenoxy] -1-methyl-2-indolecarboxylate Ethyl 4-chloro-6- [4- (chloromethyl) Phenoxy] -1-methyl-2-indolecarboxylate (1.34 g, 3.53 mmol), dimethylamine (8.0 g) and dimethylformamide (80 ml) at 0 ° C.
Stirred for hours. The reaction solution was poured into ice water, extracted with ethyl acetate (three times), the extract solution was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. By separating and purifying by chromatography, ethyl 4-chloro-6- [4-
(Dimethylaminomethyl) phenoxy] -1-methyl-
2-Indole carboxylate (0.29 g, 21.2%) was obtained.

B) Synthesis of 4-chloro-6- [4- (dimethylaminomethyl) phenoxy] -1-methyl-2-indoloylguanidine dihydrochloride Ethyl 4-chloro-6- [4- (dimethylamino) Methyl) phenoxy] -1-methyl-2-indolecarboxylate (0.29 g, 0.75 mmol), guanidine hydrochloride (1.43 g, 15.0 mmol), sodium methoxide (0.81)
g, 15.0 mmol) and methanol (30 ml) according to the method of Example 186 b).
-Chloro-6- [4- (dimethylaminomethyl) phenoxy] -1-methyl-2-indoloylguanidine-2
The hydrochloride salt (0.23 g, 66.0%) was obtained. mp 275 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 2.69 (6H, s), 3.98 (3H, s), 4.25
(2H, br-s), 7.04 (1H, d, J = 1.98Hz), 7.11 (2H, d, J = 8.58
Hz), 7.40 (1H, d, J = 1.65Hz), 7.58 (2H, d, J = 8.58Hz),
7.96 (1H, s), 8.54 to 8.66 (4H, m), 10.55 (1H, br-s), 12.0
6 (1H, br-s)

Example 199 4-Chloro-7- [4- (dimethylaminomethyl) phenoxy] -1-methyl-2-indoloylguanidine.
Synthesis of dihydrochloride By using ethyl 4-chloro-7- [4- (chloromethyl) phenoxy] -1-methyl-2-indolecarboxylate as a starting material and performing a reaction according to the method of Example 198, 4-Chloro-7- [4- (dimethylaminomethyl) phenoxy] -1-methyl-2-indoloylguanidine dihydrochloride was obtained. mp 279 to 280 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 2.68 (6H, d, J = 3.63Hz), 4.12 (3
H, s), 4.24 (2H, d, J = 3.96Hz), 6.94 (1H, d, J = 7.91Hz),
7.11 (2H, d, J = 8.91Hz), 7.23 (1H, d, J = 8.24Hz), 7.59 (2
H, d, J = 8.58Hz), 7.91 (1H, s), 8.5 to 8.8 (4H, m), 10.5
7 (1H, br-s), 12.09 (1H, br-s)

Example 200 Synthesis of 4-chloro-1-methyl-7- (4-nitrophenoxy) -2-indoloylguanidine hydrochloride The 4-chloro-1-obtained as the intermediate of Example 193.
Methyl-7- (4-nitrophenoxy) -2-indoloylguanidine was subjected to hydrochloric acid chloride treatment with hydrogen chloride / methanol to give 4-chloro-1-methyl-7- (4-nitrophenoxy) -2-indoloylguanidine. -Hydrochloride was obtained. mp 280 to 282 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 4.04 (3H, s), 7.15 (1H, d, J = 8.25H
z), 7.19 to 7.23 (2H, m), 7.31 (1H, d, J = 8.25Hz), 7.86
(1H, s), 8.26-8.30 (2H, m), 8.52 (4H, br-s), 11.97 (1
H, s)

Example 201 Synthesis of 4-chloro-1-methyl-7- (2-nitrophenoxy) -2-indoloylguanidine hydrochloride hydrochloride 4-chloro-1-obtained as the intermediate of Example 188
Methyl-7- (2-nitrophenoxy) -2-indoloylguanidine is subjected to hydrochloric acid chloride treatment with hydrogen chloride / methanol to give 4-chloro-1-methyl-7- (2-nitrophenoxy) -2-indoloylguanidine. -Hydrochloride was obtained. mp 176-178 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 4.18 (3H, s), 6.87 (1H, d, J = 8.25H
z), 7.20 to 7.24 (2H, m), 7.40 to 7.46 (1H, m), 7.70 to 7.7
7 (2H, m), 8.15 (1H, dd, J = 1.65, 8.24Hz), 8.48 (4H, br-s)
, 11.84 (1H, s)

Example 202 Synthesis of 7- [4- (aminomethyl) benzyloxy] -4-chloro-1-methyl-2-indoloylguanidine dihydrochloride a) Ethyl 7- [4- (tert-butoxy] Carbonylaminomethyl) benzyloxy] -4-chloro-1-methyl-2-indolecarboxylate synthesis Ethyl 4-chloro-7-hydroxy-1-methyl-2
-Indole carboxylate (0.44 g, 1.74 mmol),
4- (tert-Butoxycarbonylaminomethyl) benzyl chloride (0.66 g, 2.58 mmol), 60% sodium hydride (0.07 g, 1.74 mmol) and dimethylformamide (20 ml) were used according to the method of Example 196a). The reaction is carried out with ethyl 7- [4- (tert-butoxycarbonylaminomethyl) benzyloxy] -4-chloro-1.
-Methyl-2-indole carboxylate (0.61 g,
73.1%). b) 7- [4- (aminomethyl) benzyloxy] -4
-Chloro-1-methyl-2-indoloylguanidine
Synthesis of dihydrochloride ethyl 7- [4- (tert-butoxycarbonylaminomethyl) benzyloxy] -4-chloro-1-methyl-
2-indole carboxylate (0.60g, 1.27mmo
l), guanidine hydrochloride (2.42 g, 25.4 mmol), sodium methoxide (1.37 g, 25.4 mmol) and methanol (50 ml) were used according to the method of Example 196e) to carry out a 7- [4- (Aminomethyl) benzyloxy] -4-chloro-1-methyl-2-indoloylguanidine dihydrochloride (0.25 g, 43.0%) was obtained. mp 298 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 4.02 to 4.04 (2H, m), 4.28 (3H,
s), 5.29 (2H, s), 6.96 (1H, d, J = 8.58Hz), 7.12 (1H, d, J =
8.25Hz), 7.50-7.60 (4H, m), 7.77 (1H, s), 8.35 (3H, br)
-s), 8.57 (4H, br-s), 11.92 (1H, br-s)

Example 203 Synthesis of 6- [4- (aminomethyl) benzyloxy] -4-chloro-1-methyl-2-indoloylguanidine dihydrochloride Ethyl 4-chloro-6-hydroxy-1-methyl -2
-By reacting indole carboxylate as a starting material according to the method of Example 202, 6-
[4- (Aminomethyl) benzyloxy] -4-chloro-1-methyl-2-indoloylguanidine dihydrochloride was obtained. mp 267 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 4.00 to 4.04 (5H, m), 5.24 (2H,
s), 7.02 to 7.03 (1H, m), 7.27 (1H, s), 7.49 to 7.56 (4H,
m), 7.91 (1H, s), 8.39-8.67 (7H, m), 11.97 (1H, br-s)

Example 204 Synthesis of 4-chloro-7- [4- (dimethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine dihydrochloride a) Ethyl 7- [4- (aminomethyl ) Benzyloxy] -4-chloro-1-methyl-2-indolecarboxylate synthesis Ethyl 7- [4- (tert-butoxycarbonylaminomethyl) benzyloxy] -4-chloro-1-methyl-
2-indole carboxylate (0.75g, 1.59mmo
A mixture of l), trifluoroacetic acid (5 ml) and dichloromethane (50 ml) was stirred at 0 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, ice water was added to the obtained residue, and then the mixture was made alkaline with 28% ammonia water (pH = 9 to 10).
And then extracted with ethyl acetate (3 times). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give ethyl 7- [4
-(Aminomethyl) benzyloxy] -4-chloro-1
-Methyl-2-indole carboxylate (0.60 g,
> 99%).

B) Ethyl 4-chloro-7- [4- (dimethylaminomethyl) benzyloxy] -1-methyl-
Synthesis of 2-indolecarboxylate Ethyl 7- [4- (aminomethyl) benzyloxy]
-4-Chloro-1-methyl-2-indolecarboxylate (0.54 g, 1.45 mmol), 35% aqueous formaldehyde solution (1.24 g, 14.5 mmol), sodium cyanoborohydride (0.27 g, 4.34 mmol) and acetonitrile ( 20
ml) was stirred at room temperature for 1 hour. Subsequently, acetic acid was added so that the pH of the reaction solution became 6 to 7, and the mixture was further stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, ice water was added to the obtained residue, the mixture was made alkaline with 28% aqueous ammonia (pH = 9 to 10), and then extracted with ethyl acetate (three times). Wash the extract with saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography to obtain ethyl 4-chloro-7.
-[4- (Dimethylaminomethyl) benzyloxy]-
1-methyl-2-indolecarboxylate (0.32
g, 55.1%) was obtained.

C) Synthesis of 4-chloro-7- [4- (dimethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine dihydrochloride Ethyl 4-chloro-7- [4- (dimethyl Aminomethyl) benzyloxy] -1-methyl-2-indolecarboxylate (0.28 g, 0.70 mmol), guanidine hydrochloride (1.52 g, 16.0 mmol), sodium methoxide (0.
86 g, 16.0 mmol) and methanol (40 ml) were used according to the method of Example 186 b) to carry out a reaction.
4-Chloro-7- [4- (dimethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine dihydrochloride (0.10 g, 29.3%) was obtained. mp 282 ° C (decomposition) ¹ Hnmr (DMSO-d ₆ ) δ; 2.69 (6H, d, J = 2.97Hz), 4.2 ~
4.4 (5H, m), 5.32 (2H, s), 6.97 (1H, d, J = 8.58Hz), 7.13
(1H, d, J = 8.25Hz), 7.61 (4H, s), 7.77 (1H, s), 8.4 to 8.
7 (4H, m), 10.60 (1H, br-s), 11.92 (1H, br-s)

Example 205 Synthesis of 4-chloro-6- [4- (dimethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine dihydrochloride Ethyl 4-chloro-6-hydroxy-1- Methyl-2
-By reacting indolecarboxylate as a starting material according to the method of Example 204, 4-chloro-6- [4- (dimethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine・ 2
The hydrochloride salt was obtained. mp 263 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 2.70 (6H, s), 4.00 (3H, s), 4.28
(2H, s), 5.26 (2H, s), 7.05 (1H, d, J = 1.65Hz), 7.28 (1H,
s), 7.5 to 7.7 (4H, m), 7.84 (1H, s), 8.4 to 8.6 (4H, m)
, 10.47 (1H, br-s), 11.84 (1H, br-s)

The compounds of Examples 206 to 207 below were synthesized by carrying out the reaction according to the method of Example 186. Example 206 7- (3-aminobenzyloxy) -4-chloro-1-
Methyl-2-indoloylguanidine hydrochloride mp 230 ° C ¹ Hnmr (DMSO-d ₆ ) δ; 4.30 (3H, s), 5.26 (2H, s), 6.96
(1H, d, J = 8.3Hz), 6.92 to 7.28 (3H, m), 7.15 (1H, d, J = 8.3H
z), 7.30 to 7.41 (1H, m), 7.67 (1H, s), 8.47 (1H, br-s),
11.75 (1H, br-s) Example 207 6- (3-aminobenzyloxy) -4-chloro-1-
Methyl-2-indoloylguanidine hydrochloride mp 237 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 4.00 (3H, s), 5.24 (2H, s), 7.04
(1H, d, J = 1.98Hz), 7.15 (1H, d, J = 7.92Hz), 7.27 to 7.33
(3H, m), 7.40 (1H, t, J = 7.59Hz), 7.82 (1H, s), 8.45 (2H,
br-s), 8.50 (2H, br-s), 11.80 (1H, br-s)

Example 208 1,4-Dimethyl-7-[(4-piperidino) methoxy]
Synthesis of 2-indoloylguanidine dihydrochloride (a) Ethyl 4- (1-tert-butoxycarbonyl)
Synthesis of piperidine carboxylate Ethyl 4-piperidine carboxylate (25.0 g, 1
59 mmol), di-tert-butyl dicarbonate (34.7)
g, 159 mmol) and dichloromethane (200 ml) were stirred at room temperature until the raw material disappeared. Next, the reaction solution was poured into ice water and extracted with dichloromethane (twice).
The organic layer was washed with a 5% aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to give ethyl 4- (1-tert- Butoxycarbonyl) piperidinecarboxylate was obtained. (B) Synthesis of 4- (1-tert-butoxycarbonyl) piperidinemethanol Ethyl 4- (1-tert-butoxycarbonyl) piperidinecarboxylate (4.00 g, 15.6 mmol), lithium aluminum hydride (0.45 g, A mixture of 11.8 mmol) and tetrahydrofuran (50 ml) at 0-5 ° C.
Stir for hours. After completion of the reaction, excess lithium aluminum hydride was decomposed with hydrous tetrahydrofuran, and the insoluble material was filtered off. By removing the filtrate under reduced pressure, 4-
2.99 g of (1-tert-butoxycarbonyl) piperidinemethanol was obtained.

(C) 1-tert-butoxycarbonyl-
Synthesis of 4-methanesulfonyloxymethylpiperidine 4- (1-tert-butoxycarbonyl) piperidinemethanol (1.00 g, 4.64 mmol), triethylamine (0.94 g, 9.29 mmol) and dichloromethane (20 m
l) Methanesulfonyl chloride (0.59 g, 5.11 mmol) was added dropwise to the mixture at 0-5 ° C, and then 0-5
The mixture was stirred at ° C for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with 5% aqueous sodium chloride solution and dried over magnesium sulfate. By distilling off the solvent under reduced pressure, 1-tert-butoxycarbonyl-4
-Methanesulfonyloxymethylpiperidine was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.14 to 1.29 (2H, m), 1.46 (9H, s)
, 1.74 (2H, d, J = 13.9Hz), 1.90 to 1.92 (1H, m), 2.6
6 to 2.75 (2H, m), 3.01 (3H, s), 4.07 (2H, d, J = 6.3H
z), 4.13 to 4.20 (2H, m). (d) Ethyl 1,4-dimethyl-7-[[(1-tert-
Synthesis of butoxycarbonyl) piperidin-4-yl] methoxy] -2-indolecarboxylate Ethyl 1,4-dimethyl-7-hydroxy-2-indole carboxoxylate (0.20 g, 0.86 mmol), 60%
After stirring sodium hydride (0.034 g, 0.86 mmol) and dimethylformamide (10 ml) at room temperature, 1-te
After adding rt-butoxycarbonyl-4-methanesulfonyloxymethylpiperidine (0.25 g, 0.86 mmol), the mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with 5% aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain ethyl 1,4-
Dimethyl-7-[[(1-tert-butoxycarbonyl)
0.32 g of piperidin-4-yl] methoxy] -2-indolecarboxylate was obtained.

(E) 1,4-Dimethyl-7-[[(1-
Synthesis of tert-butoxycarbonyl) piperidin-4-yl] methoxy] -2-indoloylguanidine Guanidine hydrochloride (0.89) in a solution of sodium methoxide (0.50 g, 9.29 mmol) in methanol (10 ml).
g, 9.29 mmol) was added and the mixture was stirred at room temperature for 30 minutes, and then the precipitated salt was filtered off to obtain a solution, and ethyl 1,4-dimethyl-7-[[(1-tert-butoxycarbonyl ) Piperidin-4-yl] methoxy] -2-indolecarboxylate (0.20 g, 0.47 mmol) was added, followed by evaporation of methanol under reduced pressure. The residue obtained is 130
After heating at 5 ° C for 5 minutes and then standing at room temperature for 1 hour, water was poured into the reaction solution and extracted with ethyl acetate. The extract solution was washed with water,
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 1,4-dimethyl-7-[[(1
-Tert-butoxycarbonyl) piperidin-4-yl]
0.07 g of methoxy] -2-indoloylguanidine was obtained. (F) Synthesis of 1,4-dimethyl-7-[(4-piperidino) methoxy] -2-indoloylguanidine dihydrochloride 1,4-dimethyl-7-[[(1-tert-butoxycarbonyl) piperidine -4-yl] methoxy] -2-indoloylguanidine (0.07 g), trifluoroacetic acid (5
ml) and dichloromethane (30 ml) was stirred at room temperature for 2 hours. Ice water was added to the residue obtained by concentrating the reaction solution under reduced pressure, and then the mixture was made alkaline with 28% ammonia water and then extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was treated with hydrogen chloride / methanol to give 1,4-dimethyl-7-[(4-piperidino) methoxy] -2-indoloylguanidine dihydrochloride. Obtained 0.04 g. Melting point 313 ° C (decomposition)

Example 209 4-chloro-7- (4-dimethylaminophenoxy)-
Synthesis of 1-methyl-2-indoloylguanidine hydrochloride (a) Synthesis of ethyl 4-chloro-1-methyl-7- (4-nitrophenoxy) -2-indolecarboxylate Ethyl 4-chloro-7-hydroxy -1-methyl-2-
Indole carboxylate (1.00 g, 3.94 mmo
l), 1-fluoro-4-nitrobenzene (0.56 g,
3.94 mmol), 60% sodium hydride (0.16 g, 3.
A mixture of 94 mmol) and dimethylformamide (30 ml) was stirred at room temperature for 5 hours. Pour the reaction solution into ice water,
It was extracted with ethyl acetate, the extract was washed with water, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain ethyl 4-chloro-1-methyl. -7- (4-nitrophenoxy) -2-indolecarboxylate was added to 1.2
5 g was obtained. (B) Synthesis of ethyl 7- (4-aminophenoxy) -4-chloro-1-methyl-2-indolecarboxylate Ethyl 4-chloro-1-methyl-7- (4-nitrophenoxy) -2-indolecarboxy Rat (4.10.
g, 10.9 mmol), tin (II) chloride dihydrate (12.3
A mixture of 4 g, 54.7 mmol) and ethanol (150 ml) was stirred at 70 ° C. for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, ice water was poured into the obtained concentrated liquid, 28% aqueous ammonia was added to make the mixture alkaline, and the mixture was extracted with ethyl acetate. 5% of the filtrate obtained by filtering off insoluble matter
After washing with an aqueous sodium chloride solution, drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain ethyl 7- (4-aminophenoxy) -4-chloro-. 2.70 g of 1-methyl-2-indolecarboxylate was obtained.

(C) Synthesis of ethyl 4-chloro-7- (4-dimethylaminophenoxy) -1-methyl-2-indolecarboxylate Ethyl 7- (4-aminophenoxy) -4-chloro-1
-Methyl-2-indole carboxylate (2.70
g, 7.83 mmol) in acetonitrile (100 ml), and then 35% formaldehyde water (6.71) at room temperature.
g, 78.3 mmol) and sodium cyanoborohydride (1.48 g, 23.5 mmol) were added, and the pH of the reaction solution was about 4.
Acetic acid was added to maintain 0, and the mixture was further stirred for 2 hours at room temperature. Water and 2 were added to the residue obtained by distilling off the solvent under reduced pressure.
8% Ammonia water was added to the mixture to make it alkaline, which was then extracted with ethyl acetate. The extract was washed with 5% aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. By purifying by chromatography, ethyl 4-chloro-7- (4
1.57 g of -dimethylaminophenoxy) -1-methyl-2-indolecarboxylate were obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.40 ~ 1.45 (3H, m), 2.93 (6H, s)
, 4.34 ~ 4.42 (5H, m), 6.57 (1H, d, J = 8.3Hz), 6.70 ~
6.85 (2H, m), 6.92 to 6.97 (3H, m), 7.36 (1H, s). (D) 4-chloro-7- (4-dimethylaminophenoxy) -1-methyl-2-indoloylguanidine Synthesis of hydrochloride 4-chloro-7- (4-dimethylaminophenoxy)-
1-methyl-2-indolecarboxylate (1.57
g, 4.21 mmol) according to the method of Example 208 (e) to give 4-chloro-7- (4-dimethylaminophenoxy) -1-methyl-2-indoloylguanidine. Obtained. Further treatment of this compound with hydrogen chloride / methanol gave 4-chloro-7- (4
1.36 g of -dimethylaminophenoxy) -1-methyl-2-indoloylguanidine hydrochloride was obtained. Melting point 252 ° C (decomposition)

[0274] The reaction was carried out according to the method of Example 186,
The following compounds of Examples 210 to 213 were synthesized. Example 210 7- (2-Aminophenoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine dihydrochloride Melting point 187 ° C. Example 211 7- (2-Aminophenoxy) -1-methyl- 4-Trifluoromethyl-2-indoloylguanidine dimethanesulfonate (In Example 186, the title compound was obtained by treating with methanesulfonic acid / hydrated isopropyl alcohol instead of with hydrogen chloride / methanol. ) Melting point 279 to 280 ° C (decomposition) Example 212 7- (2-aminophenoxy) -1-methyl-2-indoloylguanidine dimethanesulfonate salt Melting point 260 to 261 ° C Example 213 7- (2-amino Phenoxy) -1,4-dimethyl-2-
Indoylguanidine dimethanesulfonate, melting point 279-280 ° C (decomposition)

[0275] The reaction was carried out according to the method of Example 189,
The compound of Example 214 below was synthesized. Example 214 7- (3-Aminophenoxy) -4-chloro-1-methyl-2-indoloylguanidine dimethanesulfonate mp 284-285 ° C

Example 215 Synthesis of 7- [2- (1H-imidazol-1-yl) ethoxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine dihydrochloride (a) Ethyl 7- Synthesis of (2-chloroethoxy) -1-methyl-4-trifluoromethyl-2-indolecarboxylate Ethyl 7-hydroxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate (3.00 g,
10.4 mmol) in dimethylformamide (30 ml) solution, potassium carbonate (2.17 g, 15.7 mmol), 1-bromo-2-chloroethane (2.25 g, 15.7 mmol) and potassium iodide (0.05 g). ) Was added and the mixture was stirred at room temperature for 3 hours. Next, potassium carbonate (1.45 g, 10.
4 mmol) and 1-bromo-2-chloroethane (0.69)
g, 5.2 mmol) and then stirred at 50 ° C. for 1 hour. After the reaction solution was cooled to room temperature, it was poured into saturated saline and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain ethyl 7- (2-chloroethoxy) -1-methyl-4-trifluoromethyl-2-indolecarboxylate. Obtained 0.31 g. (B) Ethyl 7- [2- (1H-imidazol-1-
Ile) ethoxy] -1-methyl-4-trifluoromethyl-2-indolecarboxylate ethyl 7- (2-chloroethoxy) -1-methyl-4-
Trifluoromethyl-2-indolecarboxylate (2.24 g, 6.4 mmol), imidazole (1.09 g, 1
6.0 mmol), 60% sodium hydride (0.36 g, 9.0
mmol) and dimethylformamide (30 ml) were stirred at 60 to 70 ° C for 1 hour. The reaction solution was cooled to room temperature, poured into ice water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give ethyl 7- [2- (1H-imidazole. -1-yl) ethoxy] -1-methyl-4-trifluoromethyl-2-indolecarboxylate (1.91 g) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.42 (3H, t, J = 7.3Hz), 4.27 (3H,
s), 4.37 (2H, q, J = 7.3Hz), 4.42-4.53 (4H, m), 6.6
3 (1H, d, J = 8.3Hz), 6.99 to 7.07 (1H, m), 7.11 (1H, br
-s), 7.31 (1H, dd, J = 1.0Hz, 8.3Hz), 7.34 ~ 7.38 (1H,
m), 7.59 (1H, br-s)

(C) Synthesis of 7- [2- (1H-imidazol-1-yl) ethoxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine dihydrochloride Ethyl 7- [2- (1H-Imidazol-1-yl) ethoxy] -1-methyl-4-trifluoromethyl-2-
Indole carboxylate (1.84g, 4.82mmol)
Was carried out according to the method of Example 208 (e) to give 7- [2- (1H-imidazol-1-yl).
Ethoxy] -1-methyl-4-trifluoromethyl-2
-0.85 g of indoylguanidine was obtained. Further, this compound (0.50 g, 1.26 mmol) was subjected to hydrochloric acid salification from hydrochloric acid / isopropyl alcohol to give 7- [2-
0.58 g of (1H-imidazol-1-yl) ethoxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine dihydrochloride was obtained. Melting point 275 ° C (decomposition)

The reaction is carried out according to the method of Example 215,
The following compounds of Examples 216 to 220 were synthesized. Example 216 1-Methyl-7- [2- (1H-1,2,4-triazol-1-yl) ethoxy] -4-trifluoromethyl-2
-Indoloylguanidine hydrochloride, melting point 270 [deg.] C. Example 217 7- [2- (1H-imidazol-1-yl) ethoxy] -1-methyl-4-trifluoromethyl-2-indoloylguanidine dimethanesulfonic acid Salt (The title compound was obtained by using methanesulfonic acid in place of hydrochloric acid in Example 215 (c).) Melting point 204-205 ° C Example 218 1-Methyl-7- [2- (1H-1, 2,4-triazol-1-yl) ethoxy] -4-trifluoromethyl-2
-Indoloylguanidine methanesulfonate, melting point 249-250 ° C Example 219 1,4-Dimethyl-7- [3- (1H-imidazole-1
-Yl) propoxy] -2-indoloylguanidine
2 Methanesulfonic acid salt Melting point 261-262 ° C Example 220 1,4-Dimethyl-7- [2- (1H-imidazole-1
-Yl) ethoxy] -2-indoloylguanidine-2
Methanesulfonate, melting point 238-240 ° C

Example 221 Synthesis of 1,4-dimethyl-7-methoxy-2-indoloylguanidine methanesulfonate (a) Synthesis of ethyl 1,4-dimethyl-7-methoxy-2-indolecarboxylate Ethyl 1,4-Dimethyl-7-hydroxy-2-indolecarboxylate (3.50 g, 15.5 mmol), potassium carbonate (4.14 g, 30.0 mmol), methyl iodide (4.2
A mixture of 6 g, 30.0 mmol) and dimethylformamide was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain ethyl 1,4-dimethyl-7-methoxy-2.
-3.21 g of indole carboxylate was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.41 (3H, t, J = 7.3Hz), 2.45 (3H,
d, J = 0.6Hz), 3.88 ((3H, s), 4.35 (2H, q, J = 7.3Hz),
4.36 (3H, s), 6.57 (1H, d, J = 7.6Hz), 6.76 (1H, dd, J =
0.6Hz, 7.6Hz), 7.25 (1H, s) (b) Synthesis of 1,4-dimethyl-7-methoxy-2-indoloylguanidine methanesulfonate ethyl 1,4-dimethyl-7-methoxy-2 -Using indolecarboxylate (3.21 g, 13.0 mmol) according to the method of Example 208 (e), 1,4-dimethyl-7-methoxy-2-indoloylguanidine was converted into 3 I got .15g. Furthermore, this compound (3.15
By treating g) with methanesulfonic acid / hydrous isopropyl alcohol, 2.83 g of 1,4-dimethyl-7-methoxy-2-indoloylguanidine methanesulfonate was obtained. Melting point 256-258 ° C

[0280] The reaction was carried out according to the method of Example 221,
The following compounds of Examples 222 to 231 were synthesized. Example 222 7-Methoxy-1-methyl-4-trifluoromethyl-2-indoloylguanidine hydrochloride (in Example 221 (b), hydrochloric acid was used instead of methanesulfonic acid to give the title compound. Melting point 309-311 ° C (decomposition) -Example 223 7-isopropoxy-1-methyl-4-
Trifluoromethyl-2-indoloylguanidine hydrochloride (The title compound was obtained in the same manner as in Example 221 (a) except that isopropyl iodide was used instead of methyl iodide.) Melting point 258- 259 ° C Example 224 7-methoxy-1-methyl-4-trifluoromethyl-2-indoloylguanidine methanesulfonate Melting point 269-270 ° C (decomposition) Example 225 7-isopropoxy-1-methyl -4-
Trifluoromethyl-2-indoloylguanidine / methanesulfonate melting point 238 [deg.] C. Example 226 7-Methoxy-1-methyl-2-indoloylguanidine / methanesulfonate melting point 215 to 216 [deg.] C.

Example 227 4-chloro-7-methoxy-1-methyl-2-indoloylguanidine methanesulfonate mp 240-242 ° C. Example 228 4-chloro-6-methoxy-1-methyl- 2-indoloylguanidine-, methanesulfonate melting point 271-273 ° C-Example 229 1,4-Dimethyl-7-isopropoxy-
2-indoloylguanidine methanesulfonate melting point 193-195 ° C Example 230 1,4-dimethyl-7-methoxy-2-indoloylguanidine hydrochloride hydrochloride melting point 268-269 ° C Example 231 1,4- Dimethyl-6-methoxy-2-indoloylguanidine methanesulfonate mp 255-257 ° C Example 232 Synthesis of 7-hydroxy-1-methyl-4-trifluoromethyl-2-indoloylguanidine hydrochloride Example 232 By carrying out the reaction according to the method of 91, 7-hydroxy-1-methyl-4-trifluoromethyl-2-
Indoylguanidine hydrochloride was obtained. Melting point 272-273 ° C (decomposition)

Example 233 Synthesis of 7-Hydroxy-1-methyl-4-trifluoromethyl-2-indoloylguanidine methanesulfonate In Example 232, substituting methanesulfonic acid for hydrochloric acid gave the title compound. Got Melting point 274-275 ° C. (decomposition) Reaction was carried out according to the method of Example 186, and the following Examples
The compounds 234 to 239 were synthesized. -Example 234 7- (4-aminobenzyloxy) -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine Dimethanesulfonate mp 194-195 ° C (decomposition) Example 235 7- (2-aminobenzyloxy) -1,
4-Dimethyl-2-indoloylguanidine dimethanesulfonate salt mp 198-200 ° C Example 236 7- (3-aminobenzyloxy) -1,
4-Dimethyl-2-indoloylguanidine Dimethanesulfonate mp 233-234 ° C Example 237 7- (4-aminobenzyloxy) -1,
4-Dimethyl-2-indoloylguanidine dimethanesulfonate salt, melting point 160-162 [deg.] C. Example 238 7- (2-aminobenzyloxy) -4
-Chloro-1-methyl-2-indoloylguanidine
2 Methanesulfonate, melting point 202-203 ° C (decomposition)

Example 239 7- (3-Aminobenzyloxy) -4-chloro-1-methyl-2-indoloylguanidine Dimethanesulfonate mp 238-239 ° C. (decomposition) Example 240 1- Methyl-2-indoloylguanidine methanesulfonate The 1-methyl-2-indoloylguanidine obtained in Example 1 was treated with methanesulfonic acid / hydrated isopropyl alcohol to give the title compound. Melting point 218 ° C. Example 241 Synthesis of 1,4-dimethyl-2-indoloylguanidine methanesulfonate The 1,4-dimethyl-2-indoloylguanidine obtained in Example 9 was converted to methanesulfonic acid / hydrated isopropyl alcohol. The title compound was obtained by treatment with. Melting point 251 to 252 ° C. The reaction was carried out according to the method of Example 1 and the following Example 24
2-243 compounds were synthesized. -Example 242 1-isopropyl-7-methoxy-4-
Methyl-2-indoloylguanidine methanesulfonate melting point 177 to 178 ° C Example 243 1-Propyl-7-methoxy-4-methyl-2-indoloylguanidine methanesulfonate melting point 183 to 184 ° C

Example 244 Synthesis of 1,4-dimethyl-7-[(pyridin-2-yl) methoxy] -2-indoloylguanidine dimethanesulfonate (a) Ethyl 1,4-dimethyl-7- [(Pyridine-2
-Yl) Methoxy] -2-indolecarboxylate synthesis Ethyl 1,4-dimethyl-7-hydroxy-2-indolecarboxylate (2.00 g, 8.57 mmol), potassium carbonate (4.74 g, 34.3 mmol) A mixture of 2-picolyl chloride hydrochloride (1.55 g, 9.43 mmol) and dimethylformamide (40 ml) was stirred at 50 ° C for 2 hours. The reaction mixture was poured into a 5% aqueous sodium chloride solution and extracted with ethyl acetate. The extract was washed with a 5% aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain ethyl 1,4-dimethyl-7-[(pyridin-2-yl) methoxy] -2-indolecarboxylate. Obtained 0.54 g. ¹ Hnmr (CDCl ₃ ) δ; 1.40 ~ 1.62 (3H, m), 2.46 (3H, d,
J = 1.0Hz), 4.37 (2H, dd, J = 7.3Hz, 14.2Hz), 4.45 (3
H, s), 5.32 (2H, s), 6.65 (1H, d, J = 7.6Hz), 6.73 ~
6.76 (1H, m), 7.23 ~ 7.27 (2H, m), 7.55 (1H, d, J = 7.
9Hz), 7.70 to 7.77 (1H, m), 8.61 to 8.64 (1H, m) (b) 1,4-Dimethyl-7-[(pyridin-2-yl) methoxy] -2-indoloylguanidine ・ 2 methane Synthesis of Sulfonate Ethyl 1,4-dimethyl-7-[(pyridin-2-yl)
Methoxy] -2-indole carboxylate (2.50
g, 7.71 mmol) and according to the method of Example 208 (e), 1,4-dimethyl-7-[(pyridine-2
-Yl) methoxy] -2-indoloylguanidine 2.
10 g were obtained. This compound (2.10 g) was treated with methanesulfonic acid / hydrated isopropyl alcohol to give 3.24 g of the title compound. Melting point 227-228 ° C

[0285] The reaction was carried out according to the method of Example 244,
The compounds of Examples 245-248 below were synthesized. Example 245 1,4-Dimethyl-7-[(pyridine-3
-Yl) methoxy] -2-indoloylguanidine-2
Methanesulfonic acid salt Melting point 217 to 218 ° C Example 246 1,4-Dimethyl-7-[(pyridine-4
-Yl) methoxy] -2-indoloylguanidine-2
Methanesulfonic acid salt Melting point 154-155 ° C Example 247 7-[(furan-2-yl) methoxy]
-1-Methyl-4-trifluoromethyl-2-indoloylguanidine hydrochloride mp 215 ° C Example 248 7-[(furan-2-yl) methoxy]
-1-Methyl-4-trifluoromethyl-2-indoloylguanidine methanesulfonate, melting point 146 ° C

The reaction was carried out according to the method of Example 84 to synthesize the compounds of Examples 249 to 252 below. Example 249 1-Methyl-7- (4-morpholino)-
4-Trifluoromethyl-2-indoloylguanidine methanesulfonate mp 245-246 ° C Example 250 4-chloro-1-methyl-7- (4-morpholino) -2-indoloylguanidine methanesulfonate Salt Melting point 246-247 ° C Example 251 1,4-Dimethyl-7- (4-morpholino) -2-indoloylguanidine methanesulfonate Melting point 244-245 ° C Example 252 4-Chloro-7-dimethyl Amino-1-
Methyl-2-indoloylguanidine methanesulfonate, melting point 252 to 253 ° C

Example 253 1-Methyl-7-[(1H-
Synthesis of tetrazol-5-yl) methoxy] -4-trifluoromethyl-2-indoloylguanidine hydrochloride (a) Ethyl 7-cyanomethoxy-1-methyl-4-
Synthesis of trifluoromethyl-2-indolecarboxylate Ethyl 7-hydroxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate (4.00 g,
13.9 mmol), potassium carbonate (4.23 g, 30.6 mmo)
l), chloroacetonitrile (1.26 g, 16.7 mmol)
A mixture of and dimethylformamide (60 ml) was stirred at room temperature for 2 hours. The filtrate obtained by removing insoluble matter by filtration was poured into ice water, extracted with diethyl ether, the extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. By purifying by column chromatography, 4.50 g of ethyl 7-cyanomethoxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate was obtained. (B) Ethyl 1-methyl-7-[(1H-tetrazol-5-yl) methoxy] -4-trifluoromethyl-
Synthesis of 2-indolecarboxylate Ethyl 7-cyanomethoxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate (1.00
g, 3.1 mmol), sodium azide (0.20 g, 3.1 mm
ol), ammonium chloride (0.16 g, 3.1 mmol) and dimethylformamide (6 ml) were stirred at 80 ° C. for 5 hours. The reaction solution was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was crystallized from ethyl acetate to give ethyl 1
1.00 g of -methyl-7-[(1H-tetrazol-5-yl) methoxy] -4-trifluoromethyl-2-indolecarboxylate was obtained. ¹ Hnmr (DMSO-d ₆ ) δ; 1.32 to 1.38 (3H, m), 4.30 to 4.3
8 (5H, m), 5.75 (2H, s), 7.09 (1H, d, J = 8.3Hz), 7.1
8 (1H, dd, J = 1.7Hz, 3.3Hz), 7.46 (1H, dd, J = 1.0Hz,
(8.3Hz)

(C) Ethyl 1-methyl-7-[(1H
Synthesis of-(1-triphenylmethyl) tetrazol-5-yl) methoxy] -4-trifluoromethyl-2-indolecarboxylate Ethyl 1-methyl-7-[(1H-tetrazole-5-
Iyl) methoxy] -4-trifluoromethyl-2-indolecarboxylate (1.00 g, 2.7 mmol), chlorotriphenylmethane (0.75 g, 2.7 mmol), triethylamine (0.82 g, 8.12 mmol) And a mixture of tetrahydrofuran (30 ml) was stirred at room temperature for 2 hours.
The insoluble material was filtered off, and the filtrate was evaporated under reduced pressure to give ethyl 1-methyl-7-[(1H- (1-triphenylmethyl) tetrazol-5-yl) methoxy] -4-trifluoromethyl-2. -Indole carboxylate was obtained. This was used in the next reaction without purification. (D) 1-Methyl-7-[(1H- (1-triphenylmethyl) tetrazol-5-yl) methoxy] -4-
Synthesis of trifluoromethyl-2-indolecarboxylic acid Ethyl 1-methyl-7-[(1H
-(1-Triphenylmethyl) tetrazol-5-yl) methoxy] -4-trifluoromethyl-2-indolecarboxylate was added to ethanol (10 ml) and 2N.
The mixture was added to a mixed solution of sodium hydroxide (15 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, pH was adjusted to 6 with acetic acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1-methyl-7-[(1H- (1-triphenylmethyl) tetrazol-5-yl) methoxy] -4-. Trifluoromethyl-2-indolecarboxylic acid was obtained. ¹ Hnmr (DMSO-d ₆ ) δ; 4.19 (3H, s), 5.72 (2H, s),
6.98 ~ 7.43 (18H, m)

(E) Synthesis of 1-methyl-7-[(1H-tetrazol-5-yl) methoxy] -4-trifluoromethyl-2-indoloylguanidine hydrochloride 1-methyl-7-[(1H -(1-Triphenylmethyl) tetrazol-5-yl) methoxy] -4-trifluoromethyl-2-indolecarboxylic acid (1.60 g,
2.7 mmol) was used and the reaction was carried out according to the method of Example 84 to give 1-methyl-7-[(1H- (1-triphenylmethyl) tetrazol-5-yl) methoxy]-
1.26 g of 4-trifluoromethyl-2-indoloylguanidine was obtained. Furthermore, this compound was added to hydrochloric acid / hydrated isopropyl alcohol, and the mixture was stirred at 70 to 80 ° C. for 0.5 hour, insoluble materials were filtered off, and the filtrate was cooled to precipitate a solid, which was collected by filtration under reduced pressure. By drying
1-methyl-7-[(1H-tetrazol-5-yl)
Methoxy] -4-trifluoromethyl-2-indoloylguanidine hydrochloride was obtained. Melting point 288-290 ° C (decomposition)

Example 254 1-Methyl-7- [2- (1
Synthesis of H-pyrrol-1-yl) ethoxy] -4-trifluoromethyl-2-indoloylguanidine methanesulfonate (a) Ethyl 1-methyl-7- [2- (1H-pyrrol-1-yl ) Ethoxy] -4-trifluoromethyl-
Synthesis of 2-indolecarboxylate Ethyl 7- (2-aminoethoxy) -1-methyl-4-
Trifluoromethyl-2-indolecarboxylate (2.91 g, 8.81 mmol) in acetic acid (30 ml),
After adding 2,5-dimethoxyfuran (1.28 g, 9.69 mmol), the mixture was stirred at 50 ° C for 4 hours and further at 70 ° C for 1 hour. Toluene was added to the reaction mixture and the mixture was concentrated under reduced pressure. Ice water was poured into the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain ethyl-1-methyl-
7- [2- (1H-pyrrol-1-yl) ethoxy]-
1.96 g of 4-trifluoromethyl-2-indolecarboxylate was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.41 (3H, t, J = 7.3Hz), 4.28 (3H,
s), 4.37 (2H, q, J = 7.3Hz), 4.40 (4H, br-s), 6.18 (1
H, dd, J = 2.0Hz, 2.3Hz), 6.61 (1H, d, J = 8.3Hz), 6.75
(1H, dd, J = 2.0Hz, 2.3Hz), 7.28 (1H, dd, J = 1.0Hz, 8.
3Hz), 7.33 to 7.37 (1H, m).

(B) 1-Methyl-7- [2- (1H-
Synthesis of pyrrol-1-yl) ethoxy] 4-trifluoromethyl-2-indolecarboxylic acid Ethyl 1-methyl-7- [2- (1H-pyrrole-1-
Iyl) ethoxy] -4-trifluoromethyl-2-indolecarboxylate (1.94 g, 5.10 mmol) in ethanol (100 ml) and tetrahydrofuran (50 m).
It was dissolved in the mixed solution of l), 3.75N sodium hydroxide (10 ml) was added, and the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, the mixture was acidified with 2N hydrochloric acid and concentrated under reduced pressure, water (100 ml) was added to the obtained concentrated liquid, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was crystallized from chloroform / ethyl acetate to give 1-methyl-7- [2- (1H-pyrrole- 1-yl) ethoxy]
1.09 g of -4-trifluoromethyl-2-indolecarboxylic acid was obtained. ¹ Hnmr (DMSO-d ₆ ) δ; 4.16 (3H, s), 4.34 to 4.52 (4H,
m), 6.01 (1H, dd, J = 2.0Hz, 2.3Hz), 6.88 (2H, dd, J =
2.0Hz, 2.3Hz), 6.92 (1H, d, J = 8.3Hz), 7.09 ~ 7.14 (1
H, m), 7.40 (1H, dd, J = 1.0Hz, 8.3Hz), 13.26 (1H, br
-s). (c) 1-methyl-7- [2- (1H-pyrrole-1
-Yl) ethoxy] -4-trifluoromethyl-2-indoloylguanidine-synthesis of methanesulfonic acid 1-methyl-7- [2- (1H-pyrrol-1-yl)
Example 86 using ethoxy] -4-trifluoromethyl-2-indolecarboxylic acid (1.00 g, 2.84 mmol).
By carrying out the reaction according to the method of 1-methyl-
7- [2- (1H-pyrrol-1-yl) ethoxy]-
0.91 g of 4-trifluoromethyl-2-indoloylguanidine was obtained. This compound was treated with methanesulfonic acid / hydrous isopropyl alcohol to give 1-methyl-7- [2- (1H-pyrrol-1-yl) ethoxy] -4-trifluoromethyl-2-indoloylguanidine methane. 0.70 g of sulfonate was obtained. Melting point 216-217 ° C

Test Example 1 Na ⁺ / H ⁺ exchange transport system inhibitory effect (in vitro test) [Test method] Iemori et al. (J. Hypertension, 8, 153)
(1990)). That is, using rat thoracic aortic media-derived smooth muscle cells, the intracellular pH during acid loading was measured.
The change was used as an index to evaluate the inhibitory effect on the Na ⁺ / H ⁺ exchange transport system. [Test Results] The IC ₅₀ value of the inhibitory action on the Na ⁺ / H ⁺ exchange transport system according to the present test method was 0.058 μM for the compound of Example 1 of the present invention and 0.
05 μM, 2.1 μM for the compound of Example 22,
0.02 μM for compound of Example 55, Example 2
0.0009 μM for compound of Example 9, Example 118
Of the control compound was 0.01 μM, dimethyl amiloride of the control compound was 0.60 μM, and 5-hexamethylene amiloride was 0.14 μM.

Test Example 2 Na ⁺ / H ⁺ exchange transport system inhibitory effect (in vitro test) [Test method] Mungre et al. Method (Exp. Cell Res., 193,
236 (1991)). That is, the rat thoracic aortic media-derived smooth muscle cells were used to evaluate the Na ⁺ / H ⁺ exchange transport system inhibitory action using the cytotoxicity upon acid loading as an index. [Test Results] The minimum effective concentration (M) of the inhibitory action on the Na ⁺ / H ⁺ exchange transport system by the present test method for the compounds of each Example
EC) was as shown in Table 1.

[0294]

[Table 1]

[0295]

[Table 2]

[0296]

[Table 3]

[0297]

[Table 4]

[0298]

[Table 5] In Table 1, * indicates that measurement could not be performed due to cytotoxicity.

Test Example 3 Arrhythmia Inhibition Test by Ischemia-Reperfusion in Rats (In Vivo Test) [Test Method] Crome et al. (J. Cardiovasc. Pharmac
ol., 8, 1249 (1986)). That is, the suppression of arrhythmia induced by recanalization after coronary artery occlusion in rats was evaluated using the suppression of ventricular tachycardia incidence, ventricular fibrillation incidence and mortality as indexes. [Test Results] With respect to the compound of Example 1 of the present invention, the inhibitory effects on the incidence of ventricular tachycardia, the incidence of ventricular fibrillation, and the mortality rate in this test are shown in Table 2.

[0300]

[Table 6] [Table 2] Reperfusion arrhythmia suppression test ─────────────────────────────────── Compound dose Ventricular tachycardia incidence Ventricular fibrillation incidence mortality rate ─────────────────────────────────── Example 1 0.3 mg / kg 50% 0% 0% 0.1 mg / kg 70% 10% 10% EIPA 1 mg / kg 43% 0% 0% 0.3 mg / kg 100% 56% 44% Control group 100% 95% 76% ───────────────────────────────────

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical indication location A61K 31/445 ADP 31/535 ABQ C07D 401/10 209 401/12 209 403/10 209 249 403/12 233 257 405/10 209 413/10 209 (72) Inventor Naohito Ohashi 3-1,98 Kasugade, Konohana-ku, Osaka City Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Atsushi Kojima 3-chome, Kasugade, Konohana-ku, Osaka No. 1-98 Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Takeshi Noguchi 3-1,98 Kasuga, Konohana-ku, Osaka City In-house Sumitomo Pharma Co., Ltd. (72) Akira Miyagishi, Kasuga, Konohana-ku, Osaka 3-1, 98 Sumitomo Pharmaceutical Co., Ltd.

Claims (27)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ₁ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group,
Halogen atom, nitro group, acyl group, carboxyl group,
Alkoxycarbonyl group, aromatic group, or formula-O
_{R 3, -NR 6 R 7,} -SO 2 NR 6 R 7 or -S
A group represented by (O) _n R ₄₀ (R ₄₀ represents an alkyl group, a substituted alkyl group or an aromatic group, and n represents 0, 1 or 2), or Wherein, A represents an oxygen atom or the formula -S (O) _n - or -N (R ₅₀₎ - represents a group represented by (R ₅₀ represents a hydrogen atom or an alkyl group), R 'is a hydrogen atom, It represents an alkyl group or a substituted alkyl group, and the ring represents a saturated heterocycle containing one 3- to 8-membered nitrogen atom. ], Which may be substituted by one or the same or different, and R ₂ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a hydroxyl group, an alkoxy group, an aromatic group or a formula —CH ₂ R ₂₀ (R ₂₀ represents an alkenyl group or an alkynyl group). R ₃ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group,
An aromatic group or a group represented by the formula —CH ₂ R ₃₀ (R ₃₀ represents an alkenyl group or an alkynyl group), R ₆
And R ₇ are each independently a hydrogen atom, an alkyl group,
A substituted alkyl group, a cycloalkyl group, an acyl group, an aromatic group, or a group represented by the formula —CH ₂ R ₆₀ (R ₆₀ represents an alkenyl group or an alkynyl group), or R ₆ and R ₇ are mutually When combined, represents a saturated 5- to 7-membered cyclic amino group which may contain other heteroatoms in the ring. However, in the above general formula, the R ₁ group and the guanidinocarbonyl group may be bonded to either the 6-membered ring portion or the 5-membered ring portion of the indole ring. ) Indoyl guanidine derivative represented by the following) or a pharmaceutically acceptable acid addition salt thereof. 2. R ₁ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a halogen atom, a nitro group, an acyl group, a carboxyl group, an alkoxycarbonyl group, an aromatic group, or a formula. -O
_{R 3, -NR 6 R 7,} -SO 2 NR 6 R 7 or -S
The indoloylguanidine derivative according to claim 1, which is a group represented by (O) _n R ₄₀ , or a pharmaceutically acceptable acid addition salt thereof. 3. R ₂ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a hydroxyl group, an alkoxy group, or a group represented by the formula —CH ₂ R ₂₀ , and R ₃ is a hydrogen atom, an alkyl group, A substituted alkyl group, a cycloalkyl group,
Or a group represented by the formula —CH ₂ R ₃₀ (R ₃₀ represents an alkenyl group or an alkynyl group), and R ₆ and R ₇
Are each independently a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, or a group represented by the formula —CH ₂ R ₆₀ , or R ₆ and R ₇ are bonded to each other to form a ring in the ring. The indoloylguanidine derivative according to claim 1, which is a saturated 5- to 7-membered cyclic amino group optionally containing another hetero atom, and R ₄₀ is an alkyl group or a substituted alkyl group, or a pharmaceutically acceptable acid addition thereof. salt. 4. R ₁ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a cycloalkyl group, a halogen atom, a nitro group, an alkanoyl group, a carboxyl group, an aryl group, an alkylsulfonyl group, or a formula —OR ₃ or —NR ₆ R ₇ is a group, R ₃ is a hydrogen atom, an alkyl group or a substituted alkyl group, and R ₆ and R ₇ are each independently a hydrogen atom, an alkyl group, a substituted alkyl group, an alkanoyl group. Or an aroyl group or a saturated 5- to 7-membered cyclic amino group in which R ₆ and R ₇ are bonded to each other and may contain another hetero atom in the ring. Derivatives or pharmaceutically acceptable acid addition salts thereof. 5. R ₁ is a hydrogen atom, an alkyl group, a substituted alkyl group (provided that the substituent is a hydroxyl group or a —NR ₆ R ₇ group), a polyhaloalkyl group, an alkenyl group, a cycloalkyl group, a halogen atom, nitro. Group, alkanoyl group,
Carboxyl group, phenyl group, alkylsulfonyl group,
Or a group represented by the formula -OR ₃₁ (R ₃₁ represents a hydrogen atom or an alkyl group, or a hydroxyl group, a carboxyl group, a phenyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, or a group represented by the formula -NR ₆ R _7. A group represented by the formula (1) represents an alkyl group substituted with
The indoloylguanidine derivative described above or a pharmaceutically acceptable acid addition salt thereof. 6. R ₁ is an alkyl group, a polyhaloalkyl group, an alkenyl group, a halogen atom, a nitro group, or a formula —OR ₃₂ (R ₃₂ represents a hydrogen atom or an alkyl group, or a hydroxyl group, a carbamoyl group, a mono-group). Or a group represented by a di-alkylcarbamoyl group or an alkyl group substituted with a group represented by the formula —NR ₆ R ₇ ) or an indoloylguanidine derivative according to claim 3 or a pharmaceutically acceptable acid addition thereof. salt. 7. A hydrogen atom, an alkyl group, a substituted alkyl group, a hydroxyl group or an alkoxy group as R ₂ .
The indoloylguanidine derivative according to 4, 5 or 6 or a pharmaceutically acceptable acid addition salt thereof. 8. The indoloylguanidine derivative according to claim 1, which is a 2-indoloylguanidine compound, or a pharmaceutically acceptable acid addition salt thereof. 9. A compound represented by the general formula (2): (In the formula, R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₂ are each independently a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a halogen atom, a nitro group. , An acyl group, a carboxyl group, an alkoxycarbonyl group, an aromatic group, or the formula —OR ₃ , —N
_{R 6 R 7, -SO 2 NR} 6 R 7 or -S (O) _n R
₄₀ (R ₄₀ represents an alkyl group or a substituted alkyl group, n
Represents 0, 1 or 2), or Wherein, A represents an oxygen atom or the formula -S (O) _n - or -N (R ₅₀₎ - represents a group represented by (R ₅₀ represents a hydrogen atom or an alkyl group), R 'is a hydrogen atom, It represents an alkyl group or a substituted alkyl group, and the ring represents a saturated heterocycle containing one 3- to 8-membered nitrogen atom. ], R ₂ represents a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a hydroxyl group, an alkoxy group, an aromatic group, or a formula —CH ₂ R ₂₀ (R ₂₀ represents an alkenyl group or an alkynyl group. Represents a group). R ₃ is a hydrogen atom,
An alkyl group, a substituted alkyl group, a cycloalkyl group, an aromatic group, or a group represented by the formula —CH ₂ R ₃₀ (R ₃₀ represents an alkenyl group or an alkynyl group), R ₆ and R ₇ are independent of each other. A hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, or the formula —CH ₂ R ₆₀
Group represented in (R ₆₀ represents an alkenyl group or an alkynyl group) or represents, or binds R ₆ and R ₇ together, the 7 membered ring may saturated 5 also contain other hetero atoms in the ring Represents a cyclic amino group. ) The indoloylguanidine derivative according to claim 1 or a pharmaceutically acceptable acid addition salt thereof. 10. The indroylguanidine derivative according to claim 9, wherein R ₈ is a hydrogen atom, and R ₁₀ is a hydrogen atom or a halogen atom, or a pharmaceutically acceptable acid addition salt thereof. 11. R ₉ is a hydrogen atom, an alkyl group, a polyhaloalkyl group, a cycloalkyl group, an alkenyl group, a halogen atom, a nitro group, an alkylsulfonyl group, or a formula —OR ₃₃ (R ₃₃ is a hydrogen atom, an alkyl group or An indroylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 9 or 10, which is a group represented by an aralkyl group). 12. R ₁₁ and R ₁₂ , independently of one another,
Hydrogen atom, an alkyl group, a substituted alkyl group (wherein the substituent is a hydroxyl group or -NR ₆ R ₇ group) polyhaloalkyl group, an alkenyl group, a cycloalkyl group, a halogen atom, a nitro group, or the formula -OR ₃ or, -NR ₆ R ₇
The indoloylguanidine derivative according to claim 9, 10 or 11 or a pharmaceutically acceptable acid addition salt thereof, which is a group represented by: 13. R ₂ is a hydrogen atom, an alkyl group, a substituted alkyl group, claim 9 is a hydroxyl group or an alkoxy group,
The indoloylguanidine derivative according to 10, 11 or 12 or a pharmaceutically acceptable acid addition salt thereof. 14. A general formula: (In the formula, R ₁ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group,
Halogen atom, nitro group, acyl group, carboxyl group,
Alkoxycarbonyl group, aromatic group, or formula-O
_{R 3, -NR 6 R 7,} -SO 2 NR 6 R 7 or -S
A group represented by (O) _n R ₄₀ (R ₄₀ represents an alkyl group, a substituted alkyl group, or an aromatic group, and n represents 0, 1 or 2), or Wherein, A represents an oxygen atom or the formula -S (O) _n - or -N (R ₅₀₎ - represents a group represented by (R ₅₀ represents a hydrogen atom or an alkyl group), R 'is a hydrogen atom, It represents an alkyl group or a substituted alkyl group, and the ring represents a saturated heterocycle containing one 3- to 8-membered nitrogen atom. ], Which may be substituted by one or the same or different, and R ₂ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a hydroxyl group, an alkoxy group, or a formula-C.
H ₂ R ₂₀ (R ₂₀ represents an alkenyl group or an alkynyl group), or an aromatic group. However, R ₂
Is aromatic, R _a represents R ₁ , and R ₂ represents a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a hydroxyl group, an alkoxy group, or the formula —CH ₂
In the case of the group represented by R ₂₀ , R _a represents one or more groups selected from the following (a) to (d), which are the same or different from each other,
(A) an alkyl group, a substituted alkyl group, an alkoxycarbonyl group, a carboxyl group, -CONR ₆ R _7, -SO ₂
An arylalkyl group or a heteroarylalkyl group having a substituent selected from the group consisting of NR ₆ R ₇ and —S (O) _n R ₄₀ in the aryl moiety and the heteroaryl moiety, (b) formula —A—R _b [A Is an oxygen atom or the formula -S
(O) _n - or -N (R ₅₀₎ - group represented by (R ₅₀
Represents a hydrogen atom or an alkyl group), R _b represents an aryl group or a heteroaryl group, and the aryl group and the heteroaryl group are an alkyl group, a substituted alkyl group, a halogen atom, a nitro group, an alkoxycarbonyl group, carboxyl _{group, -OR 3, -NR 6 R 7} , -CO
_{NR 6 R 7, -SO 2 NR} 6 R 7 and -S (O) _n R
_It may have a substituent selected from the group consisting of ₄₀ . ] A group represented by the formula (c): Wherein, A represents an oxygen atom or the formula -S (O) _n - or -N (R ₅₀₎ - represents a group represented by (R ₅₀ represents a hydrogen atom or an alkyl group), R 'is a hydrogen atom, It represents an alkyl group or a substituted alkyl group, and the ring represents a saturated heterocycle containing one 3- to 8-membered nitrogen atom. ] The group shown by
Equation (d) -A- (CH _{2) m} -R _c [A represents an oxygen atom or the formula -S (O) _n - or -N (R ₅₀₎ - group (R ₅₀ represented by a hydrogen atom or an alkyl group Represents),
R _c represents an aryl group or a heteroaryl group, and the aryl group and the heteroaryl group are an alkyl group, a substituted alkyl group, an alkoxycarbonyl group, a carboxyl group, —OR ₃₁ , —CONR ₆ R ₇ , —SO ₂ NR ₆ R ₇
And —S (O) _n R ₄₀ having a substituent selected from the group consisting of, m represents 1 to 8, R ₃₁ represents a substituted alkyl group,
It represents a cycloalkyl group or —CH ₂ R ₃₀ (R ₃₀ is an alkenyl group or an alkynyl group). ] A group represented by the formula, R ₃ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, an aromatic group, or a group represented by the formula —CH ₂ R ₃₀ (R ₃₀ represents an alkenyl group or an alkynyl group). And R ₆ and R ₇ are each independently a hydrogen atom,
An alkyl group, a substituted alkyl group, a cycloalkyl group, an acyl group, or a group represented by the formula —CH ₂ R ₆₀ (R ₆₀ represents an alkenyl group or an alkynyl group), or R ₆ and R ₇ are bonded to each other. And represents a saturated 5- to 7-membered cyclic amino group which may contain other heteroatoms in the ring. However, in the above general formula, the R ₁ , R _a and guanidinocarbonyl groups may be bonded to either the 6-membered ring portion or the 5-membered ring portion of the indole ring. )
The indoloylguanidine derivative represented by or a pharmaceutically acceptable acid addition salt thereof. 15. R _a represents an arylalkyl group or a heteroarylalkyl group, and these aryl and heteroaryl moieties are an alkyl group, a substituted alkyl group, an alkoxycarbonyl group, a carboxyl group, and —C.
_{ONR 6 R 7, -SO 2 NR} 6 R 7 and -S (O) _n
Has a substituent selected from the group consisting of R ₄₀ , or R
_a is a formula-A- _Rb [A is an oxygen atom or a formula-S (O) _n.
- or -N (R ₅₀₎ - group represented by (R ₅₀ is hydrogen atom or an alkyl group) represents, R _b represents an aryl group or a heteroaryl group, said aryl and heteroaryl groups are alkyl group, a substituted alkyl group, a halogen atom, a nitro group, an alkoxycarbonyl group, a carboxyl _{group, -OR 3, -NR 6 R 7} , -CONR
₆ R _7, which may have a substituent selected from the group consisting of -SO ₂ NR ₆ R ₇ and -S (O) _n R _40. Groups represented by] or formula -A- (CH _{2) m} -R _c [A,
Is an oxygen atom or the formula —S (O) _n — or —N
(R ₅₀₎ - group represented by (R ₅₀ is hydrogen atom or an alkyl group) represents, R _c represents an aryl group or a heteroaryl group, the aryl group and heteroaryl group, an alkyl group, a substituted alkyl Group, alkoxycarbonyl group, carboxyl group, -OR ₃₁ , -CONR ₆ R ₇ ,
Has a substituent selected from the group consisting of —SO ₂ NR ₆ R ₇ and —S (O) _n R ₄₀ , m represents 1 to 8, and R
₃₁ is a substituted alkyl group, a cycloalkyl group, -CH ₂ R
₃₀ (R ₃₀ is an alkenyl group or an alkynyl group). ] The indoloyl guanidine derivative or the pharmaceutically acceptable acid addition salt thereof according to claim 14, which represents a group represented by: 16. R ₂ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a hydroxyl group, an alkoxy group,
Represents a group represented by the formula —CH ₂ R ₂₀ (R ₂₀ represents an alkenyl group or an alkynyl group), R _a represents an arylalkyl group or a heteroarylalkyl group, and these aryl and heteroaryl moieties are each represented by alkyl group, a substituted alkyl group, an alkoxycarbonyl group, a carboxyl group, -CONR ₆ R _7, -
SO ₂ NR ₆ R ₇ and _{-S (O) n R 40 (} R 40 represents an alkyl group or a substituted alkyl group, n represents 0, 1 or 2) having a substituent selected from the group consisting of, Or, R _a is of the formula —A—R _b [A is an oxygen atom or of the formula —S
(O) _n - or -N (R ₅₀₎ - group represented by (R ₅₀
Represents a hydrogen atom or an alkyl group), R _b represents an aryl group or a heteroaryl group, and the aryl group and the heteroaryl group are an alkyl group, a substituted alkyl group, a halogen atom, a nitro group, an alkoxycarbonyl group, carboxyl _{group, -OR 3, -NR 6 R 7} , -CO
_{NR 6 R 7, -SO 2 NR} 6 R 7 and -S (O) _n R
_It may have a substituent selected from the group consisting of ₄₀ . Represents a group represented by], R ₃ represents a hydrogen atom, an alkyl group, a substituted alkyl group, a group represented by a cycloalkyl group, or a group of the formula -CH ₂ R ₃₀ (R ₃₀ represents an alkenyl group or an alkynyl group), R ₆
And R ₇ are each independently a hydrogen atom, an alkyl group,
A substituted alkyl group, a cycloalkyl group, an acyl group, or a group represented by the formula —CH ₂ R ₆₀ (R ₆₀ represents an alkenyl group or an alkynyl group), or R ₆ and R ₇ are bonded to each other, The indoloylguanidine derivative according to claim 14 or a pharmaceutically acceptable acid addition salt thereof, which represents a saturated 5- to 7-membered cyclic amino group which may contain other heteroatoms in the ring. 17. A compound represented by the general formula (2): (In the formula, R ₂ represents a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a hydroxyl group, an alkoxy group, or a formula —CH ₂ R ₂₀ , and R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₂ are represented. Are, independently of each other, a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a halogen atom, a nitro group, an acyl group, a carboxyl group, an alkoxycarbonyl group, an aromatic group, or a formula- _{OR 3, -NR 6 R 7,} -SO 2 NR 6 R 7, -S
(O) _n represents a group represented by R ₄₀ or R _a ,
At least one of R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₂ is a group represented by the formula R _a . ) The indoloylguanidine derivative according to claim 14 or a pharmaceutically acceptable acid addition salt thereof. 18. R ₈ is a hydrogen atom, and R ₉ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a halogen atom, a nitro group, an acyl group, a carboxyl group, an alkoxycarbonyl. group, or a group of the formula _{-OR 3,, -NR 6 R 7} , -SO 2 NR 6
R ₇ or —S (O) _n R ₄₀ is a group represented by R
18. The indoylylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 17, wherein ₁₀ , R ₁₁ and R ₁₂ are each independently a hydrogen atom or a group represented by the formula R _a . 19. R ₁₀ is a hydrogen atom, and R ₁₁ and R
19. The indoloylguanidine derivative according to claim 18, or a pharmaceutically acceptable acid addition salt thereof, wherein ₁₂ is independently of each other a hydrogen atom or a group represented by the formula R _a . 20. R ₉ is a hydrogen atom, an alkyl group, a substituted alkyl group, a halogen atom, a nitro group, or the formula —OR ₃
The indoloylguanidine derivative according to claim 19, which is a group represented by: or a pharmaceutically acceptable acid addition salt thereof. 21. R _a is an alkyl group, a substituted alkyl group,
Alkoxycarbonyl group, carboxyl group, -CONR
_{6 R 7, -SO 2 NR 6} R 7 and -S (O) or have a substituent selected from the group consisting of _n R ₄₀ is also an arylalkyl group, or, R _a formula -A Is a group represented by —R _b , A is an oxygen atom or a formula —S (O) _n
- or -N (R ₅₀₎ - is a group represented by, R _b is an alkyl group, a substituted alkyl group, an alkoxycarbonyl group, a carboxyl _{group, -CONR 6 R 7, -SO 2} NR
₆ R ₇ and -S (O) according to claim 20 optionally having a substituent selected from the group consisting of _n R ₄₀ is also an aryl group
The indoloylguanidine derivative described above or a pharmaceutically acceptable acid addition salt thereof. 22. The indoloylguanidine derivative according to claim 1, which is the compound according to any one of the following (1) to (24), or a pharmaceutically acceptable acid addition salt thereof. (1) 7- (2-aminoethoxy) -4-chloro-1
-Methyl-2-indoloylguanidine (2) 7- (3-aminopropoxy) -4-chloro-
1-Methyl-2-indoloylguanidine (3) 4-chloro-7- (3-dimethylaminopropoxy) -1-methyl-2-indoloylguanidine (4) 1- (3-aminopropyl) -4-chloro -2
-Indoloylguanidine (5) 6- (3-aminopropoxy) -1-methyl-
4-trifluoromethyl-2-indoloylguanidine (6) 6- (3-dimethylaminopropoxy) -1-
Methyl-4-trifluoromethyl-2-indoloylguanidine (7) 7- (3-aminopropoxy) -1,4-dimethyl-2-indoloylguanidine (8) 1-methyl-6- [2- (N -Pyrrolidinyl)
Ethoxy] -4-trifluoromethyl-2-indoloylguanidine (9) 4-chloro-7- (3-diethylaminopropoxy) -1-methyl-2-indoloylguanidine (10) 7- (3-dimethylaminopropoxy ) -1
-Methyl-4-trifluoromethyl-2-indoloylguanidine (11) 7- (3-aminopropoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine (12) 7- (2-amino Ethoxy) -1-methyl-
4-trifluoromethyl-2-indoloylguanidine (13) 7- (2-dimethylaminoethoxy) -1-
Methyl-4-trifluoromethyl-2-indoloylguanidine (14) 6- (2-dimethylaminoethoxy) -1-
Methyl-4-trifluoromethyl-2-indoloylguanidine (15) 6- (2-diethylaminoethoxy) -1-
Methyl-4-trifluoromethyl-2-indoloylguanidine (16) 7- [4- (aminomethyl) phenoxy]-
4-Chloro-1-methyl-2-indoloylguanidine (17) 6- (2-aminoethoxy) -1-methyl-
4-Trifluoromethyl-2-indoloylguanidine (18) 7- [4- (aminomethyl) benzyloxy] -4-chloro-1-methyl-2-indoloylguanidine (19) 6- [4- (amino Methyl) benzyloxy] -4-chloro-1-methyl-2-indoloylguanidine (20) 6- [4- (aminomethyl) phenoxy]-
4-Chloro-1-methyl-2-indoloylguanidine (21) 4-chloro-6- [4- (dimethylaminomethyl) phenoxy] -1-methyl-2-indoloylguanidine (22) 4-chloro-7 -[4- (Dimethylaminomethyl) phenoxy] -1-methyl-2-indoloylguanidine (23) 4-chloro-7- [4- (dimethylaminomethyl) benzyloxy] -1-methyl-2-indoloyl Guanidine (24) 4-chloro-6- [4- (dimethylaminomethyl) benzyloxy] -1-methyl-2-indoloylguanidine 23. R ₁ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a halogen atom, a nitro group, an acyl group, a carboxyl group, an alkoxycarbonyl group, an aromatic group, or a formula. -O
_{R 3, -NR 6 R 7,} -SO 2 NR 6 R 7 or -S
(O) _n represents a group represented by R _40, which may be substituted one by one or the same or different, and R ₂ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group,
A hydroxyl group, an alkoxy group, a group represented by the formula —CH ₂ R ₂₀ ,
Or an aromatic group, R _a is the same or different and may be substituted, and represents an arylalkyl group or a heteroarylalkyl group, wherein the aryl moiety and the heteroaryl moiety are an alkyl group, Substituted alkyl group, alkoxycarbonyl group, carboxyl group, -CONR
₆ R ₇ and —SO ₂ NR ₆ R ₇ have a substituent selected from the group consisting of, or R _a is a formula —A—R _b [A is an oxygen atom or a formula —S (O) _n — or -N (R ₅₀ )
Represents a group (R ₅₀ is a hydrogen atom or an alkyl group), R _b represents an aryl group or a heteroaryl group, and the aryl group and the heteroaryl group are an alkyl group, —NR ₆ R ₇ substituted alkyl group, a halogen atom, a nitro group, an alkoxycarbonyl group, a carboxyl _{group, -OR 3, -NR 6 R 7} , -CONR 6 R 7,
And a substituent selected from the group consisting of —SO ₂ NR ₆ R ₇ . ] The group shown by these, or formula -A- (CH
_{2) m} -R _c [A represents an oxygen atom or the formula -S (O) _n - or -N (R ₅₀₎ - group (R ₅₀ represented by represents a hydrogen) atom or an alkyl group, R _c is an aryl group or a heteroaryl group, the aryl group and heteroaryl group, an alkyl group, an alkyl group substituted with -NR ₆ R _7, an alkoxycarbonyl group, a carboxyl group, -OR _31, -CONR ₆ R ₇ and -SO ₂ NR ₆
Has a substituent selected from the group consisting of R ₇ and m is 1 to 8
The stands, R ₃₁ is a substituted alkyl group, a cycloalkyl group,
-CH ₂ R ₃₀ (R ₃₀ is an alkenyl group or an alkynyl group). ] The indoloyl guanidine derivative or the pharmaceutically acceptable acid addition salt thereof according to claim 14, which represents a group represented by: 24. R _a is Wherein, A represents an oxygen atom or the formula -S (O) _n - or -N (R ₅₀₎ - represents a group represented by (R ₅₀ represents a hydrogen atom or an alkyl group), R 'is a hydrogen atom, It represents an alkyl group or a substituted alkyl group, and the ring represents a saturated heterocycle containing one 3- to 8-membered nitrogen atom. ] The indoloyl guanidine derivative or the pharmaceutically acceptable acid addition salt thereof according to claim 14, which represents a group represented by: 25. Claims 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23 or 24
A medicament containing the indoloylguanidine derivative described above or a pharmaceutically acceptable acid addition salt thereof. 26. Claims 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23 or 24
A sodium / proton exchange transport system inhibitor containing the indoloylguanidine derivative described above or a pharmaceutically acceptable acid addition salt thereof. 27. Hypertension, arrhythmia, angina, cardiac hypertrophy, diabetes, organ damage due to ischemia or ischemia-reperfusion, cerebral ischemia damage, diseases caused by hyperproliferation of cells or diseases caused by damage to endothelial cells. 27. The sodium / proton exchange transport system inhibitor according to claim 26, which is a therapeutic or prophylactic agent for