JPS62149651A - Dichloroaniline derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Background of the Invention] The present invention relates to dichloroaniline derivatives having a stimulating effect on β2-adrenergic receptors, methods for producing them, pharmaceutical compositions containing them, and medical uses thereof. Regarding.

Dihaloaniline derivatives have previously been described as bronchodilators with stimulatory effects on β-adrenergic receptors.

In this way, British Patent No. 1178191 specifies that
-Shell structure: (In the above formula, the substituent halo represents a bromine or chlorine atom,
R1 represents hydrogen or hydroxy, R2 and R3 each represent hydrogen or C1-4 alkyl, R4 and R5 each represent hydrogen, "!-6 alkyl, alkenyl, alkynyl, hydroxyalkyl.

Represents or is alkoxyalkyl, dialkylaminoalkyl, cyclopurkyl, phenyl, benzyl or adamantyl (NR4R5 forms a heterocyclic ring optionally substituted with a C1-3 alkyl group) There is a description of.

[Detailed description of the invention]

We have now discovered a new group of dichloroaniline derivatives which are structurally different from the compounds described in GB 1 178 191, yet have desirable and useful active aspects.

Compounds The present invention therefore provides compounds of general formula (T), as well as physiologically acceptable salts and solvates (eg hydrates) thereof.

(In the above formula,
Represents noalkenylene or a C2-6 alkynylene chain.

Y represents a bond, C1-4 alkylene, C2-4 alkenylene or C2-4 alkynylene.

However, the total number of carbon atoms in X and Y is 8 or less.

Ar is nitro, -(OH2)qRCR is 01-3 i
7) 7 /l/jxy, -NR3R4 (R3 and R
4 each represents a hydrogen atom or a C1-4 alkyl group, or -NR3R' is a 5- to 7-membered ring, and optionally 10- or -8- or a group -Nu
- or -N(OH3)- to form a saturated heterocyclic amino group in the ring], -NR500R' (R5 is a hydrogen atom or C
1-4 represents an alkyl group, R6 is a hydrogen atom, 01-
4 alkyl, C1-4 alkoxy or -NRR group), and q represents an integer of 1 to 3], -
(CHz) rR' CR7 is -NR5SO2R8(R8
represents a C1-4 alkyl, phenyl or -1JR3R' group), -NR5COOH2N(R') 2 (each group R represents a hydrogen atom or a cl-4 alkyl group), -00R9 (R9 is hydroxy, C1-4 alkoxy or -NR3R'), -E3R (R is
hydrogen atom, or optionally a C1-4 alkyl group substituted with hydroxy, C1-4 alkoxy or -NR3R'), -dayOR, -802R, -ON or -NR11R12< RII and R are hydrogen atoms or C1
-4 alkyl group, at least one of which is hydroxy, Cl-4 alkoxy or -NR3R
' is a C2-4 alkyl substituted with a group], r represents an integer from 0 to 3], -0(0H2)900
R9 (q and R9 have the same meaning as above) or -0 (C
H2) tR13 (R13 is hydroxy, JIR3R',
-NRII R12, or optionally hydroxy, C
1-4 alkoxymodi represents a C1-4 alkoxy group substituted with -NR3R', and t is an integer of 2 or 3]. represent.

R1 and R2 each represent a hydrogen atom or a C1-3 alkyl group. However, the total number of carbon atoms of R1 and R2 is 4 or less) The compound of general formula (I) has one or two asymmetric carbon atoms R2
It should be noted that if are different groups, they have a carbon atom attached to them.

The compounds of the present invention therefore include all enantiomers, including racemates, diastereomers and mixtures thereof. Compounds in which the carbon atom of the -0H- group H is in the R configuration are preferred.

In the definition of general formula (I), alkenylate/t(,5g
includes both cis and trans structures.

- aspect, the present invention provides R1, R2, X, Y and A
r has the same meaning as in formula (I), and R7 is -NR5B0
□R8, -COR9, -8R", -SOR", -8o
2R'', -ON or -NR.

In the general formula (1), (, a chain or, for example, a bond, -C
H2-1-(OH2)2-1-(OH2)3-1-(C
H2) di, -(OH2), -1-(OH2)6-1-O
H2cm, 0-5-(CH2)20H-OH-1-(O
H2) 2c=c-1-0H-CHOH2-1-ca-
cu(ca2)2- or -0H20=OOH2-. Chain Y is, for example, a bond, -(1!H2-1-[[Hz
h-1-(CR2)3-1-(OH2)4-1-CH-
OH-1-c=o-5-cn2ca-ca- or -0H
It is 20aO-.

Preferably, the total number of carbon atoms in chains X and Y is from 4 to 8
It is. The total number of carbon atoms in gx and Y is 4.5.6
or 7 are particularly preferred.

One preferred group of compounds of formula (I) is that X is CI-6
represents an alkylene chain, and Y represents a C1-4 alkylene chain. Specific compounds of this type include those in which X represents -(CH2)3- or -(C)12)4-, and Y
10H2-1-(OH2)2- or -(OH2) 3
- is a compound.

In the compound of formula (■), R1 and R2 are each a methyl, ethyl, propyl or isopropyl group, however, if one of R1 and R2 is a propyl or isopropyl group, the other is A hydrogen atom or a methyl group.Thus, for example, R1 is a hydrogen atom, a methyl, ethyl or propyl group.R2 is, for example, a hydrogen atom or a methyl group.R1 and R2 are each preferably a hydrogen atom or a methyl group. It is.

A preferred group of compounds are those in which R1 and R2 are both hydrogen atoms, or R1 is a hydrogen atom and R2 is a C1-3 alkyl group, especially a methyl group.

When 1NR3R' in the compound of formula (I) represents a saturated heterocyclic amino group, this group Gi may be a 5.6- or 7-membered ring, and optionally 10-1-S-1 group- N
has a heteroatom selected from H- or -N[[J(3)-] in the ring. Examples of such -NR"R' groups include pyrrolidino, piperidino, hexamethyleneimino, piperazino, N-methylpiperazino, morpholino,
It is homomorpholino or thiamorpholino.

Ar is, for example, -(OH2)qR[R is 01-3 alkoxy, such as methoxy, diC1-4 alkylamino, such as dimethylamino, morpholino, piperidino,
piperazino, N-methylpiperazino, -NHCOR
6 (R' is C1-4 alkyl, e.g. methyl)
, q is 1 or 2] , -(C'Hz)r
R7 (R7 is -NR5B0□R8 (R5 represents hydrogen or methyl, R8 represents C1-4 alkyl, e.g. methyl), -NHOOOH2N(R5)2 (both groups R5 are C1-4 alkyl, e.g. (represents methyl)
, -00R'< R9 represents alkoxy of Cl-4, such as ethoxy, amino, di-C1-4 alkylamino, such as dimethylamino, morpholino, piperidino, piperazino or N-methylpiperazino), -NR
R (one or both of R11 and R42 represents a C2-4 alkyl substituted with a hydroxy or di-C1-4 alkylamino group, such as a dimethylamino group, such as an ethyl group, and the other represents a hydrogen atom), r is 0
or l], -QC! H2O0R9 (R9 is diC1
-4 alkylamino, for example dimethylamino) or -0(cH2)2R13 (B, 1B is diO1-, alkylamino, for example dimethylamine).

A preferred compound group of the present invention is represented by the following formula (Ia) [In the above formula, X represents an alkylene chain of 03-4, and Y represents 01-
3, provided that the total number of carbon atoms in X and Y is 5 or 6. Ar is C1-4 alkoxymethyl (e.g. methoxymethyl), morpholinomethyl, di-C1-4 alkylami/01-2 alkyl (e.g. dimethylaminoethyl), -0H21cOR'
(R' is 01-4 alkyl, e.g. methyl)
, -NR5S02R' (R5 is hydrogen or methyl and R8 is alkyl of 01-4, e.g. methyl),
-NHCOOH2N(R')2 (both groups R5 are C1
-4 alkyl, e.g. methyl), -0OR'
(R' is hydroxy, 01-4 alkoxy, e.g. ethoxy, amino, di-C1-4 alkylamino, e.g. dimethylamino or morpholino), -0H200
R' (R9 is amino or diC1-4 alkylamino,
For example, dimethylamino), -NR11R12 (R
and R both represent hydroxyC2-4alkyl, e.g. dimethylamino) or -0(OH2)
2R13 (R13 represents a phenyl group substituted with a group selected from diq-4 alkylamino, for example dimethylamino) and physiologically acceptable salts and solvates thereof.

Particularly preferred compounds of formula CIN) are those in which X and Y are of formula (I
It has the same meaning as in case a), and Ar is -an2hucoR
'(R'halfk"'C-a; 6 ), -NH8O2
R' (R8 fitting), -00R'(R'
is hydroxy, ethoxy, amino or morpholino] or -0H2COR'(R' is amino or dimethylamino), as well as physiologically acceptable salts and solvents thereof. It is Japanese.

Compounds of particular importance to the invention are as follows.

4-[3-[[6-[[6-(4-amino-3゜5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]furovir]benzamide, 4-[3-[[6-[ C(4-Amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino[hexyl]oxy]propyl]ethyl benzoate, N-C[3-(3-[6-[[2-(4-amino -3,
5-dichlorophenyl)-2-hydroxyethyl[amino]hexyl]oxy]propyl]phenyl]methyl
Acetamide, 4-[4-[5-[I:2-(4-amino-3゜5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]pentyloxy]phthyl]-N,N-dimethylbenzene Acetamide, 4-[3-[[66-[(”z-(4-amino-3゜5
- dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]propylbenzoic acid, 4-[4-[3-[[6-[[2-(4-ami/-3,
5-dichlorophenyl)-2-hydroxyethyl]amino[hexyl]oxy]furovir]be/diyl 3morpholine,
5-dichlorophenyl)-2-hydroxyethyl[amino]hexyl]oxy]ethyl]phenyl]methanesulfonamide, 4-[3-[6-[[[:2-(4-amino-3゜5-dichlorophenyl)-2] -hydroxyethyl]amino]hexyl[oxy]propyl]benzeneacetamide, and its physiologist-acceptable salts and solvates.

Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochloride, hydrobromide, sulfate.

Phosphate, maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluenesulfonate , methanesulfonate, sulfamate, ascorbate, salicylate, acetate, fumarate, conophosphate, lactate, glutarate, gluconate, tricarballylate, hydroxy-naphthalene carbonate These include acid salts, such as 1-hydroxy- or 3-hydroxy-2-naphthalenecarboxylic acid salts, or oleate salts. Compounds can form salts with suitable bases. Examples of such salts include alkali metals (
For example, salts of sodium and potassium) and alkaline earth metals (eg calcium or magnesium).

Utility of the Compounds/Pharmaceuticals The compounds of the invention have a stimulatory action on β2-adrenergic receptors, which constitutes a further particularly advantageous aspect. The stimulatory effect was demonstrated in isolated guinea pig trachea, where the compound induced PGF2α
It has been shown to cause relaxation of induced contractions. The compounds of the invention showed a particularly long-lasting effect in this test.

The compounds of the invention can be used in the treatment of diseases associated with reversible tracheal obstruction, such as asthma and chronic bronchitis.

The compounds of the invention are useful for treating inflammatory and allergic skin diseases,
It is also used in the treatment of congestive heart failure, gourid disease, premature birth, glaucoma, and in the treatment of conditions such as reducing gastric acidity, which is beneficial in the case of gluttony and peptic ulcers.

The invention therefore further provides compounds of formula (T), physiologically acceptable salts and solvates thereof, for use in the treatment or prevention of diseases associated with reversible tracheal obstruction in humans or animals. It is something to do.

The compounds of the invention may be formulated for administration in any convenient manner. The invention therefore falls within its scope to be formulated for use in human or veterinary medicine. Included are pharmaceutical compositions containing at least one compound of formula (I), or a physiologically acceptable salt or solvate thereof.Such compositions include, in use, the following:
Physiologically acceptable carriers or excipients, and optionally pharmaceutical auxiliaries may also be included.

The compounds may be formulated in a form suitable for administration by inhalation or insufflation, or for oral, buccal, parenteral, topical (including nasal) or rectal administration.

Administration by inhalation or insufflation is preferred.

For administration by inhalation, the compounds of the invention can be administered from a pressurized nebulizer using a suitable propellant such as dichlorodifluorometa/, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Conveniently, it is released in the form of an aerosol spray administration. In the case of pressurized aerosols, the dosage unit may be determined by providing a valve to release a metered amount.

Alternatively, for administration by inhalation or insufflation, the compounds of the invention may take the form of a dry powder composition, eg, a powder mix of the compound and a suitable powder base such as lactose or starch. Powder compositions may be administered, for example, in capsules or cartridges such as gelatin, or the powder may be administered with the aid of an inhaler or a powder blower (or the powder may be in dosage form in a blister pack). .

For oral administration, the pharmaceutical compositions may, for example, be in the form of tablets, capsules, powders, solutions, syrups or suspensions, which may be prepared by conventional means with acceptable excipients. Moyo(・.

For oral vaginal administration, the compositions may take the form of tablets, drops or lozenges formulated in conventional manner.
・.

The compounds of the invention may be formulated for parenteral administration by bonus injection or continuous infusion.

Preparations for injection may be presented in unit dosage form in ampoules or in multi-dose containers with an added preservative. It may take the form of P clouding agent, stabilizer and (
or) Contains prescription agents such as dispersants.
. The active ingredient may be in powder form for reconstitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

For topical administration, the pharmaceutical compositions may take the form of ointments, lozenges or creams formulated in conventional manner, e.g. with an aqueous or oily base, the usual suitable thickening agents and/or solvents. (・. For nasal administration, the composition is
It may take the form of a spray, formulated for example as an aqueous solution or suspension, or as an aerosol using a suitable propellant.

The compounds of the invention may be formulated as rectal compositions, eg, skewers or long-acting enemas, containing conventional herbal bases such as cocoa butter or other glycerides.

When the pharmaceutical compositions are as described above for oral, buccal, rectal or topical administration, they may be prepared in conventional manner for controlled release forms.

The daily dose of active compound proposed for human treatment is 0.
．． 005 fng to 100 mg, which is conveniently administered in one or two divided doses. The exact dosage applied will of course depend on the age of the patient, the condition and the route of administration. Therefore, appropriate dosages are 0.005 mg to 20 mg for inhalation, 0.02 mg to 100 mg for oral administration, and 0.01 mg for parenteral administration by porous injection.
mg, ~2 mg, 0.01 m if administered by injection
g to 25 mg.

Preparation of Compounds Compounds of the present invention can be prepared by several methods, including those described below. In the following method for producing the compound of formula CI) and the intermediates used in its production,
X, Y, Ar, R1 and R2 have the same meanings as in general formula (I) unless otherwise specified.

Furthermore, any substituent on the group Ar may be a radical substituent before being converted into the required substituent by conventional methods (.

It should be recognized that some of the reactions described below may affect other groups in the starting materials that are desired in the final product. , and where an ethylene or acetylene linkage is required in the compounds of the invention, the following reduction procedure (•) is particularly applicable. Therefore, care should be taken in accordance with customary practice.
One must aim to carry out the reaction using reagents that do not affect such groups or avoid their use as part of the process if such groups are present in the starting materials.

In the preparation of intermediates and final products, the final step of the reaction may be the removal of the protecting group. Conventional protecting groups, e.g.・McCormie (Frenum Press, 1973)
[”Protective Groups inOrg
anic Chemistry', 'H:, eL,
J, F.J., McOmie (Plenum Pr.
ess, 1973)] Protecting groups such as those described in K may be used (. Thus, a hydroxy group can be protected, for example, by an aralkyl group such as benzyl, diphenylmethyl or triphenylmethyl, or by a tetrahydropyrani group. It may be protected as a derivative (・. As a suitable amino protecting group.

There are aralkyl groups such as benzyl, alpha-methylbenzyl, diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl.

Conventional deprotection methods may be applied. therefore,
For example, an aralkyl group may be removed by hydrogenolysis in the presence of a metal catalyst (eg, palladium on charcoal). Tetrahydropyranyl groups can be cleaved by hydrolysis under acidic conditions. The acyl group is
It can be removed by hydrolysis with acids such as mineral acids such as hydrochloric acid or bases such as sodium hydroxide or potassium carbonate; groups such as trichloroacetyl can be removed by reduction with e.g. zinc and acetic acid. can do.

In one general process (1), the general formula (T)
The compounds may be prepared by alkylation.

Conventional alkylation methods may be applied.

Thus, for example, in one process (a),
The compound of the general formula CI) in which R1 is a hydrogen atom is a compound of the general formula (II): (In the above formula, R14 is a hydrogen atom or a protective group, and R1
5 is a hydrogen atom) and then removing the protective groups present.

Alkylation (al is the general formula (■): LOHxCH200B2YAr (■) (wherein L is a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or methanesulfonyloxy or I)-) toluene The reaction may be carried out using an alkylating agent (which is the ionahydrocarbylsulfonyloxy group of sulfonyloxy).

Alkylation is carried out in the presence of a suitable scavenging agent, for example an inorganic ring group such as sodium or potassium carbonate, an organic base such as triethylamine, diimpropylethylamine or pyridine, or an alkylene oxide such as nitylene oxide or propylene oxide. It is preferable that the process be carried out in The reaction is carried out in a solvent such as acetonitrile, or a ketone such as trihydrofuran or dioxane, a ketone such as butanone or methyl in butyl ketone, a substituted amide such as dimethylformamide, or a chlorinated hydrocarbon such as chloroform.
It is convenient to carry out at a temperature between the ring temperature and the continuous flow temperature of the solvent.

Another fl of the alkylation process, + (1) A compound of general formula (I) in which according to 3 R1 represents a hydrogen atom,
An amine of general formula (TI) as defined above except that Ri5 is a hydrogen atom or a group convertible thereto under reaction conditions is reacted with general formula (■): R2 (!0XO) in the presence of a reducing agent.
It may be prepared by alkylation with a compound of 1200H2YAr (■) and then removing the protecting group if necessary with ().

Examples of suitable R15 groups convertible to hydrogen atoms are benzyl, α-methylbenzyl, and arylmethyl groups such as benzhydryl.

Suitable reducing agents include hydrogen in the presence of a catalyst such as platinum, platinum oxide, palladium, palladium oxide, Raney nickel or rhodium on a support such as charcoal, for example 20 1 at ~100℃
~10 atm, at room temperature and pressure, or at elevated temperature and pressure,
Alcohols such as ethane or methanol, esters such as ethyl acetate, ethers such as tetrahydrofuran, or water are used as reaction solvents.
uses a solvent mixture, such as a mixture of two or more of the above solvents.

When one or both RI4 and R15 are hydrogen atoms, the reducing agent may be a hydride such as diborane, sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride. Suitable solvents for reactions with these reducing agents will depend on the specific hydride used, but such solvents may include alcohols such as methanol or ethanol or diethyl ether,
Ethers such as tert-butyl methyl ether or tetrahydrofuran are included.

Formula (If) in which R14 and R15 are each a hydrogen atom
When a compound of formula (V) is used, an intermediate imine of the following formula (V) may be formed.

The imine is reduced under the above conditions and, if necessary, the supporting group is removed in the next step to obtain a compound of general formula (I).

When using the protected intermediate of general formula [II] (and, if desired, using hydrogen and the above catalyst, the protecting group R14 convertible to a hydrogen atom under these reducing conditions is removed) K is particularly advantageous and thus obviates the need for a separate deprotection step. Suitable protecting groups of this type include arylmethyl groups such as benzyl, benzhydryl and α-methylbenzyl.

In one general process (2), (・te, general formula (
Compounds of I) can be created by reduction. For example, a compound of the general formula m may be a compound of the general formula (VD
: [In the above formula, X', ! ', X'', X3 and HiYVJ5
at least one of the groups represents a reducible group and/or Ar has a reducible group, the others have appropriate meanings as follows, i.e.
5x2 is -OH, NR"- (R" is a hydrogen atom or a protecting group), X'&j -OR"R"X-(-at),
Ar and Y) 2 as defined for formula (I)] may be prepared by reducing the intermediate and then, if necessary, removing the protecting group (.

Suitable reducible groups include x4 being -No2;
x1 groups>a-o-c-ary, x2 groups -0H2NY'
- (Yl represents a group convertible to hydrogen by catalytic hydrogenation, for example an arylmethyl group such as benzyl, benzhydryl or α-methylbenzyl), imino (-0H
, N-) group or group -C! 0NH-, and X3 is a group -0
OX-also 1t, group-0R1R"X (X haC2-a
O) Fluke = v:i or 0z-e alkynylene) or is "G" -x2-X3-ka group-0
H2N=OR2
2),,0ONR3R' or -NHOOR(-NHOO
R is a phenyl group substituted with a group having an amide bond, such as (reducible to the group -NHR12).

The reduction is carried out using any convenient reducing agent used for the reduction of ketones, imines, amides, protected amines, alkenes, alkynes and nitro groups.

Therefore, for example, when x4 in general formula (Vl)K represents a nitro group, this
It can be reduced to an amino group by using hydrogen in the presence of the above-mentioned catalyst.

When xl in general formula (Vl) represents a >C-0 group, this can be done by using hydrogen in the presence of the catalyst described above in part (1) of process (1). (I.J.
It can be reduced to the II(0H)- group. The reducing agent is, for example, a hydride such as diborane, or a metal hydride such as lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, sodium borohydride or aluminum hydride. (・0 The reaction may be carried out in a solvent, if appropriate,
It can be carried out in a 5ft alcohol such as methanol or ethanol, an ether such as tetrahydrofuran, or a /S halogenated hydrocarbon such as dichloromethane.

General formula (Vl)
- When denoting 0H2N-OR2X-, this refers to the use of hydrogen in the presence of the metal catalyst described above in part (b) of process (1).
- It can also be reduced to the bar cH2NHc 2x- group. Yes (・ is X or -X-X3- ka, i -OH
,,,N-also 0H2N-(!R" - or -ca, Nl1cHR2x-K can be reduced.

General formula (Vl) K: Nikel X2 or HaX3 car 0ONH-
Also, bar represents a cox- group or is (.
H2) q-tCONR3R' or -NHDOR17(R
When phenyl is substituted with a group having an amide bond such as By using complex metal hydrides such as lithium aluminum or sodium bis(2-methoxyethoxy)aluminum hydride, the group -0H2NH- or 10H2
X- or group-[[! I(2)qkJR3R' or -
Each can be reduced to a phenyl substituted with NHR12.

X Ka group -OR'R2X- (X Ha02-60':)
7 k keni1/ :/ or C2-6 alkynylene) or is (. If Y represents 02-4 alkenylene or C2-4 alkynylene, then this ) can be reduced to C2-6 alkylene or C2-4 alkylene, respectively, using hydrogen in the presence of the above-mentioned catalyst. or if Y is C2-4 alkynylene, this may be for example hydrogen and carbonated calcium-supported lead-poisoned palladium in a solvent such as pyridine, or diethyl ether at a low temperature such as 0°C. It can be reduced to 02-6 alkenylene or C2-4 alkenylene, respectively, by using lithium aluminum hydride in a solvent such as

Furthermore, in the general process (3), the compound of the general formula (T) has the formula (VIA): [In the above formula, R14 and R16 each represent a hydrogen atom or a protecting group, and/or hydroxy in the group Ar and ( or] the amino substituent is protected (with the proviso that at least one of R14 and/or R16 represents a protecting group and/or Ar has a protecting group). Can be manufactured with protective supplies.

Appropriate protecting groups and methods for their removal are described above. Thus, for example, R14 can represent an aralkyl group such as benzyl, which may be removed by hydrogenolysis in the presence of a metal catalyst (e.g. palladium on charcoal), and/or R16 can represent an acyl group. radicals, which may be removed by boiling with dilute mineral acids (eg, hydrochloric acid).

Compounds of formula (T) may be prepared by a process consisting of interconversion of one compound of general formula (I) into another.

Thus, for example, Ar is a group -(OH2)rOORg
Compounds of formula (1) representing a phenyl group substituted by (R' is hydroxy) can be prepared by hydrolysis of the corresponding compounds of formula (I) where R represents C1-4 alkoxy. . Hydrolysis may be carried out under basic conditions using, for example, sodium hydroxide.

The compounds of formula (I) obtained in the above general process may be in the form of salts, conveniently physiologically acceptable salts. If desired, such salts can be converted to the corresponding free acid by conventional methods.

Physiologically acceptable salts of compounds of general formula CI) can be prepared from compounds of general formula (I) in the presence of a suitable solvent such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol such as methanol, ethanol or isopropanol
may be prepared by reacting a compound of (.) with a suitable acid or base.

Physiologically acceptable salts can be prepared by conventional methods with the general formula (
Other physiologically acceptable salts of the compounds of I) are also prepared from other bases.

If a specific enantiomer of a compound of general formula (D) is required, this may be obtained by resolving the corresponding racemate of a compound of general formula (I) by conventional methods (
-0 Thus, by way of example, a suitable optically active acid can be used to form a salt with a racemate of a compound of general formula (T). The resulting isomeric mixture may be resolved into diastereomeric salts, for example by fractional crystallization, and then the required enantiomer of the compound of general formula (I) may be converted into the required free ring group and isolated. I can do it.

An enantiomer of a compound of formula (1) can be synthesized from a suitable optically active intermediate using any of the general processes described herein. Specific diastereomers can be synthesized from appropriate asymmetric starting materials by conventional methods, e.g., using any of the processes described herein, or It can be obtained by converting the isomeric mixture of the compound (I) into the appropriate diastereomeric conductor, such as a salt, and then separating it by conventional means such as fractional crystallization.

The general formula (Vl
) is described in British Patent No. 2165542A #
It is described in Book I and can be produced by several processes similar to those described in Book I.

In this way, K, for example, Xl is a group〉C=0, the general formula (
The intermediate of Vl) is a haloketone of formula (Vl):
General formula (IX): Y' NRCXOH20CR2YAr
(IX)♂ (In the above formula, Yl is hydrogen or a group convertible thereto by catalytic hydrogenation.) It can be produced by reacting with an amine. The reaction is carried out with diisopropylethylamine in a cold or hot solvent such as tetrahydrofuran, tert-butyl methyl ether, dioxane, chloroform, dimethylformamide, acetonitrile, or a ketone such as butanone or methyl isobutyl ketone, or an ester such as ethyl acetate. , in the presence of a base such as sodium charcoal or other acid scavenging agents such as propylene oxide.

An intermediate of the general formula (Vl) in which − can be reduced to the corresponding intermediate.

The intermediates of formula (II), (Iff), (IV), (WD and (Do) are known compounds or are otherwise prepared by methods analogous to those described for the preparation of known compounds. can do.

Suitable methods for preparing intermediates of formula (IV) and (IX) are described in GB 2140800A, 2159151A, 2165542A and the examples below. ~・ru.

The following examples are intended to illustrate the invention. Temperature is in °C. "Drying" means drying with magnesium sulfate or sodium sulfate unless otherwise specified. (F [[)] is silica [Merck (Merck) 93
85], but unless otherwise stated one of the following solvent systems was used: A-Toluene:Ethanol: 0.88 Ammonia, B.

Toluene: ethanol: triethylamine, O-ethyl acetate: hexane: triethylamine, D# ethyl acetate:
Methanol: triethylamine, E-cyclohexane:
Ethyl acetate: triethylamine. The following abbreviations are used: THF ffitetrahydrofuran, DMF,
, ,dimethylformamide, BTPO, ,bis(triphenylphosphine)baradium A (II) chloride,
IJA-N, N--, z77'o bilethylamine.

Intermediate 1 is 1-(4-amino-3,5-dichlorophenyl)-2-bromoethanone.

Intermediate 2 (z) -N -[4-[3-[C6-C(phenylmethyl)amine]hexyl]oxy]-1-prope (Z)
-N-C4-C3-C(6-bromohexyl)oxyl11-1-flobenyl]phenyl]methanesulfonamide (2.0 g) was added to benzylamine (6 ml) at 125° under nitrogen. The reaction mixture was heated at 125° for 3
The mixture was stirred for an hour, cooled to room temperature, and 2N hydrochloric acid (soml) and water (20 mU) were added. The generated white solid was collected, washed thoroughly with 2N filler acid, water and ether, and then dried under reduced pressure at 50' to obtain the title compound (1.0 g) as a white powder with mp 133-134. .

Intermediate 3 (Z) -N -C4-[3-[C6-[[2- (
4-amino-3,5-dichlorophenyl)-2-hy)
“loxyethyl](phenylmethyl)amino]hexyl]oxy]-1-propenyl]phenyl]methTI(F(
Intermediate 1 (520+=yg), Intermediate 2 in 25mYg)
(850mg;) and DKA (500mg)? 'Group 1 was stirred overnight. After filtration, P was concentrated to obtain an oily substance, which was dissolved in methanol (2 ml) cooled in a water bath, and sodium hydride b,
(250rnq). The pale yellow solution was stirred at room temperature overnight, the methanol was evaporated and the residue was dissolved in water (25 m
1) and ethyl acetate (25ml). The organic layer was washed with water and brine, dried, and concentrated to give a red oil, which was purified by F[] eluting with system K (75:25:1) to give the title compound as a colorless oil. (54
0 mg) was obtained. TLO (system 175:25:1
) Rf O,09゜Intermediate 4 4-Yo)"-N,N-dimethylbenzenethanamine salt 4-bromo N,N-,)methylpe/ze/ethanamine hydrochloride (0,65g) ?Ethyl acetate (10 ml) and 800 ml of sodium bicarbonate.

The aqueous layer was extracted with ethyl acetate (10ml), and the combined organic extracts were dried and concentrated to give the free base (0.57g). n-Butyllithium (1.6M in hexane, 1.7
2 mU) in THF (NOml) to the free base (0,
57 g) to the solution at -78° and the mixture was heated under nitrogen for 30
Stir for a minute. Iodine (0,
63g) solution was added dropwise and after 10 minutes the reaction was stopped by addition of saturated ammonium chloride (xoml). THF
was evaporated and the aqueous residue was dissolved in ethyl acetate (2xIsml).
Extracted with. The organic extract was mixed with 10% sodium thiodate (
Washed with 15 mU) and salt water (+5+nl), dried,
Concentration gave a brown oil. The oil in ether and dichloromethane (2ml) was treated with ethereal hydrogen chloride and one portion of the residual precipitate was taken and dried to give the title compound (0.54g) as a white solid.

Analysis actual value: c: 38.77, H: 4.87
, N: 4.39, C: 11.36, I:
40.67°0, H,4IN, HOI calculation value; 0: 38.55, H: 4. F+5, N: 4.
5, Intermediate 5 N-(4-iodophenyl)-N-methylmethanesulfonamide N-(4-iodophenyl)methanesulfonamide (4
, 3g), 50ml aqueous sodium hydroxide solution (25mx
), iodomethane (5 mU), dichloromethane (xOm
l) and tetrabutylammonium bisulfate (0.5g)
The mixture was stirred vigorously for 2 hours. Water (50ml) was added and the mixture was extracted with ether (3X50ml).

The organic extract was washed with water and brine, dried and concentrated to give a solid, which was framed with hexane, mp 106-1
yFfMi compound (4,1 g) as white crystals of 07°
I got it.

Intermediate 6 2-(4-iodophenoxy)-N,N-dimethylacetamidodimethylamine (33 gw/w in XMS, 5.85
Inl ) in triethylamine (soml) (4
-Iodofuyunoxy]acetyl chloride (9.49g
) was added dropwise under nitrogen at O0. The suspension was stirred at 20° for 2 hours and partitioned between ethyl acetate (300 ml) and aqueous sodium bicarbonate solution (300 ml).

The organic layer was dried and the solvent was evaporated to give an oil which was purified by FOE eluting with diethyl ether and m
The title compound (3,9
6g) was obtained.

Intermediate 7 4-iodo-N,N-dimethylbenzeneacetamide 4-iodophenylacetyl chloride) (5,15g
) was added in portions with dimethylamine (0.90 g) KO' in triethylamine:/(25 ml). The suspension was stirred at 00 for 2 hours and chloroform (Zoo ml
) was added. The organic layer was diluted with aqueous sodium bicarbonate solution (5%
0 ml), dried and concentrated to give a red solid (5,0 ml).
This was purified by FOE eluting with ether then ethyl acetate to give the title compound (2.58g) as a yellow solid with mp 75-77°.

Intermediate 8 N,N-dimeol-4-(4-[5-C(phenylmethyl]amino]pentyloxy]phthyl]be intermediate +6
(1,60 g) was added to benzylamine (3
, 5 ml). The solution was stirred at 120° for 3 hours, and 0.8N aqueous hydrochloric acid solution (65 ml) was added.

The mixed aqueous solution was extracted with ethyl acetate (3 x 10 ml),
The combined extracts were diluted with 8% aqueous sodium bicarbonate (50 m
The mixture was washed with brine, dried and concentrated to give an oil (0.56 g). The combined aqueous layers were re-extracted with ethyl acetate (2Xsomx), dried and concentrated to give an oil (0.92g). The two oils were combined and ethyl acetate-triethylamine (
100:1) and purified by TLO (ethyl acetate-triethylamine 100:1) Rf O,1
The title compound (1,00 g) was obtained as a pale yellow oil.

Intermediate 9 N-[3-[-[[6:6-[phenylmethylamino]
N-[(3-:I-dophenyl)methyl]acetamide (3,91 g), N-[6-[
A suspension of 2-propynyl)oxy]hexyl]benzenemethanamine (3.48 g), BTPC (100 mg) and copper iodide (60 mg) was stirred at room temperature under nitrogen for 20 hours. The reaction mixture was diluted with diethyl ether (100ml
) and filtered. Concentrate the P solution to obtain oily 'Mn (6
,62g) was obtained, and this was converted into system D (10
0: O: 1→100:10:1) and purified with TLO (ethyl acetate-triethylamine 100:1).
l ) The title compound (4.60 g) was obtained as a red oil of Rf O,12.

Intermediates 10-13 were prepared in a similar manner.

Intermediate 1O N,N-dimethyl-4-[3-[[66-[[[phenylmethyl]amino]hexyl]oxy]-1-propynyl]pe/zamide 4-iodo-N,N-dimethylbenzamide (2, 5g
) and N-[6-[[2-propynyl)oxy]amino]benzenemethanamine (2.23 g). Elution with ethyl acetate-triethylamine 7 (100;1) from Foe M gave the title compound (2.96 g) as an orange oil with TLO (ethyl acetate + a few drops of triethylamine) Rf 0.15.

Intermediate 11 N,N-dimethyl-2-[4-[3-[[6-C(phenylmethyl)amino]hexyl]oxy]Intermediate 6(3
, 91 g) and N-[6-[(2-propynyl)oxy]hexyl]benzenemethanamine (3.14 g). The product (3.87 g) was obtained by Foe purification by eluting with system 0 (83:17:1), and then using this as eluent with ethyl acetate-triethylamine (1
00: 1) was applied to the column again as above and TLO (ethyl acetate + a few drops of triethylamine) R
The title compound (1,44 g
) was obtained.

Intermediate 12 N-methyl-N-44-[3-11[6-[(phenylmethyl)amino]hexyl]oxy]-X-vinyl)
Oxy]hexyl]be7zenmethanamine (1.5g)
However, triethylamine/THF ([x, somx) was used instead of diethylamine. The title compound (2.0 g) was obtained as an orange oil (B95:5:1) Rf O,13.

Intermediate 13 4-[3-[5-02-(4-amino-3°5-dichlorophenyl)-2- and droxyethyl](phenylmethyl)amino]hexyl]oxy]-1-7'rovinyl]
Obtained from benzamide intermediate 24 (550 mg) and 4-iodobenzamide (250 mg), except that diethylamine/THF (4:1.10 m
1) and omitted adding the reaction mixture to ether and then filtering it. TLO by FOO purification of the concentrated reaction mixture by elution with system B (90:10:1)
The title compound (540 mg) was obtained as a pale yellow oil (system 90:10:1) RfO, 35.

Intermediate 14 N-[4-[3-[I:s-[[2-(4-amino-3
,5-dichlorophenyl)-2-hydroxyethyl](
phenylmethyl)amino]hexyl]oxy':] −
Intermediate 24 (1,0 g), 2-(dimethylamino)-N-(4-iodophenyl)acetamide (680 mg), dicyclohexylamine (1-7'rovinyl]phenyl)-2-(acetonitrile (t5 ml)) 45
0 mg), BTPO (50 mg) and cupric iodide (
A suspension of 10 mg) was stirred under nitrogen for 3 hours.

Ether (25 ml) was added, the precipitate was removed, the solvent was evaporated and the residue was eluted with system 0 (50:50:1). If you tear it apart, Nido, J: Li, TLO (
System A 80:20:2) The title compound (soo mg) was obtained as a yellow oil with Rf O, 53.

Intermediate 15 4-(4-(3-[[-(:(phenylmethyl]amino]hexyl]oxy]-1-7'ropinyl]4-(4
-iodobenzoyl)morpholine (4.0 g) and N-
1 [6-[[2-propynyl)oxy]hexyl]benzenemethanamine (3,09 g) All intermediates were reacted according to the method of 14. Ethyl acetate-triethylamine (1
TLC! (Ethyl acetate-triethylamine Zoo
: 1) The title compound (2.21 g) was obtained as a yellow oil of Rf O,2.

Intermediate 16 4-[4-[[5-bromopeatyl]oxy]p Intermediate 7 (2,50 g), 1-bromo-5-(3-butynyloxy)pentane (1,90 g), dicyclohexylamine (1,73 g ), BTPO (50 mg) and copper iodide (10 mg) in acetonitrile (3 om
x) for 2 hours. ether (80I]11)'
? The mixture was filtered, the p-liquid was concentrated and the residue was refluxed with ethanol (100ml) and filtered (hyflow).The solution was dissolved in 10% palladium on charcoal [50% in water].
paste, 1.0 g) for 48 h and hydrogenated on (
high flow)? Filtration and concentration gave a residue, which was eluted with ether-ethyl acetate (100:O→80:20) to give a yellow oil of F[[[[[]TLC! (ether) RfO, 12] The title compound (1.62 g) was obtained as a product.

Intermediate 17 (Z) -N -C(3-C3-[C6-[[6:
2-(4-amino-3,5-dichlorophenyl)-2
-Hydroxyethyl](phenylmethyl)amine]hexyl]oxy]-1--jlopenyl]phenyl]T! (
Intermediate fJ = 11.44 g) in F (20 m1), Intermediate 9 (2.0 g) and DEA (660 mg)
The NOFA solution was left at room temperature under nitrogen for 20 hours. 1 of the sediment
The IF' was concentrated to give an oil, which was dissolved in ice-cold methanol (20 ml) and treated portionwise with sodium borohydride (750 mg). The reaction mixture was stirred at room temperature under nitrogen for 2 hours and concentrated to an oil. Water (1,000 m) was added to this. , the mixture was extracted with ethyl acetate (3x50ml) and the combined extracts were diluted with water (so
mx) and brine (50 ml), dried and concentrated to give an oil, which was eluted with system B (95:5:1) and purified by TLO (system B95 :5:
1) The title compound (1,51 g) was obtained as a yellow oil of Rf O,13.

Intermediates 18-24 were prepared in a similar manner.

Intermediate 18 4-[4-(5-[,[z-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl](phenylmethyl)amino]pentyloxy]ph.

Obtained from Intermediate 1 (690 mg) and Intermediate 8 (1.01 g). Sodium borohydride/methanol reaction
The time continued. Elute with system 0 (50: 50: 1) and purify F'OO, then use TLO (ethyl acetate-hexane ([1), a dozen drops of triethylamine]
The title compound (1
, 12g) was obtained.

Intermediate 19 (Z) -2-[4-[3-[C6-[C2-(4-amino-3,5-dichlorophenyl]-2-hydroxyethyl](phenylmethyl)amine]hexyl]oxy:
]-1-propenyl]phenoxy N,N-dimethylacetamide Intermediate 1 (951 mg) and Intermediate II (1,42 g
Obtained from >. Elute with system B (97:3:1) to obtain F[[
By purification, TLO (system B95:5:
1) The title compound (
1.11 g) was obtained.

Intermediate 2O N-[4-[2-[[-[[z-(4-amino-3,5
-dichlorophenyl)-2-hydroxyethyl](phenylmethyl)amine]amino]oxy]ethyl]phenyl]methanesulfonamide intermediate t (0,7 g) and N-[4-[2-[C6-[
It is made from [phenylmethyl)amine]hexyl[oxy]ethyl]phenyl]methanesulfonamide (1 g).

TLO (system A 80:20:1) R
The title compound (1,2 g
) was obtained.

Intermediate 21 N-[4-[3-[[6-[[6z-(4-amino-3
,5-dichlorophenyl)-2-hydroxyethyl](
phenylmethyl)amine]hexyl]oxy]-1-propynyl]phenyl]-N-methylmethanesulfonamide Intermediate 1 (660 nog) and Intermediate 12 (1,0 g)
Obtained from. Continue the sodium borohydride/methanol reaction for 18 hours. System Ci (33:66: 1-
) 50:50;

Intermediate 22 (Z) -4-[3-C[6-[C2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl](phenylmethyl)amine]hexyl]oxy]-1
-propenyl:]-N,N-dimethyl intermediate 1 (
1.0 g) and intermediate 10 (1.39 g). Purification by elution with System B (97:3:1) gave the title compound (0.93 g) as a yellow oil of TLO (System B 95:5:1) RfO03.

Intermediate 23 4-[4-43-[[:6-02-(4-amino-3,
5-Dichlorophenyl)-2-hydroxyethyl](phenylmethyl)amine]hexyl]oxy:]-1-propynyl]benzoyl]morpholine Intermediate 1 (1,0 g) and Intermediate 15 (1,53
g). The sodium borohydride/methanol reaction continued for 60 hours. By eluting with system B (97:3:1) and purifying F [[], TLC (system B95:
5:1) The title compound (1.54 g) was obtained as an orange oil with Rf 0.25.

Intermediate 24 4-Amino-3,5-dichloro-α-[[(phenylmethyl)(:6-[[2-proviny/L,)oxy]amino]amine]methyl]benzene methanol Intermediate 1 (1, 0 g) and N-[6-[[2-propynyl)oxy]hexyl]benzenemethanamine (8
70 mg), but the first reaction step was carried out for only 25 minutes. Elute with system 0 (20:80:1) and F[
[By purification, TLO (system C20:80:
1) The title compound (1.27 g) was obtained as a colorless oil with Rf O,33.

Intermediate 25 N,N-bis[[2-phenylmethoxy]ethyl]-4
-Iodobenzenamine 2.2'-(4-iodophenylimino)bis-ethanol (2[?:), benzyl bromide (2.3 g), tetra-D-butylammonium bisulfate (0°4 g) and 50% A mixture of sodium hydroxide (20 ml) was stirred vigorously for 5 hours. The mixture was diluted with water (20 ml) and
The combined extracts were washed successively with water (50 ml) and brine (5+ ml), dried and evaporated. Hexane-ether (1
9:1 → 9:1) and purify F
The title compound (2.1 g) was obtained as a pale yellow oil.

Intermediate 26 4-amino-3,5-dichloro-α-[[66-(:[
3<4-bis[2-(phenylmethoxy)ethyl]amino]phenyl:]-2-7'ropynyl]oxy]hexyl](phenylmethyl)amine]methyl]benzenemethanoldiethylamine/tetrahydrofuran (4:1.30
Intermediate 24 (1,9 g), Intermediate 25 (1 ml) in
, 75 g), BTPO (90 mg) and iodide-@
(9 mg) The solution was stirred at room temperature under nitrogen for 2 days.

The solvent was evaporated and the residue was purified by system 0 (20:80:1
→31J:70:1) and eluted with F[[!
TLC (system C20:80:
1) The title compound (
1.75 g) was obtained.

Intermediate 27 4-Amino-3,5-dichloro-α-[[6-[[63
-[4-[2-(dimethylamino)ethoxy]phenyl]-2-propynyl)oxy]hexyl](phenylmethyl)amine]methyl]benzenemethanoldiethylamine (3θml) and acetonitrile (1
0ml) Nakano 2- (4-Yo h' 7 x /
Kishi) -N.

N-dimethylethanamine (1,57g), intermediate 24
(2,94 g), BTpc (too mg) and fyA iodide (10 mg) was stirred at room temperature under nitrogen for 16 h. The solvent was evaporated and the residue was purified by system B (95:5:
By elution with 1) and Foe purification, TLO (
System B95:5:1) The title compound (3,57 g) was obtained as a red oil of Rf O,26.

/' -- Example 1 4-43-[[6-[I:2-(4-amino-3゜5-
dichlorophenyl]-2-hydroxyethyl]amino]
hexyl]oxy]propyl]benz intermediate 13 (1
, 3 g) with hydrochloric acid (@HfJ/EtOH.

1: 9v/v, 2rn) containing ethanol (1
Hydrogenated over 10% palladium oxide on charcoal (50% aqueous paste, 280 mg) in 5 mU). The catalyst was removed on high flow, the solvent was evaporated and the residue was dissolved in 8% sodium bicarbonate.
The aqueous layer was re-extracted with ethyl acetate (25 mL) and the combined organic extracts were washed with 8 mL of bicarbonate and brine. , dried and compressed to give a semi-solid material, which was triturated with ether/ethyl acetate (~4:1), mp 91-
TLC at 94° (system A 80:20:2)
The title compound (240
mg, 22%].

Examples 2-9 were performed in a similar manner.

Example 2 N-[4-[3-[[66-[[62-(4-amino-
3,5-dichlorophenyl)-2-hydroxyethyl]
[amino]hexyl]oxy]propyl] intermediate 3 (50
0mg). Evaporation of the ethyl acetate extract gave an oil which was eluted with system B (95:5:1) to give F
[[Purification and subsequent trituration with dry ether gives the title compound (
1 oomg) was obtained.

Analysis actual value: C: 54.82, H: 7.26,
N: 7.36C24H35C1□N304S, 0.3
5C4H1oO calculated value: C: 54.63, H: 6,
95, N: 7.52% Example 3 4-[3-[[66-[[6(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]globil]ethyl benzoate Ethyl 4-[3-[[66-[[6(4-amino-3,5-dichlorophenol)-2-hydroxyethyl](phenylmethyl)amino]hexyl]oxy]-1-propynyl]benzoate (500 rng ), pre-reduced 10% palladium on charcoal (50% in water) as a hydrogenation catalyst
% paste, 60 mg).

The residue obtained by evaporation of the ethyl acetate extract was converted into system c (
'rLC (system C50:
The title compound (97 mg) was obtained as a white solid (50:1) Rf O,05.

Example 4 N-[4-[3-[[66-[[62-(4-amino-
3,5-dichlorophenyl)-2-hydroxyethyl]
Amino]amino]oxy[propyl]phenyl]-2-
(dimethylamino)acetamide concentrated HCI/EtOH
Intermediate 14 using ([ 9 v/v, z, zml)
(750 mg). The yellow oil (520 mg) obtained by concentration of the ethyl acetate extract was dissolved in methanol (5 ml) and treated with a solution of fumaric acid (120 mg) in methanol (2 ml), the methanol was evaporated and the residue was dissolved in ether. Grind to give yellow solid (61 omg)
This was recrystallized from Improper Tools (15ml) to give the title compound (IQOmg) as a white solid with mp 106-110°.

Analysis actual value: C: 56,32, H: 6,97,
N: 7,94, C [ 11.32°C27H4oC1
2N403. C4H4o4 calculated value: C: 56,79,
H: 6,76, N: 8.55, C [10.82%
Example 5 4-[3-[[66-[[62-(4-amino-3゜5
-dichlorophenyl)-2- and droxyethyl]amino]hexyl]oxy]propyl] -N)N-dimethylbenzamide. Obtained from Intermediate 22 (0.82 g). Evaporation of the ethyl acetate extract gave an oil, which was converted into system B (
95:5:1) to give an oily substance. The oil (0.42 g) in methanol (zmt) was dissolved in (E) in methanol (2 ml).
)-putenic acid (47.6 mg) and the solution was concentrated. The residue was triturated with diethyl ether, mp 10
The title compound (0,47
g) was obtained.

Analysis actual values: C: 59.0, H: 7.2, N:
7,2,C [12,6°C26H37C1□N,03
．． 0.5C4H404 calculated value: C: 59,2, H:
6.9, N: 7.4, C [ 12.5 CH Example 6 4-[-[3-[6-[[62-(4-amino-3,5
Intermediate 23 (0,70 g
). Evaporation of the ethyl acetate extract gave an oil which was eluted with system B (95:5:1) to give F [[purification] afforded the title compound as a yellow oil (391 mg). A solution of the title compound (390 mg) in methanol (2 ml) was dissolved in (E
)-putenic acid (4L 1 mg) and the solution was evaporated to give an oil which was triturated with diethyl ether, mp 1
(E) of the title compound as a white solid at 14-116°
-putenic acid salt (2:l) (40mg) was obtained.

Analysis actual value: C: 58.7,) I: 6.0, N
: 6,7,C[11,9゜(C28H39C12N
304)2. C4H404 calculated value: C: 59,0. H
: 6,8, N: 6.9, CI: 11.6 Example 7 N-[[3-[3-[[66-[[62-(4-amino-3,5-dichlorophenyl)-2- Intermediate 17 (1,
40g). The solid obtained from the ethyl acetate extract was triturated with diethyl ether and TLC (system A 80:20:2) RfO at mp 91-94°.
, 45 as a white solid (0.76 g)
I got it.

Analysis actual values: C: 60.7, H: 7.5, N:
7,9,C〔13.9゜CahH37C12N303
Calculated value: C: 61.2, H near, 3, N: 8.2, C [13.
9th Example 8 2-[4-[3-[[66-[[62-(4-amino-
3,5-dichlorophnyl)-2-hydroxyethyl]amino]hexyl]oxy]propyl]phenoxy]-N
, N-dimethylacetamide/(E)-butenedioate (salt) (2:1) pre-reduced]O% palladium on charcoal (50% aqueous paste, 115 mg) as hydrogenation catalyst
) was obtained from intermediate 19 (0.99 g). Concentration of the ethyl acetate extract gave an oil. The oil (0.70 g) in methanol (2 ml) was dissolved in methanol (
(E)・-butenenic acid (75.5 mg) in 2 ml)
The solution was concentrated. The residue was triturated with diethyl ether and TLC at mp 116-118° (system B95:
The title compound (0.63 g) was obtained as a pale tan solid with 5:1) Rf O,17.

Example 9 N-[4-[3-[[66-[[62-(4-amino-
3,5-dichlorophenyl)-2-hydroxyethyl]
Amino]hexyl[oxy]propyl]phenyl'J-
N-J thylmethanesulfonamide hydrochloride was obtained from Intermediate 21 (250 mg) using pre-reduced 10 palladium thioxide on carbon (50% aqueous paste, 50 mg) as hydrogenation catalyst. An oily substance was obtained by concentrating the ethyl acetate extract, and this was converted into system B (99:1=1→
95:5:1) to give a yellow oil (130 mg). Ether (5ml
) was treated with ethereal hydrogen chloride and the remaining oil was triturated with dry ether and analyzed by TLC (system B 95 :
The title compound (90 mg) of Rf 0056 was obtained as a yellow solid.

Analysis actual value: C: 51.14, H: 7.02,
N2 6.87, C [17.82, S: 5.00°C
25H37C1□N304S, HCI calculation value: C: 5
1.50, H: 6.57, N: 7.21, C [ 1
8,24,S: 5,50% Example 10 4-amino-3,5-dichloro-α-[[6[6-[3
-[4-[2-(dimethylamino)ethyl]phenyl]
propoxy]amino]amino]methyl]benzenemethanoldiethylamine (30 ml) and acetonitrile (1
Intermediate 4 (1,54 g) as free base in 0 ml)
, Intermediate 24 (2,94 g), BTPC (Zoo
A solution of cuprous iodide (10 mg) and cuprous iodide (10 mg) was stirred under nitrogen for 18 hours. The solution was concentrated in vacuo to give a brown oil, which was eluted with system B (95:5:1) to give F [[purification to give a yellow oil (2.4 g). The oil (2.3 g) was dissolved in hydrochloric acid (conc. HCI/EtOH,
9 v/V, 6.9 ml) containing ethanol (20 m
Hydrogenated with 10% palladium oxide on carbon (SO% aqueous paste, 500 mg) in l). The catalyst was removed on high flow, the ethanol was evaporated and the residue was dissolved in 8% sodium bicarbonate (20ml) and ethyl acetate (20ml).
l) was distributed between. The aqueous layer was extracted with ethyl acetate (20 ml).
) and the combined organic extracts were washed with sodium bicarbonate (20ml) and brine (20ml), dried and concentrated to give a yellow oil. Oily substance is system B (98:
Purification gave a pale yellow oil (1.2 g), which was triturated with hexane as a white solid with mp 41.5-43.5°. A compound (1.1 g) was obtained.

Analysis actual value: C: 63,23, H: 8,37,
N: 8.10, C [13.69°C27H40C1
2N302 calculated value: C: 63.64, H: 7.91, N: 8,25, C
[13.92% Example 11 4-[4-[5-[[62-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]pentyloxy]butyl]-N,N-dihydrochloric acid (Concentrated Hc1
/EtOH, ]: 9 v/v, 1.48 m1)
Intermediate ss (1,
oo g) was pre-reduced with 10% palladium on charcoal (1
50 mg, 50% paste in water). The reaction mixture was filtered (high flow) and Solution F was concentrated. The residue was partitioned between ethyl acetate (100ml) and 8 ml aqueous sodium bicarbonate MW (2x50ml). The dried organic layer was concentrated, and the residual oil was purified by system 0 (100:0:
1→90:10:1) to give the title compound (0,
69g) was obtained. The title compound (469 mg) in methanol (2 ml) was dissolved in n (E
)-butenic acid (5], 9 mg). The solution gave an oil which was triturated with diethyl ether to give the title compound (E)-puteneniate salt (2:1) (4o7mg) with mp 107-110°.

Analysis actual value: C: 59.9, H: 7.4-N
: 7.0. C [12. OC,I(39C1□N,0
3,0,5C,H40,calculated value:C: 59,8,H:
7.1, N: 7,2, C[ 12.2qb Example 12 N-[4-[3-[[66-[[6z-(4-amino-
3,5-dichlorophenyl)-2- and droxyethylcoamino]hexyl]oxy]ethyl] intermediate 20 (1
, 2 g) was hydrogenated as in Example 11 using previously reduced palladium 10 thioxide on carbon (50% aqueous paste, 150 mg) as catalyst. Evaporation of the ethyl acetate extract gave a yellow oil, which was converted into system B (92:8:1)
Purification eluting with F gave a pale yellow oil which was triturated with ether to give the title compound (445 mg) as a white solid with mp 62-65'.

Analysis actual value: C: 52,94, H: 6,40,
N: 7,79°C [13,96, S: 6.17°C23 [[33CI2N3048 calculated value: C: 53,
28, H: fi, 42, N: 8° 10, C [ 13,
68-S: 6,18% Example 13 4-[3-[[66-[[62-(4-amino-3゜5
-dichlorophenyl)-2-hydroxyethyl]amine]hekidushi]oxy]globil]benze, i-[3-[
[6-Bromohexyl)oxy]propylcobenzeneacetamide (950 mg) was dissolved in DMF at 100° under nitrogen.
4-Amino-α-(aminomethyl)-3,5-dichlorobenzenemethanol (900 mg) in (1,0 ml)
) and DEA (650 mg) were stirred and added to the solution. After an hour the solvent was evaporated and the residue was partitioned between 8x sodium carbonate (20ml) and ethyl acetate (20mt). The organic layer was washed with water and brine, dried, and concentrated under reduced pressure to give a yellow solid, which was triturated with ether.
The title compound (510 mg) was obtained as an off-white powder with mp i04-106°.

Analysis actual value: C: 60.58, H: 7.35,
N: 8.11, C[ 13,83C25H35C12
N303 calculated value: C: 60,48, H: 7,11, N: 8,46, C
[14,28CH Example 14 4-amino-3,5-dichloro-α-[[6[6-[3
-[4-(Methoxymethyl)phenyl]propoxy]hexyl]amino]methyl]benzene methanol (E)
-butenediore-1-(2: 1')1-[3-[[
6-bromohexyl)oxy]glovir]-4-(meth)
xymethyl)benzene (1,0 g) and 4-amino-α-(aminomethyl)-3,5-dichlorobenzene methanol (1,0 g) were reacted according to the method of Example 13. An oil was obtained by hexacondensation of the ethyl acetate extract, which was eluted with system B (90:10:) to obtain F [[].A yellow oil (620 mg) was obtained by purification. The oil in isopropatool (5 mg) was dissolved in isopropatool (2 m
l) with hot fumaric acid (20 mg) solution in 1.1
After an hour, the two-phase system was vigorously stirred to obtain a pale yellow precipitate, which was removed from P, dried under vacuum, and T at mp 110-112°.
LC (system A 80:20:2) Rf 08
The title compound (550 mg) was obtained as a pale yellow powder.

Analysis actual value: C: 59.33, H: 6,87,
N: 4.88, C [13,31°C, H3, Cl2N
203,0,5C4H40, Calculated value: C: 59,89
, H: 7.07, N: 5,17, C [13,09%
1 4-[3-[[66-[[6z-(4-amino-3゜5
-dichlorophenyl)-2-hydroxyethyl]amino]amino]ochyne]propyl]benzoic acid (600 ml) of the product according to Example 3 in ethanol (8 ml).
g) was treated with 2N sodium hydroxide (4mx) and stirred at reflux for 1 hour. Evaporate the ethanol and add water (20ml
) was added to the residue, and the mixture was neutralized with diluted hydrochloric acid. Ethyl acetate (25ml) was added and the two-phase mixture was stirred vigorously for 10 minutes. The resulting precipitate was collected, washed with ethyl acetate, and dried to obtain a cream-colored solid (450 mg), which was triturated with warm methanol (IQ ml) to give P
:IM to give the title compound (290 mg) as a white powder with mp 19 (1-191°).

Analysis actual value: C: 59.22, H: 6.82,
N: 5,62,C [14,40C24H3□C1□
N2O4 calculation value: C: 59,63, H: 6.67, N: 5,79, C
[14,67% Example 16 4-amino-3,5-dichloro-α-[[6[6-[3
-[4-[[4-morpholinyl)methyl]phenyl]propoxy]hexylcoaminecomethyl]benzene methanol The product according to example 6 (0,67
g) in dry diethyl ether (15 ml) at room temperature under nitrogen.
The solution was added dropwise to lithium aluminum hydride (300 mg) in the solution. The suspension was stirred at room temperature for 18 hours and then diluted with water (0.3 m
l), 2N aqueous sodium hydroxide solution (0.6ml
) and water (0.6 ml) to obtain a precipitate which was removed (high flow). Concentrate the solution to obtain an oil, which is eluted with system B (95:5:1) to obtain F.
[[By making M, TLC at mp 57-59°
The title compound (3zsmg) was obtained as a white solid (System E95:5:1) RfO, 22.

Example 17 4-amino-3,5-dichloro-α-[[6[6-[3
-[4-[[62-(dimethylamino)ethyl]amino]phenyl]propoxy]amino]amino]methyl]benzenemethano-/L(E)-p The product from Example 4 (440 mg) as the free base was used as an example. The mixture was treated with lithium aluminum hydride (42 omg) according to the method of No. 16.

After 7 days, water (1 ml), 2N hydroxide aqueous solution (2 ml) and water (1 ml) were successively added, the precipitate was washed off with a sieve, and the ether was evaporated to give a brown oil. I got it.

A solution of oil (320 mg) and fumaric acid (78 mg) in methanol (3 ml) was concentrated to give an oil;
This was triturated with ether to give the title compound (230 mg) as a brown solid with mp 4] -45°.

Analysis actual values: C: 56,59, H: 7.35.
N: 7,30, C to 9,61°C27H, □C11
402,1,5C4H404 Calculated value: C: 56,66
, H: 6.91, N: 8.01, ct: ]o, ]
3% Examples 18 and 19 were made by the method of Example 1: Example 18 4-Amino-3,5-dichloro-α-[[6[6-[3
-[4-[bis(2-hydroxyethyl)amino]phenyl)propoxy]aminocoamino concentrated HCI/EtO
Intermediate 26 (402 mg) was obtained using H ([ 9 v/v, 0.9 ml). Evaporation of the ethyl acetate extract gave a brown oil, which was mixed into system B (95:5:
1 → so: 20: 3) and eluted with F[
[By purification, TLC (system A 80:20
:2) The title compound (85 mg) was obtained as a pale yellow oil of Rf O,33.

δ(CDCl2) 1.2-1.63 and 1.84(-
CH2-): 3.4(-0CH2-): 3,54 and 3.81.8H, (-CH2CH20H)2: 6.
62 and 7.04.4H, (CH of 7 er ring) near,
17.2H1 (C!ri of dichloroaniline ring.

Example 19 4-Amino-3,5-dichloro-α-[[6[6-[3
-[4-[2-(dimethylamino)ethoxy]phenyl]propoxy)amino]amino]methyl]benzene methanol hydrochloric acid (ylJ HC1/EtOH, [9 v/v,
Intermediate 27 was obtained from intermediate 27 (3,42 g) using previously reduced 10% palladium on charcoal (50 tp in water, 750 mg) as hydrogenation catalyst in ethanol (30 ml') containing 10, x ml). The oil obtained by evaporation of the ethyl acetate extract was converted into system A (80:20
: 2) to elute with F
(95:5:1) and the impurity fraction was further subjected to F[[[[[]chromatography. The resulting combined oil' (493 g) in methanol (5 ml) was mixed with (E)-butene 0 (10
9mg). The solution was concentrated, the residual foam was triturated with diethyl ether and analyzed by TLC (system A 80:2
The title compound (0,361 g) was obtained as a pale yellow foam of 0:2) Rf C95.

Actual analysis values: C: 56.1, H: 7.2. N
26.2, CI: 11.0C27H4, C1□N303
．． ], 25C4H404,0,8H20 calculated value: C:
56.0. H: 7.0, N: 6.1, C [10
．． 3% or less is an example of a suitable formulation for the compounds of this invention.

The term "active ingredient" is used herein to refer to the compounds of the present invention.

Tablet (direct compression) mg/tablet Active ingredient 2.0 microcrystalline cells o
-S U8P 196.5 Magnesium Stearate BP 7.5 Compressed weight
2oo,.

The active ingredient is passed through a suitable sieve, mixed with excipients,
Compress using a mm tablet press.

Tablets of other strengths can be made by varying the ratio of active oil to microcrystalline cellulose or compressed weight and using a suitable tablet press.

The tablets can be film-coated using a suitable film-forming substance such as hydroxypropyl methylcellulose by standard techniques. Alternatively, tablets may be sugar coated.

Syrup (sucrose free) mg/sm1 dose active ingredient 2. Omg Hydroxypropyl Methyl Cellulose USP 22.5
mg (viscosity type 4000) Buffer) Flavoring agent) Coloring agent) Appropriate amount Preservative) Sweetening agent) Purified water BP Total volume 5.0 ml Hydroxypropyl methylcellulose is dispersed in hot water, cooled, and then the active ingredients and other Mix with aqueous solution containing prescription ingredients. Adjust the volume of the resulting solution and mix. Filter and clarify the syrup.

Measured amount Pressurized aerosol A, suspension aerosol mg/Tai 11 fine active ingredient per can 0,100 26.40 m
g Oleic acid BP O, Zoo 2.
64 mg trichlorofuleromethane BP 23
, 64 5.67 g Dichlorodifluoromethane BP 61.25 14.70 g The active ingredient is micronized in a liquid energy mill to a fine particle size.

The oleic acid is mixed with trichlorofluoromethane at a temperature of 10-15°C and the finely divided drug is mixed with the solution by a high shear mixer. The suspension is poured into an aluminum aerosol can, a suitable metering valve for dispensing 85 mg of suspension is crimped onto the can, and dichlorodifluoromethane is pressurized into the can through the pulp.

B, solution aerosol active ingredient 0.055 13,20 m
g ethanol-#BP 11,100 2.
66 g dichlorotetrafluoroethane BP 2
5,160 6.04 g dichlorodifureo o)
IjLnBP 37.740 9.06 g
A suitable surfactant such as BP oleate or Span 85 (sorbitan oleate) may be included.

The active ingredient is dissolved in ethanol together with oleic acid or surfactant, if used.

The alcohol solution is injected into a suitable aerosol container followed by the dichlorotetrafluoroethane. Appropriate metered pulps are crimped onto the containers and dichlorodifluoromethane is pressure-filled through the pulps into them.

Injection solution for intravenous administration mg/ml Active ingredient 0.5 mg Sodium chloride BP Appropriate amount Water for injection BP Total amount
Sodium chloride can be added to adjust the consistency of the 1.0 ml solution, and the pH can be adjusted using acids or alkalis in order to optimally stabilize the active ingredient and/or promote dissolution.

The solution is prepared, clarified, filled into appropriately sized ampoules and sealed by glass fusing. The injection solution is heat sterilized in an autoclave applying one of the acceptable cycles. Alternatively, the solution may be filter sterilized and filled into sterile ampoules under aseptic conditions. The solution can also be charged under an inert atmosphere of nitrogen or other suitable gas.

Fine active ingredient 0.200 Lactose B
P Total Quantity 25.0 Active Notes The ingredients are micronized in a liquid energy mill to a fine particle size before being mixed with regular tablet lactose in a high energy mixer. Fill the powder mixture into No. 3 gelatin capsules in a suitable capsule filling machine. The cartridge contents are administered via a powder inhaler such as a Glaxo Rotahaler.

Physiological data The stimulatory effect of the compounds of the invention at β2-adrenergic receptors is compared with imprenaline based on their ability to induce relaxation of PGF2-induced contractions σ] in guinea pig tracheal strips. Investigated by. In this test, fJl, 3.4.5.6.7.8.10.
The compounds shown in 12.13.14.15 and 17 are
Expressed as equivalent concentration (imprenaline = 1) 0.19~
It had a potency in the range of 1.8. For example, the compound of Example 1 had an effective concentration of 0.22.

Generally, compounds according to the invention are non-toxic at therapeutically effective doses. Thus, for example, the compound of Example 3:
No adverse effects were shown when administered to conscious guinea pigs at a dose of 5/-1.

Claims (1)

[Claims] 1. Compounds of general formula (I), and physiologically acceptable salts and solvates thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) {In the above formula, X is a bond, C_1_-_6 alkylene, C_2
Represents a ____6 alkenylene or a C_2_-_6 alkynylene chain. Y is a bond, C_1_-_4 alkylene, C_2
Represents ____4 alkenylene or C_2_-_4 alkynylene. However, the total number of carbon atoms in X and Y is 8 or less. Ar is nitro, -(CH_2)_qR [R is C_1_
-_3 alkoxy, -NR^3R^4 (R^3 and R
^4 each represents a hydrogen atom or an alkyl group of C_1_-_4, or -NR^3R^4 is a 5- to 7-membered ring, and optionally -O- or -S- or a group -NH- or having one or more atoms selected from -N(CH_3)- in the ring, forming a saturated heterocyclic amino group), -NR^5COR^6 (R^5 is a hydrogen atom or C_1_- _4 represents an alkyl group, R
^6 is a hydrogen atom, C_1_-_4 alkyl, C_1_
-_4 alkoxy or -NR^3R^4 group)
, q represents an integer from 1 to 3], -(CH_2)
_rR^7 [R^7 is -NR^5SO_2R^8(R^
8 is C_1_-_4 alkyl, phenyl or -NR^
3R^4 group), -NR^5COCH_2N (R
^5)_2 (Each group R^5 is a hydrogen atom or C_1
_-_4 represents an alkyl group), -COR^9(R^
9 is hydroxy, C_1_-_4 alkoxy or -N
R^3 represents R^4), -SR^1^0 (R^1^0
is a hydrogen atom, or optionally hydroxy, C_1_-
_4 alkoxy or C_1_-_4 alkyl group substituted with -NR^3R^4), -SOR^1
^0, -SO_2R^1^0, -CN or -NR^1^
1R^1^2 (R^1^1 and R^1^2 represent a hydrogen atom or a C_1_-_4 alkyl group, and at least one of them is hydroxy, C_1_-_4 alkoxy or -NR^3R^ C_2_ substituted with 4 groups
-_4 alkyl), r represents an integer from 0 to 3], -O(CH_2)_qCOR^9 (q and R^9 have the same meanings as above), or -O(CH_2)_t
R^1^3 [R^1^3 is hydroxy, -NR^3R^
4, -NR^1^1R^1^2, or optionally hydroxy, C_1_-_4 alkoxy or -NR^
represents a C_1_-_4 alkoxy group substituted with 3R^4, and t is an integer of 2 or 3] represents a phenyl group substituted with at least one substituent selected from the following. R^1 and R^2 are each a hydrogen atom or C_1_-_
3 represents an alkyl group. However, the total number of carbon atoms of R^1 and R^2 is 4 or less} 2. Claims in which the total number of carbon atoms of chains -X- and -Y- is 4, 5, 6, or 7 A compound according to item 1. 3. X is -(CH_2)_3- or -(CH_2)_4
- represents -CH_2-, -(CH_2)_2-
or -(CH_2)_3-, the compound according to claim 1 or 2. 4. Claims 1 to 3, in which R^1 and R^2 are both hydrogen atoms, or R^1 is a hydrogen atom and R^2 is an alkyl group of C_1_-_3. A compound according to any one of paragraphs. 5, Ar is -(CH_2)_qR [R is C_1_-_3
represents alkoxy, diC_1_-_4 alkylamino, morpholino, piperidino, piperazino, N-methylpiperazino, -NHCOR^6 (R^6 is alkyl of C_1_-_4), q is 1 or 2], -( CH
_2) _rR^7 [R^7 is -NR^5SO_2R^8
(R^5 represents hydrogen or methyl, R^8 is C_1_
-_4 represents alkyl), -NHCOCH_2N(
R^5)_2 (both groups R^5 represent C_1_-_4 alkyl), -COR^9 (R^9 is C_1_-_
4 alkoxy, amino, diC_1_-_4 alkylamino, morpholino, piperidino, piperazino or N-methylpiperazino), -NR^1^1R^1^2
(One or both R^1^1 and R^1^2 represent a C_2_-_4 alkyl group substituted with a hydroxy or di-C_1_-_4 alkylamino group, and the other represents a hydrogen atom), r is 0 or 1], -
OCH_2COR^9 (R^9 is diC_1_-_4 alkylamino) or -O(CH_2R^1^3(R
5. A compound according to any one of claims 1 to 4, which represents a phenyl group substituted with ^1^3 is diC_1_-_4 alkylamino. 6. The compound according to claim 1, which is general formula (Ia) and physiologically acceptable salts and solvates thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Ia) [In the above formula, X represents a C_3_-_4 alkylene chain. Y represents a C_1_-_3 alkylene chain. however,
The total number of carbon atoms in X and Y is 5 or 6. Ar is C_1_-_4 alkoxymethyl, morpholinomethyl, di-C_1_-_4 alkylamino C_1_-
_2 alkyl, -CH_2NHCOR^6 (R^6 is C
_1_+_4 alkyl), -NR^5SO_2
R^8 (R^5 is hydrogen or methyl, R^8 is C_
1_-_4 alkyl), -NHCOCH_2N
(R^5)_2 (both groups R^5 represent alkyl of C_1_-_4), -COR^9 (R^9 is hydroxy, alkoxy of C_1_-_4, amino, diC_1_-
_4 alkylamino or morpholino), -CH_
2COR^9 (R^9 is amino or diC_1_-_4 alkylamino), -NR^1^1R^1^2 (R
^1^1 and R^1^2 are both hydroxy C_2_
-_4 represents alkyl), diC_1_-_4 alkylaminoethylamino, -OCH_2COR^9 (R^9
is diC_1_-_4 alkylamino) or -O(
CH_2)_2R^1^3 (R^1^3 is JiC_1_-
_4 alkylamino) represents a phenyl group substituted with a group selected from ), -COR^9 (R^9 is hydroxy, ethoxy, amino or morpholino) or -CH_2COR
7. A compound according to claim 6, representing a phenyl group substituted with a group selected from R^9, where R^9 is amino or dimethylamino. 8. The compound according to claim 6, which is the following compound and its physiologically acceptable salts and solvates. (a) 4-[3-[[6-[[2-(4-amino-3,
5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]propyl]benzamide, (b)4-[3-[[6-[[(4-amino-3,5-
dichlorophenyl)-2-hydroxyethyl]amino]
hexyl]oxy]propyl]ethyl benzoate, (c)N-[[3-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl [oxy]propyl]phenyl]
Methyl]acetamide, (d)4-[4-[5-[[2-(4-amino-3,5
-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy[pentyloxy]butyl]-N,
N-dimethylbenzeneacetamide, (e)4-[3-[[6-[[2-(4-amino-3,
5-dichlorophenyl)-2-hydroxyethyl[amino]hexyl]oxy]propylbenzoic acid, (to)4-[4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)] -2-Hydroxyethyl]amino]hexyl[oxy]propyl]benzoyl]
Morpholine, (t)N-[4-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]ethyl]phenyl]methanesulfone Amide, (ch) 4-[3-[[6-[[2-
(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino[hexyl]oxy]propyl]
Benzeneacetamide. 9. A method for producing a compound or a physiologically acceptable salt or solvate thereof according to any one of claims 1 to 8, wherein (1a) R^1 is a hydrogen atom. In the case of manufacturing a compound of formula (I), general formula (II): ▲Mathematical formula, chemical formula, table, etc.▼(II) (In the above formula, R^1^4 is a hydrogen atom or a protective group,
R^1^5 is a hydrogen atom) The amine of the following formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the above formula, L is a leaving group, R^2, X, Y and A
r has the same meaning as in claim 1), and then, if necessary,
(1b) In the case of the production of compounds of formula (I) in which R^1 is a hydrogen atom, R^1^5 is a hydrogen atom or a group convertible thereto under the reaction conditions. The amine of the general formula (II) as defined above except that the amine of the general formula (IV): R^2COXCH_
2OCR^2YAr(IV) (in the above formula, R^2, X, Y
and Ar have the same meaning as in claim 1) in the presence of a reducing agent, and then, if necessary, remove the existing protecting group, or (2) the general formula (
VI): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI) (In the above formula, X^1 is -CH(OH)- or a group convertible thereto by reduction. X^2 is -CH_2NR ^1^4- (R^1^4 is a hydrogen atom or a protecting group) or a group convertible thereto by reduction. X^3 is -CR^1R^2X- or a group convertible thereto by reduction group (R^1 and R^2 are defined in claim 1)
). X^4 is -NH_2 or a group convertible thereto by reduction. Y and Ar have the same definition as in claim 1 or are groups convertible thereto by reduction. However, at least one of X^1, X^2, X^3 and X^4 represents a reducible group, and/or Y represents a reducible group, and/or Ar represents a reducible group. (3) General formula (VII): ▲Mathematical formulas, chemical formulas, tables, etc.▼ (VII) (In the above formula, R^1, R^2, X, Y and Ar are defined in Claim 1.
The meaning is the same as in the above, R^1^4 and R^1^6 each represent a hydrogen atom or a protective group, and (or) the group A
Hydroxy and/or amino substituents at r are protected. However, at least one of R^1^4 and R^1^6 represents a protecting group, or Ar has a protecting group), or (4) Ar is a group - The formula (CH_2)_rCOR^9 (r has the same meaning as in claim 1, R^9 is hydroxy) representing a phenyl group substituted with (
In the case of manufacturing the compound I), R^9 is C_1_-_4
by hydrolyzing the corresponding compound of formula (I) representing alkoxy of , followed by, if desired, converting the resulting compound of general formula (I) or a salt thereof into its physiologically acceptable salt or solvate. A method consisting of doing. 10. At least one compound of general formula (I) or a physiologically acceptable salt or solvate thereof according to any one of claims 1 to 8, and a physiologically acceptable carrier. or a pharmaceutical composition comprising an excipient.