JPH04225954A - Amide compound, its pharmaceutical use and new 1-substituted pyrrolidinemethylamines - Google Patents

Abstract

PURPOSE:To obtain a new amide compound useful for treating psychosomatic diseases and phrenopathy. CONSTITUTION:An amide compound expressed by formula I {R<1> is 1-4C alkoxy; R<2> is H or R<1> and R<2> are bonded to form oxyethylene; R<3> is S(O)mR<5> [R is 1-4C alkyl or phenylalkyl; (m) is 0-2] or SO2NR<6>R<7> (R<6> and R<7> are H or 1-4C alkyl); R<4> is 6-15C alkyl} and its salt or optical isomer thereof, e.g. (S)-N-[(1- hexyl-2-pyrrolidinyl)methyl]2-methoxy-5-sulfamoylbenzamide. The af orementioned compound is obtained by reacting a carboxylic acid expressed by formula II or its reactive derivative with a 1-substituted pyrrolidine-2- methylamines expressed by formula III. The resultant compound is useful as an antischizophrenic agent, a therapeutic agent for dystropy, emotional disorder, etc., a medicine such as an inhibitor for psychosomatic diseases or emesis, a therapeutic agent for diarrhea originating from stress, tension of feeling, etc., and indefinite complaint of alimentary systems.

Description

[Detailed description of the invention]

0001

[Field of Industrial Application] The present invention provides N-[(1-alkyl-2-
-pyrrolidinyl)methyl]benzamide and N-[(
1-Alkyl-2-pyrrolidinyl)methyl]-2,3-
Dihydrobenzofuran-7-carboxamide compound, a pharmacologically acceptable salt thereof or an optical isomer thereof, and 1 which serves as a raw material compound in producing the benzamide and 2,3-dihydrobenzofuran-7-carboxamide compound. - Substituted pyrrolidine-2-methylamines and optical isomers thereof.

0002

[Prior Art] Benzamide compounds having a pyrrolidine ring in the amine moiety are described in US Pat. No. 3,342,826, British Patent No. 1,394,559, or Drugs of the Future.
f the Future) Volume 11, Nos. 944-94
8, 1986, and 2,3-dihydrobenzofuran-7-carboxamide compounds are described in U.S. Pat.
No. 617,314 and U.S. Pat. No. 4,888
, No. 353. These amide compounds exhibit psychoactive effects by selectively blocking dopamine D2 receptors, resulting in atypical
cal) is characterized as an anti-schizophrenic drug. In the chemical structures of these known compounds, the number of carbon chains of the alkyl group at the 1-position of pyrrolidine is 5 or less, regardless of the type of substituent on the benzene ring. In addition, pyrrolidine-2-
Regarding methylamines, a compound in which the alkyl group at the 1st position has 6 or more carbon chains has not been synthesized. The above known amide compounds, typified by sulpiride, are effective in improving positive symptoms such as hallucinations and delusions in the treatment of patients with psychosomatic diseases and mental disorders, while they are more effective in improving negative symptoms such as cyclic obtundation, which tend to appear in the chronic phase. However, patients are still far from being satisfied with these methods, and side effects such as extrapyramidal tract disorder (EPS) and abnormal prolactin secretion are not always satisfactory. Therefore, the present inventors conducted extensive research in order to develop an amide compound that has a strong effect of improving negative symptoms and has even weaker side effects such as EPS.

0003

[Problem to be solved by the invention] By the way, grits (
Glitz, D. A. ) et al., serotonin 1A (5HT
1A) Drugs, Vol. 41, No. 1 that the agonist buspirone and others exhibit antidepressant and anxiolytic effects that are thought to be related to the improvement of the above-mentioned negative symptoms.
1-18, 1991. In addition, Hicks, P.B., in a catalepsy induction test suggesting EPS, a side effect of haloperidol,
8-OH-DP, a serotonin 1A (5HT1A) agonist
Life Science, Vol. 47, No. 1609, reported that catalepsy is suppressed when AT, buspirone, or ipsapirone are used together.
-1615 pages, reported in 1990. Similarly, Wadenberg, M.L. et al.
The catalepsy-inducing effect of raclopride is 8-OH-DP.
The Journal of the
Journal of Neural Transmission - General Section
smission- General Section
), Vol. 83, pp. 43-53, 1991. Therefore, in order to solve the above-mentioned problems, the present inventors developed a novel amide compound having affinity for the 5HT1A receptor, namely a novel benzamide derivative having a pyrrolidine ring in the amine moiety, and a 2,3-dihydrobenzofuran-7- We searched for carboxamide derivatives. As a result, we surprisingly found that 5HT
It was found that there is a high affinity for the 1A receptor, and that the affinity is higher than that for the dopamine D2 receptor.

0004

[Means for Solving the Problems] The present invention has been completed based on such new findings, and is based on the general formula (I)

[
[In the formula, R1 is an alkoxy group having 1 to 4 carbon atoms, R1 is an alkoxy group having 1 to 4 carbon atoms,
2 is hydrogen or a group in which R1 and R2 are bonded to each other to form oxyethylene which may be substituted with at least one alkyl having 1 to 4 carbon atoms, and R3 is a group represented by the general formula -
S(O)m R5 (R5 represents an alkyl group having 1 to 4 carbon atoms or an optionally substituted phenylalkyl group, m is 0, 1,
It is 2. ) or the general formula -SO2
The group represented by NR6 R7 (R6 and R7 are each hydrogen or an alkyl group having 1 to 4 carbon atoms), and R4 represents an alkyl group having 6 to 15 carbon atoms. ], a pharmacologically acceptable salt thereof or an optical isomer thereof, and general formula (II)

1-substituted pyrrolidine-2-methylamines represented by the formula (wherein R4 represents an alkyl group having 6 to 15 carbon atoms) and optical isomers thereof.

To explain the above definition in more detail, an alkyl group having 1 to 4 carbon atoms includes methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, etc., and an alkoxy group having 1 to 4 carbon atoms. means methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, etc., and the alkyl group having 6 to 15 carbon chains means hexyl,
Heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, etc., and a cycloalkyl group having 3 to 7 carbon atoms (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) is further bonded to these groups. Good too. A group forming oxyethylene which may be substituted with at least one alkyl having 1 to 4 carbon atoms means oxyethylene (-O
CH2 CH2 -), oxymethylethylene [-OC
H(CH3)CH2 -, -OCH2 CH(CH3)
-], oxydimethylethylene [-OC(CH3)2
CH2 -, -OCH2 C(CH3)2 -], etc., the optionally substituted phenylalkyl group is an alkyl group such as benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, etc. The substituents include halogen (chlorine, bromine, fluorine, etc.), alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, and halogen-substituted carbon atoms. Number 1 to 4 alkyl groups (trifluoromethyl, 2
, 2,2-trifluoroethyl, pentafluoroethyl, etc.), nitro, amino, and the like.

[0006] Among the compounds of general formula (I) of the present invention, preferred are compounds in which R1 is methoxy, R2 is hydrogen, or R1 and R2 are bonded to each other to form -OC(CH3).
2 CH2-, R3 is methylthio, sulfamoyl or N-methylsulfamoyl, R4 is hexyl, octyl, nonyl or decyl, a pharmacologically acceptable salt thereof or an optical isomer thereof is also more preferred The compound group includes the following compounds or pharmacologically acceptable salts thereof.

(S)-N-[(1-hexyl-2-pyrrolidinyl)methyl]-2-methoxy-5-sulfamoylbenzamide (S)-N-[(1-hexyl-2-pyrrolidinyl)methyl] -2,2-dimethyl-5-(N-methylsulfamoyl)-2,3-dihydrobenzofuran-7-carboxamide (S)-N-[(1-octyl-2-pyrrolidinyl)methyl]-2,2 -dimethyl-5-sulfamoyl-2,
3-dihydrobenzofuran-7-carboxamide (R)
-N-[(1-nonyl-2-pyrrolidinyl)methyl]-
2-Methoxy-5-sulfamoylbenzamide (R)
-N-[(1-nonyl-2-pyrrolidinyl)methyl]-
2-Methoxy-5-methylsulfanylbenzamide (R)-N-[(1-nonyl-2-pyrrolidinyl)methyl]-2-methoxy-5-methylthiobenzamide (S
)-N-[(1-nonyl-2-pyrrolidinyl)methyl]
-2,2-dimethyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide (R) -N-
[(1-nonyl-2-pyrrolidinyl)methyl]-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide (S)-N-[(1-nonyl-2-pyrrolidinyl)methyl]-5-sulfamoyl- 2,3-dihydrobenzofuran-7-carboxamide (R)-N-[(1-decyl-2-pyrrolidinyl)methyl]-2-methoxy-5-sulfamoylbenzamide (R)-N-[(1-decyl -2-pyrrolidinyl)methyl]-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide

The compound of the present invention of the general formula (I) has the general formula (
III)

[Image Omitted] A carboxylic acid or a reactive derivative thereof represented by [Formula 5] (wherein each symbol has the same meaning as above) and the general formula (II) of the compound of the present invention

1- represented by [Chemical formula 6] (In the formula, each symbol has the same meaning as above.)
It is produced by reacting substituted pyrrolidine-2-methylamines.

[0009] Since this method essentially involves amidation, per se known amidation methods, peptide synthesis methods, etc. can be applied. (1) When the compound of general formula (III) is a free carboxylic acid, the reaction is performed with dicyclohexylcarbodiimide,
Titanium tetrachloride, phosphorus halides (e.g. phosphorus trichloride,
phosphorus oxychloride, etc.), diethyl chlorphosphite,
The reaction is carried out in the presence of a condensing agent such as o-phenylenechlorophosphite or ethyldichlorophosphite in an inert solvent under cooling, at room temperature, or under heating. In addition, the compound (
It is also possible to react II) with phosphorus halide in an inert solvent in advance and then condense it with compound (III). For example, when the phosphorus halide is phosphorus trichloride, approximately 1/2 mole of phosphorus trichloride is added to compound (II) in an inert solvent in advance, and triethylamine, pyridine, N
, N-dimethylaniline or the like in the presence of a tertiary base under cooling or at room temperature, and then reacted with compound (III) in an inert solvent at room temperature or with heating, preferably under reflux. .

(2) As the reactive derivative of the carboxylic acid of general formula (III), acid halides such as acid chlorides,
When using an acid bromide, the reaction is carried out in an inert solvent in the presence of a tertiary base such as triethylamine, pyridine, N,N-dimethylaniline, etc. under cooling or at room temperature, or with sodium hydroxide, hydroxide, etc. It is carried out in the presence of an alkali such as potassium in water under cooling or at room temperature.

(3) When an acid azide is used as the reactive derivative of compound (III), the reaction is carried out in the presence of an alkali such as sodium hydroxide or potassium hydroxide in water under cooling or at room temperature.

(4) When using an ester such as methyl ester, ethyl ester, p-nitrophenyl ester, p-chlorophenyl ester, etc. as the reactive derivative of compound (III), the reaction is carried out in an inert solvent (compound (II) (It can also be used in excess to serve as a solvent.) The reaction is carried out at room temperature or under heating, preferably under heating and reflux.

(5) As the reactive derivative of compound (III), symmetric acid anhydrides or mixed acid anhydrides, such as alkyl carbonic acid mixed acid anhydrides, alkyl phosphoric acid mixed acid anhydrides, alkyl phosphorous acid mixed acid anhydrides When using sulfuric acid mixed acid anhydride, etc., the reaction is carried out in an inert solvent in the presence of a tertiary base such as triethylamine, pyridine, N,N-dimethylaniline, etc., under cooling, at room temperature, or under heating. .

(6) When an active amide such as acid imidazolide, acid pyrrolidide, 2,4-dimethylpyrazolide, etc. is used as the reactive derivative of compound (III), the reaction is carried out in an inert solvent at room temperature or under heating. It will be held in

Compounds of general formula (II) are also new, for example, starting from 2-pyrrolidinone, alkylation,
It can be produced by condensation with nitromethane and then reduction reaction. The optically active compound of general formula (II) can be produced by optical resolution using an optically active acid (for example, tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) in a conventional manner. can. Alternatively, the compound of general formula (II) can be stereospecifically produced by performing esterification, amidation, alkylation, or reduction reaction using (R) or (S)-proline or pyroglutamic acid as a starting material. You can also do it. The compound (I) of the present invention can also be produced by alkylating a compound in which R4 is hydrogen.

Examples of the inert solvent used in each of the above condensation reactions include benzene, toluene, xylene, methanol, ethanol, ethyl ether, dioxane,
Tetrahydrofuran, chloroform, dichloromethane,
Examples include dichloroethane, hexamethylphosphoric amide, diethylene glycol, dimethylformamide, etc., or a mixed solution thereof, which is appropriately selected depending on the type of reactive derivative.

The compound of the present invention also contains racemic mixtures, diastereomers and optical isomers resulting from the asymmetric carbon at the 2-position of pyrrolidine or the asymmetric carbon at the 2-position of dihydrobenzofuran. If desired, the racemic mixture can be optically resolved by a conventional method using an optically active acid (eg, tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) by taking advantage of its basicity. In addition, optically active compound (II) prepared in advance
By using as a starting material, it is also possible to stereoselectively synthesize the target compound (I) having a desired stereoconfiguration. Diastereomers can also be separated into their respective enantiomers by known methods.

The compounds of general formula (I) thus obtained are hydrochlorides, hydrobromides, phosphates, sulfates, toluenesulfonates, citrates, lactates, maleates, fumarates. , tartrate, and other pharmacologically acceptable acid addition salts. As shown in the following experimental examples, the compounds of the present invention are clearly different from conventional benzamides and 2,3-dihydrobenzofuran-7-carboxamides having an alkyl group with a carbon chain number of 5 or less at the 1-position of pyrrolidine. It has been revealed that this protein has high affinity for serotonin 1A receptor. In addition, since its affinity is higher than that for dopamine D2 receptors, the compound of the present invention is extremely effective not only in improving the positive symptoms of schizophrenia patients but also in improving the negative symptoms.
In addition, it is useful as an anti-schizophrenic drug with extremely low side effects such as EPS. Furthermore, these characteristics
The compounds of the present invention can be used as therapeutic agents for depression, anxiety, dyskinesia, abnormal behavior such as excitement and aggression associated with old age or cerebrovascular disorders, and alcoholism, and emotional disorders, as well as gastric and duodenal ulcers. It is useful as a medicine for psychosomatic diseases such as vomiting, as a suppressant for vomiting, or as a treatment for diarrhea and digestive system complaints caused by stress or emotional tension.

Experimental example 1. Dopamine D2 Binding Test A specific dopamine D2 receptor binding test was published in the European Journal of Pharmacology.
The method was carried out according to the method described in 1977, Vol. 46, p. 377, 1977. Crude synaptosome fraction was isolated from the striatum of 9-10 week old Wistar rats, and mixed with 120mM sodium chloride, 5mM potassium chloride, 2mM calcium chloride, 1mM
M magnesium chloride, 10 μM pargyline
line) and 50 containing 0.1% ascorbic acid.
It was suspended in mM Tris-HCl buffer (pH 7.1) and used in the experiment. The synaptosomal suspension was then mixed with several concentrations of the test compound and tritiated spiperone (final concentration 0.
2 nM) was added thereto, and the mixture was reacted at 37°C for 20 minutes. After the reaction, the reaction solution was treated with Whatman (registered trademark) GF.
/B Filter with suction through a glass filter and add 50mM Tris-
After washing the filter with hydrochloric acid buffer (pH 7.7), the radioactivity remaining on the filter was measured using a liquid scintillation counter. Non-specific binding was reduced to 10−4 M (±
)-determined in the presence of sulpiride. 50% inhibitory concentration (I
C50) was determined graphically to obtain the inhibition constant (Ki value). The test results of the example compounds are shown in Table 1 along with the Ki test values of the control compounds (A-G).

Experimental example 2. Serotonin 1A binding test A specific serotonin 1A (5-HT1A) receptor binding test was published in the Journal of Neurochemistry.
of Neurochemistry), No. 44
Vol., p. 1685, 1985. A crude synaptosome fraction was isolated from the hippocampus of a 9-10 week old Wistar rat, and 50%
It was suspended in mM Tris-HCl buffer (pH 7.4) and used in the experiment. Next, several concentrations of the test compound and tritiated 8-OH-DPAT (final concentration 0.2 nM) were added to the synaptosome suspension, and the mixture was reacted at 37°C for 12 minutes. After the reaction, the reaction solution was suction-filtered using a Whatman (registered trademark) GF/B glass filter, and 50mM
After washing the filter with Tris-HCl buffer (pH 7.4), the radioactivity remaining on the filter was measured using a liquid scintillation counter. Reduce non-specific binding to 10-
Determined in the presence of 5M serotonin (5-HT). 50%
The inhibitory concentration (IC50) was determined graphically and the inhibition constant (
Ki value) was determined. The test results of the example compounds are shown in Table 1 along with the Ki values of the control compounds (A-G).

[0021]

[Table 1]

Control compound Compound A: (R)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxy-5-sulfamoylbenzamide [(+)-sulpiride] Compound B: (S
)-N-[(1-ethyl-2-pyrrolidinyl)methyl]
-2-methoxy-5-sulfamoylbenzamide
[(-)-Sulpiride] Compound C: (R)-N-[(1
-n-butyl-2-pyrrolidinyl)methyl]-2-methoxy-5-sulfamoylbenzamide Compound D: (S)-N-[(1-n-butyl-2-pyrrolidinyl)methyl]-2-methoxy- 5-Sulfamoylbenzamide Compound E: (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxy-5-methylthiobenzamide Compound F: (R)-N-[(1-n -butyl-2-pyrrolidinyl)methyl]-2-methoxy-5-methylthiobenzamide Compound G: (R)-N-[(1-n-butyl-2-pyrrolidinyl)methyl]-2-methoxy-5-methylsulfonyl benzamide

[0023] When the compound of the present invention is used as a medicine, it may be prepared by mixing it with pharmaceutical additives such as excipients, fillers, diluents, etc. as appropriate to prepare tablets, pills, capsules, powders, liquids, or Administered as an injection. The amount varies depending on the compound selected, severity of disease, age, etc.
The usual dose for adults is 0.01 to 10 mg/kg.

Preparation Example Tablets containing 10.0 mg of compound (I) can be prepared according to the following formulation. Compound (I)
10.0mg
lactose
30.0mg
corn starch
18.8mg crystalline cellulose
28.0mg
hydroxypropylcellulose
1.0mg talc

2.0mg Magnesium stearate 0.2mg
──────────────────────
────
90
．． 0mg

Compound (I) is pulverized using an atomizer to form a fine powder with an average particle size of 10 μm or less. Compound(
I) After mixing lactose, corn starch and crystalline cellulose in a kneader, hydroxypropylcellulose is added and kneaded for 20 minutes. The mixture was granulated through a 200 mesh sieve, dried in a hot air dryer at 50°C until the moisture content was 3 to 4%, and after passing through a 24 mesh sieve, talc and magnesium stearate were mixed. ,
The tablets are compressed using a rotary tablet press using a flat punch with a diameter of 6 mm.

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto. Example 1 (S) obtained from L-proline by known methods
- 5.7 g of pyrrolidine-2-carboxamide, 8.3 g of hexyl bromide and 20 g of potassium carbonate are added to a mixture of 50 ml of dimethylformamide and 40 ml of toluene, and the mixture is stirred at 40°C for 7 hours. This mixture was concentrated under reduced pressure,
The resulting residue is extracted with ethyl acetate and washed with water. Dry over magnesium sulfate, concentrate under reduced pressure, add petroleum ether to the resulting residue, and filter the crystals to obtain a melting point of 103-104°C.
6.3 g of (S)-1-hexylpyrrolidine-2-carboxamide are obtained. 2 g of (S)-1-hexylpyrrolidine-2-carboxamide was added to 40 g of tetrahydrofuran.
ml, and 0.9 g of lithium aluminum hydride is added little by little. After this mixture was stirred at 40° C. for 3 hours, ice-cooled water was added dropwise little by little, followed by the addition of 15 ml of 2N sodium hydroxide for hydrolysis. Add ether, stir well, remove the organic layer by decanting, dry and concentrate, and distill the resulting oil, which has a boiling point of 103-105℃/0.7mm.
1.2 g of (S)-(-)-2-aminomethyl-1-hexylpyrrolidine with Hg, [α]D = -87.4° (c = 0.5, methanol) are obtained.

Example 2 (S)- obtained from L-proline by a known method
6 g of pyrrolidine-2-carboxamide, 11 g of nonyl bromide, and 11 g of potassium carbonate are added to a mixture of 50 ml of dimethylformamide and 50 ml of toluene, and the mixture is stirred at 40° C. for 13 hours. This mixture is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate and washed with water. After drying over magnesium sulfate and concentrating under reduced pressure, hexane was added to the resulting residue and the crystals were filtered to give (S)-1 with a melting point of 110-111°C.
8.6 g of -nonylpyrrolidine-2-carboxamide are obtained. 4 g of (S)-1-nonylpyrrolidine-2-carboxamide is added to 50 ml of tetrahydrofuran, and 1.6 g of lithium aluminum hydride is added little by little. After stirring this mixture at 40° C. for 4 hours, ice-cooled water was added dropwise little by little, followed by the addition of 30 ml of 2N sodium hydroxide for hydrolysis. Ether was added and stirred well, the organic layer was decanted, dried and concentrated, and the resulting oil was distilled to give a boiling point of 110-113℃/0.3mmHg, [α]D
=-69.3° (c=1, methanol) (S)-(-
)-2-aminomethyl-1-nonylpyrrolidine 2.7g
is obtained.

Example 3 1 part sodium hydroxide flakes in 125 ml toluene
After stirring under reflux for 30 minutes, a mixed solution of 25 g of 2-pyrrolidinone and 52.3 g of hexyl bromide was added dropwise. After the dropwise addition, the mixture was further stirred under reflux for 2.5 hours, then ice water was added and the organic layer was separated. After washing with water, drying and concentrating under reduced pressure, 1-hexyl-2
52.7 g of pyrrolidinone are obtained as an oil. 1
- 35 g of hexyl-2-pyrrolidinone and 2 dimethyl sulfate
Add 1.1 ml of methanol 15 ml solution and
Warm to ℃ and stir for 2 hours. This reaction solution is cooled for 2 hours.
8% sodium methoxide-methanol solution 46.2m
After stirring at room temperature for 1 hour, nitromethane 1
Add 4.4 ml dropwise, stir at room temperature for 1 hour, and leave overnight. The reaction solution is concentrated under reduced pressure, and ice water and ether are added to the resulting residue. The organic layer was separated, washed with water, dried and concentrated under reduced pressure to obtain 1-hexyl-2-nitromethylenepyrrolidine 37
g is obtained as an oil. 27 g of 1-hexyl-2-nitromethylenepyrrolidine was dissolved in 250 ml of methanol, about 5 g of Raney nickel was added, and the mixture was reacted in a 500 ml autoclave at an initial hydrogen pressure of 90 atm. After the reaction is complete, Raney nickel is removed by filtration, the solvent is concentrated under reduced pressure, and the resulting residue is distilled to give a boiling point of 85-93℃/0.3-0.5m
2-aminomethyl-1-hexylpyrrolidine 1 in mHg
8 g is obtained. This racemic 2-aminomethyl-1-
Dissolve 1.8 g of hexylpyrrolidine in 10 ml of isopropyl alcohol, and add 2.0 g of L-(+)-tartaric acid to this solution.
Dissolve 1 g in 8.5 ml of water and add. When the precipitated crystals are collected by filtration and recrystallized with aqueous isopropyl alcohol,
Melting point 162-164°C, [α]D = +41.2° (c
= 1, water) 0.8 g of 2L-(+)-tartrate are obtained. When this 2L-(+)-tartrate is converted to the free base using sodium hydroxide in water according to a conventional method, extracted with ether, dried, and concentrated under reduced pressure, [α]D = +94.3°
(c=1, water) oil can be obtained. It can be seen from the results of Example 1 that this product is (R)-(+)-2-aminomethyl-1-hexylpyrrolidine. Further, 1.8 g of racemic 2-aminomethyl-1-hexylpyrrolidine is dissolved in 5 ml of isopropyl alcohol, and 2.1 g of D-(-)-tartaric acid dissolved in 4 ml of water is added to this solution. The precipitated crystals are collected by filtration and recrystallized with aqueous isopropyl alcohol, with a melting point of 162-164°C.
α〕D = -41.4° (c = 1, water) 2D-(-)
- 0.8 g of tartrate are obtained. This 2D-(-)-tartrate was converted to the free base using sodium hydroxide in water according to a conventional method, extracted with ether, dried, and concentrated under reduced pressure to obtain [α]D = -91.8° (c = 1 , water) can be obtained. This was obtained from the results of Example 1 (
It can be seen that it is S)-(-)-2-aminomethyl-1-hexylpyrrolidine.

Example 4 Flake sodium hydroxide 52 kg in 600 ml toluene
g, add 1 g of tetrabutylammonium bromide, and add 2
After stirring under reflux for an hour, a mixed solution of 110 g of 2-pyrrolidinone and 250 g of octyl bromide was added dropwise. After the dropwise addition, the mixture was further stirred under reflux for 3 hours, then ice water was added and the organic layer was separated. washing with water,
After drying, concentrate under reduced pressure and distill the resulting residue to a boiling point of 111
216 g of 1-octyl-2-pyrrolidinone are obtained as an oil at ˜139° C./0.6 mmHg. 114 m of dimethyl sulfate to 216 g of 1-octyl-2-pyrrolidinone
1, heated to 50-70°C and stirred for 2 hours. 232 g of 28% sodium methoxide-methanol solution was added dropwise to this reaction solution under cooling, and after stirring at room temperature for 2 hours,
Add 65 ml of nitromethane dropwise, stir at room temperature for 2 hours, and leave overnight. Add ice water and ethyl acetate to the reaction solution. The organic layer is separated, washed with water, dried and concentrated under reduced pressure to obtain 260 g of 1-octyl-2-nitromethylenepyrrolidine as an oil. 260 g of 1-octyl-2-nitromethylenepyrrolidine was dissolved in 2 liters of methanol, about 50 g of Raney nickel was added thereto, and the mixture was reacted in a 5 liter autoclave at an initial hydrogen pressure of 60 atm. After completion of the reaction, the Raney nickel was filtered off, the solvent was concentrated under reduced pressure, and the resulting residue was distilled to obtain 173 g of 2-aminomethyl-1-octylpyrrolidine with a boiling point of 138° C./1.0 mmHg. 167 g of this racemic 2-aminomethyl-1-octylpyrrolidine was dissolved in 500 ml of isopropyl alcohol, and 177 g of L-(+)-tartaric acid was dissolved in 200 ml of water.
Dissolve in ml and add. The precipitated crystals were collected by filtration and recrystallized with aqueous ethanol to give a melting point of 164°C and [α]D =
115 g of 2L-(+)-tartrate of +38.5° (c=1, water) are obtained. This 2L-(+)-tartrate is converted into a free base using sodium hydroxide in water according to a conventional method, extracted with ether, dried and concentrated under reduced pressure, and the resulting residue is distilled. 0.3mmHg
, [α]D = +73.6° (c = 1, methanol)
(R)-(+)-2-aminomethyl-1-octylpyrrolidine is obtained. Further, the filtrate obtained when salt is formed using the above-mentioned L-(+)-tartaric acid is concentrated under reduced pressure. This was returned to the free base using sodium hydroxide in water, extracted with ether, dried and concentrated under reduced pressure. Of the 81 g of residue obtained, 50
g is dissolved in 200 ml of isopropyl alcohol, and to this solution is added 50 g of D-(-)-tartaric acid dissolved in 50 ml of water. The precipitated crystals are collected by filtration and recrystallized with aqueous ethanol, melting point 162-164°C, [α]D = -3
2D-(-)-tartrate 36 at 8.9° (c=1, water)
．． 4g is obtained. This 2D-(-)-tartrate was converted into a free base using sodium hydroxide in water in a conventional manner, extracted with ether, dried and concentrated under reduced pressure, and the resulting residue was distilled, with a melting point of 105°C/0. 3mmHg, [α]
(S)- of D = -75.3° (c = 1, methanol)
(-)-2-Aminomethyl-1-octylpyrrolidine is obtained.

Example 5 48 ml of flaked sodium hydroxide in 600 ml of toluene
．． After stirring under reflux for 1.5 hours, a mixed solution of 103 g of 2-pyrrolidinone and 250 g of nonyl bromide was added dropwise. After the dropwise addition, the mixture was further stirred under reflux for 3.5 hours, then ice water was added and the organic layer was separated. After washing with water, drying, and concentrating under reduced pressure, the resulting residue was distilled to yield 1-nonyl-
222 g of 2-pyrrolidinone are obtained as an oil. 1
-220g of nonyl-2-pyrrolidinone to 11g of dimethyl sulfate
Add 44 g, heat to 60-70°C, and stir for 2 hours. To this reaction solution, 221 g of a 28% sodium methoxide-methanol solution was added dropwise under cooling, and after stirring at room temperature for 2 hours, 70 g of nitromethane was added dropwise, stirred for 1 hour at room temperature, and left overnight. Add ice water and ethyl acetate to the reaction solution. The organic layer is separated, washed with water, dried and concentrated under reduced pressure to obtain 250 g of 1-nonyl-2-nitromethylenepyrrolidine as an oil. 250 g of 1-nonyl-2-nitromethylenepyrrolidine was dissolved in 2 liters of methanol, about 50 g of Raney nickel was added thereto, and the mixture was reacted in a 5 liter autoclave at an initial hydrogen pressure of 55 atm. After the reaction, the Raney nickel was removed by filtration, the solvent was concentrated under reduced pressure, and the resulting residue was distilled to give 2-
145 g of aminomethyl-1-nonylpyrrolidine are obtained. 145 g of this racemic 2-aminomethyl-1-nonylpyrrolidine is dissolved in 500 ml of ethanol, and 145 g of L-(+)-tartaric acid dissolved in 130 ml of water is added to this solution. The precipitated crystals are collected by filtration and recrystallized with aqueous ethanol to give a melting point of 164-167°C, [α]D = +
2L-(+)-tartrate 6 at 37.6° (c=1, water)
5g is obtained. This 2L-(+)-tartrate was converted into a free base using sodium hydroxide in water according to a conventional method, extracted with ether, dried and concentrated under reduced pressure, and the resulting residue was distilled, with a melting point of 111°C/0. 3mmHg, [α]D
=+70.5° (c=1, methanol) can be obtained. This product was obtained from the results of Example 2 (R
)-(+)-2-aminomethyl-1-nonylprolidine. Further, the filtrate obtained when salt is formed using the above-mentioned L-(+)-tartaric acid is concentrated under reduced pressure. This was returned to the free base using sodium hydroxide in water, extracted with ether, dried and concentrated under reduced pressure. 110 g of the resulting residue was dissolved in 500 ml of ethanol, and 58 g of D-(-)-tartaric acid was added to this solution in 100 ml of water. Dissolve and add. When the precipitated crystals are filtered and recrystallized with aqueous ethanol, the melting point is 16.
68.5 g of 2D-(-)-tartrate at 4-167[deg.] C., [α]D = -37.9° (c = 1, water) are obtained. This 2D-(-)-tartrate was converted to the free base using sodium hydroxide in water according to a conventional method, extracted with ether,
After drying and concentrating under reduced pressure, the resulting residue is distilled to give a melting point of 11
1℃/0.3mmHg, [α]D = -71.1°(
c=1, methanol) can be obtained as an oil. From the results of Example 2, this product is (S)-(-)-2-
It can be seen that it is aminomethyl-1-nonylpyrrolidine.

Example 6 45 ml of flaked sodium hydroxide in 600 ml of toluene
．． 2 g of tetrabutylammonium bromide and 1 g of tetrabutylammonium bromide were added thereto, and after stirring under reflux for 1 hour, a mixed solution of 96 g of 2-pyrrolidinone and 250 g of decyl bromide was added dropwise. After the dropwise addition, the mixture was further stirred under reflux for 3 hours, then ice water was added and the organic layer was separated. washing with water,
After drying, concentrate under reduced pressure and distill the resulting residue to a boiling point of 150
1-decyl-2-pyrrolidinone 2 at °C/0.3 mmHg
39 g are obtained as an oil. Add 147 g of dimethyl sulfate to 239 g of 1-decyl-2-pyrrolidinone and make 60~
Warm to 70°C and stir for 2 hours. Add 225% of a 28% sodium methoxide-methanol solution to this reaction solution while cooling.
After stirring at room temperature for 3.5 hours, 71 g of nitromethane was added dropwise, stirring at room temperature for 1 hour, and leaving it overnight. Add ice water and ethyl acetate to the reaction solution. The organic layer was separated, washed with water, dried, and concentrated under reduced pressure to obtain 250 g of 1-decyl-2-nitromethylenepyrrolidine as an oil. 1-decyl-2-nitromethylenepyrrolidine 250g
Dissolve in 2 liters of methanol and add about 5 liters of Raney nickel.
0 g was added and reacted in a 5 liter autoclave at an initial hydrogen pressure of 70 atm. After the reaction is complete, Raney nickel is removed by filtration, the solvent is concentrated under reduced pressure, and the resulting residue is distilled to give a boiling point of 1.
2-aminomethyl- at 20-145°C/0.3mmHg
175 g of 1-decylpyrrolidine are obtained. Dissolve 175 g of this racemic 2-aminomethyl-1-decylpyrrolidine in 500 ml of ethanol, and add L-(+) to this solution.
- Add 153 g of tartaric acid dissolved in 130 ml of water. When the precipitated crystals are filtered and recrystallized with aqueous ethanol,
Melting point 167-169°C, [α]D = +37.5° (c
38.5 g of 2L-(+)-tartrate of 1, water) are obtained. This 2L-(+)-tartrate is converted into a free base using sodium hydroxide in water according to a conventional method, extracted with ether, dried, concentrated under reduced pressure, and the resulting residue is distilled.
Melting point 115℃/0.3mmHg, [α]D = +65
．． (R)-(+)-2- at 6° (c=1, methanol)
Aminomethyl-1-decylpyrrolidine is obtained. Further, the filtrate obtained when salt is formed using the above-mentioned L-(+)-tartaric acid is concentrated under reduced pressure. This was converted into a free base using sodium hydroxide in water, extracted with ether, dried and concentrated under reduced pressure. 150 g of the resulting residue was dissolved in 500 ml of ethanol, and 47 g of D-(-)-tartaric acid was added to this solution in water. 100ml
Dissolve and add. The precipitated crystals are collected by filtration and recrystallized with aqueous ethanol to give a melting point of 166-169°C, [α]D
42.5 g of 2D-(-)-tartrate of =-36.4° (c=1, water) are obtained. This 2D-(-)-tartrate was converted into a free base using sodium hydroxide in water using a conventional method, extracted with ether, dried and concentrated under reduced pressure, and the resulting residue was distilled, with a melting point of 120°C/0. 3mmHg,
(S)-(-)-2-aminomethyl-1-decylpyrrolidine with [α]D=-64.8° (c=1, methanol) is obtained.

Example 7 (S)- obtained from L-proline by a known method
8 g of pyrrolidine-2-carboxamide, 17.5 g of lauryl bromide and 24 g of potassium carbonate are added to a mixture of 130 ml of dimethylformamide and 130 ml of toluene, and the mixture is stirred at 50°C for 40 hours. This mixture was concentrated under reduced pressure,
The resulting residue is extracted with ethyl acetate and washed with water. After drying over magnesium sulfate and concentrating under reduced pressure, hexane is added to the resulting residue, and the crystals are filtered to give (
S)-1-dodecylpyrrolidine-2-carboxamide 1
5.6 g is obtained. 10 g of this (S)-1-dodecylpyrrolidine-2-carboxamide was added to 150 ml of tetrahydrofuran, and 2.0 g of lithium aluminum hydride was added.
Add 2g little by little. After stirring this mixture at 50° C. for 3 hours, water was added dropwise little by little under ice cooling, and then 40 ml of 2N sodium hydroxide was added for hydrolysis. Ether was added and stirred well, the organic layer was decanted, dried and concentrated, and the resulting oil was distilled to give a boiling point of 180-185℃/
7.2 g of (S)-(-)-2-aminomethyl-1-dodecylpyrrolidine are obtained at 2 mmHg, [α]D = -58.5° (c = 1, methanol).

Example 8 2.34 g of 2-methoxy-5-sulfamoylbenzoic acid
and 3 ml of triethylamine to 10 ml of dimethylformamide.
ml and tetrahydrofuran (10 ml), -1
The mixture was cooled to 0° C. and 1.4 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 1 hour, a solution of 2.25 g of (R)-(+)-2-aminomethyl-1-hexylpyrrolidine obtained in Example 3 in 20 ml of tetrahydrofuran was added dropwise at the same temperature, and then overnight at room temperature. Stir. The reaction solution is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Add isopropyl ether to the resulting residue, collect the precipitated crystals by filtration, and recrystallize with a mixed solvent of isopropyl alcohol and isopropyl ether to obtain (R)-N-[(1-hexyl-2-pyrrolidinyl)methyl]-2 2.4 g of -methoxy-5-sulfamoylbenzamide are obtained. Melting point 139-14
2°C, [α]D = +74.5° (c = 1, dimethylformamide)

Example 9 2.34 g of 2-methoxy-5-sulfamoylbenzoic acid
and 3 ml of triethylamine to 12 ml of dimethylformamide.
ml and tetrahydrofuran 20ml, -1
The mixture was cooled to 0° C. and 1.4 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 50 minutes, a solution of 2.25 g of (S)-(-)-2-aminomethyl-1-hexylpyrrolidine obtained in Example 1 or Example 3 in 15 ml of tetrahydrofuran was added dropwise at the same temperature. Further at room temperature 4.
Stir for 5 hours. The reaction solution is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Isopropyl ether is added to the resulting residue, the precipitated crystals are collected by filtration, and recrystallized with a mixed solvent of isopropyl alcohol and isopropyl ether to give (S)-N-[(
2.3 g of 1-hexyl-2-pyrrolidinyl)methyl]-2-methoxy-5-sulfamoylbenzamide are obtained. Melting point 139-142℃, [α]D = -75.0
°(c=1, dimethylformamide)

Example 10 2.57 g of (S)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid and 3.1 ml of triethylamine were mixed with 10 ml of dimethylformamide.
Add to a mixture of -10 ml and 10 ml of tetrahydrofuran.
The mixture was cooled to ℃ and 1.4 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 30 minutes, a solution of 2.4 g of (R)-(+)-2-aminomethyl-1-hexylpyrrolidine obtained in Example 3 in 10 ml of tetrahydrofuran was added dropwise at the same temperature, and then at room temperature for 7 Stir for an hour. The reaction solution is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Add isopropyl ether to the resulting residue, collect the precipitated crystals by filtration, and recrystallize with a mixed solvent of isopropyl alcohol and isopropyl ether to obtain (R,S)-N-[(1-hexyl-2-pyrrolidinyl)methyl]. 2.3 g of -2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide are obtained. Melting point 131-132℃, [α]
D = +64.1° (c = 1, dimethylformamide)

Example 11 1.44 g of (S)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid and 1.8 ml of triethylamine were mixed with 10 ml of dimethylformamide.
Add to a mixture of 10 ml of tetrahydrofuran and -15
The mixture was cooled to 0.degree. C. and 0.8 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 30 minutes, (S)-(-)-2-aminomethyl- obtained in Example 1 or Example 3.
A solution of 1.3 g of 1-hexylpyrrolidine in 10 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was further stirred overnight at room temperature. The reaction solution is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Add isopropyl ether to the resulting residue, collect the precipitated crystals by filtration, and recrystallize with a mixed solvent of isopropyl alcohol and isopropyl ether to obtain (S,S)-N-[(1-hexyl-2-pyrrolidinyl)methyl]. -2-methyl-5-
Sulfamoyl-2,3-dihydrobenzofuran-7-
0.8 g of carboxamide is obtained. Melting point 117-11
8°C, [α]D = -75.1° (c = 1, dimethylformamide)

Example 12 150 mg of (R)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid and 180 μl of triethylamine were added to 1 ml of dimethylformamide.
and 1 ml of tetrahydrofuran, cooled to -15°C, and 83 μl of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, a solution of 107 mg of (R)-(+)-2-aminomethyl-1-hexylpyrrolidine in 1 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. When the obtained solid is recrystallized from a mixed solvent of ethyl acetate and hexane, (R,R)-[(1-hexyl-2-pyrrolidinyl)methyl]-2-methyl-5-
Sulfamoyl-2,3-dihydrobenzofuran-7-
20 mg of carboxamide are obtained. Melting point 126-12
8℃

Example 13 150 mg of (R)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid and 180 μl of triethylamine were added to 1 ml of dimethylformamide.
and 1 ml of tetrahydrofuran, cooled to -15°C, and 83 μl of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, a solution of 107 mg of (S)-(-)-2-aminomethyl-1-hexylpyrrolidine in 1 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. When the obtained solid is recrystallized from a mixed solvent of ethyl acetate and hexane, (S,R)-[(1-hexyl-2-pyrrolidinyl)methyl]-2-methyl-5-
Sulfamoyl-2,3-dihydrobenzofuran-7-
100 mg of carboxamide are obtained. Melting point 128-1
30℃

Example 14 2,2-dimethyl-5-(N-methylsulfamoyl)
-2,3-dihydrobenzofuran-7-carboxylic acid 1.
01 g of triethylamine and 1.04 ml of triethylamine were added to a mixture of 6 ml of dimethylformamide and 10 ml of tetrahydrofuran, and the mixture was cooled to -15°C.
．． Add 45 ml dropwise. After stirring at the same temperature for 20 minutes, (R)
A solution of 0.8 g of -(+)-2-aminomethyl-1-hexylpyrrolidine in 5 ml of tetrahydrofuran is added dropwise at the same temperature, and the mixture is stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Isopropyl ether is added to the resulting residue, the precipitated crystals are collected by filtration, and recrystallized with a mixed solvent of ethyl acetate and isopropyl ether to give (R)-N-[(1-hexyl-2-pyrrolidinyl)
1.01 g of methyl]-2,2-dimethyl-5-(N-methylsulfamoyl)-2,3-dihydrobenzofuran-7-carboxamide are obtained. Melting point 126-128
°C, [α]D = +60.8° (c = 1, dimethylformamide)

Example 15 2,2-dimethyl-5-(N-methylsulfamoyl)
-2,3-dihydrobenzofuran-7-carboxylic acid 1.
01 g of triethylamine and 1.04 ml of triethylamine were added to a mixture of 6 ml of dimethylformamide and 10 ml of tetrahydrofuran, and the mixture was cooled to -15°C.
．． Add 45 ml dropwise. After stirring at the same temperature for 20 minutes, (S)
A solution of 0.8 g of -(-)-2-aminomethyl-1-hexylpyrrolidine in 5 ml of tetrahydrofuran is added dropwise at the same temperature, and the mixture is stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Isopropyl ether is added to the resulting residue, the precipitated crystals are collected by filtration, and recrystallized with a mixed solvent of ethyl acetate and isopropyl ether to give (S)-N-[(1-hexyl-2-pyrrolidinyl)
0.63 g of methyl]-2,2-dimethyl-5-(N-methylsulfamoyl)-2,3-dihydrobenzofuran-7-carboxamide are obtained. Melting point 126-128
°C, [α]D = +61.9° (c = 1, dimethylformamide)

Example 16 950 mg of 2,2-dimethyl-5-methylthio-2,3-dihydrobenzofuran-7-carboxylic acid and 1.2 ml of triethylamine were added to a mixture of 10 ml of dimethylformamide and 20 ml of tetrahydrofuran, and the mixture was cooled to -15°C. Add 550 μl of isobutyl chloroformate dropwise. After stirring at the same temperature for 20 minutes, a solution of 800 mg of (R)-(+)-2-aminomethyl-1-hexylpyrrolidine in 5 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. When the resulting residue is purified by chromatography,
1.1 g of (R)-[(1-hexyl-2-pyrrolidinyl)methyl]-2,2-dimethyl-5-methylthio-2,3-dihydrobenzofuran-7-carboxamide are obtained as an oil. 1H-NMR 100MHz (CDCl3) 0
．． 86 (t, 3H), 1.1-3.4 (18H), 1.
52 (s, 3H), 1.56 (s, 3H), 2.47 (
s, 3H), 3.03 (s, 2H), 3.76 (m, 1
H), 7.22 (d, 1H), 7.90 (d, 1H),
8.10(br, 1H), [α]D = +61.2°(
c=1, dimethylformamide)

Example 17 5-Methylthio-2,3-dihydrobenzofuran-7-
840 mg of carboxylic acid and 1.2 ml of triethylamine were mixed with 10 ml of dimethylformamide and 2 ml of tetrahydrofuran.
0 ml of the mixed solution, cooled to -15°C, and 550 μl of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, a solution of 800 mg of (R)-(+)-2-aminomethyl-1-hexylpyrrolidine in 5 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. When the resulting residue is purified by chromatography, (R
)-[(1-hexyl-2-pyrrolidinyl)methyl]-
5-Methylthio-2,3-dihydrobenzofuran-7-
750 mg of carboxamide are obtained as an oil. 1H-NMR 100MHz (CDCl3) 0
．． 86 (t, 3H), 1.1-3.4 (20H), 2.
48 (s, 3H), 3.72 (m, 1H), 4.70 (
t, 2H), 7.26 (d, 1H), 7.86 (d, 1
H), 7.94 (br, 1H), [α]D = +63.
3° (c=1, dimethylformamide)

Example 18 1.5 g of 2-methoxy-5-sulfamoylbenzoic acid and 1 g of N-methylmorpholine were mixed with 30 g of dimethylformamide.
ml, cooled to -10°C, and 1 g of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, (R)-(+)-2-aminomethyl- obtained according to Example 4.
A solution of 1.5 g of 1-octylpyrrolidine in 20 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was further stirred overnight at room temperature. The reaction solution is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Add isopropyl ether to the resulting residue, collect the precipitated crystals by filtration, and recrystallize with a mixed solvent of isopropyl alcohol and isopropyl ether to obtain (R)-N-[(1-octyl-2-pyrrolidinyl)methyl]-2 1.6 g of -methoxy-5-sulfamoylbenzamide are obtained. Melting point 1
24-125°C, [α]D = +49.2° (c = 1,
methanol)

Example 19 1.5 g of 2-methoxy-5-sulfamoylbenzoic acid and 1 g of N-methylmorpholine were mixed with 20 g of dimethylformamide.
ml, cooled to -10°C, and 1 g of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, (S)-(-)-2-aminomethyl- obtained according to Example 4.
A solution of 1.5 g of 1-octylpyrrolidine in 20 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was further stirred overnight at room temperature. The reaction solution is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Add isopropyl ether to the resulting residue, collect the precipitated crystals by filtration, and recrystallize with a mixed solvent of isopropyl alcohol and isopropyl ether to obtain (S)-N-[(1-octyl-2-pyrrolidinyl)methyl]-2 0.9 g of -methoxy-5-sulfamoylbenzamide is obtained. Melting point 1
24-125°C, [α]D = -55.3° (c = 1,
methanol)

Example 20 560 mg of (S)-2-methyl-5-methylthio-2,3-dihydrobenzofuran-7-carboxylic acid and 770 μl of triethylamine were added to a mixture of 10 ml of dimethylformamide and 10 ml of tetrahydrofuran, and the mixture was cooled to -15°C. Add 340 μl of isobutyl chloroformate dropwise. After stirring at the same temperature for 20 minutes, a solution of 530 ml of (R)-(+)-2-aminomethyl-1-octylpyrrolidine in 5 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. The resulting residue was purified by chromatography to yield (R,S)-[(1-octyl-2-pyrrolidinyl)methyl]-2-methyl-5-methylthio-2,3-
Dihydrobenzofuran-7-carboxamide is obtained as an oil. 1H-NMR 100MHz (CDCl3) 0
．． 84 (t, 3H), 1.1-3.5 (24H), 1.
50 (d, 3H), 2.46 (s, 3H), 3.77 (
m, 1H), 5.02 (m, 1H), 7.22 (m, 1
H), 7.85 (d, 1H), 8.08 (br, 1H)
, [α]D = +55.1° (c = 1, dimethylformamide)

Example 21 0.79 g of 2,2-dimethyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid and 0.93 ml of triethylamine were added to 7 ml of dimethylformamide.
and 7 ml of tetrahydrofuran, cooled to -15°C, and 0.4 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, a solution of 0.64 g of (R)-(+)-2-aminomethyl-1-octylpyrrolidine in 5 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield (R)-N-[(1-octyl-2-pyrrolidinyl)methyl]-2,2-dimethyl-5
-sulfamoyl-2,3-dihydrobenzofuran-7
-0.95 g of carboxamide are obtained as amorphous crystals. 1H-NMR 100MHz (CDCl3) 0
．． 84 (t, 3H), 1.55 (3H), 1.57 (3
H), 3.50 (s, 2H), 3.74 (m, 1H),
1.0-3.4 (22H), 5.52 (br, 2H),
7.82 (d, 1H), 8.16 (br, 1H), 8.
57 (d, 1H), [α]D = +59.0° (c = 1
, dimethylformamide)

Example 22 0.61 g of 2,2-dimethyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid and 0.7 ml of triethylamine were added to a mixture of 7 ml of dimethylformamide and 7 ml of tetrahydrofuran, and the mixture was heated at -15°C. 0.31 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, a solution of 0.5 g of (S)-(-)-2-aminomethyl-1-octylpyrrolidine in 3 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield (S)-N-[(1-octyl-
2-pyrrolidinyl)methyl]-2,2-dimethyl-5-
Sulfamoyl-2,3-dihydrobenzofuran-7-
0.61 g of carboxamide is obtained as amorphous crystals. 1H-NMR 100MHz (CDCl3) 0
．． 84 (t, 3H), 1.23 (s, 10H), 1.5
6 (s, 6H), 3.10 (s, 2H), 1.00-3
．． 94 (13H), 5.40 (br, 2H), 7.82
(d, 1H), 8.16 (br, 1H), 8.57 (d
, 1H), [α]D = +56.5° (c = 1, dimethylformamide)

Example 23 5-ethylthio-2,3-dihydrobenzofuran-7-
0.6 g of carboxylic acid and 0.74 ml of triethylamine were mixed with 6 ml of dimethylformamide and 12 ml of tetrahydrofuran.
ml of the mixed solution, cooled to -15°C, and 0.3 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, a solution of 0.49 g of (R)-(+)-2-aminomethyl-1-octylpyrrolidine in 3 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. When the resulting residue is purified by column chromatography,
0.8 g of (R)-N-[(1-octyl-2-pyrrolidinyl)methyl]-5-ethylthio-2,3-dihydrobenzofuran-7-carboxamide is obtained as an oil. 1H-NMR 100MHz (CDCl3) 0
．． 85 (t, 3H), 1.04-3.44 (32H),
3.72 (m, 1H), 4.70 (t, 2H), 7.3
3 (d, 1H), 7.96 (d, 1H), 8.00 (b
r, 1H), [α]D = +59.8° (c = 1, dimethyl sulfoxide)

Example 24 5-benzylthio-2,3-dihydrobenzofuran-7
-0.6g of carboxylic acid and 0.58ml of triethylamine
was added to 12 ml of tetrahydrofuran, cooled to -15°C, and 0.24 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, a solution of 0.38 g of (R)-(+)-2-aminomethyl-1-octylpyrrolidine in 3 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. When the resulting residue was purified by column chromatography, (R)-N-[(1-octyl-
2-pyrrolidinyl)methyl]-5-benzylthio-2,
3-dihydrobenzofuran-7-carboxamide 0.7
5 g are obtained as an oil. 1H-NMR 100MHz (CDCl3) 0
．． 85 (t, 3H), 1.04-3.46 (24H),
3.68 (m, 1H), 4.04 (s, 2H), 4.6
8 (t, 2H), 7.20 (d, 1H), 7.24 (s
, 5H), 7.92 (br, 1H), 8.00 (d, 1
H), [α]D = +50.0° (c = 1, dimethyl sulfoxide)

Example 25 2-methoxy-5-sulfamoylbenzoic acid and N-
1g of methylmorpholine to 30ml of dimethylformamide
In addition, the mixture was cooled to -10°C and 1.2 g of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, Example 5
(R)-(+)-2-aminomethyl-1 obtained by
- 2g of nonylpyrrolidine in 20ml of tetrahydrofuran
The solution was added dropwise at the same temperature and further stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Isopropyl ether is added to the resulting residue, the precipitated crystals are collected by filtration, and recrystallized with a mixed solvent of isopropyl alcohol and isopropyl ether to give (R)-N-[(1-nonyl-2-pyrrolidinyl)methyl]-2. 1.7 g of -methoxy-5-sulfamoylbenzamide are obtained. Melting point 115-11
7℃, [α]D = +53.5° (c = 1, methanol)

Example 26 2 g of 2-methoxy-5-sulfamoylbenzoic acid and N-
1g of methylmorpholine to 30ml of dimethylformamide
In addition, the mixture was cooled to -10°C and 1.2 g of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, Example 2
Alternatively, a solution of 2 g of (S)-(-)-2-aminomethyl-1-nonylpyrrolidine obtained in Example 5 in 20 ml of tetrahydrofuran is added dropwise at the same temperature, and the mixture is further stirred overnight at room temperature. The reaction solution is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Add isopropyl ether to the resulting residue, collect the precipitated crystals by filtration, and recrystallize with a mixed solvent of isopropyl alcohol and isopropyl ether to obtain (S)-N-[(1-nonyl-2-pyrrolidinyl)methyl]-2 -methoxy-5
-2.4 g of sulfamoylbenzamide are obtained. Melting point 115-116°C, [α]D = -53.5° (c =
1, methanol)

Example 27 2 g of 2-methoxy-5-methylsulfonylbenzoic acid is suspended in 50 ml of toluene, and 2.5 ml of thionyl chloride and 0.2 ml of dimethylformamide are added. Add this mixture to 7
After heating to 0° C. and stirring for 2.5 hours, the mixture was dried under reduced pressure. The resulting residue was dissolved in 20 ml of dichloromethane to give (R)-(+)-2-aminomethyl-1- obtained in Example 5.
Add 1.9 g of nonylpyrrolidine to a solution of 20 ml of dichloromethane. The reaction solution was left at room temperature overnight, concentrated under reduced pressure, and an aqueous potassium carbonate solution and ethyl acetate were added to the resulting residue. The organic layer is separated, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. When the obtained solid was recrystallized from a mixed solvent of ethyl acetate and isopropyl ether, 2.9 g of (R)-N-[(1-nonyl-2-pyrrolidinyl)methyl]-2-methoxy-5-methylsulfonylbenzamide was obtained. can get. Melting point 86-87°C, [α]D = +54.6° (c = 1, methanol)

Example 28 2-methoxy-5-methylsulfonylbenzoic acid 1.61
Add g and 2.5 ml of triethylamine to a mixture of 5 ml of dimethylformamide and 10 ml of tetrahydrofuran,
Cool to -15°C and add 1 ml of isobutyl chloroformate dropwise. After stirring at the same temperature for 20 minutes, (S)-(-)-2
A solution of 1.7 g of -aminomethyl-1-nonylpyrrolidine in 10 ml of tetrahydrofuran was added dropwise at the same temperature.
Stir for 0 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate,
After drying, concentrate under reduced pressure. Add hexane to the resulting residue,
The precipitated crystals were collected by filtration and recrystallized with a mixed solvent of ethyl acetate and isopropyl ether to give (S)-N-[(1-
Nonyl-2-pyrrolidinyl)methyl]-2-methoxy-
2.5 g of 5-methylsulfonylbenzamide are obtained. Melting point 86-88°C, [α]D = -52.7° (c =
1, methanol)

Example 29 2 g of 2-methoxy-5-methylthiobenzoic acid was suspended in 50 ml of toluene, and 2.9 ml of thionyl chloride was added. This mixed solution is heated to 60 to 70°C, stirred for 1.5 hours, and then dried under reduced pressure. The resulting residue was dissolved in 20 ml of dichloromethane to give (R)-(+)-2- obtained in Example 5.
Add 2.2 g of aminomethyl-1-nonylpyrrolidine to a solution of 30 ml of dichloromethane. The reaction solution is left at room temperature overnight, concentrated under reduced pressure, and an aqueous potassium carbonate solution and ethyl acetate are added to the resulting residue. The organic layer is separated, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel chromatography, resulting in (
R)-N-[(1-nonyl-2-pyrrolidinyl)methyl]-2-methoxy-5-methylthiobenzamide 3.5
g is obtained as an oil. 1H-NMR 100MHz (CDCl3) 0
．． 86 (t, 3H), 1.0-3.4 (24H), 2.
48 (s, 3H), 3.56-3.94 (m, 1H),
6.88 (d, 1H), 7.34 (dd, 1H), 8.
14 (d, 1H), 8.28 (br, 1H), [α]D
=+55.2° (c=1, methanol)

Example 30 1.39 g of 2-methoxy-5-methylthiobenzoic acid and 2.5 ml of triethylamine were added to 5 ml of dimethylformamide.
Add to a mixture of 10 ml of tetrahydrofuran and -15
Cool to 0.degree. C. and add 1 ml of isobutyl chloroformate dropwise. After stirring at the same temperature for 20 minutes, a solution of 1.7 g of (S)-(-)-2-aminomethyl-1-nonylpyrrolidine in 10 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to produce (S)-N-[(1-nonyl-2
1 g of -pyrrolidinyl)methyl]-2-methoxy-5-methylthiobenzamide is obtained as an oil. 1H-NMR 100MHz (CDCl3) 0
．． 86 (t, 3H), 1.0-3.4 (24H), 2.
48 (s, 3H), 3.56-3.94 (m, 1H),
6.88 (d, 1H), 7.34 (dd, 1H), 8.
14 (d, 1H), 8.28 (br, 1H), [α]D
=-44.8° (c=1, methanol)

Example 31 0.54 g of 2,2-dimethyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid and 0.5 ml of N-methylmorpholine were added to 7 ml of dimethylformamide.
Add to a mixture of 1 and 7 ml of tetrahydrofuran and heat at -15°C.
0.29 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, (R)-(+)-2-
A solution of 0.5 g of aminomethyl-1-nonylpyrrolidine in 3 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give (R)-N-[(1-nonyl-
2-pyrrolidinyl)methyl]-2,2-dimethyl-5-
Sulfamoyl-2,3-dihydrobenzofuran-7-
0.48 g of carboxamide is obtained as amorphous crystals. 1H-NMR 100MHz (CDCl3) 0
．． 86 (t, 3H), 1.23 (s, 12H), 1.5
7 (s, 6H), 3.11 (s, 2H), 1.03-3
．． 46 (12H), 3.60-3.89 (m, 1H),
5.45 (br, 2H), 7.82 (d, 1H), 8.
16 (br, 1H), 8.55 (d, 1H), [α]D
=+49.5° (c=1, dimethylformamide)

Example 32 0.54 g of 2,2-dimethyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid and 0.5 ml of N-methylmorpholine were added to 7 ml of dimethylformamide.
Add to a mixture of 1 and 7 ml of tetrahydrofuran and heat at -15°C.
0.29 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, (S)-(-)-2-
A solution of 0.5 g of aminomethyl-1-nonylpyrrolidine in 3 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield (S)-N-[(1-nonyl-
2-pyrrolidinyl)methyl]-2,2-dimethyl-5-
Sulfamoyl-2,3-dihydrobenzofuran-7-
0.48 g of carboxamide is obtained as amorphous crystals. 1H-NMR 100MHz (CDCl3) 0
．． 86 (t, 3H), 1.23 (s, 12H), 1.5
7 (s, 6H), 3.11 (s, 2H), 1.03-3
．． 46 (12H), 3.60-3.89 (m, 1H),
5.45 (br, 2H), 7.82 (d, 1H), 8.
16 (br, 1H), 8.55 (d, 1H), [α]D
=-54.8° (c=1, dimethylformamide)

Example 33 2,2-dimethyl-5-(N-methylsulfamoyl)
-2,3-dihydrobenzofuran-7-carboxylic acid 0.
75 g and 0.61 ml of triethylamine were added to a mixture of 6 ml of dimethylformamide and 6 ml of tetrahydrofuran, cooled to -15°C, and 0.6 ml of isobutyl chloroformate was added.
Add 29 ml dropwise. After stirring at the same temperature for 20 minutes, (R)-
(+)-2-Aminomethyl-1-nonylpyrrolidine 0.
A solution of 5 g in 3 ml of tetrahydrofuran was added dropwise at the same temperature.
Stir for 30 minutes at the same temperature. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give (R)-N-[(
0.48 g of 1-nonyl-2-pyrrolidinyl)methyl]-2,2-dimethyl-5-methylsulfamoyl)-2,3-dihydrobenzofuran-7-carboxamide are obtained as an oil. If this is a hydrochloride, (R)-N-[(1-nonyl-2
-pyrrolidinyl)methyl]-2,2-dimethyl-5-(
500 mg of N-methylsulfamoyl)-2,3-dihydrobenzofuran-7-carboxamide monohydrochloride is obtained as amorphous crystals. 1H-NMR 100MHz (D2O) 0.86
(t, 3H), 1.23 (s, 12H), 1.57 (s
, 6H), 3.11 (s, 2H), 0.98-2.50
(18H), 1.70 (s, 6H), 2.63 (s, 3
H), 3.10-4.18 (9H), 5.45 (br,
2H), 7.90 (d, 1H), 8.24 (d, 1H)
, [α]D = -7.6° (c = 1, dimethylformamide)

Example 34 2,2-dimethyl-5-(N-methylsulfamoyl)
-2,3-dihydrobenzofuran-7-carboxylic acid 0.
75 g and 0.61 ml of triethylamine were added to a mixture of 6 ml of dimethylformamide and 6 ml of tetrahydrofuran, cooled to -15°C, and 0.6 ml of isobutyl chloroformate was added.
Add 29 ml dropwise. After stirring at the same temperature for 20 minutes, (S)-
(-)-2-Aminomethyl-1-nonylpyrrolidine 0.
A solution of 5 g in 3 ml of tetrahydrofuran was added dropwise at the same temperature.
Stir for 30 minutes at the same temperature. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield (S)-N-[(
0.77 g of 1-nonyl-2-pyrrolidinyl)methyl]-2,2-dimethyl-5-methylsulfamoyl)-2,3-dihydrobenzofuran-7-carboxamide are obtained as an oil. If this is a hydrochloride, (S)-N-[(1-nonyl-2
-pyrrolidinyl)methyl]-2,2-dimethyl-5-(
610 mg of N-methylsulfamoyl)-2,3-dihydrobenzofuran-7-carboxamide monohydrochloride is obtained as amorphous crystals. 1H-NMR 100MHz (D2O) 0.86
(t, 3H), 1.23 (s, 12H), 1.57 (s
, 6H), 3.11 (s, 2H), 0.98-2.50
(18H), 1.70 (s, 6H), 2.63 (s, 3
H), 3.10-4.18 (9H), 5.45 (br,
2H), 7.90 (d, 1H), 8.24 (d, 1H)
, [α]D = +7.0° (c = 1, dimethylformamide)

Example 35 0.53 g of 2,2-dimethyl-5-methylthio-2,3-dihydrobenzofuran-7-carboxylic acid and 0.66 ml of triethylamine were added to a mixture of 5 ml of dimethylformamide and 7 ml of tetrahydrofuran, and the mixture was heated at -15°C. 0.29 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, a solution of 0.5 g of (R)-(+)-2-aminomethyl-1-nonylpyrrolidine in 3 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield (R)-N-[(1-nonyl-2-pyrrolidinyl)methyl]-2,2-dimethyl-5-methylthio-2,3-dihydrobenzofuran-7- 340 mg of carboxamide are obtained as an oil. 1H-NMR 100MHz (CDCl3) 0
．． 86 (t, 3H), 1.53 (s, 3H), 1.55
(s, 3H), 2.47 (s, 3H), 3.02 (s,
2H), 3.60-3.97 (m, 1H), 0.98-
3.44 (25H), 7.22 (d, 1H), 7.87
(d, 1H), 8.15 (br. 1H), [α]D =
+55.5° (c=1, dimethylformamide)

Example 36 0.53 g of 2,2-dimethyl-5-methylthio-2,3-dihydrobenzofuran-7-carboxylic acid and 0.66 ml of triethylamine were added to a mixture of 5 ml of dimethylformamide and 7 ml of tetrahydrofuran, and the mixture was heated at -15°C. 0.29 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, a solution of 0.5 g of (S)-(-)-2-aminomethyl-1-nonylpyrrolidine in 3 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield (S)-N-[(1-nonyl-2-pyrrolidinyl)methyl]-2,2-dimethyl-5-methylthio-2,3-dihydrobenzofuran-7- 250 mg of carboxamide are obtained as an oil. 1H-NMR 100MHz (CDCl3) 0
．． 86 (t, 3H), 1.53 (s, 3H), 1.55
(s, 3H), 2.47 (s, 3H), 3.02 (s,
2H), 3.60-3.97 (m, 1H), 0.98-
3.44 (25H), 7.22 (d, 1H), 7.87
(d, 1H), 8.15 (br. 1H), [α]D =
-57.2° (c=1, dimethylformamide)

Example 37 5-Sulfamoyl-2,3-dihydrobenzofuran-
0.59 g of 7-carboxylic acid and 0.76 g of triethylamine
ml is added to a mixed solution of 8 ml of dimethylformamide and 10 ml of tetrahydrofuran, cooled to -15°C, and 0.34 ml of isobutyl chloroformate is added dropwise. After stirring at the same temperature for 20 minutes, (R)-(+)-2-aminomethyl-1
-Nonylpyrrolidine 0.56g Tetrahydrofuran 4m
1 solution was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Petroleum ether and isopropyl ether are added to the resulting residue, and the precipitated crystals are collected by filtration and recrystallized with a mixed solvent of ethyl acetate and petroleum ether to yield (R)-N-[(1-nonyl-2-pyrrolidinyl). 0.55 g of methyl]-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide are obtained. Melting point 126-128℃, [α
]D = +60.7° (c=1, dimethylformamide)

Example 38 5-sulfamoyl-2,3-dihydrobenzofuran-
0.59 g of 7-carboxylic acid and 0.76 g of triethylamine
ml is added to a mixed solution of 8 ml of dimethylformamide and 10 ml of tetrahydrofuran, cooled to -15°C, and 0.34 ml of isobutyl chloroformate is added dropwise. At the same temperature 2
After stirring for 0 minutes, (S)-(-)-2-aminomethyl-1-
Nonylpyrrolidine 0.56g Tetrahydrofuran 4ml
The solution was added dropwise at the same temperature and stirred for 30 minutes at the same temperature. 2 more
After stirring for a period of time, the reaction solution is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Petroleum ether and isopropyl ether are added to the resulting residue, and the precipitated crystals are collected by filtration and recrystallized with a mixed solvent of ethyl acetate and petroleum ether to yield (S)-N-[(1-nonyl-2-pyrrolidinyl). 0.65 g of methyl]-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide are obtained. Melting point 127-128℃, [α]
D = -48.0° (c = 1, dimethylformamide)

Example 39 5-Methylthio-2,3-dihydrobenzofuran-7-
Carboxylic acid 0.46g and triethylamine 0.66ml
5 ml of dimethylformamide and 7 ml of tetrahydrofuran
ml of the mixed solution, cooled to -15°C, and 0.29 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, a solution of 0.5 g of (R)-(+)-2-aminomethyl-1-nonylpyrrolidine in 3 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. When the resulting residue was purified by column chromatography, (R
)-N-[(1-nonyl-2-pyrrolidinyl)methyl]
-5-methylthio-2,3-dihydrobenzofuran-7
- 320 mg of carboxamide are obtained as an oil. 1 H-NMR 100MHz (CDCl3) 2
．． 47 (s, 3H), 4.69 (t, 2H), 0.72
-3.90 (30H), 7.26 (d, 1H), 7.8
6 (d, 1H), 7.95 (br, 1H), [α]D
=+61.9° (c=1, dimethylformamide)

Example 40 5-Methylthio-2,3-dihydrobenzofuran-7-
Carboxylic acid 0.46g and triethylamine 0.66ml
5 ml of dimethylformamide and 7 ml of tetrahydrofuran
ml of the mixed solution, cooled to -15°C, and 0.29 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, a solution of 0.5 g of (S)-(-)-2-aminomethyl-1-nonylpyrrolidine in 3 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. When the resulting residue was purified by column chromatography, (S
)-N-[(1-nonyl-2-pyrrolidinyl)methyl]
-5-methylthio-2,3-dihydrobenzofuran-7
- 360 mg of carboxamide are obtained as an oil. 1 H-NMR 100MHz (CDCl3) 2
．． 47 (s, 3H), 4.69 (t, 2H), 0.72
-3.90 (30H), 7.26 (d, 1H), 7.8
6 (d, 1H), 7.95 (br, 1H), [α]D
=-55.0° (c=1, dimethylformamide)

Example 41 2-methoxy-5-sulfamoylbenzoic acid and N-
1.05g of methylmorpholine to 3 parts of dimethylformamide
0 ml, cooled to -10°C, and 1.2 g of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, a solution of 2.1 g of (R)-(+)-2-aminomethyl-1-decylpyrrolidine obtained in Example 6 in 20 ml of tetrahydrofuran was added dropwise at the same temperature, and then overnight at room temperature. Stir. The reaction solution is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Isopropyl ether is added to the resulting residue, the precipitated crystals are collected by filtration, and recrystallized with a mixed solvent of isopropyl alcohol and isopropyl ether to form (R)-N-[(1-decyl-2-
1.3 g of pyrrolidinyl)methyl]-2-methoxy-5-sulfamoylbenzamide are obtained. Melting point 119~
120°C, [α]D = +51.9° (c = 1, methanol)

Example 42 2-methoxy-5-sulfamoylbenzoic acid and N-
1.05g of methylmorpholine to 3 parts of dimethylformamide
0 ml, cooled to -10°C, and 1.2 g of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, a solution of 2.1 g of (S)-(-)-2-aminomethyl-1-decylpyrrolidine obtained in Example 6 in 20 ml of tetrahydrofuran was added dropwise at the same temperature, and then overnight at room temperature. Stir. The reaction solution is concentrated under reduced pressure, and the resulting residue is extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Isopropyl ether is added to the resulting residue, the precipitated crystals are collected by filtration, and recrystallized with a mixed solvent of isopropyl alcohol and isopropyl ether to form (S)-N-[(1-decyl-2-
1.3 g of pyrrolidinyl)methyl]-2-methoxy-5-sulfamoylbenzamide are obtained. Melting point 119~
120°C, [α]D = -50.8° (c = 1, methanol)

Example 43 0.79 g of 2,2-dimethyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid and 0.93 ml of triethylamine were added to 7 ml of dimethylformamide.
and 7 ml of tetrahydrofuran, cooled to -15°C, and 0.4 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, a solution of 0.72 g of (R)-(+)-2-aminomethyl-1-decylpyrrolidine in 5 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with sodium bicarbonate, dried, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give (R)-N-[(1-decyl-2-
0.81 g of pyrrolidinyl)methyl]-2,2-dimethyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide is obtained as amorphous crystals. 1 H-NMR 100MHz (CDCl3) 0
．． 85 (t, 3H), 1.55 (3H), 1.56 (3
H), 3.09 (2H), 3.76 (m, 1H), 1.
0-3.4 (26H), 5.5 (br, 2H), 7.8
2 (d, 1H), 8.16 (br, 1H), 8.57 (
d, 1H), [α]D = +55.2° (c = 1, dimethylformamide)

Example 44 0.56 g of 2,2-dimethyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylic acid and 0.6 ml of triethylamine were added to a mixture of 7 ml of dimethylformamide and 7 ml of tetrahydrofuran, and the mixture was heated at -15°C. 0.27 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, a solution of 0.5 g of (S)-(-)-2-aminomethyl-1-decylpyrrolidine in 3 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield (S)-N-[(1-decyl-2-
0.54 g of pyrrolidinyl)methyl]-2,2-dimethyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide is obtained as amorphous crystals. 1 H-NMR 100MHz (CDCl3) 0
．． 85 (t, 3H), 1.23 (s, 14H), 1.5
6 (s, 6H), 3.09 (s, 2H), 0.96-3
．． 94 (13H), 5.36 (br, 2H), 7.81
(d, 1H), 8.22 (br, 1H), 8.54 (d
, 1H), [α]D = -45.3° (c = 1, dimethylformamide)

Example 45 5-sulfamoyl-2,3-dihydrobenzofuran-
0.72g of 7-carboxylic acid and 0.93g of triethylamine
ml is added to a mixed solution of 10 ml of dimethylformamide and 10 ml of tetrahydrofuran, cooled to -15°C, and 0.41 ml of isobutyl chloroformate is added dropwise. After stirring at the same temperature for 20 minutes, (R)-(+)-2-aminomethyl-1
-decylpyrrolidine 0.72g tetrahydrofuran 4
ml solution was added dropwise at the same temperature and stirred for 30 minutes at the same temperature. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Isopropyl ether is added to the resulting residue, the precipitated crystals are collected by filtration, and crystallized with a mixed solvent of ethyl acetate and hexane to give (R)-N-[(1-decyl-2-pyrrolidinyl)methyl]-5- 0.76 g of sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide is obtained. Melting point 125-126℃, [α]D = +59.2
° (c=1, dimethylformamide)

Example 46 1.15 g of 2-methoxy-5-sulfamoylbenzoic acid
and 1.5 ml of triethylamine were added to a mixture of 10 ml of dimethylformamide and 10 ml of tetrahydrofuran,
Cooled to -15℃ and 0.7 m of isobutyl chloroformate
Add 1 dropwise. After stirring at the same temperature for 20 minutes, a solution of 1.4 g of (S)-(-)-2-aminomethyl-1-dodecylpyrrolidine in 10 ml of tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. Hexane is added to the resulting residue, the precipitated crystals are collected by filtration, and recrystallized with a mixed solvent of ethyl acetate and hexane to give (S)-N-[(1-dodecyl-2-pyrrolidinyl)methyl]-2- 1.1 g of methoxy-5-sulfamoylbenzamide are obtained. Melting point 119-121
°C, [α]D = -47.2° (c = 1, methanol)

Example 47 1.5 g of 2-methoxy-5-methylthiobenzoic acid and 2.4 ml of triethylamine were added to 15 ml of dimethylformamide.
Add to a mixture of -15 ml and 15 ml of tetrahydrofuran,
The mixture was cooled to ℃ and 1.1 ml of isobutyl chloroformate was added dropwise. After stirring at the same temperature for 20 minutes, (S)-(-)-2-
A solution of 2.0 g of aminomethyl-1-dodecylpyrrolidine in 15 ml of tetrahydrofuran was added dropwise at the same temperature.
Stir for 0 minutes. After further stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate, washed with aqueous sodium bicarbonate,
After drying, concentrate under reduced pressure. The resulting residue was purified by column chromatography to yield (S)-N-[(1-dodecyl-2-pyrrolidinyl)methyl]-2-methoxy-5
1.6 g of methylthiobenzamide are obtained as an oil. 1 H-NMR 100MHz (CDCl3) 0
．． 88 (3H), 1.0-3.5 (30H), 2.48
(s, 3H), 3.6-3.9 (m, 1H), 3.92
(s, 3H), 6.88 (d, 1H), 7.35 (dd
, 1H), 8.13 (d, 1H), 8.3 (br, 1H
), [α]D = -46.3° (c = 1, methanol)

Claims (3)

[Claims] Claim 1: General formula (I) [In the formula, R1 represents an alkoxy group having 1 to 4 carbon atoms, R
2 is hydrogen or a group in which R1 and R2 are bonded to each other to form oxyethylene which may be substituted with at least one alkyl having 1 to 4 carbon atoms, and R3 is a group represented by the general formula -
S(O)m R5 (R5 represents an alkyl group having 1 to 4 carbon atoms or an optionally substituted phenylalkyl group, m is 0, 1,
It is 2. ) or a group represented by the general formula -SO2
A group represented by NR6 R7 (R6 and R7 are each hydrogen or an alkyl group having 1 to 4 carbon atoms), and R4 represents an alkyl group having 6 to 15 carbon chains. ], a pharmacologically acceptable salt thereof, or an optical isomer thereof. 2. A pharmaceutical composition containing the compound according to claim 1 as an active ingredient. 3. 1-substituted pyrrolidine-2-methylamines represented by the general formula (II) (wherein R4 represents an alkyl group having 6 to 15 carbon atoms) and their optical properties. Isomers.