JPS60185762A - Proline derivative - Google Patents

Abstract

NEW MATERIAL:The proline derivative of formula I (R1 is H, lower alkyl or phenyl; R2, R3 and R4 are H or lower alkyl) and its salt. EXAMPLE:N-[ (R)-1-Ethoxycarbonyl-2-ethoxycarbonylmethylthioethyl ]-alanyl-(S)- proline-t-butyl ester. USE:It has angiotensinase-inhibiting and expectorant activities and low toxicity, and is useful as a hypotensor and expectorant. It can be administered orally or parenterally to man and animal. PREPARATION:The compound of formula I can be prepared e.g. by reacting the cysteine derivative of formula II with the propionic acid derivative of formula IIIin a solvent such as tetrahydrofuran, etc. in the presence of an acid acceptor, e.g. sodium carbonate, triethylamine, etc. at about 0-30 deg.C. The molar ratio of the compound of formula III to the compound of formula II is preferably 1-1.2.

Description

[Detailed description of the invention] Technical field The present invention relates to novel proline derivatives and salts thereof.

The proline derivative of the present invention has the following general formula (1)% formula% [In the formula, R1 represents a hydrogen atom, a lower alkyl group, or a phenyl group, and R, R3, and R4 are the same or different hydrogen atoms. Or it represents a lower alkyl group. ] In the above general formula (1), R
Examples of the lower alkyl group defined by -R4 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and hexyl groups. Further, the compound of the above general formula (1) has four asymmetric carbon atoms in the molecule and has 16 optical isomers, and the present invention includes all of these isomers.

The proline derivatives and salts thereof of the present invention have angiotensin-converting enzyme inhibitory action and detan-reducing action, and have low toxicity, and are useful as antihypertensive agents and detan-removal agents.

The salts of the proline derivatives of the present invention include pharmaceutically acceptable acid addition salts. Examples of acidic compounds that form acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid; Examples include organic acids. Furthermore, among the proline derivatives of the present invention, those having an acidic group can be made into salts by reacting them with pharmaceutically acceptable bases, and the present invention also includes such salts. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium bicarbonate, lysine, arginine, ornithine, morpholine, piperazine, piperidine, ethylamine, dimethylamine, triethylamine, dicyclohexylamine. For example, organic bases such as

The proline derivative of the present invention can be produced, for example, by various methods shown below.

Reaction formula-1〉 (2>', (3) , (1a) group (R4 is the same as above); X represents a halogen atom, an alkylsulfonyloxy group, or an arylsulfonyloxy group.] The above propion As the halogen atom represented by can be exemplified by a pt-luenesulfonyloxy group, respectively.

According to the method shown in Reaction Formula-1 above, compound (1a) is obtained by combining cysteine derivative (2) and propion M derivative (3). The condensation reaction is carried out in a suitable solvent in the presence of a deoxidizing agent. As a solvent,
For example, ethers such as tetrahydrofuran (THF) and dioxane, aprotic polar solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoric acid triamide (1-IMPA), etc. can be used.Acid deoxidizer Examples include alkali metal carbonates or alkali metal bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, 1,8-diazabicyclo(5,4,O)undecane-7- En (DBU)
Organic tertiary amines such as, etc. can be used. The deoxidizing agent is usually used in an amount of about 1 to 2 times the amount of cysteine derivative (2), preferably about 1 to 1.2 times the amount of the cysteine derivative (2). The propionic acid derivative (3) is usually used in at least an equimolar amount, preferably about 1 to 1.2 times the molar amount of the cysteine derivative (2). The reaction is generally carried out at a temperature of about 0 to 30°C, preferably at or near room temperature, and is completed in about 3 to 72 hours.

Reaction formula-2〉 C00R2COOR3 (Ia') C00R2COOR3 (18'M (In the formula, R1, R2 and R3 are the same as above. R5a is a lower alkoxy group, or according to the method shown in Reaction formula-2 above, the compound ( 1a')
Compound (18'') can be obtained by treating with an acid in the presence of a scavenger such as anisole, thioanisole or dimethyl sulfide.

In the acid treatment reaction, examples of acids include trifluoroacetic acid, hydrochloric acid, hydrobromic acid, and acetic acid. The reaction is carried out using, for example, diethyl ether, THF.

The reaction can be carried out in a solvent such as ethers such as dioxane, esters such as methyl acetate and ethyl acetate, and halogenated hydrocarbons such as methylene chloride and chloroform. When using trifluoroacetic acid as the acid, no solvent is required and this method is preferred.

In addition, scavengers such as anisole are usually used for compounds (i
about 1 to 10 times the molar amount of a'), preferably about 3 to 5 times
Used in twice the molar amount. The reaction is carried out at a temperature of about 0 to 50°C, preferably about 0 to 25°C, for about 1 to 10 hours.

<Reaction formula-3> (2) (4) (5) [In the formula, R, R, and R3 are the same as above. ]The above reaction formula-
According to 3, cysteine derivatives (2) and pyruvate (4)
Compound (5) is obtained by reacting with.

This reaction is carried out by a reductive bond formation reaction using a metal hydrogen complex, that is, by reducing the Schiff base produced by the reaction of cysteine derivative (2) and pyruvic acid (4) using a metal hydrogen complex. As the metal hydrogen complex compound, for example, sodium borohydride, lithium borohydride, cyanosodium borohydride, cyanolithium borohydride, etc. can be used. The diisocomplex compound is generally used in an amount of about 2 to 6 times, preferably about 2 to 3 times, the amount of the cysteine derivative (2). Also, pyruvic acid (
4) is about 1 to 5 times the molar amount of cysteine derivative (2),
Preferably, about 3 to 5 times the molar amount is used. The above reaction is
It is carried out in an inert solvent that does not adversely affect the reaction.

Examples of the solvent include water, ethanol, methanol,
Alcohols such as 2-propertool, ethers such as diethyl ether, THF, dioxane, DMF, DMS
Aprotic polar solvents such as O and the like can be used alone or as a mixed solvent. The reaction is usually completed at a temperature of 0 to 50°C, preferably at or around room temperature, in about 3 to 24 hours. In addition, when using cyanosodium borohydride or cyanolithium borohydride, the pf is usually pf-16.5 to 8.5.
The reaction proceeds rapidly at a neutral temperature, preferably around neutrality.

<Reaction formula-4> (6) (7) , (ib) (In the formula, R1 is the same as above. R2a1R3a and R4a each represent a lower alkyl group.) According to the above reaction formula-4, the above reaction formula - The compound (1b) of the present invention is obtained by reacting the carboxylic acid (6) obtained from 1 to 3 with the amine (7). The reaction is carried out according to the usual amide bond forming reaction by the following various methods.

(b) In the presence of a condensing agent, carboxylic acid (6) and amine (
(7) A method of dehydration condensation reaction with
(c) Active ester method, in which carboxylic acid (6) is an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc. amine (7)
(d) Carboxylic acid halide method, that is, carboxylic acid (6)
(e) Other methods include, for example, converting carboxylic acid (6) into an acid anhydride using a dehydrating agent such as acetic anhydride, and reacting the amine (7) with the acid anhydride: carboxylic acid ( A method in which an ester of 6) and a lower alcohol is reacted with amine (7) under high pressure and high temperature.

Each of the above methods is carried out under substantially the same conditions as the known secondary method. A particularly preferred method is the method (a) above. To explain the method in detail, the condensing agent specifically includes N,
N-dicyclohexylcarbodiimide (DCC), D
CC-N-hydroxysuccinimide, DCG-N-hydroxybenzotriazole, DCC-N-hydroxy-5-norbornene-2,3-dicarboximide, diphenylphosphorylamide (DPPA)-triethylamine, diethylphosphorylcyani Date (D.E.
PC)-triethylamine, etc. can be used. The reaction is generally carried out in a suitable solvent, and various known solvents that do not adversely affect the reaction can be used. Specific examples include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, THF, and dioxane, methyl acetate, ethyl acetate, etc. Esters of, DMFlDMSO
Examples include aprotic polar solvents such as lHMPA.

The amount of amine (7) used is carvone! The condensing agent is usually at least an equimolar amount, preferably about 1 to 1.2 times the molar amount of carboxylic acid (6).
), preferably about 1 to 1.2 times the molar amount
The molar amount can be doubled. The reaction is usually -20 to 30
℃, preferably about -10℃ to room temperature, about 3 to 24℃
It will be completed in time.

Reaction formula-5> (1C) (1d) [In the formula, R1, R2 and R3 are the same as above. At least one of R2 and R3 represents a lower alkyl group. ] According to the above reaction formula-5, the compound (1d) of the present invention in which R2, R3 and R4 in general formula (1) are hydrogen atoms, R2
and R3 is a lower alkyl group. The above hydrolysis reaction is carried out in a suitable solvent in the presence of a basic compound. Examples of solvents include methanol,
Lower alcohols such as ethanol, diethyl ether,
A mixed solvent of ethers such as THF and dioxane, acetonitrile, etc., and water can be used. As the basic compound, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. can be used. The dibasic compound usually has about 3 to 30% of the compound (1C) of the present invention.
The amount used is 5 times the molar amount, preferably 3 to 3.3 times the molar amount. The reaction normally proceeds suitably at 0 to 40°C, preferably at room temperature, and is completed in about 0.5 to 12 hours.

The target compounds obtained by the reactions shown in each of the above reaction formulas can be easily isolated and purified by conventional separation means. Such means include solvent extraction method, dilution method, distillation method,
Examples include recrystallization method, column chromatography, prevariative thin layer chromatography, ion exchange chromatography, and gel chromatography.

When the compound (1) of the present invention and its salts are used as a pharmaceutical, such as an antihypertensive agent, they can be administered to humans and animals as is or together with a conventional pharmaceutical carrier. Usually, the above-mentioned compound or its salt is prepared in a suitable dosage unit form depending on the route of administration. Examples of the dosage unit form include oral preparations such as tablets, capsules, granules, and oral solutions, parenteral topical preparations such as creams and ointments, and parenteral preparations such as injections. It is administered orally; topical preparations are administered by application, etc.; injections, etc. are administered intravenously alone or together with normal fluid replacement such as glucose and amino acids, or intramuscularly, intradermally, subcutaneously, or intraperitoneally. be done. The above-mentioned dosage unit forms are prepared according to conventional methods, and the carriers used are not particularly different from those commonly used.

For example, tablets are made by mixing the compound of the present invention or a salt thereof as an active ingredient with excipients such as gelatin, starch, lactose, magnesium stearate, talc, and gum arabic. Capsules are prepared by mixing the above-mentioned active ingredient with an activating pharmaceutical filler or diluent, and then filling the mixture into hard gelatin capsules, soft capsules, or the like. Parenteral preparations such as injections are prepared by dissolving or suspending the active ingredient in a sterile liquid carrier, preferably water or saline. The active ingredient m blended into each of the above forms is appropriately determined depending on each form, but is generally about 1 to 500 mA.

The dosage of each form of the preparation prepared above is determined appropriately depending on the dosage unit form, administration route, and the degree of disease, age, weight, etc. of the patient to whom it is administered, but usually among the various forms. The amount of active ingredient is approximately 0.00 per 1 body weight per day.
1 to 501 G, which is administered once to three times a day.

衷-]LJI Hereinafter, production examples of the compounds of the present invention will be given as Examples. Further, as a reference example, an example of producing a raw material compound for producing the compound of the present invention will be given.

Reference Example 1 Production of N-((R)-1-ethoxycarbonyl-2-ethoxycarbonylmethylthioethyl)-alanine-t-butyl ester/A and B-isomers S-ethoxycarbonylmethyl-L-cysteine ethyl ester 5 .30 and 4.70 of 2-bromopropionic acid-1-butyl ester were dissolved in HMPAlomQ, and 2.30 of triethylamine was added. After stirring at room temperature for 62 hours, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, then with saturated brine, and dried over anhydrous sodium sulfate. The extract was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (solvent: ether: n-hexane = 5:3), and the octa-isomer of the target compound was obtained as a colorless oily substance from the preceding fraction. Yield 2.1g
.

[α]2°=+26.9° (C=1.l methanol) 'H-NMR (CD(13): δ value 1.27 (3HSd1J=7f(z), 1.29
(6H, t, J=7Hz), 1.44 (91-1,
s), 2,15 (IH, brs), 2.94 (2H, d, J=5Hz), 3.30 (
IH, q, J=7Hz), 3.33 (2H,s), 3.53 (IH,t, J=5Hz), 4.19.4
．． 20 (4H, q, J=7Hz) The B-isomer of the target compound was obtained as a colorless oil from the afterflow. Yield 2.24CJ.

[α)20=-43,1° (C=1.1, methanol) 'H-NMR (CDCQ3): δ value 1.29 (3H, d, J=7Hz), 1, 29
(6, H, t, J=7Hz > , 1.46 (9H
,s), 2.0 (1H,brs), 2.82 (IH, dd, J=7.13Hz), 3.05 (1H, dd, J=6.13Hz), 3.30 (IH, q, J=7Hz), 3.31
(2H,s), 3.57 (1HS dd, J=6.7Hz), 4,
19.4. 21 (4H, Q, J-7Hz) Reference Example 2 Production of N-((R)-1-ethoxycarbonyl-2-ethoxycarbonylmethylthioethylnin 8-isomer N-(( R)-1-ethoxycarbonyl-2-ethoxycarbonylmethylthioethyl]
-octa-isomer of alanine-t-butyl ester 1.04
Anisole 0.930 was added to a solution of G in trifluoroacetic acid (TFA), and the mixture was stirred at room temperature for 2 hours. TFA was distilled off under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH.
8 and then washed with ether. Citric acid was added to the aqueous layer to adjust the pH to 4, followed by extraction with methylene chloride. The extract was dried over anhydrous sodium sulfate and then evaporated under reduced pressure to obtain the octa-isomer of the target compound as an amorphous substance. Yield 0.5Cl
.

[α)”=+17.3° (c=0.95, methanol) 'H-NMR (CDCQ3): δ value 1, 29 (6HSt, J=7Hz), 1, 43 (
3H, d, J=7Hz), 2, 90 (IHSd-d
, J=7.13Hz), 3,16 (1)1, d-d1J=6.13Hz), 3,30 (2H18), 3,44 (I Hl q, J='7Hz), 3,
65 (IH, dd, J=6.7Hz), 4, 20,
4.23 (4H,Q,J=71-(z) Reference Example 3 N-((R)-1-ethoxycarbonyl-2-ethoxycarbonylmethylthioethyl)-alanine B-isomer in Reference Example 1 The obtained N-((R)-1-ethoxycarbonyl-2-toxylponylmethylthioethyl)
- B-isomer of alanine-t-butyl ester 1.09
Anisole 0.97Q was added to 5 ml of TFA solution of 0.0 and treated in the same manner as in Reference Example 2 to obtain the B-isomer of the target compound as an amorphous substance. Collection 1
i0.43g.

[α)20=-32.0' (c-0.8, methanol) IH-NMR (CDCQ3): δ value 1, 29, 1.30 (6H, t, J = 7Hz), 1, 46 (3H .d, J=7Hz), 2, 79
(IHS dd, J=9.13Hz), 3,12 (1H,dd,J=5.13Hz), 3,27 (2)1,s), 3,35 (IHS q,J= 7Hz), 3, 48
(IH, dd, J=5.9Hz), 4, 20, 4.
21 (4H, qS J-7Hz) Example 1 N-((R)-1-ethoxycarbonyl-2-ethoxycarbonylmethylthioethyl)-alanyl-(S)-
Production of proline-t-butyl ester/octa-isomer N-((R)-1-ethoxycarbonyl-2-ethoxycarbonylmethylthioethyl) obtained in Reference Example 2
- octa-isomer of alanine 52010.

(S)-proline-t-butyl ester 31910 and diethyl cyanophosphate 304 m (l DMF 5 m + 11
1 solution, add triethylamine 18811J under water cooling and stirring.
A DMF3mQ solution of was slowly added dropwise. After stirring for 12 hours while gradually returning to room temperature, ice water was added to the reaction solution.
The mixture was further made weakly alkaline with a saturated aqueous sodium hydrogen carbonate solution, and then extracted with ethyl acetate.

The extract was washed with water, then with saturated brine, and dried over anhydrous sodium sulfate. The extract was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: chloroform:
Purify with methanol = 10:1) to obtain the target compound
The isomer was obtained as a colorless oil. Yield 400■.

[α)”=-46,2° (c=1.0, methanol) IH-NMR (CDCQ3): δ value 1.29.1.33 (6H1t, J=7Hz>, 1.3-1.5 (3H), 1.44.1.46 (9H, each S), 1.8-3.8
(13H,m), 4.08 (4H,q,J-7t-1z) Example 2 N-((R)-1-ethoxycarbonyl-2-ethoxycarbonylmethylthioethylnyl-(S)-proline-t -Production of butyl ester/B-isomer N- ((R)-1-ethoxycarbonyl-2-ethoxycarbonylmethylthioethyl) obtained in Reference Example 3
- From the B-isomer of alanine 4501G, the B-isomer of the target compound was obtained as a colorless oily substance in the same manner as in Example 1. Yield 560a+g.

(α)20=-93.6° (c=1.0, methanol> IH-NMR (CDC (!3): δ value 1, 29, 1.
33 (6H, t, J=7Hz>, 1, 3 ~ 1.5 (31 (), 1, 44, 1. 46 (91-1, each S) 1, 8 ~
3.8 (13H, m) 4,08 (4H, q, J=7Hz) Example 3 N-((R)-1-■toxycarbonyl-2-ethoxycarbonylmethylthioethyl]-alanyl-(S)-
N-((R)-1-■Toxycarbonyl-2-ethoxycarbonylmethylthioethyl]-alanyl-(S)-proline-1 obtained in Example 1) 2401 g of anisole was added to a TFA34 solution of A-isomer 340RQ of -butyl ester, and the reaction was carried out in the same manner as in Reference Example 2 to obtain the 8-isomer of the target compound as a colorless oil. Yield: 801 nO .

Maleic acid 23111 (l of ether 3III) was added to a solution of 80 g of the 8-isomer obtained in the above reaction in ether 2-2 with stirring.
12 solution is added to precipitate. The precipitate was collected and dried to obtain a maleate salt of the target compound.

Yield 3011G.

[α)20=-3. 2° (c = 0.4, methanol)'H-NMR (CD300): δ value 1, 28, 1.33 (6HS t, J = 7Hz), 1, 57 (3HS t, J = 7Hz > , 1 ,9
~2.3 (4HS m), 3,1 ~3.9 (5
H, m), 3,, 46 (2HS s), 4, 19 (2H, q, J=7Hz), 4, 32
(1H, Q, J-7Hz > , 4, 3 ~ 4.5
(IH,m>, 6,29 (2H,s) Example 4 N-((R)-1-ethoxycarbonyl-■toxylponylmethylthioethyl]-alanyl-(S)-
Preparation of B-isomer of proline and its maleate salt N-((R)-1-ethoxycarbonyl-2-ethoxycarbonylmethylthioethyl) obtained in Example 2
From 1 g of B-isomer of -alanyl-(S)-proline-t-butyl ester, the B-isomer of the target compound was obtained as a colorless oil in the same manner as in Reference Example 2. Yield 340mg.

From 340 mg of the B-isomer obtained in the above reaction, the maleate salt of the target compound was obtained in the same manner as in Example 3. Yield 132
0mo.

(α)2'=-54,6° (c=0.9, methanol) IH-NMR (CD30D): δ value 1.28.1.33 (6)-1,t, J-7H2), 1 .61 (31-(, d, J=71-1z), 1.
9-2.4 (4H, m>, 3.2-3.8 (5H, m), 3.42 (2H, S), 4.20 (4H, QSJ=7Hz), 4.32 (
IH, q, J=7Hz), 4.3-4.5 (1H,
m), 6.29 (2H,s) Reference Example 4 N-((R)-1-ethoxycarbonyl-2-((R,
5) -1-Ethoxycarbonylhexylthio S-((R,S)-1-ethoxycarbonylhexyl)-1-cysteine ethyl ester 7,70% of pyruvic acid was added to a mixture of 25% of ethanol and 10% of water. After the mixture was neutralized with a 4N aqueous sodium hydroxide solution, 3.2 g of cyanosodium borohydride was gradually added under stirring while cooling with water, and the reaction was carried out at room temperature for 14 hours. After the reaction,
Ethanol was distilled off, the mixture was made weakly alkaline by adding a saturated aqueous sodium bicarbonate solution, washed with ether, the aqueous layer was separated, the pH was adjusted to 4 with 10% hydrochloric acid, and the mixture was extracted with ethyl acetate.
The extract was washed with water, then with saturated brine, and dried over anhydrous sodium sulfate. The extract was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: chloroform:
The target compound was obtained as a colorless amorphous substance. Yield 7, OQ.

(α)2G,=r. 4° (c-1.l ethanol)'H-NMR (CDCQ3): δ value 0, 89 (
3H, tl J=5Hz), 1, 29 (6H, tl
J=7Hz), 1, 39 (3HS dl J=7
Hz), 1,3 to 2.1 (8H, m), 2,7 to 3.8 (5H, m), 4, 21, 4.22 (4H1 q, J-7Hz) Reference examples 5 to 8 above Each compound listed in Table 1 below was obtained in the same manner as in Reference Example 4.

Reference Example 9 N-((R)-1-ethoxycarbonyl-((R.S)
-1-t-butoxycarbonylhexylthio]ethyl)
-Production of (R.S)-Alanine From 5.5 g of S- ((R.S)-1-t-butoxycarbonylhexyl)-L-cysteine ethyl ester, the target compound was extracted colorlessly in the same manner as in Reference Example 4. Obtained as an amorphous material. Yield 5.370 [α-8-+11. Oo (C=1.2, ethanol) 'H-NMR (CDCQ3): δ value 0, 89 (3H, t, J=5Hz >, 1, 29 (
3H1t, J-7Hz), 1, 48 (9H, s), 1, 3 to 2.0 (1 1H, m), 2, 8 to 3.
8 (581m), 4,22 (2H,Q,J-7Hz) Example 5 N-iR)-1-ethoxycarbonyl-((R,S)
-1-ethoxycarbonylhexylthio]ethyl)-(
Production of R,S)-alanyl-(S)-proline-t-butyl ester N-[(R)-1-ethoxycarbonyl-2-((R,S)-1-ethoxy) obtained in Reference Example 4 carbonylhexylthio]ethyl)-(R.S)-alanine2. From OQ, the target compound was obtained as a colorless oil in the same manner as in Example 1. Yield 2.8o.

[α) 19--46.2° (C-0.9, ethanol) 'H-NMR (CDC (13): δ value 0, 88 (3
H, t, J=5Hz), 1, 28 (6HSt, J-
7Hz), 1, 3-1.5 (3H), 1, 44, 1.46 (9H, each S), 1, 5-2.
3 (12H, m), 2,8 to 3.0 (2H, m), 3,1 to 3.8 (681m), 4, 19 (4H, q, J-7Hz) Examples 6 to 9 Above implementation The compounds listed in Table 2 below were obtained in the same manner as in Example 5.

Example 1O N-((R)-1-ethoxycarbonyl-2-[(R,
5) -1-t-butoxycarbonylhexylthio)ethyl)-(R,S)-alanyl-(S)-proline-t-
Production of butyl ester N-((R)-1-ethoxycarbonyl-2-((R,S)-1-t-butoxycarbonylhexylthio]ethyl)-(R) obtained in Reference Example 9.

S)-alanine 1. From OQ, the residue treated in the same manner as in Example 1 was subjected to silica gel column chromatography (solvent: chloroform: methanol = 20:
1) to obtain the target compound as a colorless oil. Yield 1.03a.

'H-NMR (CD(13): δ value 0.88 (3H1tSJ-5Hz), 1.28 (
3H, t, J=7Hz), 1.44.1.47 (9
H, each S), 1.48 (9H, s), 1.3-2.4 (15H, m), 2.8-3.0 (2H, m), 3.1-3.8 (6H , m), 4.19 (2H,Q, J=7Hz) Example 11 N-((R)-1-ethoxycarbonyl-2-[(R,
5)-1-ethoxycarbonylhexylthio)ethyl)
-(R,S)-alanyl-(S)-proline and its L
-Production of arginine salt N-((R) obtained in Example 5
-1-ethoxycarbonyl-2-((R,5)-1-ethoxycarbonylhexylthio)ethyl)-(R,S)
-alanyl-(S)-proline-t-butyl ester 4
From 07 mg, the target compound was obtained as a colorless amorphous substance in the same manner as in Reference Example 2.

Yield: 110ml 111° To a stirred solution of 3001g of the compound obtained in the above reaction in 5% ethanol was added a 1.5-solution of 110% 9-arginine. After water and ethanol were distilled off, the residue was dried under reduced pressure to obtain the L-arginine salt of the target compound as a colorless powder. Yield: 3421 (1° colorless crystals, mp 50-55°C, [α] 2°--33.0' (c = 0.96, ethanol) Examples 12-15 The following procedure was carried out in the same manner as in Example 11 above. Each compound listed in Table 3 was obtained.

Example 16 N-((R)-1-ethoxycarbonyl-2-[(R,
5)-1-carboxyhexylthio]ethyl)-(R,
N-1R)-1 obtained in Production Example 10 of S)-alanyl-(S)-proline and its 2.L-arginine salt
-Ethoxycarbonyl-2-[(R,5)-1-t-butoxycarbonylhexylthio]ethyl)-(R.

S)-alanyl-(S)-proline-1-butyl ester 500+o was reacted in the same manner as in Reference Example 2, and the treated residue was purified by silica gel column chromatography (solvent: chloroform:methanol-10:1). The target compound was obtained as a colorless oil. Yield 187i
+a.

IH-NMR (CD300): δ value 0.88 (3H1t, J=5Hz), 1.28 (
3H, tSJ=7Hz), 1.3~2.4 (15H
, m), 2.8-3.8 (8H, m), 3.48 (IHLS), 4.21 (2H, q, J = 7 Hz) 721 g of the compound obtained in the above reaction and 2 equivalents of arginine 5619, the desired compound, 2.L-arginine salt, was obtained as a colorless powder in the same manner as in Example 11. Yield 11C) so.

Colorless crystals, mp92-97℃, ) Example 17 N-((R)-1-carboxy-2-((R.

5)-1-carboxyhexylthio)ethyl]-(R,
Production of S)-alanyl-(S)-proline N-((R)-1-ethoxycarbonyl-2-((R,5)-1-ethoxycarbonylhexylthio)ethyl)- obtained in Example 11 (R,S)-alanyl-(S)
- To a solution of 472 g of proline in ethanol, 3.3 g of a 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2.5 hours. Add a small amount of water to the reaction solution and add DOWEX 50W.
-X8 (H+). After washing thoroughly with water, the product was
% pyridine and the product fractions were lyophilized. The resulting powdery substance was collected, washed with ether, and then dried under reduced pressure to obtain the target compound as colorless crystals. Yield 106
-90 Colorless crystal, mp98-104℃, [α)''--66,8° (c-0,48, ethanol) IH-NMR (CD30D): δ value 0.90 (3H1t1J=5Hz), 1.1 ~2.
5 (1581m), 2.9 to 3.9 (5H, m), 4.1 to 4.6 (3H, m) (and above) Procedural amendment (acid) 1. Indication of case 1982 Patent Application No. 34701 2 Invention 0
Name P0S/Derivative 3, Person making the amendment 4 Agent 10 Sawa no Tsuru Building, 2 Hirano-cho, Higashi-ku, Osaka City FFI story 06-2
03-0941 (Government) Spontaneous 6 Amendment to increase the number of inventions due to amendment Contents (1) In the 4th to 3rd lines from the bottom of page 2 of the specification, the words ``and detanning action... and detanning agent'' are added. Correct the following.

"An antihypertensive agent, an antihypertensive agent, and a glaucoma treatment agent that has antihypertensive effect and intraocular pressure lowering effect, and is low in toxicity." (Above) Procedural amendment (voluntary) November 8, 1980 Patent Office Director Manabu Shiga Patent Application No. 34701 of 1980 2 Name of the invention Proline derivative 3 Relationship to the case of the person making the amendment Patent applicant Otsuka Pharmaceutical Factory Co., Ltd. 4 Deputy Director 2-10 Hirano-cho, Higashi-ku, Osaka Sawano Tsuru Pill Sponsored 6 Item 7 of “Detailed Description of the Invention” in the specification to be amended Contents of the amendment As attached in the attached sheet Contents of the amendment 1) In page 44, line 13 of the description [4, 1 to 4 .6 (
3H, m) Correct J as follows.

r 4.1-4.6 (3H, m) Reference Example 1O N-[(R)-1-ethoxycarbonyl-2-((R,
5)-1-ethoxycarbonylbutylthio]ethyl]
-Production of (R,S)-alanine S-((RlS)-1-ethoxycarbonylheptyl)
-L-cysteine ethyl ester 11.3G, pyruvic acid 15.6O, 4N sodium hydroxide aqueous solution and sodium cyanoborohydride 4.50G were reacted and treated in the same manner as in Reference Example 4 to obtain the target compound. Obtained as a crystalline material. Yield 6.80 (α) --3,1'' (C-1,2, ethanol) 'H-NMR (CD CQ 3): δ value 0.8
8 (3H1t, J-5Hz), 1.2-1.5 (9
H, 3Hx3), 1.3-2.1 (10H, m>, 2.7-3.8 (581m>, 4.20 (4H, q1J=7Hz) Example 18 N-[(R)-1 -ethoxycarbonyl-2-((R,
5)-1-ethoxycarbonylbutylthio)ethyl]
Production of -(R,S)-alanyl-(S)-butyl-1-butyl esterN-[(R)-1-ethoxycarbonyl-toxycarbonylbutylthio)ethyl]-( RLS)
- The target compound was obtained as a colorless oily substance from alanine 9001G in the same manner as in Example 1. Yield: 111.1o.

(α to 28.6” (c-0.7, ethanol) 'H NMR (CDCQ3): δ value 0, 88 (3H, t, J-5Hz), 1, 2 to 1.4
(9H, 3HX3), 1, 44, 1.47 (9H,
Each S), 1, 5 ~ 2.3 (14H, m>, 2, 7 ~ 3.0 (2H, m), 3, 1 ~ 3.8 (5H, m), 4, 19 (4H, q , J-7Hz>, 4, 0 ~ 4
．． 3 (IH,m) Example 19 N-[(R)-1-ethoxycarbonyl-2-( (R
,S)-1-ethoxycarbonylhebutylthio)ethyl]-(R,S)-alanyl-(S)-proline and its male inate salt N-[(R)- obtained in Example 18 1-Ethoxycarbonyl-2-((R,5)-1-ethoxycarbonylbutylthio)ethylco(R,S)-alanyl-(S)
The target compound was obtained as a colorless non-crystalline substance from 900 mo of -proline-t-butyl ester in the same manner as in Reference Example 2. Yield 1650u.

From the compound 230u obtained in the above reaction, the maleate salt of the target compound was obtained in the same manner as in Example 3. Yield 250u.

(α)25=-25,1° (c=o, 6, ethanol)' H-NMR (CD30D): δ value 0.
9 (31-(, t, J=5Hz>, 1.1~1.6
(9H, 3Hx3), 1.6~2.4 (14H, m)
, 3.1-3.9 (7H, m>, 4.21 (4H1qSJ-7Hz), 4, 2-4.
5 (1)-1,m) , 6.28 (2H,s) Reference Example 11 N-[(R)-1-ethoxycarbonyl-2-(1-ethoxycarbonylhexylthio)ethyl]-alanine-t
~Production of butyl ester A and B isomers 5-((R,5)-1-ethoxycarbonylhexyl)
-6.1 g of 1-cystine ethyl ester and 4.2 g of t-butyl bromopropionic acid were added to HMPA2.
Triethylamine dissolved in 0+IQ2. Added OQ.

After stirring in the room for 72 hours, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and then with saturated saline,
It was dried with anhydrous sodium sulfate. The extract was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (solvent: ether: n-hexane-1:3) to obtain isomer A of the target compound as a colorless oily substance from the preceding fraction.

Yield 2.2o0 (α)18=+13. Oo (c-1,0, ethanol °C -ol) 'H-NMR (CDC123): δ value 0.88 (3H, 3J = 7Hz>, 1.27 (3H, d, J = 7Hz), 1.28 (6
H, t, J=7Hz), 1.45 (9H, S), 1.3-1.9 (8H, m), 2.23 (1H, s), 2.7-3.0 (2H, m), 3.2 to 3.6 (3H, m), 4.20 (4HS (1, J = 7Hz) The B-isomer of the target compound was obtained as a colorless oily substance from the effluent. Yield 1 .7G.

(α) −−30,8° (c=1.2, ethanol) 'HNMR (CDC123): δ value 0.88 (3H, t, J=7Hz), 1.28 (
3H, d, J-7Hz), 1.28 (6H, t, J
=7Hz>, 1.3~1.9 (8H, m), 2.04 (IHSs), 2.6~3.0 (2H, m), 3, 1~3t6 (381m>, 4 .20 (4
H, q, J-7Hz) Reference Example 12 N-((R)-1-ethoxycarbonyl-2-(1-ethoxycarbonylhexylthio)ethyl)-alanine.
Production of octa-isomer N-((R)- obtained in Reference Example 11
TEA51Q was added to 1.710 g of 1-ethoxycarbonyl-2-(1-ethoxycarbonylhexylthio)ethyl]-alanine-t-butyl ester 8-isomer, and the mixture was stirred at room temperature for 2 hours.

TFA was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8, and the mixture was washed with ether. 10% in the water layer
After adding hydrochloric acid to adjust the pH to 4, the mixture was extracted with methylene chloride.

The extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the A-isomer of the target compound. Yield 1.370° [α) = +6.9° (c = 0.7, ethanol) 'H-NMR (CDC; Q3): δ value 0
．． 88 (3H1t, J=7Hz), 1.2-1.5
(9H, 3HX3), 1.3-2.0 (8H, m>, 2.9-3.9 (5H, m>, 4.21.4.23 (4H, q.

J=7Hz>, 6, 8 (IH, brs) Reference Example 13 N-((R)-1-ethoxycarbonyl--(1-ethoxycarbonylhexylthio)ethylcoualanine.B
- N- ( (R) obtained in Reference Example 11 for the production of isomer
Add TFA5- to 1.40 g of -1-ethoxycarbonyl-2-(1-ethoxycarbonylhexylthio)ethylcoualanine-t-butyl ester B-isomer, and react and treat in the same manner as in Reference Example 12. The B-isomer of the target compound was obtained. Yield 1.25Q.

[α]. --16.2° (c=0.9, ethanol) 'H-NMR (CDCQ3): δ value 0, 88 (3, t, J=7) 1z), 1, 2 to 1.5
(9H, 3HX3), 1, 3-2. O (8)-1
, m), 2,6 to 3.8 (5H, m), 4, 20, 4.24 (41-(, Q.

J-7Hz), 5,8 (IH,brs) Example 2O N-((R)-1-ethoxycarbonyl-2=(1
-Ethoxycarbonylhexylthio)ethyltoalanyl-(S)-Proline-t-butyl ester 8-isomer production To the N''-((R)-1-ethoxycarbonyl-yl obtained in Reference Example 12) xylthio)ethylcoualanine A isomer 1.
26 I, (S)-proline-t-butylnisdel 62
911 g and diethyl cyanophosphate (DEPC) 666
111! 5 parts of a DMF solution of 37111 g of triethylamine were slowly added dropwise to the solution under cold stirring. After stirring for 12 hours while gradually returning the temperature to room temperature, ice water was added to the reaction mixture, and the mixture was made slightly alkaline with a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate.

The extract was washed with water and then with saturated brine, and dried over anhydrous sodium chloride. The extract was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (solvent: chloroform:
Purification with methanol (20=1) gave the octa-isomer of the target compound as a colorless oil. Yield i. 60g.

[α) = -23.1° (C = 1.2, ethanol) 'H NMR (CDCQ3): δ value 0, 88 (3
H, t, J=7Hz), 1, 29 (3)-116. J
-7Hz>, 1, 29 (6H, t, J=7Hz), 1
, 44, 1.47 (9H, each S), 1, 3 ~ 2.7
(1 2HSm), 2, 27 (IH, brs
), 2, 8 ~ 3.0 (2H, m>, 3, 1 ~ 3.8 (5H, m), 4, 20 (4HSq, J-7Hz), 4, 4 ~ 4.
7 (1)-ISm) Example 21 N-((R)-1-ethoxycarbonyl-2-(1-ethoxycarbonylhexylthioethyl)-7ranyl(
N-((R)-1-ethoxycarbonyl-nylhexylthio)ethyltoalanine B-isomer obtained in Reference Example 13 1.
From 08CI, the target compound B-
The isomer was obtained as a colorless oil. Yield 1.56G.

(α) = -63.7' (c = 1.0, ethanol) 'H NMR (CDC (13): δ value 0, 88 (3
H, t, J-7Hz), 1, 1~1.5 (9H, 3H
X3), 1, 44, 1.46 (9H, each S), 1, 3
~2.5 (1 2H, m), 2, 26 (IH, b
rs), 2,6 ~ 3.0 (2H, m), 3, 1 ~ 3.8 (5H, m), 4, 20 (4H, Q, J-7Hz), 4, 3 ~ 4
．． 5 (IH,m) Example 22 N- ( (R)-1-ethoxycarbonyl-2-(1
-Ethoxycarbonylhexylthio)ethyltualanyl-(S)-proline octa-isomer and its L-arginine salt N- ( (R)
-1-Ethoxycarbonyl-2-(1-ethoxycarbonylhexylthio)ethyl)-alanyl-(S)-proline-t-butyl ester A isomer 5301111 was added with 25% HBr-acetic acid for 40 minutes at room temperature. Stirred. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to give a pt-18 solution, and the mixture was washed with ether. −
*ss: After adjusting the pH to 4 by adding io% hydrochloric acid, extraction was performed with methylene chloride. The extract was dried over anhydrous sodium sulfate and then evaporated under reduced pressure to obtain the octa-isomer of the target compound as a colorless oil. Yield 14521L 8-isomer 242mo of ethanol 41 obtained in the above reaction
Add L-arginine 89-Q 1, 511Q to the Q solution with stirring.
Aqueous solution was added. After water and ethanol were distilled off, the residue was dried under reduced pressure to obtain the desired compound, arginine salt, as a pale yellow powder. Yield: 1431g.

(α)25=-12.5° (c=0.3, ethanol) 'H NMR (CD3 0D): δ value 0, 90 (3
H, t, J=7Hz), 1, 2~1.5 (9H, 3H
x3), 1, 5 ~ 2.5 (16H, m), 2, 6 ~ 3.8 (10HSm), 4, 19 (4HS (1, J = 7Hz), 4, 3 ~ 4
．． 5 (IH,m) Example 23 N- ( (R)-1-ethoxycarbonyl-2-(1
-Ethoxycarbonylhexylthio)ethyltualanyl-(S)-proline B-isomer and its L-arginine salt, production of maleate N((R)-1-ethoxycarbonyl obtained in Example 21 -2-(1-Ethoxycarbonylhexylthio)ethyltualanyl-(S)-proline-t-butyl ester B-isomer 52211) to obtain the colorless B-isomer of the target compound in the same manner as in Example 22. Obtained as an oil. Yield: 230 mil.

From 230 mg of the B-isomer obtained in the above reaction, the L-arginine salt of the target compound was obtained as a colorless powder in the same manner as in Example 22. Yield 2701111.

(α) 25--27.7° (c-0.3, ethanol) 'H-NMR (CD3 0D): δ value 0.90 (3
HS t, J-7Hz>, 1.2~1.5 (9H, 3
Hx3), 1.5-2.3 (16)1. m), 2
．． 7-3.8 (108% m), 4.19 (4H
, Q, J-7Hz) , 4.3-4.5 (1H, m) In addition, maleate salt was obtained as a colorless oily substance from B-isomer 380ia by the same operation. Yield: 382 false 9°5 [α), = -38,3' (c-0,7, ethanol)' H-NMR (CDCQa): δ value 0.
88 (3H, t, J-7H2) 1.2-1.5 (9H13Hx3), 1.5-2.5
(12H, m>, 3.0-3.9 (5H, m), 4, 20 (4H10, J-7Hz), 4.3-4
．． 5 (IH, m) , 6.32 (2H, s) Reference example 14 N-((R) -1-ethoxycarbonyl-2-(1-
Preparation of A and B isomers of 7-lanine-t-butyl ester (S-((R,5)-1-ethoxycarbonylheptyl)
-L-cysteine ethyl ester 5.5o, 2-bromopropionic acid-t-butyl ester 3.6Q, triethylamine 2.4- in l-IMPAI6Ig,
By reacting and treating in the same manner as in Reference Example 11, the Aji isomer (previous fraction in silica gel column chromatography) and B isomer (later fraction in silica gel column chromatography) of the target compound were obtained as colorless oily substances.

A isomer: yield 1.9 g [α) −+18.6′ (c-0,7, ethanol)′H-NMR (CDC123): δ value 0.87 (3H, t, J=5Hz), 1. 28 (3
H, d, J-7Hz>, 1.29 <6)-1, t, J
-7Hz), 1.44 (9H, s), 1.3 to 1.8 (10H, m), 2.8 to 3.0 (2H, m), 3.2 to 3.6 (3) ( , m>, 4.20 (4H, qSJ-7Hz) B isomer; yield 1.9Q [α) −-26,0′ (c-0,7, ethanol)′ H-N MR (CD CQ 3 ): δ value 0.8
8 (3H, t, J-5Hz), 1.28 (3H, d
, J-7Hz), 1.29 (6HS t, J-7Hz
), 1.47 (9H1s), 1.3-2.0 (10H, m), 2.6-3.2 (2H, m), 3.2-3.6 (3H, m), 4. 20 (4H, q, J-7Hz) Reference Example 15 N-((R) -1-ethoxycarbonyl-2-(1-
Production of ethoxycarbonylhebutylthio)ethyl)-alanine 8-isomer N-((R)
-1-Ethoxycarbonyl-2-(1-ethoxycarbonylhebutylthio)ethyl]-alanine-1-butyl ester A-isomer 1.80 was reacted and treated in the same manner as in Reference Example 12 to obtain the target compound. The octa-isomer was obtained. Yield 1.5Q.

(α) = +16.5° (c-0.7, ethanol) 'H-NMR (CDCQs): δ value 0.
88 (3H, t, J-7)-1z), 1.29 (
68,t, J-7)1z), 1.40 (3)1. d,
J=7Hz), 1.5-2.1 (10H, m), 2.7-3.2 (2HS m), 3.2-3.7 (3H, m), 4.20 (4H, q , J-7Hz), 6.41 (
1H,brs) Reference Example 16 N-((R)-1-ethoxycarbonyl-2=(1-1
Toxicarponylhebutylthio)ethylshealanine
Production of B-isomer N-((R)- obtained in Reference Example 14
The target compound was obtained by reacting and treating in the same manner as in Reference Example 12 using 1.8 g of 1-ethoxycarbonyl-2-(1-ethoxycarbonylhebutylthio)ethyl)-alanine-t-butyl ester B-isomer. B-isomer was obtained. Yield 1.30 [α) = -12,3° (C = 0.6, ethanol) 'HNMR (CDCQa): δ value 0.88 (3) -1,t, J = 7Hz), 1.30
(61-1, t, J-7Hz), 1.43 (3H, d
, J=7Hz), 1.5-2.1 (10H, m>, 2, 5-3.1 (21-1, m), 3.1-3.5 (3)1.m), 4 .20, 4.24 (4H, q.

J=7Hz>, 5,59 (I H, brs ) Example 24 N-((R)-1-ethoxycarbonyl-2-(1-ethoxycarbonylhebutylthio)ethyl]-alanyl-
Production of (S)-proline-t-butyl ester/8-isomer N-((R)-1-ethoxycarbonyl-nylhebutylthio)ethylshealanine/A-isomer 1 obtained in Reference Example 15
．． 2g, (S)-proline-t-butyl ester 530
1nlll, DEPC550mg, triethylamine 0
．． The A-isomer of the target compound was obtained as a colorless oil by reacting and treating in the same manner as in Example 20 using 43+tt2. Yield 1,360.

[α) = -12.4° (c=0.6, ethane l)' l-1- NMR (CD C Q 3
): δ value 0, 87 (3H, t, J-7Hz), 1,
29 (6H, 3 J=7Hz>, 1, 31 (3H,
d, J=7Hz), 1, 44, 1.47 (9H, each S
), 1, 5 ~2. 2 (14H, m> , 2, 7
~3.0 (21-1, m), 3,1 ~3.9 (
5)-1,m) ,4,20 (4H,a,J-7Hz
), 4, 0 ~4. 5 (1)-1, m) Example 2
5 N-((R)-1-ethoxycarbonyl-2-(1-ethoxycarbonylhebutylthio)ethyl)-alanyl-
Production of (S)-proline-t-butyl ester/B-isomer
．． From 050, the target compound B-
The isomer was obtained as a colorless oil. Yield 1.3o.

[α) --67, 5° (c=1.0, ethanol)' H-NMR (CD CQ 3 ): δ value 0.
88 (3H, t, J=7)-1z), 1.2 to 1.5
(9H, 3f-1x3) 1.44.1.46 (91
-(, each S), 1.6 to 2.5 (14H1m>, 2.6 to 3.8 (7H, m), 4.19 (4) (1q, J-7Hz), 4.2 to 4 ．．
5 (IH,m) Example 26 N-((R)-1-ethoxycarbonyl-2=(1-ethoxycarbonylheptylthioethylcoualanyl-(
N-iR)'-1-ethoxycarbonyl-2-(1-ethoxycarbonyl to butylthio) obtained in Example 24 of production of S)-proline octa-isomer and its maleate salt
398 Il1 g of ethylcoualanyl-(S)-proline-t-butyl ester 8-isomer was reacted and treated in the same manner as in Reference Example 2 to obtain the 8-isomer of the target compound as a colorless oily substance. Yield 270I! a.

From the compound 270+io obtained in the above reaction, the maleate salt of the target compound was obtained in the same manner as in Example 3. Yield 310
110.

[α) = -28.3° (C-o.6, ethanol) 'H-NMR (CD9 0D): 6 values 0, 90 (
3H, tlJ-7Hz).

1, 1-1.6 (9H, 3HX3), 1, 5-2.
4 (14H, m>, 3, 0 ~ 3.9 (7H, m), 4, 21 (4) 1, q, J = 7Hz), 6, 28
(2H,s) Example 27 N" ((R)-1-ethoxycarbonyl-2-(1
-Ethoxycarbonylhebutylthio)ethyl]-alanine-(S)-Proline B isomer and its L-arginine salt, N-((R)-1-ethoxycarbonyl- obtained in Example 25) Example 22 from 1 g of 2-(1-ethoxycarbonylbutylthio)ethylcoualanyl-(S)-proline-t-butyl ester B-isomer 450II
In the same manner as above, the L-arginine salt of the target compound was obtained as a colorless (non-crystalline) powder. Collectionffi516mo.

(α), = -36.9° (C = 0.5, ethanol) ' H - NMR (CD C Q 3)
: δ value 0, 87 (3H, t, J-7Hz), 1, 2~
1.5 (9H, 3H, x3), 1,5 ~ 2.5 (
18H, m), 2, 7 - 3.8 (10H, m), 4, 20 (4H, q, J = 7Hz), 4, 5 - 4.
6 (IH,m) N-((R)-1-ethoxycarnyl-2-(1-ethoxycarbonylhebutylthio)ethyl)-alanyl-(
S)-proline-t-butyl ester B-isomer 43
The maleate salt of the target compound was obtained from C) mg in the same manner as in Example 3. Yield 1457+ng.

[α to 38.3° (C=0.8, ethanol) 1) 1-NMR (CD3 0D): δ value 0, 90 (
3H, t, J-7Hz), 1, 2-1.5 (9t-1
, 3Hx3), 1, 6 ~ 2.5 (1 4H, m) 2, 8 ~ 3.8 (7HSm), 4, 22 (4H, q, J = 7Hz), 4, 5 ~ 4
．． 6 (IHSm), 6, 28 (2H, s) J (and above) Procedural official document (spontaneous) April 11, 1985 1 Indication of the case 1982 Patent Application No. 34701 2 Name of the invention Proline Derivative 3 Relationship with the case of the person making the amendment Patent applicant Otsuka Pharmaceutical Factory Co., Ltd. 4 Agent 2-10, Hirano-cho, Higashi-ku, Osaka, Sawanotsuru Building (6521) Patent attorney Eiji Saegusa 5 Date of amendment order I" Spontaneous 6 Amendment Section 7 "Detailed Description of the Invention" in the subject specification Contents of the amendment 1) In the 4th line of page 11 of the specification, "halocarboxylic acid" is corrected to "haloformic acid".

2) In the fourth line of page 12 of the specification, "rN,N-dicyclo" is corrected to "IN,N'-dicyclo".

3) On page 12, line 9 of the specification, "phosphorylamide" is corrected to "phosphorylacito."

4) On page 12, line 10 of the specification, "diethyl phosphorol" is corrected to "diethyl phosphorol."

5) On page 15 of the specification, lines 14-15, it says “Cream,...
``...topically administered agents,'' should be deleted.

6) On page 15, lines 16-17 of the specification, “Local...
...Administered," should be deleted.

7) On page 16, line 6 of the specification, the word "excipient" is corrected to "preparation."

8) On page 16, line 11 of the specification, "salt water" is corrected to "physiological saline J."゛9) 1.Old... is listed on page 17, line 4 of the specification. ”
The statement is corrected as follows.

[List...] Furthermore, on each side, silica gel chromatography of two or four isomers of the reaction product of s-[1-ethoxycarbonylalkyl)-L-cysteine ethyl ester and 2-bromopropion 1-1-butyl ester (Ether-n-hexane system) In the two fractions separated, the 8-isomer,
The afterflow fraction is designated as the B-isomer. Hereinafter, a compound derived using this 8-isomer will be referred to as an 8-isomer, and a compound derived using this B-isomer will be referred to as a B-isomer. 10) r2.15 (IH, b) on page 18, line 8 of the specification
rs), J is corrected to (11-1, br s), J.

11) On page 19, line 5 of the specification, “2.0 (IH, br
s >, J is r2. O(IHLbr s), J
I am corrected.

12) On page 23, line 17 of the specification, “1.3 to 1.5 (
3H>, J is 11.3 to 1.5 (3H, m),
Correct it with J.

13) On page 24, line 16 of the specification, “1.3 to 1.5 (
3H>, J is [1,3~1.5(3H,m>,J
I am corrected.

14) The structural formula of the compound listed in Table 1 on page 30 of the specification box is corrected as follows.

[ ”] 5) “1.3 to 1.5 (
3H), J and 11.3 to 1.5 (3HSm), J
I am corrected.

16) The structural formula of compound 61 in Table 2 on page 35 of the specification is corrected as follows.

17) "r'H-NMR (CDC93: δ value") in "Example No. 8" in Table 2 on page 36 of the specification.
1.3-1.5 (3H), J and rl, 3-1.5
(Corrected as 3H, rri>, J.

18) In the bottom line of page 38 of the specification, the phrase ``1 solution'' is corrected to ``aqueous solution.''

19) The structural formula of the compound in Table 3 on page 40 of the specification is corrected as follows.

20> In the second line of page 44 of the specification, the word "pyridine" is corrected to read "pyridine aqueous solution."

21) 14.1 to 4, 6 on page 44, line 13 of the specification
(3H, rTl) J and Aruwoji (7) pass iT positive T.

14.1 to 4.6 (3H, m> Reference Example 1O N-[(R)-1-
,5)-1-ethoxyluponi! Preparation of S-((R,5)-1-ethoxyl-lheptyl)-L-cysteine ethyl ester, 11.3 g of pyrupic acid, 15. The desired compound was obtained as a colorless amorphous substance by reacting and treating in the same manner as in Reference Example 4 using '6C1,4N aqueous sodium hydroxide solution and 4.5 g of sodium cyanoborohydride. Yield 6.8g Le'HNMR (CDC93): δ value 0.88 (3H, t, J=5H2), 1, 2-1
．． 5(9to1,3HX3) ,1,. 3-2.1 (1
0H, m>, 2.7 to 3.8 (51-1, m), 4.20 (41-1, q, J=71-1z> Example 18 N-[(R>-1-techn.1 ~xycarbonyl-2-((R
,5i1-■1~xycarbonylhebutylthio)ethyl]-(R,'S)-alanyl-(S)-proline-1-
Production of butyl ester N-[(R11-■toxycarbonyl-2-((R,5)-1-ethoxycarbonylbutylthio)ethyl]-(R,S)-alanine 900m0
In the same manner as in Example 1, the target compound was obtained as a colorless oily substance. Yield 1.1g.

[α)25=-28,6° (c=0.7, ethanol) 'HNMR (CDCQ3): δ value 0.88 (31-1, t, J=5Hz>, 1, 2
~1. 4 (91-1, 3 to 1 x 3), 1.4
4.1.47 (9H, each S), 1.5-2.3 (14
1-1, m), 2, 7-3.0 (21-1, m>, 3.1-3.8 (5H, m), 4.19 (4H, q, J=7Hz>, 4, 0-4.3
(11-1, m) Example 19 N-E (R>-'1-■1~xycarbonyl-2-(
(R,5)-1-Ethoxycarbonylhebutyldio]ethyl] to (R,S)-alanine-(S)-proline and its maleate salt N-[, (R) obtained in Example 18 ~1-ztogishicarbonyl-2- ((R,5)-1-ethoxycarsonylheptylthiΔ]edyl]-(R,S)-alanyl-
From 900 mos of (S)-proline-butyl ester, the target compound was obtained as an amorphous substance in the same manner as in Reference Example 2. Yield 650mg.

From 1q of the above reaction and 230mu of the compound, the maleate salt of the target compound was obtained in the same manner as in Example 3. Collection 12
50mL [α) ~25.1° (c=0.6, ethanol) 'l-l-1-N (CD30D): δ value 0.9 (3
1-1, t, J=5 t1z), 1.1 to 1.6
(9H, 3l-1x3), 1.6~2.4 (14H,
m>, 3.1 to 3.9 (7H, m), 4,, 21 (4,1-1, q, J=7 to Iz)
, 4.2 to 4.5 (111, m), 6.28 (21-1, s> Reference example '11 N-[(R>-1-■ nylhexylthio)ethyl)-alanine-
Preparation of 1-butyl ester A and B isomers S-((R,5)-1-ethoxycar small nylhexyl)
-6.1 g of 1-cystine ethyl ester and 4.2 Q of 2-bromopropionic acid to t-butyl ester were added to l-I
MPA was dissolved in 20 mQ and 2.0 CI of triethylamine was added. Ice water was added to the 1-change reaction mixture that was stirred at room temperature for 72 hours, and the mixture was extracted with ethyl acetate. The extract was washed with water and then with saturated saline, and dried over anhydrous sodium sulfate. Reduce the extract to J, distill off the residue, and apply the residue to a silica gel column Chroma 1 to Graphi (solvent: ether: n-hekylene-1:3)
The A-isomer of the target compound was obtained as a colorless oily substance from the preceding fraction.

Yield 2.2g.

(α), = +13.0' (c=1.0, ethanol)' H-NMR (CD CQ 3): 61 nights 0.
88 (31-1, t, J=71-17>, 1.27(
31-1, d, , no 7117> , 1.28 (6
H, t, J=7 FI 7 > , 1.45 (91-l
, S), 1, 3-1.9 (81-1, m), 2.23 (1-1, S), 2, 7-3.0 (2+-1, m), 3.2- 3.6 (31-1, m), 4, 20 (4H, q, J = 7 Hz>) The B-isomer of the target compound was obtained as a colorless oily substance from the afterflow. Yield: 1.7 CI.

(α) = -30,8° (c=1.2, ethanol) 'tl-HMR (CDC93): δ1 straight 0.88 (
31-1, t, J=71-(Z), 1.28(31-1
, d, J=71-12>, 1.28 (61-l, shi, J
= 7 l-1z), 1.3-1.9 (8hl,
m〉, 2,04 (1+1, S〉, 2.6~3.0 (2+-1, m), 3.1~3.6 (31-1, m), 4.20 (4+-1, q, J=7 (Z) Reference Example 12 Production of N-((R)-1-ethoxycarbonyl-2-(1-ethoxycarbonylethyl)-alanine 8-isomer N obtained in Reference Example 11 -((R>-1-ethoxycarbonyl-2-(
To 1.71 CI of 1-ethoxycarnylhexyldio)edyl]-alanine-1-butyl ester A-isomer was added 7 Jl of 5 ml of FA, and the mixture was stirred at room temperature for 2 hours.

TFA was distilled off under reduced pressure, and a saturated aqueous solution of hydrogen carbonate and helium was added to adjust the pH to 8, followed by washing with ether. 10 in the water layer
% hydrochloric acid was added to make the solution I) l-14, and then extracted with methylene chloride. After drying the extract over anhydrous sodium sulfate, the octa-isomer of the target compound was obtained by distillation under reduced pressure.
J to 7.

[α) = +6.9° (c-0,7, ethanol) 'HNMR (CDC93): δ value 0.88 (31-+, soil, J = 71-IZ),
1.2-1.5 (91-(,31-I X 3>, 1,
3-2. 0 (,8H, m), 2.9~3.9(
51-1, m), 4.21.4.23 (4H, CI, J = 71-1 z), 6, 8 (IH, br &> Reference Example 13 N, -((R)-1- 1 hexycarbonyl-2-(1
-Hexycarbonylhexylthio)ethyl]-alanine B-isomer 'J43mReference Example 11N
-((R)-1-ethoxycarbonyl-2-(1-■1
-alanine-
↑-Butyl ester/B-isomer 1.40g T F
A 5 mQ was added and the reaction was carried out in the same manner as in Reference Example 12 to obtain the B-isomer of the target compound. Yield 1. ．． 25Q.

[αRice--16.2° (, c=0.9, ethanol) 'H-NMR (CDC93): δ value 0, 88 (3 to 1, t S J = 71-lz), 1
．． 2~1.5 (9th, 31-1 x 3), 1.3~
2.0 (81-1, m), 2.6-3.8 (51-1, m), 4.20.4.24 (4H, q, J = 7 l-1y), 5, 8 ( 11-1, br S) Example 20 If-((R), 1-■ Toxicity 2-('I
-Ethoxyl small nylhexyldef 1) Production of ethyl-to-alanyl-(S)-proline-t-butyl ester 8-isomer Nyl-2-(1-ethyl)hexical small nylhexyldio)ethyl)-alanine A isomer 1 piece 1.26 g, (
DMF of S)-proline-1-butyl ester 629m(] and diethyl cyanphosphate (DEPC>666...Q)
Add 371 ethylamine to 5 mQ solution under ice-cooling and stirring.
mg of DMF) d liquid 5flllll? was slowly dripped. After stirring for 12 hours while gradually returning the temperature to room temperature, ice water was added to the reaction mixture, and the mixture was further made weakly alkaline with a saturated aqueous solution of hydrogen carbonate, followed by extraction with ethyl acetate.

The extract was washed with water and then with saturated brine, and dried over anhydrous sodium sulfate. The extract was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: chloroborum:methanol-20:1) to obtain the target compound.
The isomer was obtained as a colorless oil. Yield: 1.60g.

(α) = -23,1° (c = 1.2, ethanol) 'l-1-NN4R (CDCQ3): δ value 0, 88
(3t1, t, J=71-17>, 1.29(31
-1, d, J=7 Iz), 1, 29. (61
-1, J = 71-IZ), 1, 44
, 1. 47 (9 points 1, each S), 1.3~2
．． 7 (12H, m>, 2. 27 (I H, br s), 2, 8 ~ 3. 0 (2 to 1, m), 3, 1 ~
3. 8 (5 t1, m), 4.20 (4H, q
, J=7Hz>, 4.4-4.7 (IH,m>
N-((R)-1-■Toxical small nitrogen-2-(1-ethoxycarbonylhexylthio) obtained in Reference Example 13)
Example 2 from 1.08g of ethylcoualanine B isomer
The B-isomer of the target compound was obtained as a colorless oil in the same manner as in Example 0. Yield 1.56 CI.

[α) = −63,7° (c=1.0, ethanol) 'HNMR (CDCQ3): δ value 0.88 (3H, t, J=7112), 1.1 to 1.
5 (9H, 3l-1x3), 1.44.1.46 (
9H1 each S), 1y3~2.5 (121-1, m>,
2, 26 (IH, br s), 2.6 to 3.0 (2H, m), 3.1 to 3.8 (5 to 1.m), 4.20 (41
-1, q, J=7t-1z), 4.3~4.5 (IH
,rn) Example 22 N-((R)-1-ethoxycarbonyl-(1-■toxylponylhexylthio)ethyl]-alanyl-(
N=( (R)-1-ethoxycarbonyl-2-(1-ethoxycarlebonylhexylthiA) obtained in Production Example 20 of S)-proline octa-isomer and its L-arginine salt [edyl]-alanyl-(S)-proline-1
-Butyl ester A isomer 53Qmg to 25% HBr
- 31 jL of acetic acid) and stirred at room temperature for 40 minutes. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to make p l-1 8, and the mixture was washed with ether. The aqueous layer was adjusted to pH 4 by adding 10% hydrochloric acid, and then extracted with methylene chloride. The extract was dried over anhydrous sulfuric acid and 1 helium, and then evaporated under reduced pressure to obtain the octa-isomer of the target compound as a colorless oil. Yield: 452 mg.

In the above reaction, 242 m (l) of the 1-digit 8-isomer was added to a 4. mQ solution of L-arginine with stirring,
5mQ aqueous solution was added. After water and ethanol were distilled off, the residue was dried under reduced pressure to obtain L-alkinine salt of the target compound as a pale yellow powder. Yield: 14,311g.

(α) = -12.5° (c = 0.3, ethanol) 'H-NMR (CD3 0D): δ value 0, 90 (3
H, t, J=7Hz>, 1, 2~1.5 (9H, 3H
x3), 1,5~2.5 (16 t1, m),
2, 6~'3. '8 (1 0H, m), 4
, 19 (41-1, q, J=7Hz>, 4, 3 ~ 4
．． 5 (11-1, m> Example 23 N- ( (R)-1-ethoxycarbonyl-2-(1
-ethoxycarbonylhexylthio)ethyl)-alanyl-(S)-proline B-isomer and its L-arginine salt, production of maleate N-((R), -1- ■ Tokiji carbonyl-2-(1-ethoxycarbonylhexylthio)ethyl)-alanyl-(S)-proline-t-butyl ester B-isomer 522 m (l), the target compound B- The isomer was obtained as a colorless oil. Yield 230 mg.

From 230 mg of the B-isomer obtained in the above reaction, the desired compound, arginine salt, was obtained as a colorless powder in the same manner as in Example 22. Yield 1270 mu.

[α),, −27,7° (c=0.3, ethanol) 'H-NMR (CD3 0D): δ1 direct 0,90
(3t1, t, J=71-1z), 1.2~1.5
(9H1,311x3), 1,5~2.3 (161-
lSm>, 2.7-3. ' 8 (10H, m>, 4.
19 (41-1, q, J=7 tolz), 4.3~
4.5 (IH, m> In addition, maleate salt was obtained as a colorless oil from 380,111 g of B-isomer by the same operation. Yield: 82 mL [α) = -38,3° (c = 0.7, ethane 'H-NMR (CDC93): δ value 0, 88 (3t1, t, J=, 7Hz>, 1.2~
1.5 (9H13 days x 3), 1, 5-2.5
(12 t1, m), 3.0~3.9 (51-1
, m>, 4.20 (41-1, qSJ=7Hz>, 4.3-4.
5 (IH, m>, 6, 32 (2F+, S) Reference example 14'
-Preparation of butyl ester A and B isomers S-(('R,S)-1-ethoxycarbonylheptyl)-L-cysteine ethyl ester 5.5CI, 2-
16ynQ to HMP using 3.6 g of bromopropion 1-t-butyl ester and 2.4 mQ of toluethylamine.
During the reaction, the same reaction as in Reference Example 11 occurred. By treatment, the A isomer (first flow fraction from silica gel column chromatography) and B isomer (after flow fraction from silica gel column chromatography) of the target compound were obtained as colorless oily substances.

A isomer; yield 1.9 g (α) −+18.6° (c = 0.7, ethanol) 'HNMR (CDC93): δ value 0.87 (31-1, -, J = 5 1-I
Z), 1.28 (31-1, d, J=7117),
1.29 (6H1t, J=71-IZ), 1.1 (9
H,s>, 1.3-1.8 (101-1, ITl), 2.8-3.
0 (2H, rn>, 3, 2-3.6 (31-1, 1 block)), 4.20
(4th, (1, J=7Hz>B isomer; yield 1.9q (α) −26, Oo (c=0.7, ethanol) Month 1-NMR (CDCQ 3 ): δ count 0.88 (3
1-1, t, J=51-(z), 1, 28 (3 to 1,
d, J=7 F+2>, 1.29 (6t1, t,
J=71-12>, 1.47 (9 to 1, S), 1, '3~3.0 (10H1m), 2.6~3.2 (2+-1, m), 3.2~3 .6(31-1, m), 4.2o(4+-+, Q, J=71-(Z) Reference Example 15 N-((R)-1-1-hexical smallyl-2-(1
-Ethyl 71) Ethyl-
N obtained in Reference Example 14 for the production of No7ranine △-isomer
-((R)-1-■ Toxycarbonyl-2-(1-
-xycarbonylheptylthio)ethyl]=alanine-1-butyl ester, 1.8 g of the 8-isomer (in 8, pre-reaction treatment was carried out in the same manner as in Reference Example 12) to obtain the A-isomer of the target compound. Yield: 1.5g.

[α)=+16.5° (c=0.7,"]tanol)'l-l-1-N (CDCQ3): δ11 negative 0.8
8 (31-1, t, J=7Hz), '1.29 (6th,
t, J=71-1z), 1.40(31-(, d, J=
71-1z), 1.5-2.1 (101-(,rr))
, 2.7-3.2 (21-1, m), 3.2-3.7 (31-(, m), 4, 20 (41-1, q, J=7H2>, 6.41(
IHlbrs) Reference Example '1G N-((I)-1-oxycarbonyl-2-(1
-Ethoxylic small nylheptylthia 1) Production of ethylcoualanine B-isomer N-(((
R) -1-Ethoxylic small nyl-2-(1-■1~xical small nylhepdylthio)ethyl)-7 Ranine monobutyl ester 1B=Reference example 1 using 1.8 g of isomer
The target compound 8 can be obtained by pre-reaction treatment in the same manner as in 2.
-isomer (W) Yield 1.30 [α bow - -12.3° (c=0.6, ethanol>'l-l-1-N (CI)C93): δ1100.8
8 (3rd, y, J = 71-IZ), 1.30
(61-ISt, J=7)-1z), 1.43 (3
1-(, d, J=7H2>, L 5~2.1 (10th, m), 2.5~3.1 (2H1 [Eng. 1), 3.1~.3.5 (3H, m ), 4.20.4.24 (4H,Q.

J=7H2), 5, 59 (11-1, brs) Example 24 tl-((I or)-1-Sat)~xical small Niru 2-(
1-Process 1~xical small nil hebburti A) niburu]-
Production of alanyl-(S>-butylene↑-butyl ester 8-isomer 1~gical small nylhebutyldio)ethylcoualanine A-iso 11 1.2g, (
S)-bu1ni1rin-1-butil] Nistil 530m
0. DEPC550m(], I-ri-upper delamine 0.4
The A-isomer of the target compound was obtained as a silent oil by reacting and treating as in Example 20 using 3mQ. Yield: 1.36 g.

[α), = -12,4° (C = 0.6, ethanol) "H-NMR (CDC93): δ value 0, 87 (3 points 1, 2, ,) = 7 1-1
7 > , 1.29' (6H, J=7 t17
> , 1.31 (31-1, cl, J=7 to 1z)
, 1.44.1.47 (91-1, each S), 1.5-2
．． 2 (14+-1,1η), 2.7~3.0 (2+-
1, m), 3, 1-3. '9 (511, 1° block]), 4.20
(4N, cl, J = 71-1z), 4, 0-4.
5 (1, rn>Example 25
Process 1 - Oxycarbonylheptylthiaethyl]-1 Ranyl (S) - Production of proline-thibutyl ester B-isomer N-((R)-1-11-xycarbonyl-2-(1- Ethoxynonol 71<nylhebutylthio)ethyl]-alanine B-isomer 1.05
The B-isomer of the target compound was obtained as a colorless oil in the same manner as in Example 20. Yield 1.3 CI.

(α)1)=-67,5° (c=j, 0, ethanol) 't-l-NMR (CDC93): δ value 0,88 (3
1-1, [, J = 71-Iz), 1, 2~
1.5 (9H, 3t 1×3), 1.44.1.4
6 (9H1 each S), 1, 6-2.5 (14 points 1, m), 2,
6 to 3.8 (7 points 1.ITI), 4.19 (4+-1
, Q, J=71-IZ), 4.2-4.5 (11-1,
m) Example 26 N-((R)-1-1-Xical small nyl-2-(1-
Production of N-((R)-1-ethoxycarbonyl- 2-(1-■1~xical small diylheptyldio〉ethyl)-7 ranyl(S)-proline-1-butyl ester 8-isomer 398m () was reacted in the same manner as in Reference Example 2't! Treatment 8- of the target compound
The isomer was obtained as a colorless oil. Yield 270mg.

From 270 mg of the compound obtained in the above reaction, the maleate salt of the target compound was obtained in the same manner as in Example 3. 1 roll amount 310mc+.

(α) = -2B, 3° (c = 0.6, ethanol) 'HNMR (CD3 0D): δ1 direct 0.90 (3
1-1, t, J=7Hz>, 1.1~1.6 (91-
1,3HX3), 1.5-2.4 (141-(,m)
, 3, 0~3', 9 (71-1, m>, 4.21
(41-1,q, J=71-1z), 6.28 (21
-1,s> Example 27 N-C(Rh-1-ethoxycarbonyl-2-(1-ethoxycarpo-nylhebutylthio)ethyl]-alanyl-
Preparation of (S)-proline B isomer and its l-arginine salt, maleate salt Example 25 From 450 mg of ethoxylic acid-alanyl-(S)-proline-1-butyl ester B-isomer, the L-alkinine salt of the target compound was prepared in the same manner as in Example 22.
3 (amorphous) powder. Yield: 516 mg.

[α), = -36,9° (C=0.5, ethanol) 'It NMR (CD093): δ (direct 0, 8
7 (31-1, t', J=71-1z>, 1.2~1
．． 5(,9+-1,31-IX3), 1, 5
~2.5 (18 t1, m), 2.7~3.8 (
10th, m), 4.20 (4+-1, q, J=71-1z), 4.5~
4.6 (1I-1,m> N-((R)-1-ethoxycarbonyl-2-(1-1
From 130 mg of 1-oxycarbonylheptylthia I) edyl]-alanyl-(S)-broline-1-butyl ester B-isomer, the maleate salt of the target compound was obtained in the same manner as in Example 3. Yield 457 mg.

(α) −−38,3° (c=0.8, ethanol) “11-NMR (CD30D): δ value 0, 9'0 (3) −1, t S J=7 F+2>
, 1, 2-1.5 (91-1, 3t 1×3)
, 1.6-2.5 (141-1,11]), 2.8-3
．． 8 (7H, m>, 4.22 (4 to 1, (1, J=7Hz), 4.5~
4.6 (1t-L m), 6.28 (2+-1, s) J (or more)

Claims (1)

[Claims] (1) General formula [In the formula, R4 represents a hydrogen atom, a lower alkyl group, or an engineering group, and R1R3 and R4 are the same or different and represent a hydrogen atom or a lower alkyl group. ] A proline derivative represented by and its salt.