JPH03148255A - Mercaptofatty acid derivatives - Google Patents

Abstract

NEW MATERIAL:A mercaptofatty acid derivative expressed by formula I (R1 is H or lower alkyl; R2 is lower alkyl; m is 0 or 1; n is 1 or 2) and salts thereof. EXAMPLE:N-(2-Mercaptopropionyl)-D,L-methionine sulfone. USE:A hypertension treating agent. The compound expressed by formula I exhibits excellent angiotensin I conversion enzyme inhibiting action. PREPARATION:For example, an aminocarboxylic acid derivative expressed by formula II is reacted with a mercaptofatty acid expressed by formula III or reactive derivative thereof to provide the mercaptofatty acids expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to I; mercapto fatty acid derivatives useful for uses such as agents for treating hypertension.

More specifically, the present invention is based on the following formula (1) %Formula %(1) In the formula, R1 represents a hydrogen atom or a lower alkyl group, R2 represents a lower alkyl group, m represents 0 or l, and n represents The present invention relates to mercapto fatty acid derivatives and salts thereof, which are represented by: 1 or 2.

The present inventors have conducted research on mercapto fatty acid derivatives. As a result, we succeeded in producing synthetic leather of derivatives represented by the above formula (1) that have not been previously described in known literature.

Therefore, it is an object of the present invention to provide compounds of formula (I) as described above.

The above objects and many other objects and advantages of the present invention will become more apparent from the following description.

In the formula above, the lower alkyl groups of R6 and R3 are C1 to C4 alkyl groups, particularly preferably Cr.
An example is an alkyl group of Cz.

The compound of formula (1) of the present invention can be produced, for example, by method (A) or method (B) below.

(A) Method An aminocarboxylic acid derivative represented by the following formula (It) OOH where R2 and n have the same meanings as above and the following formula () % formula % () where R and m are A method of reacting a mercapto fatty acid represented by or a reactive derivative thereof, which has the same meaning as above.

(B) Method following formula (IV) X(CHz)mcHcONHcH(CHz)nsO2R
1(IV)OOH In the formula, A thio compound or an alkali metal thereof, which represents a group, an aroyl group, an N-dealylcarbamoyl group, an N-arylcarbamoyl group, an N-alkylthiocarbamoyl group, an N-arylthiocarbamoyl group, an alkoxycarbonyl group, or an aryloxycarbonyl group. The following formula (VI) 1 R,S(CL)mcHcONHcH(CHz)nsOJ obtained by reacting with a salt
t (Vl)OOH In the formula, R, , R, , m, n and R3 have the same meanings as above. A method of treating a compound represented by the following with an acid or alkali or reducing it.

In the present invention, when carrying out the above method (A), the mercapto fatty acid of the formula (III) can preferably have its mercapto group protected with an appropriate protecting group that can be easily removed. . Examples of such protecting groups include, for example, acetyl group, benzoyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, ethylcarbamoyl group, t-butoxycarbonyl group, benzyl'1&, p-methoxybenzyl group. , p-nitrobenzyl group, benzhydryl group, di-p-methoxybenzhydryl group, trityl group, m-nitrophenyl 7
Examples include enacylmethyl group, inbutyloxymethyl group, phenylthiomethyl group, acetamidomethyl group, and tetrahydropyranyl group.

The reaction can be carried out using a reactive derivative of the mercapto fatty acid of the formula (III), such as active esters, acid anhydrides, acid halides of the mercapto fatty acid of the formula (III). For example, The reaction can also be carried out in the presence of a suitable activating agent, and when the reaction is carried out in the form of a mercapto fatty acid of formula (II), it can be carried out in the presence of such an activating agent. , particularly preferred.

Examples of such active esters include formula (III)
Examples of compounds such as cyanomethyl ester, p-nitrophenyl ester, 2.4.5-)lichlorophenyl ester, pentachlorophenyl ester, N-hydroxyphthalic imide ester, N-hydroxysuccinimide ester, 8-hydroxyquinolyl Examples include ester, 2-hydroxyphenyl ester, 2-hydroxypyridyl ester, and 2-pyridylthiol ester. In addition, as the acid halide,
Preferred examples include acid chloride and acid bromide. Further, a preferable example of the activator is N,N-dicyclohexylcarbodiimide.

The above-mentioned protecting group can be introduced by a method known per se. For example, activated forms of compounds corresponding to these protecting groups, such as halides or acid halides, may be used alone in a solvent such as water, ether, benzene, methanol, ethanol, liquid ammonia, dimethylformamide, or trifluoroacetic acid, or For example,
Reaction conditions include using a temperature range of -80°C to 90°C in the presence or absence of an alkali such as sodium hydroxide, potassium hydroxide, potassium hydrogen carbonate, or an acid such as hydrobromic acid or hydrochloric acid. can be suitably selected depending on the characteristics of each protecting group.

(A) In carrying out the process, an aminocarboxylic acid derivative of formula (n) is combined with an aminocarboxylic acid derivative of formula (I) in the presence or absence of an activating agent.
The reaction temperature for reacting the mercapto fatty acid or its reactive derivative in ff) can be selected as appropriate, but for example,
Examples of reaction temperatures include about -5°C to about 80°C, more preferably about 10°C to room temperature.

The reaction can be carried out in a solvent if desired, and such solvents include, for example, ethers such as tetrahydrofuran and dioxane; esters such as ethyl acetate and isoamyl acetate; for example, N,N-dimethylformamide. , N-methyl-2-pyrrolidone, N, N
- N-alkylamides such as dimethylacetamide;
Appropriate solvents such as dimethyl sulfoxide, hexamethylphosphonylamide, and water can be used alone or in combination.

The compound of formula (11) and the compound of formula (I[[) are:
Although they react stoichiometrically, these two components do not necessarily have to exist in an equivalent relationship in the reaction system, and good results can be obtained depending on the quantitative ratio of the two components depending on the combination of raw materials and other conditions. can be selected as appropriate.

In the condensation reaction of the compound of formula (n) as described above and the compound of formula (III), a compound in which the mercapto group of the compound of formula (I[[) is a protected group as exemplified above is used. In some cases, the target compound of formula (1) can be obtained by removing the protecting group after the reaction. The protective group can be removed by a known removal means, for example, by acid or alkali treatment or reduction treatment.

For example, by treatment with metallic sodium in the presence of liquid ammonia, or in a liquid medium such as a suitable solvent, such as water, methanol, ethanol, acetic acid, etc., such as hydrochloric acid, hydrobromic acid, etc. acid, or sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia,
With an alkali such as methylamine, ethylamine, trimethylamine, hydrazine, hydrazine hydrate, sodium methylate, or a reducing agent such as sodium borohydride, for example from about -5°C to about 80'C! It can be removed by reacting at temperatures such as .

This reaction is preferably carried out under a nitrogen atmosphere, or under a hydrogen atmosphere.

The mercapto fatty acid derivatives of formula (I) of the present invention obtained as described above are neutralized if necessary, and subjected to methods known per se, such as extraction, dissolution, various chromatography, crystallization, and recrystallization. Isolation or purification can be carried out by appropriately selecting or combining means such as , reprecipitation, etc.

(t) of formula (I) of the present invention thus obtained.

The compounds can form salts with bases. Examples of such salts include ammonium salts, alkali metal salts,
Examples include sodium salts, potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and further amine salts. Formula (1) of the present invention
The salts of the mercapto fatty acid derivatives are preferably physiologically acceptable salts as exemplified above.

In the present invention, when carrying out the method (B), the compound of the formula (IV) is reacted with the thio compound of the formula (V) or an alkali metal salt thereof to form the compound of the formula (Vl). Then, R3 in formula (Vl) may be converted to a hydrogen atom by treating this with an acid or alkali or by reducing it.

In this embodiment, the compound of the formula (■) used as a raw material compound in the above method (A) and the compound of the formula (n) used as a raw material compound in the method (A) and the following formula (■) 1 In the formula, R, , X, and m have the same meanings as described above, and X is preferably C1 or Br.

This reaction can be carried out in the same manner as in method (A) above, in which the compound of formula (II) is reacted with the compound of formula (I[[).

When reacting the compound of formula (rV) with the compound of formula (V), an appropriate solvent such as benzene, toluene, dioxane, dimethylformamide chloroform, ether, or water is usually used alone or in combination. and, if necessary, in the presence of a deoxidizing agent such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, pyridine, dimethylaniline, triethylamine, etc., from about -5°C to about 80°C, more preferably from about -5°C to
It can be carried out at temperatures around room temperature.

The compound of formula (Vl) thus obtained can be treated with an acid or an alkali, or subjected to reduction treatment to remove the R group to obtain the target compound of formula (I).

In this embodiment, the reaction for removing the R group can be carried out in the same manner as in Method A, when the mercapto group of the compound of formula (III) is protected and the protecting group is removed.

Examples of R in the compound of formula (V) include alkanoyl groups such as acetyl, propionyl, butyryl; aroyl groups such as benzoyl, p-nitrobenzoyl, p-methylbenzoyl, p-chlorobenzoyl; N-methylcarbamoyl; , N-alkylcarbamoyl group such as N-ethylcarbamoyl, N-propylcarbamoyl; N-
N-arylcarbamoyl groups such as phenylcarbamoyl; N-alkylthiocarbamoyl groups such as N-methylthiocarbamoyl and N-ethylthiocarbamoyl: N-
Examples include N-arylthiocarbamoyl groups such as phenylthiocarbamoyl; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl; and aryloxycarbonyl groups such as benzyloxycarbonyl and p-methoxybenzyloxycarbonyl. .

The mercapto fatty acid derivatives of the formula CI) of the present invention obtained by removing the R group from the compound of the formula (Vl) in this way are neutralized if necessary, and similarly to method A, the mercapto fatty acid derivatives of the formula CI) of the present invention are obtained by Means I: For example, isolation or purification can be carried out by appropriately selecting or combining means such as extraction, dissolution, various chromatography, crystallization, recrystallization, and reprecipitation.

Furthermore, if necessary, physiologically acceptable salts can also be produced in the same manner as in Method A.

The target compounds of formula (I), which can be obtained as described above, for example by method (A) or method (B), can exist as diastereomers or racemates, and in the present invention, compounds of the formula (Ri is an expression that includes these.

The compound of formula (1) of the present invention was tested for its enzyme inhibitory effect using angiotensin I convertase isolated from the lungs of domestic rabbits using hyperly-L-histidyl-L-leucine as a substrate, and found that it was an excellent angiotensin inhibitor! It showed convertase inhibitory effect. Therefore, the compounds of the present invention are useful as agents for treating angiotensin-related hypertension.

Example 1-1 Production of N-(2-mercaptopropionyl)-D,L-methionine sulfone, 54.6 g (0.3 mol) of L-methionine sulfone
was dissolved in IN-sodium hydroxide 300+d, and 75.0 g (0.35 mol) of σ-bromozolopionyl bromide and IN-sodium hydroxide 350- were dissolved at O-10°C.
Add drops alternately while maintaining weak alkalinity. After the dropwise addition was completed, the reaction was carried out at room temperature for 2 hours, then the mixture was made strongly acidic with hydrochloric acid while cooling, the resulting oil was extracted with ethyl acetate, the ethyl acetate layer was washed with water, and after drying over anhydrous sodium sulfate, the solvent was removed. After evaporation, white crude crystals are obtained. When this is recrystallized from ethyl acetate, 71.0 g (yield 75%) of L-methionine sulfone is obtained. Melting point: 138-140°C.

N-(2-bromopropionyl)-D obtained here,
L-methionine sulfone 30.0g (0-094 mol)
is dissolved in 100-dimethylformamide. Separately, thiobenzoic acid 16. Og (0,114 mol) and potassium hydroxide 6.4 g (0,114 mol) were mixed with ethanol 5
A solution of raw potassium thiobenzoate dissolved in ethanol is slowly added to the above solution. After reacting for 4 hours at room temperature, insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to obtain a reddish-brown oil that is purified by silica gel chromatography.

(Solvent: benzene-ethyl acetate) The obtained crude crystals are recrystallized from ethyl acetate to obtain 14.8 g (yield 36%) of N-(2-benzoylthiopropionyl sulfone. Melting point 12
3 to 125°C0 To 4g (0.02 mol) of the N-(2-benzoylthiopropionyl)-D,L-methionine sulfone obtained in 22 was added concentrated ammonia water 20- and reacted at room temperature for 2 hours. After that, water is added and the by-produced benzamide is extracted with ethyl acetate. The aqueous layer was made strongly acidic by adding hydrochloric acid, the resulting oil was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The white crude crystals obtained were recrystallized from ethyl acetate. (2-mercaptopropionyl)-D,L-methionine sulfone 1.9 g (yield 36%)
) is obtained. Melting point 131-133°C0 Infrared absorption spectrum 1650 (CONH) 1310 (so2) 11
20 (sob) Example 1-2 N-(2-mercaptopropionyl)-S-ethyl-L
- Example of cysteine sulfone! In the same manner as in -1, using S-ethyl-L-cysteine sulfone in place of D,L-methionine sulfone, the title compound is obtained as colorless crystals. Melting point 98~
102°C0 Example! -3N- (2-mercaptopropionyl) -D,L-ethionine sulfone In the same manner as in Example 1-1, instead of D,L-methionine sulfone. Using L-methionine sulfone, the title compound is obtained as colorless crystals.

Melting point: 135-140°C.

Example ! -4 N-(2-Mercaptopropionylthyl-L-cystine sulfone) In the same manner as in Example 1-1, S-methyl-L-cystine sulfone was used instead of D,L-methionine sulfone to form the title compound into colorless crystals. Melting point: 114
~116℃.

Example 1-5 N-(mercaptoacetyl)-D. L-methionine sulfone The title compound is obtained as colorless crystals in the same manner as in Example 1-1, using chloroacetyl chloride in place of q-bromopropionyl bromide. Melting point 121'C
.

Example 2-1 N-(3-mercapto-2-methylpropionyl)-D
．． To prepare L-ethionine sulfone, 9.5 g (0.1 mol) of L-ethionine sulfone 1 was dissolved in IN-sodium hydroxide lOO-, and 3-benzoylthio-2
-Methylpropionyl chloride 26.7g (0.1
1 mol) and IN-sodium hydroxide 110-1
At 0°C, the mixture is added dropwise alternately while maintaining weak alkalinity.

After completion of the dropwise addition, the reaction was carried out at room temperature for 3 hours, then the mixture was made strongly acidic with hydrochloric acid while cooling, the resulting oil was extracted with ethyl acetate, the ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to give a white crude product. Obtain crystals. When this is recrystallized from ethyl acetate, N-(3-benzoylthio-2-methylpropionyl)-D,L-ethionine sulfone 2 4.4
g (yield 61%) is obtained. Melting point 123-12
5℃.

8.0 g of N-(3-benzoylthio-2-methylpropionyl)-D,L-ethionine sulfone obtained here.
(0.02 mol), add 40"- of concentrated ammonia water,
After reacting for an hour at room temperature, excess ammonia is distilled off under reduced pressure and the precipitated benzamide is extracted with ethyl acetate. The aqueous layer was made strongly acidic by adding hydrochloric acid, the resulting oil was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The white crude crystals obtained were recrystallized from ethyl acetate. (3-mercapto-2-methylpropionyl)-
4.9 g (yield 82%) of D,L-ethionine sulfone are obtained. Melting point 111-116°C.

Infrared absorption spectrum 1600 (CONH)! 300.1260.112
0(So,) Example 2-2 N-(3-mercaptopropionyl)-D,L ethionine sulfone 3-benzoylthio-2-
By using 3-benzoylthiopropionyl chloride in place of methylpropionyl chloride, the title compound is obtained as colorless crystals. Melting point 121-122°C.

Example 2-3 N- (3-mercaptopropionyl)=D. L-methionine sulfone In the same manner as in Example 2-1, D,L-ethionine sulfone and 3-benzoylthio-2-methylpropionyl chloride were each replaced.

The title compound is obtained as colorless crystals using L-methionine sulfone and 3-benzoylthiopropionyl chloride. Melting point: 99-100°C.

Example 2-4 N-(3-mercapto-2-methylpropionyl)-D
, L-methionine sulfone In the same manner as in Example 2-1, the title compound is obtained as colorless crystals by using L-methionine sulfone instead of D,L-ethionine sulfone.

Melting point 116-118°C0 Example 2-5 N-(3-mercaptopropionyl)-S-dityl L
Cystine Sulfone In the same manner as in Example 2-1, S-ethyl-L-cystine sulfone and 3-benzoylthiopropionyl chloride were used instead of D,L-ethionine sulfone and 3-benzoylthio-2-methylpropionyl chloride, respectively. The title compound is obtained as colorless crystals. Melting point 102-105°C.

Example 2-6 N-(3-mercapto-2-methylpropionyl)-S
-Ethyl-L-cystine sulfone In the same manner as in Example 2-1, using S-ethyl-L-cystine sulfone in place of D,L-ethionine sulfone, the title compound is obtained as colorless crystals. Melting point 125-127°C.

Example 3 Preparation of N-(2-mercaptopropionyl)-D,L-methionine sulfone 2-(2-tetrahydropyranylthio)propionic acid 1
．． 1 g (0.0 0 5 8 mol) and 0.67 g (0.0058 mol) of N-oxysuccinimide were dissolved in methylene chloride lO-, and 1.2 g (0.0 0 0 0) of dicyclohexylcarbodiimide was dissolved under water cooling. After stirring for 3 hours, the mixture was left in the refrigerator overnight. The resulting dicyclohexylurea is removed, and the filtrate is concentrated under reduced pressure.

The residue was dissolved in 10-ethyl acetate and 0.72 g (0.0 g) of D,L-methionine sulfone was added.

A solution of 0.004 mol) dissolved in 0.5 N sodium hydroxide 8- was added under water cooling and stirred for 4 hours. The ethyl acetate layer is extracted with a 4% aqueous sodium bicarbonate solution, combined with the aqueous layer, made strongly acidic with hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, the residue was dissolved in ethyl acetate, and dicyclohexylamine was added to precipitate white crystals of N- [2- (2-
tetrahydropyranylthio)propionyl] -D,L
- Obtaining the dicyclohexylamine salt of methionine sulfone. Melting point 165-168°C.

When this dicyclohexylamine salt is treated with hydrochloric acid, the compound N-(2-mercaptozolopionyl)-D,L-methionine sulfone of Example 1-1 is obtained.

Example 4 Preparation of N-(3-mercaptopropionyl)-D,L-ethionine sulfone, 5.9 g (0.03 mol) of L-ethionine sulfone was dissolved in 60 a+l of 0.5N sodium hydroxide F. )
l,3-(N-ethylcarbamoylthio)propionyl chloride 6.5 g (0,033 mol) and IN-
Sodium hydroxide 33- is alternately added dropwise while keeping the mixture slightly alkaline at o-io°C. After completion of the dropwise addition, the mixture was reacted overnight at room temperature, then made strongly acidic with hydrochloric acid while cooling, extracted with ethyl acetate, the ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. Treatment of the residue with ether provides N-[3-(N-ethylcarbamoylthio)propionyl]-D,L-ethionine sulfonka.

The acid obtained here was dissolved in 3N sodium hydroxide, and after stirring at room temperature for 3 hours, the reaction solution was washed with ether, made strongly acidic with hydrochloric acid, and the resulting oil was extracted with ethyl acetate, washed with water, After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the resulting white crystals were recrystallized from ethyl acetate.
N-(3-mercaptopropionyl)-D,L-ethionine sulfone is obtained. Melting point: 121-122°C.

Infrared absorption spectrum 1635 (CONH)! 305.1260.11l
105 (so Example 5 N-(3-mercapto-2-methylpropionyl) -
Dicyclohexylamine salt of D,L-ethionine sulfone N-(3-mercapto-2-methylpropionyl)-D,L-ethionine sulfone 30 obtained in Example 2-1
Dissolve 0 mg in ethyl acetate, add 200 mg of dicyclohexylamine, and heat.

After cooling, the precipitated white crystals were collected by filtration, and the title compound 400
mg is obtained. Melting point 150-153°C0 Example 6 Potassium salt of N-(3-mercaptopropionyl)-D,L-ethionine sulfone N-(3-mercaptopropionyl)-D,L-ethionine obtained in Example 4 Add 180 potassium 2-ethylhexanoate to the ethyl acetate solution of sulfone 280+111i.
Add a solution of Iag in ethyl acetate and stir. Ether is added to this, and the resulting oil is washed with ether and then with hexane, and then dried under reduced pressure to obtain the title compound.

Reference example: Test of angiotensin convertase inhibitory effect Angiotensin 1 convertase (ACE) inhibitory effect
Shman and Cheung [Biochem, P
har+++aco1. .

20.1637 (1971)), the measurement was carried out as follows using ACE isolated from rabbit lung and using hyperly-L-histidyl-L-leucine as a substrate.

Measurement method Hypri-L-Histidyl-L-Leucine (substrate)
．． Dissolved in 1M potassium phosphate buffer (pH 8,3),
A 12.5mM substrate solution was prepared. In addition, test compounds were dissolved in the same buffer solution to prepare test solutions of various concentrations. Angiotensin 1 convertase (AC) purified from rabbit lung
E) The solution (activity: 1.34μ/-) was diluted with the same buffer and adjusted so that its absorbance value was approximately 0.4 (oxygen solution).

Mix 0.10- of the test solution and 0.05- of the enzyme solution, and heat at 37°C.
After incubating for 5 minutes with a substrate solution of 0.10-
was added and incubated at 37°C for 30 minutes. Next, 0.25 mj2 of IN hydrochloric acid was added under water cooling to stop the reaction, and after the reaction, 1.5-mj2 of ethyl acetate was added, stirred for 15 seconds, and then centrifuged to separate the ethyl acetate layer. - was collected. The ethyl acetate layer was evaporated to dryness and the angiotensin 1 convertase f
Raw hippuric acid was obtained from the matrix by F. 1 for this
M Sodium chloride! - and stirred for 15 seconds, then
Ultraviolet absorption at 28 nm was measured.

Control samples with enzyme activity of 0% and 100% were operated in the same manner, and compared with this, the inhibition rate of the test solution at each concentration was calculated, and from the relationship between concentration and inhibition rate, the inhibitory effect of each compound was evaluated on the enzyme activity. The following table shows the concentration (IC6°) that inhibits the activity of 50%.

As shown in the results, all the compounds of the present invention have excellent angiotensin converting enzyme inhibitory activity.

Compound A: N-(2-mercaptoproonivir)-D,L-methionine sulfone (Example 1-1 and Example 4) IC,. (PM) CH.

l5-CHCONHCHCH2CH, So, CH30O
H 0,45 B: N-(2-mercaptopropionyl)-5-ethyl-L-cystine sulfone (Example 1-2) CH.

l5-CHCONHCHCHx-Sow-C2Hs0O
H 7,7 C: N-(2-mercaptopropionyl)-, L-ethionine sulfone (Example 1-3) C11.

HS-CHCoNHCHCH! CH, SO2C!
H% blind ool D: N-(2-mercaptopropionyl)-5-methyl-L-cystine sulfone (Example 1-4) 13 15-CHCONHCHCH, -5O□-CH.

ool E: N-(mercaptoacetyl)-ly, L-methionine sulfone (Example 1-5) HS-CH*C0NHCHCHsCHzSOtCHi0
OH F: N-(3-mercapto-2-methylpropionyl)-D,L-ethionine sulfone (Example 2-1) CI.

HS-C1bCHCONHCHCHHzCIbSO□C,
H.

0OH 0,52 G: N-(3-mercaptopropionyl)-〇, L-ethionine sulfone (Example 2-2 and Example 4) HS-CH*CHtCONHCHCH2CH2SOzC
Js0OH H: N-(3-mercaptopropionyl)-D, L-methionine sulfone (Example 2-3) HS-CHtCH, CONHCHCH, CM, 5oIC
II0OH 1:N-(3-mercapto-2-methylpropionyl)
-D,L-methionine sulfone (Example 2-4) CH.

l5-CI(2CICON)ICIICH2CToSO
zCHs0OH J:N-(3-mercapto-2-methylpropionyl)
-3-ethyl-L-cystine sulfone (Example 2-6) CI.

1s-CHxCHCONHCHCHzSO*CtHso
o1 5.6 K: N-(2-mercaptopropionyl)-L-cysteine (control example) CH.

1s-CHCONHCHCHz-SH Wordoo15t,: N-(3-mercaptopropionyl)-L-cysteine (control example) MS-CI, CH, -CONHCHCH, -SHOOH 9 M: N-(2-acetylthiopropionyl) -S-acetyl-L-cysteine (control example) CH3 amount CI 3CO-S-CI (CONHCHCH, -5-C
OCH.

OOH 〉100 N: N-(2-penzoylthioglobionyl)-S
-Benzoyl-L-cystine 0OH Q: N-(3-penzoylthiogropionyl)-5
-benzoyl-L-cysteine ool R: N-[(2s)-3-benzylthio-2-methylglobionyl]; S-benzyl-L-cysteine Renine-angiotensin-aldosterone system plays an important role in blood pressure regulation It is hormonal. Angiotensin I produced by renin is biologically almost inactive, but raw angiotensin ■, which is absorbed by angiotensin converting enzyme (ACE), is the most powerful pressor substance in the body, either directly or by stimulating the vasomotor center, or by stimulating catecholamines. Acts on vasoconstriction indirectly through secretion promotion.

It also stimulates aldosterone secretion and the lip brown center to increase body fluid volume, both of which ultimately have a pressor effect. Therefore, drugs that inhibit ACE can be used as therapeutic agents for hypertension.

Claims (1)

[Claims] 1. The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) In the formula, R_1 represents a hydrogen atom or a lower alkyl group, R_2 represents a lower alkyl group, and m is Mercapto fatty acid derivatives and salts thereof, represented by: 0 or 1, and n represents 1 or 2.