JPS58140065A - Mercaptobenzyl fatty acid derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formulaI(R1 is H, lower alkyl, benzoyl, carboxy-lower-alkyl, or carboxy(aryl-substituted).lower alkyl; R2 is lower alkyl; A is S or SO2; m is 0 or 1; n is 1 or 2; * represents asymmetric carbon) and its salt. EXAMPLE:N-[2-Benzyl-3-(ethylthio)propanoyl]-S-methyl-L-cysteine. USE:Remedy for hypertension. Useful also as a remedy for hepatic diseases and inflammatory diseases. PROCESS:The compound of formulaIcan be prepared by reacting the aminocarboxylic acid compound of formula II with the mercaptobenzyl fatty acid of formula III (R1 is lower alkyl, benzoyl, carboxy-lower alkyl or carboxy (aryl- substituted) lower alkyl) or its reactive derivative at 0 deg.C room temperature.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to mercaptopencil fatty acid derivatives and intermediates for their production, which are useful for uses such as agents for treating hypertension, liver diseases, and inflammatory diseases, and methods for producing the same.

More specifically, the present invention is expressed by the following formula (1) However, during the ceremony.

R1 represents a hydrogen atom, a lower alkyl group, a benzoyl group, a carboxy lower alkyl group or a carboxy-aryl monosubstituted lower alkyl group.

R2 represents a lower alkyl group, A represents S or SO.

% indicates 0 or 1; % indicates 1 or 2; and pot indicates an asymmetric carbon atom. Furthermore, the present invention also relates to a method for producing a Juden 8AFi upper compound. The above formula (1) compound and its salts are compounds that have not been described in any known literature.

The present inventor has conducted research on mercapto fatty acid derivatives. As a result, we succeeded in synthesizing mercaptopenyl fatty acid derivatives and salts thereof, which have not been described in any prior art literature and can be represented by the above formula.

Therefore, it is an object of the present invention to provide a compound of the formula (2) and a process for its preparation.

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

In the formula (1), the lower alkyl groups of R1 and R3 include alkyl groups of c 1 and J . Particularly preferably Cρ
The alkyl group can be exemplified by the following.

In addition, the lower alkyl group in the carboxy lower alkyl group of R-C1 is a C1 to C4 linear or branched alkyl group, particularly preferably a C1 to Ci carboxynormal or inalkyl group, or a carboxy-aryl group. Examples of the lower alkyl group in the substituted lower alkyl group include the same lower alkyl groups as mentioned above, and examples of the aryl group include phenylene or benzolcarene acid groups.

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

(A) Law - The following formula (Rei) oon However, in the formula, R represents a lower alkyl group, A represents S or SO, duck represents l or snow, and * represents an asymmetric carbon atom. An annocaronic acid compound represented by the following formula (), where RS represents a lower alkyl group, a penzol group, and Cal represents an xy-lower alkyl group or a xy-aryl substituted lower alkyl group.

愼 indicates O or l, and The jar shows an asymmetric carbon atom.

A method of reacting a mercaptobenzyl fatty acid represented by the formula or its reactive derivative.

(B) Hosetsu- The following formula (1’) However, during the ceremony.

R1 represents a lower alkyl group.

A indicates S or SO.

Sensei indicates O or L.

Duck indicates 1 or 2, and * indicates an asymmetric carbon atom. A method of treating a mercaptobensyl fatty acid derivative represented by the following with acid or alkali.

(C) Noritomi- The following formula (11) However, during the ceremony.

R8 represents a lower alkyl group, A indicates S or SO snow.

愼 indicates O or l.

A mercaptobenzyl fatty acid enzyme conductor or an alkali metal salt thereof represented by the following formula (f) Rτ-X
(&) However, in the formula, Rτ represents a lower alkyl group, a car-xyalkyl group, or car represents a xyaryl group.

X represents a hydrogen atom.

A method of reacting a compound represented by

In the present invention, in the above method (A), in the above formula (1), R8 is Rz of the formula (1'), that is, a lower alkyl group,
The above formula (I
') Suitable for the production of mercaptobenzyl fatty acid derivatives and salts thereof.

When carrying out method (A) above in the present invention.

The reaction can be carried out using reactive derivatives of mercaptobenzyl fatty acid of formula (1), such as active esters of mercaptobenzyl fatty acid of formula (1), #! Examples include dianhydride, acid hacylinide, and the like. The first reaction can also be carried out in the presence of an appropriate activator.

When carrying out the reaction in the form of a mercaptobenzyl fatty acid (formula), it is particularly preferred to carry out the reaction in the presence of such an activator.

Examples of such active esters include cyanomethyl ester, p-nitrophenyl ester, p-nitrophenyl ester, IJ dichlorophenyl ester,
Pentachlorophenyl ester, N-hydroxyphthalic acid ester.

N-hydroxysuccinic acid ester, 8-hydroxyquinolyl ester, 2-hydroxyphenyl ester, 2-m-human-xibilisol ester.

Examples include 2-pyridolthiol ester. Moreover, as the above-mentioned acid halide.

Preferred examples include acid chloride and acid chloride. Further, a preferable example of the above-mentioned activator is N,N-dicyclohexylcarbucciimide.

(A) Method OII is applied to a compound of the formula (1) Adenocalline in the presence or absence of an activating agent and a compound of the formula (厘) mercagutopenzyl fat* [or its reactivity]. The reaction temperature at which the derivative is reacted can be selected as appropriate, and may be, for example, about -5°C to about ao°C, more preferably about 10°C to room temperature.

The reaction can be carried out in a solvent (if desired).

Such solvents include, for example, tetrahydrofuran,
For example, ether glues such as nooxane.

Esters such as ethyl acetate and inamyl acetate II4! For example, IV, N-dimethylformand, N-methyl-2-pyrrolidone, N,N-dimethylacedooxide, etc.ON-alkylands 1Other Vmethylsulfoxide, hexamethylphosnenylamide, water, etc. Examples of appropriate solvents include those that can be used alone or in combination.

In addition, the reaction can be carried out in the presence of an alkali if necessary, and in particular when an acid anhydride or an acid halide is used as the reactive fs conductor of the mercagtopensol fatty acid of the above formula (1), the reaction can be carried out in the presence of an alkali. For example, it is preferable to carry out the reaction in the presence of an alkali such as sodium hydroxide, potassium hydroxide, or sodium carbonate.

The compound of formula (1) and the compound of formula (seal) react stoichiometrically, but these two components do not necessarily have to be present in the reaction yarn in an exact relationship, and the ratio of the two components is They can be appropriately selected depending on the combination of and other conditions to obtain good results.

The formula of the present invention (one of the mercaptopenyl fatty acid complexes) obtained by the above-mentioned 5K process can be neutralized if necessary, and can be processed by means known per se, such as extraction, dissolution, various chromatographies, etc. Crystallization, precious crystals.

Akane is obtained by isolating or purifying by appropriately selecting or combining means such as external precipitation.

The compound of formula (■') of the present invention obtained by K in this way is
Can form salts with bases. Examples of such salts are ammonium salts, alkali metal salts such as sodium and potassium salts.

Examples of alkaline earth metal salts include calcium salts, magnesium salts, and amine salts.

The salts of the mercagutopene V fatty acid derivatives of formula (1') of the present invention are preferably physiologically acceptable salts such as those exemplified above.

In the present invention, the above method (B) is based on the above formula (1') in which R3 in the above formula (1) is a hydrogen atom shown in the formula (1').
:) Suitable for the production of conductors for mercagut fatty acids.

In the present invention, when implementing the above CB) method, the above formula (1) is
Mercaptopenzole fatty acid or its alkali metal salt in which 1 is a benzoyl group is reacted with the formula (1).
A mercaptopencil fatty fermentation conductor represented by the above formula (1) in which 81 is a benzoyl group is formed, and this is treated with a t-acid or alkali to convert the benzoyl group into a hydrogen atom.

In this embodiment, the compound of the formula (1) used as the raw material compound can be obtained by reacting the compound of formula (1) used as the raw material compound in the method (A) with 2-penzyl-S-benzoylthio fatty acid, This reaction is described above (A
) can be done legally.

To convert a benzoyl group in a compound to a hydrogen atom to form a compound of formula (1), for example, treatment with metallic sodium in the presence of liquid ammonia or a %-exhausted solvent, In liquid media such as water, methanol, ethanol, acetic acid, inorganic acids such as hydrochloric acid, hydrobromic acid, or sodium hydroxide, potassium hydroxide, sodium hydroxide, ammonia, methylamine, ethyl acetate, etc.
hmm.

It can be removed by reacting with an alkali such as trimethylammonium, hydrazine, hydra V hydrate, sodium methylate, etc. at a temperature of, for example, about -5°C to about 80°C. During this reaction, % under nitrogen atmosphere.
Alternatively, it is preferable to carry out under a hydrogen atmosphere.

The formula (1 mercaptopenyl fatty acid derivatives) of the present invention obtained by removing the benzoyl group from the compound of formula (1#) in this way is neutralized if necessary, and as in Method A, Means, for example, extraction, dissolution, various chromatography, crystallization, recrystallization, reprecipitation, etc., are appropriately selected or combined to form a single or 'III
It can be made from t.

Furthermore, if necessary, physiologically acceptable salted rice cakes can be produced in the same manner as in Method A.

In the present invention, the above CC) method uses 8 in the above formula (1).
Suitable for the method for producing mercaptopenyl fatty acid derivatives of the above formula (L'') where 1 is the formula (Rτ of 1), that is, a lower alkyl group, a carboxy lower alkyl group, or a carboxy-aryl substituted lower alkyl group It is.

When carrying out the above method (C) in the present invention.

The above formula (1) in which R1 is a hydrogen atom
It can be carried out by reacting the mercaptopentyl fatty acid derivative represented by ') with the compound represented by the above formula (W).

In this embodiment, the above formula (one compound -
can be obtained, for example, by the above method (B). In carrying out the method (C), one reaction can be carried out as desired, and examples of the solvent include alcohols such as methanol and ethanol. Ethers such as tetrahydrofuran and dioxane, halo-substituted hydrocarbons such as methylene chloride and chloroform, etc. #4 + such as N,N-dimethylformand, N-
N-alkylamides such as methyl-2-pyrrolidone, N,#-dimethylacetoand, nitriles such as acetonitrile, aromatic hydrocarbons such as benzene and toluene, and other pyrrolidines.

Examples include water, and these appropriate solvents may be used alone or in combination.

The reaction may be carried out with, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, metrilam methylate, or sodium ethylate.

The reaction temperature, which can be carried out in the presence of a deoxidizing agent such as triethylamine, can be selected as appropriate.

For example, from about 150°C to about 150°C, more preferably from room temperature to about 1
Let us exemplify a reaction temperature of 00°C.

The compound of formula (1') and the compound of formula (l) react stoichiometrically, but these two components do not necessarily have to be present in the reaction system in equal amounts, and the quantitative ratio of the two components depends on the raw materials. They can be appropriately selected depending on the combination of and other conditions to obtain good results.

The formula (* ##) mercaptopenyl fatty acid derivatives of the present invention thus obtained can be neutralized if necessary;
Similar to method A, means known per se, such as extraction,
Transferred, various black 1 thornfish.

Isolation or expression can be carried out by appropriately selecting or combining means such as crystallization, recrystallization, and reprecipitation.

If necessary, physiologically acceptable salted rice cakes can also be produced in the same manner as in Method A.

The target compound of formula (1) which can be obtained as described above, for example, by method (A), method (B) or method (C), has 0 asymmetric carbon atoms.

This is shown in the above formula.Therefore, the compound of the present invention (1) can exist as Fi diastereo!- or as a racemate.In the present invention, formula (1) is an expression including these. It is.

The compound of formula (1) of the present invention is angiotensin isolated from the lungs of domestic rabbits! When the enzyme inhibitory effect was tested using Hypri-L-Histidyl-L-Leucine as a substrate, it showed an excellent inhibitory effect on aygiotensin convertase. It is useful as a treatment agent for diseases.

Furthermore, when the compound of the present invention is administered to rats with D-galactosaone-induced hepatitis, the serum GOT and GPT values are significantly reduced. From this, the compounds of the present invention are also useful as agents for treating liver diseases.

Example 1 N-[2-benzyl-3-(ethylthio)f4/mother/4
Preparation of S-methyl-L-cysteine & 41N, IN-sodium hydroxide 4011j and ether 40-, 2-penzol-3-(ethylthio)pro/4-noyl Chloride%
L71N and IN-sodium hydroxide 40-5 to 1
While stirring at 0° C., the mixture is added dropwise alternately while maintaining weak alkalinity. After finishing the descent, stir overnight at room temperature. The aqueous layer is separated and made strongly acidic with hydrochloric acid, the resulting oil is extracted with ethyl acetate, the ethyl acetate layer is washed with saturated brine, and dried over magnesium hydroxide. The residue after evaporation of the solvent was purified by silica column chromatography (benzene-ethyl acetate) to give N-[2-benzyl-3-(ethylthio)lobanoyl]-8-methyl-L-cystine 9L911. obtain. (
)! -) Melting point 1 (1-7°C (ethyl acetate) 154! The following compound is obtained in the same manner as in Example 1.

ON-IJ-benzyl-3-(ethylthio)gropanoyl]-8-ethyl-L-cystine melting point 9G-9T°C Q N-[2-benzyl-3-(methylthio)gropanoyl]-8-methyl-L-cystine melting point 61- 69
' 54G Q#-[2-benzyl-3-(methylthio)gropanoyl]-8-ethyl-L-cysteine Melting point 86-87°C l 530 Example 2 N-(3-benzoylthio-2-pene Vrugropanoyl) )-8-ethyl-L-cysteine S-ethyl-L-
cysteine IL9j to IA/-sodium hydroxide 80-
and ether 80-, 3-peydiylthio-2-benzylpropanoyl chloride l'LS & and 1N-sodium hydroxide 80- was added at 5 to 10°C with stirring and while maintaining the slightly alkaline state, alternating Km After completing the addition, stir overnight at room temperature. Extract with ether, make the aqueous layer strongly acidic with hydrochloric acid, extract the resulting oil with ethyl acetate,
Wash the ethyl acetate layer with saturated brine.

Dry with anhydrous 4IIL#R magnesium. The residue after removal of the solvent was purified by silica column chromatography (benzene-ethyl acetate) to obtain N-(3-benzoylthio-2
-Pendylptetrapanoyl>4-ethyl-L-cysteine! Obtain lLO# (I11chi).

Melting point '16-'19℃ 1! ! 20,110 The following compound is obtained in the same manner as in Example 2.

1! 515,1290,1115,110@ON-(3
-pensoylthio-2-benzylprotanoyl)-D
L-Ethionine Melting point 15B-157℃ 1595.1B40,890 ON-(3-Pensoylthio-2-PeneVlup163I
, 1515, 1290, 1110°911 Q#-(a-benzoylthio-2-pencylpro-14noyl)-8-ethyl-L-cystine sulfone Melting point 144-14°C 1650, Is! 2,1!80,1108°98 ON-Cm-benzoylthio-2-benzylpropanoyl)-8-methyl-L-cystine Colorless oil 162! O, @O1l ◎ #-(i-benzoylthio-lazy-pencil pro 74
(noyl)-8-methyl-L-cystine sulfone
Melting point 11s8-162℃ 1835.152!0.1g80,1110゜■] Example 3 N-(!-Pen V Roux 3-Mercagtogropanoyl)-
Preparation of 8-ethyl-L-cysteine N-(3-pensoylthio-2-benzylpropanoyl)-8-ethyl-L
-Sistine! 7.6JFt Methanol 30- and 2
8% ammonia water was dissolved in 4011JK of water and stirred at room temperature for an hour. The reaction solution was concentrated under reduced pressure to remove methanol, water was added, and the mixture was extracted with ethyl acetate. The aqueous layer is made strongly acidic with hydrochloric acid, saturated with common salt, and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated brine and then dried over anhydrous magnesium sulfate. The residue after solvent distillation was purified by silica dull column chromatography (benzene-ethyl acetate) to give N-(2
-benzyl-3-)lkkabudob ■panoyl)-8-ethyl-L-cysteine 1171 (@!-) is obtained.

Melting point 0-7! 'C tss.

The following compound is obtained in the same manner as in Run @8.

(p) #-(1-henzyl-3-merkagtopwapanoyl)-L-methionine melting point 14B-14it t@B! , 1640 ◎ N-(2-penzol-3-mercaptopropanoyl)-L-methionine sulfone Melting point 10G-11g°C 11140, 1520 m 1290, 11
20ON-C2-benzol-3-mercap)flonoyl)-DL-ethionine melting point 11g-1111"C 1635,1540 ON-C2-benzol-3-mercazoto!-arm/4l)-DL-ethionine sulfone Melting point 109-118℃ 1640.1580.1310.11!OQ N-(
2-benzyl-3-mercapto (benzyl)-8-
Ethyl 9L #cysteine sulfone Melting point approximately 80℃ 17 fl 5 e 1640 g Z 530 e
l! 90 t12G to 9A/-(!-benzo-3-mercapdoglobanoyl)-8-methyl-L-cystine colorless oil 1840.11! ! 5 ON-Ct-PenVk-3-11L'KaftofHAnoyl)-8-Methyl-L-cysteine sulfone Melting point 14mer 151"c isag, tsso, itfu 0.1110 Example 4 A/7 [: Preparation of 2-benzyl-3-(cargoxymethylthio)f■panoyl]-8-methyl-L-cisnine N-C2-penzol-3-mercaptopropanoyl)-
1.5 fl of 8-methyl-L-cysteine and 2.1 fl of monochloroacetic acid a4phyt-potassium! ! ilj
Add to the aqueous solution and stir overnight at room temperature.The reaction solution was made strongly acidic with hydrochloric acid, extracted with ethyl acetate, and washed with saturated brine.
Dry with anhydrous magnesium acetate. The solvent was distilled off, and the residue was purified by silica glu column chromatography (benzene-ethyl acetate) to give N-[2-penzol-3-(cargoxymethylthio)prepanoyl]-8-methyl-L-cysteine. (A) (141i# and its stereoisomers (B
)alTj.

(A) Electrical melting point 1!1-1!3℃ (ether-hexane) Elemental analysis s Calculated value C as CiB H@NO6SB
,51,73龜H,5,,'rOkNL Mamachi real column value C
,5L6? sH, &791#&? 5l11@40,16
38 NMR (MtrOH-d, + CDCLs) δ5ttt
(sff;s.

S, CH,),! ? -&0(IH,s), &2-L4(
3B, 愼) 1 Table 68 (IH, t, J, = 6H dew), 7.
11 (iB, s, aromatic water 1g) ME s/at 3F1 (M”) CB) Electrical melting point! 114-111'c (ether-hexane) Elemental analysis tcmH, Calculated value as 81 to N, C, !II 1. τsth, t'ro 蟇N, 龜i
Fu plus side value c, 5tsssB, at meaning N, &? m! 111 NMR (Mmoll-44+CDCL, )J t 1
．． 96 (1#, a.

S, CB Lu), is ・ (!g, d, Jz
6Hm) g! II (4B, a), 11! -s,
, 4 (1M, s).

tie(tH,t,Jm@Bg),? ,! i! (i#.

a, aromatic hydrogen) MS ina/13th t(At”) The following compound is obtained in the same manner as in Example 4.

ON-[-benzo-3-(cal&mid-dimethylthio)propanoyl-8-ethyl-L-cysteine (A) and its stereoisomers (J) 1720.11140.158
0 8-dicyclohexylamne salt tM point 1tl-241 ct layer 133110.1722.1 Ding oo.

1642.1530 ON-[-benzyl-3-(l-calxyethylthio)ppanoyl]-8-ethyl=L-cysteine 1636.1510 2-Potassium salt I Melting point 155-165℃◎ N-[2-
Benzol-3-(l-calxyethylthio)gulonoyl]-8-methyl-L-cysteine 11138.1!130 2-potassium salt g Melting point 1 g! -111i℃ON-[R-
Beni/Nru B-(M-1ypy-M*'/Pen v Ru?
#) 7" (d-noyl) S-ethyl-L-cystine 1833, IM!!! g-1/cyclohexylamine salt l melting point 128-132
℃ ◎ N-[2-benzo-3-(a-cal-xybenzylthio)crocnoyl)-8-1f-L-cysteine 1@8ji, 15[2-dicyclohexylamone salt 1m point xgo-130℃ ON- C2-Benzol-3-(2-carxyethylthio)crocnoyl)-8-ethyl-L-cysteine l・40.1510 2-disycvhexyluaquine salt tMA100-106℃ (gN-[2-Benzol-3- (2-calxyethylthio)f-panoyl)-8-)f-L-cysteine Melting point 10G-102°C 530 Example 5 Preparation of N-(proverb-(1-calfoxy3-phenylprostein) Procedure of Example 4 Using fiKN-(2,mercaptopropanoyl)-8-methyl-L-cysteine instead of N-(2-pentrue-3-mercaptofcl,l-menoyl)-S-)t-thyl-1°-cysteine in In place of cool acetic acid, 2-bromo-4-phenylbutanoic acid [boiling point 1-0-171"C (1)] was used and treated in the same manner to obtain a colorless oily substance, N-Cz-(i-calI). Kissy 3-
Phenylglopylthio)faA)yl]-s-methyl-L-cysteine was obtained, which was converted into a dicyclohexylyatron salt by a conventional method and recrystallized repeatedly from a mixed solvent of ethyl acetate and methanol to obtain a compound with a melting point of 1 g 1 l-1711. The dicyclohexylamine salt of the title compound is obtained at . Colorless crystal.

Elemental analysis s C, H, NO, S, ・2C,, calculated value as HuN 寞c, stag 蓼H1甑ao8#, 562-夷醐value zero G, 4! ! L@11M, 9.45 N, 5■1 Example 6 Production of #-(2-(1-carlxy-3-phenylpropylthio)gulonoyl)-8-ethyl-L-cysteine Example 5 In place of N-(2-mercaptopropanoyl)-8-methyl-L-cysteine in the procedure of
#-(2-(1-carboxy-3-phenylpropylthio)furonoylthio)-
A dicyclohexylamine salt of 8-ethyl-L-cysteine is obtained.

Colorless crystal.

1 point 180-190℃
tsgo.

ri’1411j1

Claims (1)

[Claims] 1. The following formula (S) OOH, provided that in the formula. R1 is a hydrogen atom, a lower alkyl group, a benzoyl group, a xy lower alkyl group or a xyaryl-substituted lower alkyl group, k is a lower alkyl group, and A is the amount of S or SO. Indicates 0 or 'il. Deaf indicates 1 or 2, and * indicates an asymmetric carbon atom. Mercaptopenzyl fatty acid derivatives and their salts represented by: 2 Formula (1) below, where R represents a lower alkyl group, A represents S or 11SO, 悌 represents 1 or 8, and * represents an asymmetric carbon atom. . A 7-chamber noripunshun compound represented by the following formula (), where: R% represents a lower alkyl group, a benzoyl group, a carboxy lower alkyl group, or a carboxy-aryl substituted lower alkyl group. Inertia represents O or l, and * represents an asymmetric carbon atom. The following formula (I) is reacted with a mercaptobenzyl fatty acid represented by
') However, in the formula, R', , E, , A, m, n and * have the same meaning as 9 above. A method for producing a mercaptopencyl fatty acid enzyme conductor and its salts. Tortoise The following formula (1') COOH (Tomi) However, in the formula. R1 represents a lower alkyl group. A represents S or SO. Sensei indicates O or L. % indicates 1 or snow, and * indicates an asymmetric carbon atom. Mercaptopencil fat expressed as #! The four specialized classes,
The following formula (which is characterized by acid or alkali treatment)
I#) COOH However, in the formula. R, A, tn, s, and pot are as defined above. A method for producing mercagutopenzyl fatty acid sieve conductors and salts thereof. Table The following formula (1') COOH However, in the formula. R8 represents a lower alkyl group. A represents S or SO. Sensei indicates 0 or l. The negative indicates l or 2, and the pot indicates an asymmetric carbon atom. Mercaptopencyl fatty tltvj conductors or their alkali metal salts represented by the following formula (W) Rτ-
X (1/) However, in the formula. Rτ is a lower alkyl group, a carboxy lower alkyl group, or a carboxy-aryl substitution. It represents a lower alkyl group, and X represents a halodane atom. Rτs ”@ * As collection 1% and Qin Ifi, the same meaning as above. A process for producing mercagtopene adipose derivatives and salts thereof.