FR2467198A1 - MERCAPTOACYL AMINO ACID DERIVATIVES SUBSTITUTED ON SULFUR ATOM BY A-AMINO OR A-IMINO GROUP WITH PROTECTED NITROGEN ATOM - Google Patents

Abstract

Compound of formula: (CF DRAWING IN BOPI) in which R2 is a hydrogen atom or an alkyl or trifluoromethyl radical; n is 0 or 1; A1 and A2 are each an alpha-amino acid or alpha-imino acid residue, the A1 residue being linked to the R5 group by its alpha-amino or alpha-imino group and linked to the sulfur atom by its carboxyl group, and the remainder A2 being linked to the adjacent carbonyl group via its alpha-amino or alpha-imino group; and R5 is a protecting group for the nitrogen atom. These compounds can be used as intermediates for the preparation of corresponding aminoacylated derivatives, with antihypertensive action.

Description

Derivatives of mercaptoacyl amino acids, substituted on the sulfur atom

  by a C-amino or O-imino protected nitrogen group. The compounds of formula:

I 12

  R-A1-S- (CH2) n -CH-C-A2O10, and their alkyl esters and salts thereof, are inhibitors of the action of the

  angiotensin, and can be used to treat hypertension.

  voltage. In formula I, and throughout the specification, the symbols have the following definitions: R 1 is a hydrogen atom or an alkanoyl or benzoyl radical; R2 is a hydrogen atom or an alkyl or trifluoromethyl radical; n is 0 or 1; and

  A1 and A2 are each a residue of α-amino acid or α-

  imino-acid, the remainder A being linked to the group R1 by its aamino or E-imino group and being bonded to the sulfur atom by its carboxyl group, and the remainder A2 being joined to the

  adjacent carbonyl group by its α-amino group or a-

imino.

  The term "alkyl" as used throughout the specification refers to groups having

from 1 to 7 carbon atoms.

  The term "alkanoyl" as used throughout the specification refers to a] canoyl groups having from 2 to 7 carbon atoms. The acetyl radical

  is the preferred alkanoyl radical.

  The residues of α-amino acid and α-imino acid which are represented by A1 and A2 can be either of natural origin or synthetic. Exemplary groupings are the remains

  proline, 4-hydroxyproline, 4-chloroproline, 4-

  fluoroproline, 4,4-difluoroproline, 4,4-ethylenedioxy-

  proline, 4-methoxyproline, 4-thiazolidinecarboxylic acid, tryptophan, glycine, alanine, leucine, isoleucine,

valine and phenylalanine.

  The preferred compounds of formula I are those which correspond to the formula: ## STR2 ## ## STR2 ##

0 O

  as well as their alkyl esters and their salts. In formula II, and throughout the specification, R3 is hydrogen or fluorine and R4 is hydrogen, hydroxy or methoxy, chlorine or fluorine, or united to the carbon atom to which they are attached,

  R3 and R4 form an ethylenedioxy group.

  Compounds of formula I in which the aamino or α-imino residues of A1 and A2 are in the range are also preferred.

laevorotatory configuration (L).

  The products of this invention can be prepared by first reacting an α-amino acid or α-imino acid (protected nitrogen atom) having the formula: III R5-A1 with a mercaptoacyl amino acid having for formula: IV R12HHS- (CH2) n-ClH-A2,

O

  or with an alkyl ester of this acid. The R5 group protecting the particular nitrogen is not critical; are exemplary of the known protective groups

  tert-butyloxycarbonyl, benzyloxycarbonyl and ortho-nitrophenyl-

  sulfenyl. Any other nitrogen protecting group can also be used which can then be removed under mild conditions provided that it protects against

  racemization of A1 during the activation step described above.

  below. The group R5 may of course also be an alkanoyl or benzoyl radical as defined by R 1, although these groups are not considered protective groups in that they are not as easy to remove as the above mentioned protective groups and that they can not offer protection against racemisation. The above reaction yields a compound having the formula

V R

  R5-A-S- (CH2) n-CuI-ClA2 or an alkyl ester thereof, and is carried out by first activating the carboxyl group of a compound of formula III, with the aid of a procedure recognized in the art. For example, activation may be by reaction of a compound of formula III with N, N'-carbonyl-bis-imidazole

  or with a mixture of base and alkyl chloroformate.

  The reaction of a compound of formula III (activated carboxyl group) can be carried out in an organic solvent, for example a halogenated hydrocarbon, preferably in the presence of an organic base. The conditions of the reaction are not crucial, and the reaction can very well be conducted at the

ambient temperature.

  The R5 blocking group of a compound of formula V can be removed using a procedure known in the art to yield the corresponding product of formula I wherein R 1 is a hydrogen atom. The products of formula I in which R 1 is an alkanoyl or benzoyl radical can also be prepared from a product in which R 1 is a hydrogen atom, by reacting the latter with the alkanoic acid anhydride or the benzoyl halide

appropriate, as the case may be.

  The starting materials of formula IV, as well as their methods of preparation, are described in the literature see, for example, U.S. Patent Nos. 4,046,889, 4,105,776 and 4,053,651. As described here, one can condense a

  α-amino acid or α-imino acid (A2) with a haloacid

alkanoic compound of formula:

VI R

12

X- (CH2) -CH-1-OH

  wherein X is a halogen atom, preferably chlorine or bromine, by one of the known procedures according to which the acid of formula VI is activated prior to its reaction with A2 acid; which involves the formation of a mixed anhydride, a symmetrical anhydride, an acid chloride, an active ester, or the use of the reagent K

  Woodward, EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydro-

  quinoline) or a similar reagent. The product of this reaction is a compound of the formula: ## STR1 ## by subjecting a compound of formula VII to a displacement reaction with the anion of a thioacid of formula:

VIII ,,

R6-C-SH

  in which R 6 is an alkyl, aryl or arylalkyl radical, a compound of formula: IX o R II 2 is obtained

R6-C-S- (CH2) -CH-C-A2

  which can then be converted into the mercapto compound of formula IV by ammonolysis. The technique also reveals several other processes for preparing the compounds of

formula IV.

  Depending on the nature of the substituents R, the products of formula I may have one or more asymmetric carbon atoms, and therefore exist in forms

  stereoisomers or in the form of racemic mixtures.

  All these forms fall within the scope of the invention. In the syntheses described above, one of the enantiomers or the racemate can be used as starting material. When the racemate is used as starting material, the stereoisomers obtained in the product can be separated by conventional techniques, by

  for example by chromatography or by fractional crystallization.

  The following examples are embodiments

specific features of the invention.

EXAMPLE 1

  (S) -1- [3 - [(1-Acetyl-L-prolyl) thio] -2-methyl-1-oxopropyl] -L-

proline

  A) (S) -1- [3- [1- (t-Butyloxycarbonyl) -L-prolyl] thio] -2-methyl-

  1-oxopropyl] -L-proline 1.290 g of (tert-butyloxycarbonyl) -Lproline in 10 ml of dichloromethane are taken up by stirring in an ice bath, 972 mg of N, N'-carbonyl-bis-imidazole are added. end of a

  hour, 1.085 g of (S) -1- (3-mercapto-2-methyl-1-

  oxopropyl) -L-proline in 5 ml of dichloromethane and 0.7 ml of

2467198-

  triethylamine. After another hour, the ice bath is removed and the reaction allowed to proceed for about 16 hours at room temperature. The dichloromethane is removed in vacuo and the residue is taken up in ethyl acetate and then washed with 10% potassium sulfate to give 2.4 g of product. This product is purified in a silica gel column which is eluted with a 200: 37 mixture of ethyl acetate and buffer (the buffer is a 20: 6: 11 mixture of pyridine, acetic acid and the like). of water). The combined fractions are taken up in ethyl acetate and washed with 10% potassium sulphate to give 1.8 g of

composed of the title.

  B) (S) -1- [3 - [(1-Acetyl-L-prolyl) thio] -2-methyl-1-oxopropyl] -

  L-proline is treated for 15 minutes at room temperature

  1.8 g of (S) -1- [3 - [[1- (tert-butyloxycarbonyl) -L-

  prolyl] thio] -2-methyl-1-oxopropyl] -L-proline in 5 ml of trifluoroacetic acid and 5 ml of anisole. The reaction mixture is concentrated in vacuo and treated twice with a mixture of ether and hexane. The residue is dried over potassium hydroxide in vacuo and acetylated in 10 ml of anhydrous pyridine with 0.41 ml of acetic anhydride for two hours. The reaction mixture was concentrated in vacuo, the water removed twice, and the residue freeze-dried. Purification on a sulfonated polystyrene cation exchange resin, using water as eluent, followed by crystallization from a mixture of ethyl acetate and ether gives 700 mg

  of the title compound, mp 81-83 ° C.

EXAMPLE 2

  (S) -1- [2 - [(1-Acetyl-L-prolyl) thio-l - oxopropyl] -L-proline

  A) (S) -1- [2 - [[1- (tert-butyloxycarbonyl) -L-prolyl] thio] -1-

oxopropyl] -L-proline

  1.075 g of (tert-butyloxycarbonyl) -L-

  proline in 10 ml of dichloromethane and cool with

  stirring in an ice bath; 810 mg of N, N'-

  carbonyl-bis-imidazole. After one hour, 1.015 g of S-1- (2mercapto-2-methyl-1-oxopropyl) -L-proline in 5 ml of dichloromethane and 0.7 ml of triethylamine are added. After another hour, the ice bath is removed and the reaction allowed to proceed for about 16 hours at room temperature. The mixture is concentrated in vacuo, taken up in ethyl acetate and washed with 10% potassium sulfate to give 2.0 g of product. This product is purified in a column of silica gel, which is eluted with a 120: 20: 6: 11 mixture of ethyl acetate, pyridine, acetic acid and water, and The mixture is crystallized from 1: 2 ethyl acetate / hexane to give 1.076 g of the title compound.

melting 143-144 C.

  B) (S) -1- [2 - [(1-Acetyl-L-prolyl) thio] -1-oxopropyl] -L-proline is stirred for 15 minutes at room temperature.

  1.076 g of (S) -1- [2 - [[1- (tert-butyloxycarbonyl) -L-

  prolyl] thio] -1-oxopropyl] L-proline per 5 ml of trifluorinated acid

  acetic acid and 2 ml of anisole. The reaction mixture is concentrated in vacuo and treated twice with a mixture of ether and hexane. The residue is dried over potassium hydroxide under vacuum and acetylated for 2.5 hours in 5 ml of anhydrous pyridine with 0.23 ml of acetic anhydride. The reaction mixture was concentrated to dryness in vacuo and lyophilized in water. Purification on a sulfonated polystyrene cation exchange resin followed by

  lyophilization gives 700 mg of the title compound.

EXAMPLE 3

  (s) -1- [2-r (N-Acetyl-L-phenylalanyl) thio-1-oxopropyl] -L-

proline

  A) (S) -1- [2- [N- (tert-Butyloxycarbonyl) -L-phenylalanyl] thio] -

1-oxopropyl] -L-proline

  1.325 g of (tert-butyloxycarbonyl) -L-

  phenylalanine in 10 ml of dichloromethane and cooled with stirring in an ice bath; 810 mg of N, N'-carbonyl-bis-imidazole are added. After one hour, 1.015 g of (S) -1- (2-mercapto-1-oxopropyl) -L-proline in 5 ml of dichloromethane and 0.7 ml of triethylamine are added. After another hour, the ice bath is removed and the reaction allowed to proceed for about 16 hours at room temperature. The mixture is concentrated in vacuo, taken up in ethyl acetate and washed with 10% potassium sulfate to give 2.3 g of product. This product is purified in a column of silica gel which is eluted with a mixture of ethyl acetate and buffer (the buffer is a 20: 6: 11 mixture of pyridine, acetic acid and water) and crystallized from a mixture of ether and hexane to give 1.553 g of the title compound, m.p.

59-62 C.

  B) (S) -1- [2 - [(N-Acetyl-L-phenylalanyl) thio] -1-oxopropyl] -

  L-proline is treated for 15 minutes at room temperature

  1.553 g of (S) -1- [2 - [[N- (tert-butyloxycarbonyl) -L-

  phenylalanyl] thio-1-oxopropyl] -L-proline, with 6 ml of trifluoroacetic acid and 3 ml of anisole. The reaction mixture was concentrated in vacuo and the residue triturated with ether to give 1.1 g of product. This product is acetylated for two hours at room temperature in 6 ml of anhydrous pyridine with 0.28 ml of acetic anhydride, concentrated in vacuo, the residue is taken up in ethyl acetate and washed with ethyl acetate. potassium sulfate 10%. The organic layer is dried and concentrated to dryness in vacuo. The residue is crystallized from ethyl acetate, which

  gives 600 mg of the title compound, mp 191-192 C.

EXAMPLE 4

  (S) -1- [3 - [(1-Benzoyl-L-prolyl) thio] -2-methyl-1-oxopropyll-L-

  By replacing acetic anhydride with benzoyl chloride in the procedure of Example 1, we obtain

the title compound.

EXAMPLE 5

  (S) -1- [3 - [(1-Acetyl-L-tryptophyl) thio] -2-methyl-1-oxopropyl-L

  proline By replacing tert-butyloxycarbonyl-L-proline with tertbutyloxycarbonyl-L-tryptophan in the procedure

  of Example 1, the title compound is obtained.

EXAMPLE 6

  (S) -] - [3 - [(1-Acetyl-L-isoleucyl) thio] -2-methyl-l-oxopropyll-L-

  proline By replacing tert-butyloxycarbonyl-L-proline with tertbutyloxycarbonyl-L-isoleucine in the procedure

  of Example 1, the title compound is obtained.

EXAMPLE 7

  (S) -1- [3- (1-Acetyl-L-phenylalanyl) thio].-2-methyl-1-oxopropyl] -L-4,4-ethylenedioxyproline By replacing tert-butyloxycarbonyl-L-proline with

  tert-butyloxycarbonyl-L-phenylalanine and S-1- (3-mercapto)

  2-methyl-1-oxopropyl) -L-proline by S-1- (3-mercapto-2-

  methyl-1-oxopropyl) -L-4,4-ethylenedioxyproline in the

  procedure of Example 1, the title compound is obtained.

EXAMPLES 8-28

  Following the procedure of Example 1, but replacing tertbutyloxycarbonyl-L-proline with the derivative

  amino acid indicated in column I below and (S) -1-

  (3-mercapto-2-methyl-1-oxopropyl) -L-proline by the compound indicated in column II below, the compound is obtained.

  indicated in column III below.

  As they are used below, the symbols

  "Boc" and "Ac" refer respectively to the tert-butyl radicals

  oxycarbonyl and acetyl. Other symbols are conventional. T column Boc-Gly Boc-Val Boc-Phe Boc -Ala Boc-Leu Column II CH s

1 3 5

HS-CH2CHCO-N C02H

CH (S

1 3 0

HS-CH2CHCO-N C02H

CH, S

13 5

  HS-CH2CHCO-1n C02H CF Cl3 to HS-CH2-CEiCO-N O2H CCH

CH 3

1 30 C

  HS-CH 2 -CiCO-N O2 i Column III CHA 1 3 Ac-Gly-SCH2CHCO-N I C02H

CH S

1 3 r Ac-Val-SCH2CHCO-N O 2H

2-

CH Ss

IH3 3 S '

Ac-Phe-S-CH2CHCO-N-CO 2H

CF -N.

1 3 L

Ac-Ala-S-CH2CHCO-N-CO H

2 2

  OCH3 Ac-Leu-S-CHCO-N 2 Ac-Leu-S-Cyl 2CHiCO-N ---- 2H

Example

he -. CD lo Co 4t

H QODq ---- DH-SK -

  Hz0z HEOD - Oy DHD HD-S-Iqd-DV ID HzOD-N-ODHDzHHD-S-Gtq -DV

IH IOú I

H H HO HzOD-.-- O O DHDHD-S-elI-DV

I E I

  H <HH zOD-r --- O) HD HD-S-DV HI ooHD III auuOloD H zOD rN-O DHD-SH EH OD r -ODHZ zHD-SH ID H QD ú-ODH z HO H zOD- DHD ZHD-SH Et.1 aa H zOD N-OD-HD-zHD-SH I oEHD II aUUO [D) LI IF qIad-DOo Gtld- 0oo ú1 I GUUOTOD lwu o c'N "-l -'1 Column II 1H3 rs

HS-CHCO-N- CO2H

F-q 0 0 CH3 0

HS-CHCO-N CO2H

O-i

CHO -

  ## STR5 ## 3C Ac-Trp-S-CHCO-N: Co 2 H Ac -S 2 Cl 2Co-: 2 Boc-Ala Boc-Leu Boc-Phe Boc-Trp Boc-Trp ro DC 'M)

Example

  Column I Column III Example Column I CH,

HS-CE H CO-N, H

C1 HS-CHCO-N Co2H CF3 r: LC

S-UUO-N IC02H

F CH3

1 3 -C

HS-CHCO-N O2H

F F CH

HsCHO-co

tib-UIoo-N: C 2 OH CH

CH3 1A

  Ac-Phe-S-CHCO-N- - CO2H Cl ClH3. hC02H

CF 3 C

  Ac-Val-S-umu-3 O 2 H Ac-1-S-CHCO-N. CO2H F Ac-Leu-S-CHCO-N. J CO2H CH 3Ac-Phe-S-CO-CO2 Ac-Phe-S-CpHCO-1Co02H Boc-Phe Boc-Val Boc-Ile Boc-Leu Boc-Phe Do 4S% o Co Column II Column-III HEOD- ----- DHD- Sd-1L- DV

H H

E 1 HD úHDO

III GUUOIOD

HZOD I -N-ODHD-SH

  I suoIoE I IIDO II BLtUOTOD dil-DOo

I GUUOIOD

o (3%% o -,

EXAMPLE 29

  (S) -1- [2- [(N-Actyl-L-trypptophyl) thio] -1-oxopropyl I-L-proline

  By replacing tert-butyloxycarbonyl-L-phenyl-

  alanine by tert-butyloxycarbonyl-L-tryptophan in the procedure of Example 3, the title compound is obtained.

Claims (1)

CLAIM   Compound of the formula: R2 R5-A 1 -S- (CH2) n-CH-C-A2 The   wherein R2 is a hydrogen atom or an alkyl or trifluoromethyl radical; n is 0 or 1; A1 and A2 are each a residue of amino acid or imino acid, the remainder A1 being linked to the group R5 by its grouping   0-amino or 0-imino and linked to the sulfur atom by its group   and the A2 moiety is attached to the adjacent carbonyl group by its "-amino or O -imino group;   and R5 is a protecting group of the nitrogen atom.