FR2468589A1 - AMINOACYLATED MERCAPTOACYL AMINO ACID DERIVATIVES WITH ANTIHYPERTENSIVE ACTION - Google Patents

Abstract

Compounds of formula:

Description

Aminoacylated derivatives of mercaptoacyl amino acids, active

  antihypertensive Formula compounds

I R2

  R1-A 1 -S- (CH2) n CH-C-A2O as well as their alkyl esters and salts 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 A1 being linked to the group R1 by its, aamino or a-imino group and being bonded to the sulfur atom by its carboxyl group, and the rest 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 alkanoyl 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 according to the invention are those which correspond to the formula: II R

R2 <N4-OH,

R1-A1-S- (CH2) n-CH-oH

O 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 R -A R5-A1 with a mercaptoacyl amino -acid having the formula: IV R

HS- (CH2) -CH-C-A

  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 can of course also be an alkanoyl or benzoyl radical as defined by R1, although these groups are not considered as protective groups in that they are not as easy to eliminate as the groups above mentioned protectors and that they can not offer protection against racemization. The above reaction yields a compound having the formula

R2

  R5-A-s-(CH2) n-CH1-C-A2 'or an alkyl ester of this compound, and is carried out by first activating the carboxyl group of a compound of formula III, using 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 R blocking group of a compound of formula V can be removed using a procedure known in the art to obtain 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 - (CH 2) n - CH - OH where 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 beforehand its reaction with the acid A2, 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 formula:

VII R

  X- (CH 2) n -CH-C-AO 2 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

  It 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.

  The compounds of this invention form basic salts with different organic and inorganic bases, which are also within the scope of this invention. These salts include ammonium salts, alkali metal salts such as sodium and potassium salts (which are preferred), alkaline earth metal salts such as calcium and magnesium salts, salts formed with organic bases, e.g. dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as arginine, lysine, and amino acids Similar. Nontoxic and physiologically acceptable salts are preferred, but other salts are also useful, for example to isolate or

purify the product.

  The compounds of formula I, as well as their esters

  and their salts, can be used as anti-

  hypertensives. They inhibit the conversion of a decapeptide, angiotensin I, to angiotensin II, and are therefore useful for decreasing or relieving angiotensin-induced hypertension. The action of an enzyme, renin, on angiotensinogen, a pseudo-globulin in blood plasma, produces angiotensin I. Angiotensin I is transformed by the angiotensin converting enzyme (ETA) into angiotensin II. The latter is an active presser that has been made responsible for various forms of hypertension in various species of mammals, rats and dogs, for example. The compounds of this invention are involved in the angiotensinogen - (renin) - angiotensin I - (ETA) - angiotensin II sequence by inhibiting the angiotensin converting enzyme and decreasing or suppressing the formation of the pressor product, angiotensin II . Thus, by administering a composition which contains at least one compound of formula I, angiotensin-induced hypertension is relieved in the mammalian species that suffers from it. A single dose, or preferably two to four staggered daily doses, administered at a rate of about 0.1 to 100 mg per kilogram of body weight per day, preferably from about 1 to 50 mg per kilogram of body weight and per day, is suitable for lowering blood pressure. The substance is preferably administered orally, but it is also possible to use parenteral routes such as the subcutaneous, intramuscular,

  intravenous or intraperitoneal.

  The compounds of formula I may be, in view of their use for the reduction of blood pressure, in the form of compositions such as tablets, capsules or elixirs for oral administration, or in the form of solutions or sterile suspensions for parenteral administration. About 10 to 500 mg of a compound or mixture of compounds of formula I are conditioned with a physiologically acceptable carrier, carrier, excipient, binder, preservative, stabilizer, flavoring agent, etc. in a dosage form

  as required by the accepted pharmaceutical practice.

  The amount of active ingredient in these compositions or preparations is such that a suitable dosage is obtained

within the specified range.

  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-l-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 are taken up in 10 ml of dichloromethane, with stirring in an ice-bath, and 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-yl) are added.

  oxopropyl) -L-proline in 5 ml of dichloromethane and 0.7 ml of 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 The mixture is treated 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 - [(N-Acetyl-L-phenylalanyl) thio] -l-oxopropyl] -L

proline

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

1-oxopropy1] -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-1-1-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) -l-r3 - [(1-Benzoyl-L-prolyl) thio] -2-methyl-1-oxopropyl] -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) -1- [3 - [(1-Acetyl-L-isoleucyl) thio] -2-methyl-1-oxopropyl] -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. H O-O3H EHD-S-nl- DV H ZO --- O DH; 3 HD-S-e YV-oV

QSJE H)

HzO D-N-O DHD HD-S-ela-DoV

YS-N úH2

Hz0 N-DHDz HDS-TVA-0v '

YS-7J HD

HzOT t-0DHD- HD-SH H: O

HZO7-N-O:) HD-EHD-SH

HZOD -ODHD HD-SH

Hzo :) N-ODHDZH) D-SH S úHa

HZO- -N-ODHDZHDS-AIT-DV

  Ii úHUUOoD III 9uuoTo; D HzOD N-OZ) HD ZHD-SH Hi yuuoIoD

ISOI H ;:

  He. GUUoOTO I euuOlOD oe Go O0 \ 0 -4- nalIooa -I -1 eIv-DOO IT aqd-DOo IT eA-DOO AKI-DoO HzOD -r - N-ODHD-S-AI 9-DV

ES) H

  HZEO3 N-ODHDZHD-S-aqd-DV H 3 ID Hz lOD --- N-ODH3D ZHD-S-tlqd-DV HO Hz OD1 - -ODHDzHD-S-aI-Dv E úHD a a

HZOD, N-ODHD-SH

Ju H3 H Z03-r --- N-ODHD ZHD-SH

DX HD

  TO HzOD D -OD3HDzHD-SH EtH1 atld-Dos

H ZO-- N-ODHD ZHD-SH

  HO HO AT-DOO H zOD-N-ODHD ZEH-S-da-o oW H uuoH; III GuUO [OD H zO3D NOD-H3-zHD-SH II uuooD

GUUOTOD II

  oo oo o r oo o r oo o r oo n oo o r oo o r oo o r oo oo o r oo oo o r oo oo o r oo oo oo o r oo oo n o

H J8H

? - HZ

  HOTO-HOD -ODHO-S-Gdd-DV s-t HzOD I N-ODHD-S-na - OV L I

HZ00 N-HDHD-S-VIV-DV

Not a word

H Z NO ZHD -SH

HzOD N-ODHD-SH

LJ 1

? .T -? H

 o -I,: f -

H OD -ODHD-SH

HJ EH

H N- O

HzOD T -ODHD-SH I ,, J

H ZOD --- N-ODHD-SH

DX E 1

  III 0% CooQu-Doo nei-DOE 6T IeTV-DOE 8T

GUUOTOD II

I GUUOTOD

HZ D 3 -T-O-S-aa- o E a

H úHD

HZOD N-OD3H3-s-na_-zv a

H ZOD -N- ODHD-S- @ I-DV

HzOD- - -OD3HD- S-T A-DoV T3

H EOD --- N-ODHD-SH

H> <EH

HOD, N-ODHD-SH

aX E 1 HH aa

H ZOD- - N-ODHD-SH

HZO N-O: H;) - SH

4) 1H T; :) HZOD N-ODHD-S-aqd-D

H, ú

HO III uuoIoTOD

H ZOD --N-ODHD-SH

  1HD HH CHID HI II GUUOTOD atld-DO I GLTUOIOD 0% o cL O0 \ 0 -e 04j -I nmdDOs nui-oOg TIA-DOgH ZOD-N-ODHD-Sd.j- od HDO EHDO HE 0 Il - [- -: - ODHD-SH HD uoHo II auuouou oN 0%% 0 o -u ('J uL -4

III GUUOTOD

I auuoloD a-rclwe7à

EXAMPLE 29

  (S) -1- [2 - [(N-Acetyl-L-tryptophyl) thio] -l-oxopropyl] -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 (12)

  A compound of the formula: R 1 -Al-S- (CH 2) n -CH-C-A2 o and its alkyl esters and salts, wherein R 1 is hydrogen, alkanoyl or benzoyl; 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 residue A1 being attached to the group R 1 by its α-amino or α-imino group and bonded to the sulfur atom by its carboxyl group, and the remainder A2 being linked to the carbonyl group   adjacent by its α-amino or α-imino group.   2. Compound according to claim 1, R is a hydrogen atom.   3. Compound according to claim 1, R1 is an alkanoyl radical.   4. Compound according to claim 1, R is a benzoyl radical.   5. Compound according to claim 1, R2 is a hydrogen atom.   6. Compound according to claim 1, R2 is an alkyl radical.   7. Compound according to claim 1,   R2 is the trifluoromethyl radical.   8. Compound according to claim 1, n is 0.   wherein in which in which in which in which wherein 9. The compound of claim 1, wherein n is 1.   The compound of claim 1 wherein   A1 and A2 are each a residue of 4-fluoroproline, 4,4-   difluoroproline, 4,4-ethylenedioxyproline, 4-methoxy-   proline, 4-thiazolidinecarboxylic acid, tryptophan, glycine, alanine, leucine, isoleucine, valine or phenylalanine.   The compound of claim 10 wherein the α-amino or α-imino residues of A1 and A2 are in the L.sub.12 configuration. Compound according to claim 1, having the formula: R R4 R2 C-OH,   R1-Aj-S- (CH2) n -CH-C-N-OH and its alkyl esters and salts, wherein R1 is hydrogen, alkanoyl or benzoyl; R2 is a hydrogen atom or an alkyl or trifluoromethyl radical; R3 is a hydrogen or fluorine atom; and R4 is a hydrogen atom, a hydroxy or methoxy group, a chlorine or fluorine atom, or, joined to the carbon atom to which they are attached, R3 and R4 form an ethylenedioxy group.   13. The compound of claim 1 which is   (S) -1- [3 - [(1-acetyl-L-prolyl) thio] -2-methyl-1-oxopropyl] -L-   proline. 14. A compound according to claim 1, which is the   (S) -1- [2 - [(1-acetyl-L-prolyl) thio] -l-oxopropyl] -L-proline.   The compound of claim 1 which is (S) -1- [2 - [(N-acetyl-L-phenylalanyl) thio] -1-oxopropyl-L-proline.   Pharmaceutical composition with antihypertensive action   tensive, characterized in that its active ingredient is at   at least one compound according to claim 1.