GB2066240A

GB2066240A - Derivatives of mercaptoacyl amino acids

Info

Publication number: GB2066240A
Application number: GB8038137A
Authority: GB
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1979-12-10
Filing date: 1980-11-27
Publication date: 1981-07-08
Also published as: JPS5692861A; IT1141125B; IT8026521A0; FR2473517A1; DE3046374A1

Abstract

Carbothioic acid derivatives of certain mercaptoacyl amino acids inhibit the conversion of angiotensin I to angiotensin II in mammals and are useful for the treatment of hypertension. They are of the formula <IMAGE> wherein R1 is H, alkyl, aryl, aralkyl, acyl or <IMAGE> R2 is H, alkyl, CF3 or CF3CF2; R3 is CH2, S, CH(OH), CH(O alkyl), CH(O aryl), CH(S alkyl), CH(S aryl), C(O alkyl)2, C(S alkyl)2, <IMAGE> C Cl2, CF2, CHCl or CHF and R4 is CH2 or (R3=CH2)S, or R3 + R4 is CH=CH; and n is 0-2.

Description

SPECIFICATION Derivatives of mercaptoacyl amino acids This invention provides new compounds having the formula

such compounds having been found to have hypotensive activiy. In the formula I, and throughout the specification, the symbols are as defined below.

R1 is hydrogen, alkyl, aryl, arylalkyl, a hydrolyzable acyl protecting group (such as

wherein R5 is alkyl or aryl),

P2 is hydrogen, alkyl, trifluoromethyl or pentafluoroethyl; R3 is -CH2-, -S-, -CH(OH)-, -CH(O-alkyl)-, -CH(O-aryl)-, -CH(O-aryl)-,-CH(S-alkyl)-, -CH(S-aryl)-, -C(O-alkyl)2-, -C(S-alkyl)2-,

-CC12-, -CF2-, -CHCI-, or -CHF- and R4 is -CH2- or -S-; with the proviso that if R4 is -S-, R2 is -CH2-; or together, R3 and R4 can be -CH=CH-; and n isO, 1 or 2.

The term "aryl", as used throughout the specification either by itself or as part of a larger group, refers to phenyl or phenyl substituted with one, two or three halogen, alkyl, alkoxy, hydroxy,

nitro, amino, alkylamino, dialkylamino, trifluoromethyl, cyano or carboxyl groups. Phenyl is the preferred aryl group.

The term "alkyl", as used throughout the specification either by itself or as part of a larger group, refers to groups having 1 to 8 carbon atoms. Alkyl groups having 1 to 3 carbon atoms are preferred.

The term "alkoxy", as used throughout the specification either by itself or as part of a larger group, refers to groups having 1 to 8 carbon atoms. Alkoxy groups having 1 to 3 carbon atoms are preferred.

The term "halogen", as used throughout the specification either by itself or as part of a larger group, refers to fluorine, chlorine, bromine and iodine. The preferred halogen groups are chlorine and bromine.

The compounds of formula I may be used as hypotensive agents and the invention extends to pharmaceutical compositions comprising such compounds and a pharmaceutical carrier. They inhibit the conversion of the decapeptide angiotensin I to angiotensin II and, therefore, are useful in reducing or relieving angiotensin related hypertension. The action of the enzyme resin on angiotensinogen, a pseudo-globulin in blood plasma, produces angiotensin I. Angiotension I is converted by angiotensin converting enzyme (ACE) to angiotensin 11. The latter is an active pressor substance which has been implicated as the causative agent in various forms of hypertension in various mammalian species, e.g., rats and dogs.The compounds of this invention intervene in the angiotensinogen(rnnin)angiotensin I (ACE) angiotension II sequence by inhibiting angiotension converting enzyme and reducing or eliminating the formation of the pressor substance angiotensin II. Thus by the administration of a composition containing one or a combination of the compounds of this invention, angiotensin dependent hypertension in the species uf mammal suffering therefrom is alleviated. A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to 100 mg. per kilogram of body weight per day, preferably about 1 to 15 mg. per kilogram of body weight per day is appropriate to reduce blood pressure.

The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, intravenous or intraperitoneal routes can also be employed.

The compounds of this invention can also be formulated in combination with a diuretic for the treatment of hypertension. A combination product comprising a compound of this invention and a diuretic can be administered in an effective amount which comprises a total daily dosage of about 30 to 600 mg., preferably about 30 to 300 mg. of a compound of this invention, and about 15 to 300 mg., preferably about 15 to 200 mg.

of the diuretic, to a mammalian species in need thereof. Exemplary of the diuretics contemplated for use in combination with a compound of this invention are the thiazide diuretics e.g., chlorthiazide, hydrochlorthiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methychlothiazide, trichlormethiazide, polythiazide or benzthiazide as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetanide, traimterene, amiloride and spironolactone and salts of such compounds.

The compounds of formula I can be formulated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions of suspensions for parenteral administration. About 10 to 500 mg. of a compound or mixture or compounds of formula I is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.

The compounds of this invention are readily prepared from the corresponding carboxylic acid having the formula II

wherein R; can be any one of the R1 groups other than hydrogen. The conversion of an acid of formula II to the corresponding carbothioic acid of formula I can be accomplished by reacting the precursor acid successively with an alkyl haloformate (e.g., ethyl chloroformate) and sodium hydrosulfide. The addition of alkyl haloformate can be carried out in the presence of an organic base (.e.g., triethylamine) at a reduced temperature. The reaction can be run in an anhydrous organic solvent, preferably an ethereal solvent such as tetrahydrofuran. The subsequent reaction with sodium hydrosulfide can be run at room temperature and can be accomplished by adding the sodium hydrosulfide to the first reaction mixture.

The compounds of formula I wherein R1 is hydrogen can be prepared from a corresponding compound of formula I wherein R1 is a hydrolyzable acyl protecting group. The removal of the acyl protecting group can be accomplished by treatment with ammonia or sodium hydroxide in water.

The compounds of formula II, and methods for their preparation, have been described in the patent and nonpatent literature.

Those compounds of formula Il wherein R3 is -OH2- or -CH(OH)-, R4 is -OH2- and R2 is hydrogen or alkyl, are described in United States patents 4,046,889, issued September 6, 1979; 4,105,776, issued August 8,1978; and 4,154,840, issued May 15,1979.

Those compounds of formula Il wherein R3 is -CH2-, -0012--CF2-, -CHCI-, or -CHF-, R4 is -CH2-, and R2 is hydrogen, alkyl or trifluoromethyl are disclosed in United States patent 4,154,935, issued May 15, 1979.

Those compounds of formula ll wherein R3 and P4 together are -CH=CH- and R2 is hydrogen or alkyl are disclosed in United States patents 4,129,566, issued December 1978 and 4,154,942, issued May 1979.

Those compounds offormula Il wherein R3 is -S-and R4 is -CH2- or P3 is -CH2- and R4 is-S-, and R2 is hydrogen or alkyl are disclosed in Belgian patent 861,454, issued June 2, 1978.

Those compounds of formula II wherein R2 is trifluoromethyl or pentafluoroethyl and P3 and R4 each is -CH2- or -S- or R3 and P4 together are -OH=CH-, are disclosed in British patent specification 2,014,132, published August22, 1979.

Those compounds of formula II wherein P3 is -CH()-alkyl)-, -CH(O-aryl)-, -CH(S-alkyl)-, or -CH(S- aryl)-, P4is -CH2- and R2is hydrogen or alkyl are disclosed in Belgian patent 878,191 issued on February 11,1980.

Those compounds of formula II wherein P3 is -C(O-alkyl)s-, -C(S-alkyi)P-,

and R4 is -CH2- are disclosed in United Kingdom patent application No. 7942291(2039478).

The products of formula I have at least one asymmetric carbon atom. If R2 is other than hydrogen, the products have two asymmetric carbon atoms. The compounds, therefore, exist in stereoisomeric forms or in racemic or diastereomeric mixtures thereof All of these are within the scope of this invention. The synthesis described above can be run using reactants that are racemic or diastereomeric mixtures or stereoisomers.

When the reactants are racemic or diasteromeric mixtures, the steroisomers of the resulting product can be separated using art-recognized techniques. The L-isomer with respect to the carbon of the amino acid constitutes the preferred isomeric form. The following examples are specific embodiments of this invention.

EXAMPLE 1 (S)- l-[3-(A cetylthio)-2-methyl- 1-oxopropy8-L-2-pyrrolidinecarbothioic acid A solution of (S)-1 -[3-(acetylthio)-2-methyl-1 -oxopropyl]-L-proline (10.36 g) and triethylamine (5.56 ml) in 300 ml of dry tetrahydrofuran is cooled to -15 C under argon and treated with ethyl chloroformate (3.84 ml).

After stirring the mixture at -15OC for 90 minutes, sodium hydrosulfide (4.0 g) is added and the mixture is stirred at room temperature for about 16 hours. The mixture is then acidified with hydrochloric acid, extracted with ether, and the extracts washed with brine, dried and evaporated to yield 9.9 g of crude product. Two crystallizations from ether yield the title compound, melting point 65-67"C.

EXAMPLE2 (SJ- 7-[3-mercapto-2-methyl- 1-oxopropyl]-L-2-pyrrolidinecarbothioic acid (S)-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-L-2-pyrrolidinecarbothioic acid (0.01 mole) is dissolved in water, purged with argon and treated with 1N sodium hydroxide (0.02 mole). The solution is stirred for 30 minutes at ambient temperature and acidifed with hyrochloric acid. The mixture is extracted with ether and the extracts washed with brine, dried and evaporated to yield the title compound.

EXAMPLES 3-20 Following the procedure of Example 1, but substituting the compound listed in column I Tor (S)-l -[3-(acetylthio)-2-methyl-l -oxopropyl]-L-proline, yields the compound listed in column II.

Column I Column II 3. 1 -[3-(acetylthio)-2-methyl-1 -oxopropyl]- 1 -[3-(acetylthio)-2-methyl-l -oxopropyl]- 4-methoxy-L-proline 4-methoxy-L-2-pyrrolidinecarbothioic acid 4. 1 -[3-(benzoylthio)-2-methyl-1 -oxopropyl]- 1 -[3-(benzoylthio)-2-methyl-1 -oxopropyl]- 4,4-dimethyoxy-L-proline 4,4-dimethoxy-L-2-pyrrolidinecarbothioic acid 5. 1 -[3-(benzoylthio)-2-methyl-l -oxopropyl]- 1 -[3-(benzoylthio)-2-methyl-l -oxopropyl]- 4-chloro-L-proline 4-chloro-L-2-pyrrolidinecarbothioic acid 6. 1 -[3-(acetylthio)-2-methyl-1 -oxopropyl]- 1 -[3-(acetylthio)-2-methyl-1 -oxopropyl]- 4-fluoro-L-proline 4-fluoro-L-2-pyrrolidinecarbothioic acid 7. 1 -[3-)acetylthio(-2-methyl-1 -oxopropyl]- 1 -[3-(acetylthio)-2-methyl-l -oxopropyl]- 4,4-dichloro-L-proline 4,4-dichloro-L-2-pyrrolidinecarbothioic acid 8. 1 -[3-(acetylthio)-2-methyl-1 -oxopropyl]- 1 -[3-(acetylthio)-2-methyl-1 -oxopropyl]- 4,4-difluoro-L-proline 4,4-difluoro-L-2-pyrrolidinecarbothioic acid 9. 1 -[3-(acetylthio)-2-methyl-l -oxopropyl]- 1 -[3-(acetylthio)-2-methyl-l -oxopropyl]- 4-hydroxyl-L-proli ne 4-hydroxy-L-2-pyrrolidinecarbothioic acid 10. 3-[3-(acetylthio)-2-methyl-l -oxopropyl]- 3-[3-(acetylthio)-2-methyl-1 -oxopropyl]- L-thiazolidine-4-carboxylic acid L-thiazolidine-4-carbothioic acid 11. 3-[3-(acetylthio-2-methyl-l -oxopropyl]- 3i3-(acetylthio)-2-methyl-l -oxopropyl]- L-thiazolidine-2-carboxylic acid L-thiazolidine-2-carbothioic acid 12. 1 -[3-(acetylthio)-2-methyl-1 -oxopropyl] 1 -[3-(acetylthio)-2-methyl-1 -oxopropyl]- 4,4-ethylenedioxy-L-proline 4,4-ethylenedioxy-L-2-pyrro lidine carbothioic acid 13. 1 -[3-(acetylthio)-2-methyl-1 -oxopropyl]- 1 -[3-(acetylthio)-2-methyl-l -oxopropyl]- 4,4-ethylenedithio-L-proline 4,4-ethylenedithio-L-2-pyrrolidine- carbothioic acid 14. 1 [3-(acetylthio)-2-(trifluoromethyl)-1 - 1 -[3-(acetylthio)-2-(trifl uoromethyl)- oxopropyl]-L-proline 1-oxopropyl]-L-2-pyrrolidinecarbo- thioic acid 15. 1-[3-(acetylthio)-2-(trifluoromethyl-1- 1-[3-(acetylthio)-2-trifluoromethyl)- oxopropyl]-L-3,4-dehydroproline 1-oxopropyl]-L-3,4-dehydropyrrolidine- 2-carbothioic acid 16. 1 -[3-(acetylthio)-2-methyl-1-oxopropyl]- 1 -[3-(acetylthio)-2.methyl-1-oxopropyl]- 4-(methylthio)-L-proline 4-(methylthio)-L-2-pyrrolidinecarbo thioic acid 17. 1 -[3-(acetylthio)-2-methyl-1 -oxopropyl]- 1 -[3-(acetylthio)-2-methyl-l -oxopropyi]- 4-(phenyloxy)-L-proline 4-(phenyloxy)-L-2-pyrrolidinecarbo thioic acid 18. 1 -[3-(acetylthio)-2-methyl-1-oxopropyl]- 1 -[3-(acetylthio)-2-methyl-1 -oxopropyl]- 4-(phenylthio)-L-proline 4-(phenylthio)-L-2-pyrrolidinecarbo thioic acid 19. 1-[3-(acetylthio)-2-methyl-1 -oxopropyl]- 1 -[3-(acetylthio)-2-methyl-1 -oxopropyl]- 4,4-(dimethylthio)-L-proline 4,4-(dimethylthio)-L-2-pyrrolidine carbothioic acid 20. 1,1 -[dithiobis(2-D-methyl-3-prnpanoyl)]- 1,1 -[dithiobis(2-D-methyl-3-propanoyl)]- bis-L-proline bis-L-2-pyrrolidinecarbothioic acid

Claims

CLAIMS 1. Acompound having

wherein R1 is hydrogen, alkyl, aryl, arylalkyl, a hydrolyzable acyl protecting group, or

R2 is hydrogen, alkyl, trifluoromethyl or pentafluoroethyl; P3 is -OH2-, -S-, -CH(OH)-, -CH(O-alkyl)-, -CH(O-aryl)-, -CH(S-alkyl)-, -CH(S-aryl)-, -C(O-alkyl)z-, -C(S-alkyl)-,

-0012-, -CF2-, -CHOl-, or -CHF- and R4 is -CH2- or -S-, with the proviso that if R4 is-S-, R3 is -CH2-; or together, P3 and R4 are -CH=CH-; and n is 0, 1 or 2.
2. A compound in accordance with claim 1 wherein R1 is hydrogen, alkyl, aryl, arylalkyl, 0 or P5-O- wherein R5 is alkyl or aryl.
3. A compound in accordance with claim 2 wherein n is 1.
4. A compound in accordance with claim 3 wherein P3 is -CH2- and R4 is S.
5. A compound in accordance with claim 3 wherein P3 is -S-.
6. A compound in accordance with claim 3 wherein P3 is -CH(OH)-.
7. A compound in accordance with claim 3 wherein P3 is -CH(O-alkyl)-.
8. A compound in accordance with claim 7 wherein P3 is -CH(OCH3)-.
9. A compound in accordance with claim 3 wherein P3 is -CH(O-aryl)-.
10. A compound in accordance with claim 3 wherein P3 is -CH(S-alkyl)-.
11. A compound in accordance with claim 3 wherein P3 is -CH(S-aryl)-.
12. A compound in accordance with claim 3 wherein P3 is -C(O-alkyl)2-.
13. A compound in accordance with claim 12 wherein P3 is -C(OCH3)2-.
14. A compound in accordance with claim 3 wherein P3 is -C(S-alkyl)2-.
15. A compound in accordance with claim 3 wherein P3 is
16. A compound in accordance with claim 3 wherein P3 is
17. A compound in accordance with claim 3 wherein P3 is -CC12-.
18. A compound in accordance with claim 3 wherein P3 is -CF2-.
19. A compound in accordance with claim 3 wherein P3 is -CHCI-.
20. A compound in accordance with claim 3 wherein P3 is -OH F-.
21. A compound in accordance with claim 3 wherein P3 and R4 are together -CH=CH-.
22. A compound in accordance with claim 3 wherein P3 is -CH2- and R4 is -CH2-.
23. The compound in accordance with claim 1 (S)-l -[3-(acetylthio)-2-methyl-1 -oxopropyl]-L-2- pyrrolidinecarbothioic acid.
24. A process for preparing a compound of the formula

wherein R1 is hydrogen, alkyl, aryl, arylalkyl, a hydrolyzable acyl protecting group, or

P is hvdroaen. alkvl. trifluoromethyl or pentafluoroethyl; P3 is -OH2-, -S-, -CH(OH)-, -CH(O-alkyl)-, -OH(O-aryl)-, -CH(S-alkyl)-, -CH(S-aryl)-, -C(O-alkyl)2-, -C(S-alkyl)2-,

-CC12-, -CF2-, -CHCI-, or -CHF- and R4 is -CH2- or -S- with the proviso that if R4 is -S-, P3 is -OH2-; or together, P3 and R4 are -CH=CH-; and n is 0,1 or 2, which comprises reacting a compound of the formula

wherein R1 is other than hydrogen with an alkyl haloformate in the presence of an organic base and then reacting the resulting product with sodium hydrosulfide at room temperature to yield the compounds of formula I wherein R1 is other than hydrogen and reacting the compounds of formula I wherein R1 is a hydrolyzable acyl protecting group with ammonia or sodium hydroxide in water to yield the compounds of formula I wherein R1 is hydrogen.
25. A compound in accordance with claim 1, when prepared by a process in accordance with claim 24.
26. A compound in accordance with claim 1, as named in any of the Examples.
27. A compound in accordance with any one of Claims 1-23, 25 and 26 for use in the treatment of hypertension.
28. A pharmaceutical composition comprising a compound in accordance with any one of Claims 1-23, 25 and 26 and a pharmaceutical carrier.
29. A compound in accordance with claim 28 which includes a diuretic
30. A compound in accordance with claim 28 in the form of a tablet, capsule or elixir for oral administration or a sterile solution or suspension for parenteral administration.
31. A compound in accordance with claim 28 which includes an excipient, binder, preservative, stabilizer or flavor.