IE50222B1 - Substituted acyldihydropyrazole carboxylic acid derivatives,substituted acylproline derivatives and related compounds - Google Patents

Description

SUBSTITUTED ACYLDIEYDROPYRAZOLE CARBOXYLIC ACID DERIVATIVES, SUBSTITUTED ACYLPROLINE DERIVATIVES AND RELATED COMPOUNDS The present invention relates to substituted acyldihycLropyrazole and acylproline carboxylic acid derivatives of the following general formulae: ?5 R3X /R2 /C\ o CH (CH,) 0 » I 2 >11 -CH-C—OR, R„- (CH) —CH—C—N s m aad II Rr ?7 Nx CH.

R„-(CH) -CH-C-N3 m •CH0 II -C—OR 1' and .base addition salts thereof, wherein: Εη is hydrogen, alkyl, aryl or arylalkyl; Rg is hydrogen and R^ is hydrogen, hydroxy, alkoxy or halogen, or together Rg and R^ can be =0 'Ό or -X-(CHg)t-X- wherein X is oxygen or sulfur and t, is or 3; R^ is hydrogen or alkyl; R^ is hydrogen, alkyl or trifluoromethyl; Rr, is aryl; is halogen or tosyl; m is 0, 1 or 2; and n is 1 or 2.

The term aryl, as used throughout the specification, either hy itself or as part of a larger group, refers to phenyl or phenyl substituted with 1, 2 or 3 0 halogen, alkyl, alkoxy, sulfamyl, hydroxy, alkyl-C-, nitro, amin.o, alkylamino, di alkyl amino, trifluoromethyl, 8028 cyano or carboxyl groups. Phenyl is the preferred aryl group.

The terms alkyl and alkoxy, as used throughout the specification (unless otherwise defined), either hy themselves or as part of a larger group, refer to groups having 1 to 7 carbon atoms. Groups having 1, 2 or 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 foregoing definitions apply throughout the specification and claims.

Compounds of general formula I wherein: Εη represents hydrogen or alkyl; and Sj represents hydrogen or halogen; and represents halogen; and m represents 0 or 1; and n represents 2 are disclosed in our U.S. Patent Specification No. 4,154,935 and are specifically dis20 claimed and excluded from the present application.

U.S. Patent No. 4,154,935 discloses (at column 2 lines 17 to 64) a general synthesis of substituted acylamino acids by the reaction of an appropriate haloalkanoic acid with an appropriate amino acid and indicates that any method can be used which will form amide bonds (Methoden der Organischen Chemie (H°ubenWeyl) part I, p. 736 et seq Part II, p. 1 et seq.(1974)) It will be apparent to a person skilled in the art that compounds of the present invention can be made according to such a synthesis.

The compounds of formula I and II are valuable intermediates and starting materials in the preparation of compounds of the following general formulae and base addition salts thereof: III s II R.—C—S — (CH) ο I R. |4 II -CH—C—N A c«, (αφη O -CH-C—OR, and ?5 R. |4 XCH, R,—-C —S—(CH) — CH—CΟ ΠΙ -N-CH—C — OR 1' Ihe compounds of formulae III and IV and base addition salts thereof are useful as hypotensive agents. 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 renin on angiotensinogen, a pseudoglobulin in blood plasma, produces angiotensin I. Angiotensin I is converted by angiotensin converting enzyme (ACE) to angiotensin II. 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 formulae III and IV intervene in the angiotensinogen—*· (renin)—^-angiotensin I—* (ACE) —►angiotensin II sequence by inhibiting angiotensin 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 compounds, of formulae III and IV angiotensindependent hypertension in the species of mammal suffering therefrom is alleviated.

The compounds of general formulae III and IV and methods for their preparation are described and claimed in our copending patent application No. 5oMc (Specification No. SOSfbO ). present application has been divided.

The compounds of this invention form salts with various inorganic and organic bases which are also withii the scope of the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases, e.g. dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, salts with amino acids like arginine, lysine and the like The non-toxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g. in isolating or purifying the product.

The compounds of formulae Σ and ΣΣ each contain at least one asymmetric carbon and accordingly exist in stereoisomeric forms or in racemic mixtures thereof.

They can be utilized as starting materials either as the racemate or as one of the enantiomers. The stereoisomers can be separated e.g. by conventional fractional crystallization of a diastereomeric salt mixture formed e.g. with an optically active amine.

The compounds of the present invention can be reacted with a dithioacid of the following general formula: V wherein Rg is hydrogen or a cation such as ammonium or an alkali metal, to produce the hypotensively active compounds of formulae III and IV.

The preparation of dithioacids of formula V Is 5 described in Houben-Weyl, Methoden der Organischen Chemie, Vol. 9( Thieme Verlag, Stuttgart, 1955 and in Barton and Ellis, Comprehensive Organic Chemistry, Vol. 3, Pergamon Press, 1979.

It is theorized that the activity of the racemic 10 products of general formulae III and IV is due mostly to the L-isomers with respect to the carbon of the carboxyl group of the amino acid, and accordingly the corresponding isomers of the compounds of formulae I and II are likewise preferred.

Claims (11)

1. CLAIMS :1. Subject to tbe foregoing disclaimer, a compound having the general formula I or II: Vs R 3\ / R 2 / C \ W , CH -οΟ ?2 fl R O -(CH) —CH—C—N t? m •OR, Π r £ r. 0 N x CHI 5 I 4 II I I 2 R„-(CH) -CH-C-N-CH-C—OR 1' or a base addition salt thereof, wherein: is hydrogen, alkyl, aryl or arylalkyl; Rg is hydrogen and R^ is hydrogen, hydroxy, alkoxy or halogen, or together Rg and R^ can be =0 or -X-(CHg) t -X- wherein X is oxygen or sulfur and t is 2 or 3; ~ R^ is hydrogen or alkyl; R. is hydrogen, alkyl or trifluoromethyl; R ? is aryl; Rg is halogen or tosyl; m is 0, Ί or 2; and n is 1 or 2.

2. A compound in accordance with claim 1, wherein R 1 is hydrogen.

3. - A compound or base addition salt in accordance with claim 1 or 2, wherein R^ and R^ each is hydrogen and m is 1. /, A conpound or base addition salt of the general· formula I defined in any preceding claim, wherein R 2 is hydrogen and R^ is hydrogen, hydroxy, alkoxy or halogen.

4. 5. A compound or base addition salt of the general formula I defined in any one of claims 1 to 3, wherein 5 R 2 and Rj are =0.

5. 6. A compound or base addition salt of the general formula I defined in any one of claims 1 to 3, wherein R 2 and Rj are -X-(CH 2 ) t -X-.

6. 7. A compound or base addition salt of the general 10 formula I defined in any preceding claim, wherein n is 1.

7. 8. A compound or base addition salt of the general formula II defined in any preceding claim, wherein R? is phenyl.

8. 9. An enantiomer of a compound or base addition salt· 15 in accordance with any one of the preceding claims.

9. 10. A separated stereoisomer of a compound or base addition salt in accordance with any one of claims 1 to 8.

10.

11. The L-isomer 20 the carboxyl group base addition salt 1 to 8 or 10. with respect to the carbon atom of of the amino acid of a compound or in accordance with any one of claims