Novel carboxyalkyl peptides and thioethers and ethers of peptides as antihypertensive agents

Claim 1

Novel compounds having the general formula wherein x and y are 0 or 1, X may be S, O or N-R 9 and R 9 may be -H or -CH 3 , m is 0 or 1, and R 10 is H, CH3, F, C1 or Br; R 2 is COOH, CH 2 COOH, COSH, CH 2 COSH, CH 2 SH, CH 2 CH 2 SH, a physiologically acceptable non-toxic salt of any of them; COOY; CH 2 COOY, COSY, CH 2 COSY, CH 2 SY or CH 2 CH 2 SY, wherein Y is phenyl, benzyl or a 1-5 carbon alkyl group, wherein either of A 1 and A 2 may be H, phenyl, benzyl or a 1-5 alkyl group; R 4 and R 5 together form a ring with the nitrogen and carbon atoms to which they are respectively attached, which ring is one of the structures: it being understood that any of these structures may be monosubstituted with -OH, -OCN 3 , F, 0 Cl, Br, I, phenyl, hydroxyphenyl, -SH, -SCH 3 , -NHCH 3 , -CH 2 NH 2 ,-CH 3 , -CH 2 0H,propyl, guanidino, nitroguanidino or thioguanidino and that the five or six-membered rings may be disubstituted with -OH, F, Cl, Br, I, OCH 3 , or any combination of two of these substituents; R 6 is NH 2 , -DM or -SM, wherein M may be H, an alkyl group of 1-3 carbon atoms or any other ester moiety hydrolyzable under mammalian in vitro conditions to -OH, or an ionically bonded anion of a physiologically acceptable non-toxic salt; R 7 is H 1 -CH 3 , halomethyl, hydroxymethyl, aminomethyl or mercaptomethyl; R 8 is H-, CH 3 , amino, halomethyl, hydroxymethyl, aminomethyl, dihalomethyl, trihalomethyl, mercaptomethyl, methoxymethyl, methylthiomethyl, methoxycarbonylmethyl, cyanomethyl, benzyl, acetoxymethyl, CH 2 = CH - CH 2 , isobutyl, mercaptoalkyl of 2-3 carbon atoms, hydroxyalkyl of 2-3 carbon atoms, ethyl, acetylthioethyl, benzamido, acetamido, phthaloylaminoalkylene wherein the alkylene group has 1-4 carbon atoms, alkoxycarbonyl isoalkylene wherein the alkyl group contains 1-6 carbons and the isoalkylene group contains 3-5 carbons, benzoylamine, alkanoylamine of 1-6 carbons, alkylamide of 1-6 carbons, phenylamine or alkylamine of 1-6 carbons. (A) R 1 and R 3 are th.e same or different and are each any of (i) mono-N substituted alkylene of 2-4 carbons wherein the N substituent is benzoyl, Boc, Cbo, Tos, formyl or acetyl; (ii) hydroxyphenyl or hydroxyphenyl-(1-6C)-alkylene hydroxyalkylene having 1-4 carbons, or thiol analogs thereof, (iii) mercaptoalkylene of 1-6 carbons; (iv) phenylalkylene wherein the alkylene group has 1-6 carbons, C 1 -C 5 straight or branched chain alkyl or phenyl, (v) phenylthioalkylene, phenoxyalkylene, benzyloxyalkylene or benzylthioalkylene wherein the alkylene group has 1-6 carbons; (vi) alkylthioalkylene wherein the alkyl and alkylene groups have 1-6 carbons; (vii) alkoxyphenyl or alkoxybenzyl in which the alkoxy group has 1-6 carbons, phenoxyphenyl, phenoxybenzyl, benzyloxybenzyl or benzyloxyphenyl or a thioether analog of any of them; wherein n = 0 - 4 and B = H or a 1-6 carbon alkyl group; or an -SB analog thereof; (ix) (CH 2 ) p COOZ or (CH 2 ) p COSZ wherein p = 0 - 3 and Z is H, phenyl, benzyl, a 1-6 carbon alkyl group, or an anion of a physiologically acceptable salt; or wherein n and Z each have the same significance as above; wherein n = 0 - 4, D is phenyl, thienyl or a 1-3 carbon alkyl group; phydroxyphenyl - (CH 2 ) n - C (CH 3 ) 2 - or p-mercaptophenyl-( CH2 ) n - C (CH 3 ) 2 - wherein n has the same significance as above. (xiii) p - mercaptophenyl - (CH 2 ) n - CH 2 - or p-hydroxyphenyl-(CH 2 ) n - CH2 - wherein the phenyl ring has one or two nitro or amino substituents and n has the same significance as above; wherein n has the same significant as above. (xv) NH 2 - alkylene or NO 2 - alkylene containing one hydroxy or mercapto substituent and having 1-6 carbon atoms; (xvi) hvdroxv- or mercapto-phenoxybenzyl: - or n-wherein q = 1 - 5 and z and n have the same significance as--above. , wherein Z, q and n all have the same wherein G is an alkacyl or alkacyloxy group of 1-6 carbons, a benzoyl or benzoyloxy group, or a phenylalkacyl or phenyl- alkacyloxy group wherein the alkacyl or alkacyloxy group contains 2-6 carbons and q and n have the same significance as set forth above; wherein n has the significance stated above and K is selected from carboxyphenyl, aminophenyl, nitrophenyl, halophenyl,' hydroxyphenyl, alkylthiophenyl, alkylphenyl, mercaptophenyl, cyanophenyl, mercapto-carbonylphenyl, alkylcarbonylphenyl, alkylcarbonyloxphenyl, hydrazinophenyl, ureidophenyl, alkyl- carbonylaminophenyl, alkylcarbonylthiophenyl, alkaloxyphenyl and hydroxy minophenyl, wherein all alkyl groups contain 1-6 carbon atoms; wherein n has the significance stated above and L is selected from cycloalkyl groups of 3-7 carbons which may be unsubstituted with up to two groups selected from among carboxy, amino, nitro, halo, hydroxy, mercapto, mercaptocarbonyl, hydroxyamino, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylcarbonylamino, alkylcarbonylthio, cyano, hydrazino, ureido and alkyloxy, wherein all alkyl groups contain 1-6 carbon atoms; (xxii) guanidino alkylene, thioguanidinoalkylene, or nitroguanidino alkylene in which the alkylene groups contain 1-6 carbon atoms; (xxiii) ring substituted aryl groups in which the ring substituents may be the same or different and may comprise up to five per ring of any of the following: - NH 2 ,-OZ, -SZ, halogen, -CN, -NO, -COOZ, COSZ, CONH 2 , -NHNH 2 , alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkyl, dihaloalkyl, trihalomethyl, hydroxyamino, alkylcarbonylthio, phenoxy, and benzyloxy wherein the alkyl groups contain 1 - 6 carbon atoms and Z has the same significance as above; (xxiv) amidoalkylene or alkylcarbonyl-aminoalkylene wherein the alkyl and alkylene groups contain 1 - 6 carbon atoms; (xxv) hydroxyaminoalkylene of 1 - 6 carbons; (xxvi) vinyl and substituted vinyl groups in which the substituents may be alkyl, aryl, cycloalkyl or heterocyclic groups; (xxvii) unsubstituted heterocyclic groups selected from among phenothiazinyl, pyrrolidinyl, pyrrolyl, quinolinyl, imidazolyl, pyridyl, thyminyl, benzothiazinyl, indolyl, thienyl, purinyl, piperidinyl, morpholinyl, azaindolyl, pyra- zinyl, pyrimidyl, piperonyl, piperazinyl, furanyl, thiazolyl, and thiazolidinyl, cytcsinyl; (xxviii) alkylene or alkenyl groups of 1 - 6 carbons substituted with one of the heterocyclic rings from (xxvii) above; (xxix) groups from (xxvii) or (xxviii) above, containing up to four ring substituents onthe heterocyclic ring selected from among -OZ, -SZ, -COSZ, -NO 2 , -NH 2 ,-COSZ, halogen, haloalkyl, dihaloalkyl, trihalomethyl, cyano, -CONH 2 , alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyl-amino, alkylcarbonylthio, phenoxy, benzyloxy, ,-NHNH 2 and HONH - wherein Z has the same significance as above; (xxx) groups from (xxvii) , (xxviii) or (xxix) attached to (xxxi) mono-, di- or tri-alkyl-, alkenyl- or phenyl-silyl or selenyl wherein the alkyl or alkenyl groups contain 1 - 6 carbons. B. When R 1 is a group from among (xi) - (xxxi) above, R 3 may also be any of H, 1 - 5 carbon straight or branched chain alkyl, phenyl, -OH, alkoxy of 1 - 5 carbons, benzyloxy, benzyloxyalkylene or phenoxyalkylene wherein the alkylene has 1 - 5 carbons, alkoxyalkylene having 1 - 5 carbons in the alkoxy and alkylene groups, aminoalkylene of 1 - 6 carbons, alkenyl of 1 - 6 carbons, benzyl, hydroxyalkyl of 1 - 6 carbons, mercaptoalkyl of 1 - 6 carbons, histidinyl, haloalkyl of 1 - 6 carbons, 4 -aminoethyl-benzyl, acetamidoalkyl of 1 - 5 carbons, benzylthiomethylene, or dimethylaminoalkyl of 1 - 5 carbons. C . When R3 is a group from among (k) - (xxxi) above, R 1 may also be any of H, C 1 - C 8 straight or branched chain alkyl, phenyl, benzyl, unsubstituted aminoalkylene of 2 - 6 carbons, hydroxyalkylene of 1 - 6 carbons, hydroxyphenyl, phenoxyalkylene or benzyloxyalkylene wherein the alkylene group has 1 - 6 carbons, cycloalkyl of 3 - 6 carbons, cycloalkyl methyl, 3 indolyl-phenylethyl, methylthioethyl, 3- indolyl alkyl wherein the alkyl group contains 1 - 5 carbons, imidazolyl, imidazolylalkyl wherein the alkyl group contains 1 - 5 carbons, phenoxymethyl, phenylthiomethyl, 4-aminomethyl benzyl, 2-aminophenethyl, naphthylethyl, 4-halophenethyl, 3,4-dihalophenethyl or phenoxyphenethyl, or D. R 1 and R 2 together may form with -CH a lactone ring of the formula: induce D-penicillamine-like adverse effects, applicants prepared and disclosed in copending application Ser. No. 187992 filed September 17, 1980, a series of compounds having analogous side chain structure to an effective substrate for the enzyme, benzoyl-Phe-Ala-pro. The analogous compounds possess an ether or thioether linkage and a substituted carboxymethyl proximate to the ether or thioether. In some compounds, the substituted carboxymethyl group is replaced by corresponding substituted thiocarboxymethyl or mercaptomethyl group.