Novel complex amido and imido derivatives of carboxyalkyl peptides and thioethers and ethers of peptides

Claim 1

Novel compounds of 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 , R 10 is H,. CH 3 , F, Cl or Br; m is 0 or 1 ; R 2 is COOH, CH 2 COOH, COSH, CH 2 COSH, CH 2 SH, CH 2 CH 2 SH, a physiologically acceptable nontoxic salt of any of them; COOY, CH 2 COOY, COSY, CH 2 SY, or CH 2 CH 2 SY wherein Y is phenyl, benzyl or a 1 - 5 carbon alkyl group ; or wherein either of A 1 and A 2 may be H, phenyl, benzyl or a 1 - 5 carbon 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, -OC 3 , F, Cl, Br, I, phenyl, hydroxyphenyl, -SH, -SCH 3 , -NHCH 3 , -CH 2 NH 2 , - CH 3 , -CH 2 OH, propyl, guanidino, nitro guanidino or thioguanidino and that any of the 5- or 6- membered rings may be disubstituted with -OH, F, Cl, Br, I, OCH 3 or any combination of two of this group of substituents; R 6 is -OM or -SM, wherein M may .be H, an alkyl group of 1-3 carbon atoms or any other ester moiety hydrolizable under mammalian in vivo conditions to -OH, or an ionically bonded anion of a physiologically acceptable nontoxic salt; R 7 is H-, CH 3 -, halomethyl, hydroxymethyl, aminomethyl or mercaptomethyl; R 7 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, acetylthioethyl, benzamido, acetamido, phthaloylaminoalkylene wherein the alkylene group has 1-4 carbon atoms, a-alkoxycarbonyl isoalkylene wherein the alkyl group contains 1-5 carbons and the isoalkylene group contains 3 - 5 carbons, benzoylamine, alkanoylamine of 1 - 5 carbons, alkylamide of 1 - 5 carbons, phenylamine, alkylamine of 1 - 5 carbons, or ethyl; and A. R 1 and R 3 may each be of the general formula wherein A 3 is: I. alkylene of 1-6 carbons, branched chain alkyl of 1 - 6 carbons, cycloalkyl alkylene, alkylaycloalkylalkylene, or alkylcycloalkylene; II. aralkylene wherein the alkyl group is 1 - 6 carbons or alkylaryl; III. phenyl; IV. alkylaralkylene wherein the alkyl groups may be the same or different and are 1-6 carbons in length; V. substituted alkylene, substituted branched chain alkyl, substituted cycloalkylalkylene, substituted alkyl cycloalkylalkylene, substituted alkylcycloalkylene, substituted alkylaryl, substituted aralkylene, substituted phenyl or substituted alkylaralkylene wherein the substituent or substituents may be the same or different, may be included in an alkylene chain or pendent thereto, and are selected from amino, halo, hydroxy, mercapto, NO 2 , carboxy, CONH 2 , lower alkyl, halomethyl, hydroxymethyl, aminomethyl, dihalomethyl, trihalomethyl, cyano, mercaptomethyl, methoxymethyl, methylthiomethyl, methoxycarbonylmethyl, cyanomethyl, benzyl, acetoxymethyl, CH 2 =CH-CH 2 -, isobutyl, mercaptoalkyl of 2-3 carbon atoms, hydroxyalkyl of 2-3 carbonatoms, acetylthioethyl, benzamido, acetamido, phthaloylaminoalkylene wherein the alkylene group has 1-4 carbon atoms, α-alkoxycarbonyl isoalkylene wherein the alkyl group contains 1-5 carbons and ther isoalkylene group contains 3-5 carbons, benzoylamino, alkanoylamino of 1-5 carbons, alkylamide of 1-5 carboos, phenylamine of 1-5 carbons, lower alkoxy, aryloxy, lower alkylamino, dilower alkylamino, acylamino, arylamino, guanidino, imidazolyl, indolyl, lower alkylthio, arylthio, carboxy amido and carbolower alkoxy; V.I. alkylenethio- or alkylenethioalkylene of 1-6 carbons, alkylthioalkylene of 1-6 carbons; VII. alkyleneoxy or alkyleneoxyalkylene wherein the alkyl groups may be the same or different and are 1-6 carbons; VIII. alkoxyphenyl or alkoxybenzyl in which the alkoxy groupuhas 1-3 carbons, phenoxyphenyl- phenoxybenzyl, benzyloxybenzyl or benzyloxyphenyl or a thioether analog of any of them; wherein n=0-4, m=0-4, and B=H or a 1-5 carbon alkyl group or an SB analog thereof; or wherein n and m have the same significance as above, Y is phenyl, benzyl or a 1-5 carbon alkyl group; wherein T and W may be the same or different and are alkylene;aryl, benzyl or cycl oal kyl ; and P and Q may be the same,or one of them may be H or they may combine to form a ring with the nitrogen to which they are attached. Either or both of and Q may be selected from any of the following : (a) C 1 -C 6 straight or branched chain alkyl groups or C 1 -C 6 straight or branched chain alkenyl groups, any one of which may be substituted with any of halo hydroxy, alkoxy, aryloxy amino; alkylamino, dialkylamino, alkylacylamino, arylamino,guanidino, thioguanidino, nitroguanidino, hydrazino, ureido, nitro, mercaptocarbonyl, hydroxyamino, histidinyl, cyano, imidazolyl, indolyl, mercapto, alkylthio, arylthio, carboxy amido or carboalkoxy, wherein the alkyl groups contain 1-6 carbon atoms; (b) cycloalkyl or cycloalkyl alkylene wherein cycloalkyl has 4-12 carbons, and alkylene 1-5 carbons, which may be substituted with any of -OH, -5H, halo, COOH, COSH, CONH 2 , NO 2 NH 2 , NO 2 , CH 3 -OCH 3 , , hydrazine, ureido, -SCH 3 , hydroxyamino, cyano, guanidino, thioguanidino or nitroguanidino groups; (c) aralkyl or alkaryl groups which may be ring substituted with one or more of the following: SH, halo, CH 2 OO H , CH 2 CONH 2 ,CH 2 CONH-alkyl, COSH, COOH, CONH 2 CONH-alkyl; CH 2 COSH, CH 2 SH, CH 2 OH, OH, NO 2 , amino, alkyl, alkoxy, aralkyloxy,alkylthio, and aralkylthio groups, wherein the alkyl groups contain 1-6 carbons and may also alternatively be chain substituted with -CH 3 , -OH, -OCH 3 , -NHOH or a thio or nitro derivative thereof, -COOH, or COSH; (d) an aryl heterocyclic or adamantanyl group which may be ring-substituted with at least one group selected from halo, -OH, -0-alkyl, -0-aryl, NH 2 , NN-alkyl, nitroguanidino, hydrazino,ureido, nitro, mercaptocarbonyl, hydroxymina, cyno imidazolyl,indanyl, histidinyl, -SH, when P and Q join with N to form a ring, the ring may be any 4-10 membered heterocyclic ring which contains a nitrogen with only two of its valences attached to other ring members. B. Alternatively R 1 may be and R 3 may be (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 or a thiol analog of either; (iii) mercaptoalkylene of 1 - 6 carbons; (iv) phenylakylene wherein the alkylene group has 1-6 carbons; (v.) phenylthioalkylene or benzylthioalkylene wherein the alkylene group has 1- 6 carbons; (vi) alkylthioalkylene wherein the alkyl and alkylene groups have 1 3 carbons; Wherein x and γ are 0 or 1, X nay be S, 0 or - N-R q and R q may be -H or -CN 3 ; R 10 is H, CH 3 , F, Cl or Br; m is 0 or 1, R 2 is COOH,CH 2 COOH, COSH, CH 2 COSH, CH 2 SH, CH 2 ,CH 2 SH, a physiologically acceptable nontoxic salt of any of them; COOY, CH 2 COOY, COSY, CH 2 SY, or CH 2 CH 2 SY wherein Y is phenyl, benzyl or a 1-5 carbon alkyl group, or wherein either of A 1 and A 2 may be H, phenyl, benzyl or a 1-5 carbon 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: or wherein G is an alkacyl or alkacyloxy group of 1 6 carbons, a benzoyl or benzoyloxy group, or a phenylalkacyl or phenylalkacyloxy 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, alkylcarbonyloxyphenyl, hydrazinophenyl, ureidophenyl, alkylcarbonylaminophenyl, alkylcarbonylthiophenyl, alkyloxyphenyl and hydroxyaminophenyl, 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 or substituted with up to two groups selected from among carboxy, amino, nitro, halo, hydroxy, mercapto, mercaptocarbonyl, hydroxyamino, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylcarbonylamino, alkylcarbonylthio, cyanohydrazino, ureido and alkyloxy, wherein all alkyl groups contain 1 6 carbon atoms: (xxii) guanidino alkylene, thioguanidinoalkylene, or nitroguanidino alkylene in which the alkylane 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 the following: NH 2 , -OZ, · SZ, halogen, .-CN -NO 2 , -COOZ, COSZ, CONH 2 , NHNH 2 , alkyl, alkylcarbonyl, alkylcarbonyloxy,alkylcarbonylamino, haloalkyl, dihaloalkyl, trihalomethy, hydroxyamino, alKyl: carbonylthio, phenoxy, and benzyloxy wherein the alkyl groups contain1- 6 carbon. atoms and Z has the same significance as above; (xxiv) amidoaalkylene 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 from among phenothiazinyl, pyrrolidinyl, pyrrolyl, quinolinyl, imidazolyl,pyridyl, thyminyl, benzothiazinyl,. indolyl, thienyl; puriny, piperidinyl, morpholinyl, azaindolyl, pyrazinyl, pyrimidyl, piperonyl, piperazinyl, furanyl, thiazolyl and thiazolidinyl, cytasinyl; (xxviii) alkylene or alkenyl groups 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 on the heterocyclic ring selected from among - OZ, SZ,- COOZ,- N0 2 - NH 2 , COSZ, halogen, haloalkyl, dihaloalkyl,trihalomethyl, cyano, CONH 2 alkyl, alkylcarbonyl, alkylcarbonyloxy, alkyl- carbonylthio, phenoxy, benzyloxy, and HONH wherein Z has the same significance as above; (xxx) groups from (xxvii), (xxviii) or (xxix) attached to one valence of an etheric. -O- or -S-; (xxxi) mono- di- or tri-alkyl, alkenyl- or phenyl-silyl or -selenyl wherein the alkyl or alkenyl groups contain 1- 6 carbons; (xxxii) any of H, 1-5 carbon straight or branched chain alkyl, phenyl, -OH, alkoxy of 1 6 carbons, benzyloxy, benzyloxyalkylene or phenoxyalkylene wherein the alkylene has 1- 5 carbons, alkoxyalkylene having 1 - 5 carbons in the alkoxy and alkelene 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 - aminomethyl-benzyl, acetamidoalkyl of 1 - 5 carbons, benzylthiomethylene, or dimethylaminoalkyl of 1 -5 carbons. C. Alternatively, R 3 may be and R 1 may be any of groups (i) - (xxxii) above or 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, imidazolyl- alkyl wherein the alkyl group contains 1 - 5 carbons, phenoxymethyl, phenylthiomethyl, 4-aminomethyl benzyl, 2-aminophene- thyl, naphthylethyl, 4-halophenethyl, 3, 4-dihalophenethyl or phenoxyphenethyl, or R and R 2 together may form with -CH a lactone ring of the formula: or an analogous six-membered ring