Patent ID: 6204260
Filing Date: 2001-03-20
Classification: A61P,C07D

Abstract:
A method for the antagonism of the vasopressin V.sub.1a receptor comprising administering to a mammal in need of such antagonism a pharmaceutically effective amount of a 2-(azetidin-2-on-1-yl)acetic acid derivative of Formula I ##STR15##whereR.sup.1 is hydrogen, C.sub.1 -C.sub.5 alkyl, --C(O)NR.sup.5 X', (C.sub.1 -C.sub.4 alkylene)C(O)NR.sup.5 X', hydroxy substituted C.sub.1 -C.sub.5 alkyl, C.sub.1 -C.sub.5 acyl optionally substituted as the ethylene glycol ketal, C.sub.3 -C.sub.6 cycloalkylcarbonyl, benzoyl, phenyl, phenyl(C.sup.1 -C.sup.4 alkylene), phenoxyacetyl, phenylacetyl where the phenyl is optionally substituted with halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, or trifluoromethyl, or .alpha.-hydroxy-.alpha.-benzoylbenzyl;R.sup.2 is hydrogen, or hydroxy substituted C.sub.1 -C.sub.5 alkyl;R.sup.3 is phthalimido, azido, phenoxyacetamido, 4,5-diphenyloxazol-2-on-3-yl, or a structure selected from the group consisting of ##STR16##R.sup.4 is:phenethyl, or 2-arylethen-1-yl where aryl is selected from the group consisting of furyl, pyrrolyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyrimidinyl, thiadiazolyl, oxadiazolyl, quinolyl, isoquinolyl, naphthyl, and phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, nitro, halo, carboxy, and amido;Q is --O--, --S--, or --NR.sup.5 --;R.sup.5 is hydrogen, hydroxy, C.sub.1 -C.sub.4 alkoxycarbonyl, benzyl, or C.sub.1 -C.sub.4 alkyl;R.sup.6 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 cycloalkyl, phenyl, or phenyl(C.sub.1 -C.sub.4 alkylene) optionally substituted on the alkylene chain with C.sub.1 -C.sub.4 alkoxycarbonyl;X and X' are independently hydrogen, C.sub.1 -C.sub.6 alkyl, 2-(trimethylsilyl)ethyl, C.sub.1 -C.sub.4 alkyl .omega.-substituted with C.sub.1 -C.sub.4 alkoxy, Y, (optionally substituted C.sub.1 -C.sub.4 alkylene)-Y, or (optionally substituted C.sub.2 -C.sub.4 alkylene)-NR.sup.7 R.sup.8 ;Y is phenyl, optionally substituted phenyl, diphenylmethyl, C.sub.3 -C.sub.6 cycloalkyl, naphthyl, tetrahydronaphthyl, indanyl, fluorenyl, pyrrolyl, 1-(C.sub.1 -C.sub.4 alkyl)pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, furyl, benzodioxanyl, tetrahydrofuryl, pyrrolidinyl, 1-(C.sub.1 -C.sub.4 alkyl)pyrrolidinyl, 1-benzylpyrrolidinyl, piperidinyl, 1-benzylpiperidin-4-yl, or quinuclidinyl;R.sup.7 is hydrogen, or C.sub.1 -C.sub.4 alkyl;R.sup.8 is C.sub.1 -C.sub.4 alkyl, phenyl, or pyridinyl optionally substituted with nitro;R.sup.7 and R.sup.8 taken together with the nitrogen atom to which they are attached form morpholinyl, optionally substituted piperazinyl, or pyrrolidinyl;R.sup.5 and X' taken together with the nitrogen to which they are attached form:2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl;piperidinyl optionally substituted at the 4-position with hydroxy, pyrrolidin-1-yl, piperidin-1-yl, benzyl, or piperidin-1-yl(C.sub.1 -C.sub.4 alkylene);piperidinyl mono- or disubstituted with methyl;piperazinyl optionally substituted at the 4-position with C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, phenyl, phenyl(C.sub.1 -C.sub.4 alkylene), .alpha.-methylbenzyl, N-(C.sub.1 -C.sub.4 alkyl)acetamid-2-yl, or C.sub.1 -C.sub.4 alkoxycarbonyl;1,2,3,4-tetrahydroisoquinolin-2-yl; orhomopiperazinyl substituted in the 4-position with C.sub.1 -C.sub.4 alkyl;R.sup.2, Q, and X taken together with the bridging carbon atoms to which they are attached form the lactone ##STR17##R.sup.10 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, phenyl(C.sub.1 -C.sub.4 alkylene) where the phenyl is optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy or halo, naphthyl, thienyl, furyl, benzothienyl, benzofuryl, or phenyl optionally monosubstituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy or halo;R.sup.11 is C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl optionally substituted with one or two substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C.sub.1 -C.sub.4 alkyl)amino, di(C.sub.1 -C.sub.4 alkyl)amino, C.sub.1 -C.sub.4 alkylsulfonylamino, and nitro, naphthyl optionally substituted with one or two substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C.sub.1 -C.sub.4 alkyl)amino, di(C.sub.1 -C.sub.4 alkyl)amino, and nitro, or C.sub.1 -C.sub.4 alkoxycarbonyl;R.sup.12 is:C.sub.1 -C.sub.4 alkyl optionally monosubstituted with a substituent selected from the group consisting of hydroxy, protected carboxy, carbamoyl, thiobenzyl and C.sub.1 -C.sub.4 thioalkyl;phenyl optionally substituted with one or two substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C.sub.1 -C.sub.4 alkyl)amino, di(C.sub.1 -C.sub.4 alkyl)amino, C.sub.1 -C.sub.4 alkylsulfonylamino, and nitro;naphthyl optionally substituted with one or two substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C.sub.1 -C.sub.4 alkyl)amino, di(C.sub.1 -C.sub.4 alkyl)amino, and nitro; orC.sub.1 -C.sub.4 alkoxycarbonyl;R.sup.13 is:C.sub.1 -C.sub.4 alkoxycarbonyl;benzyloxycarbonyl where the phenyl group is optionally substituted with one or two substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halogen, cyano, nitro, amino, carbamoyl, hydroxy, mono(C.sub.1 -C.sub.4 alkyl)amino, and di(C.sub.1 -C.sub.4 alkyl)amino;benzoyl where the phenyl group is optionally substituted with one or two substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C.sub.1 -C.sub.4 alkyl)amino, di(C.sub.1 -C.sub.4 alkyl)amino, C.sub.1 -C.sub.4 alkylsulfonylamino, and nitro; andR.sup.14 and R.sup.15 are:C.sub.1 -C.sub.5 alkanoyloxy;benzoyloxy optionally substituted with one or two substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halogen, cyano, nitro, amino and C.sub.1 -C.sub.4 alkoxycarbonyl;benzyloxy;diphenylmethoxy; ortriphenylmethoxy; orone of R.sup.14 and R.sup.15 is hydrogen and the other is:C.sub.1 -C.sub.5 alkanoyloxy;benzoyloxy optionally substituted with one or two substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halogen, cyano, nitro, amino and C.sub.1 -C.sub.4 alkoxycarbonyl;benzyloxy;diphenylmethoxy; ortriphenylmethoxy;providing that R.sup.2 may be other than hydrogen only when R.sup.1 is hydroxy substituted C.sub.1 -C.sub.5 alkyl; and hydrates, solvates and pharmaceutically acceptable acid addition salts thereof.