Non-peptidyl vasopressin V1a antagonists

A method for the antagonism of the vasopressin V1a 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

• where
• R1 is hydrogen, C1-C5 alkyl, —C(O)NR5X′, (C1-C4 alkylene)C(O)NR5X′, hydroxy substituted C1-C5 alkyl, C1-C5 acyl optionally substituted as the ethylene glycol ketal, C3-C6 cycloalkylcarbonyl, benzoyl, phenyl, phenyl(C1-C4 alkylene), phenoxyacetyl, phenylacetyl where the phenyl is optionally substituted with halo, C1-C4 alkyl, C1-C4 alkoxy, or trifluoromethyl, or α-hydroxy-α-benzoylbenzyl;
• R2 is hydrogen, or hydroxy substituted C1-C5 alkyl;
• R3 is phthalimido, azido, phenoxyacetamido, 4,5-diphenyloxazol-2-on-3-yl, or a structure selected from the group consisting of
• R4 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 C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, nitro, halo, carboxy, and amido;
• Q is —O—, —S—, or —NR5—;
• R5 is hydrogen, hydroxy, C1-C4 alkoxycarbonyl, benzyl, or C1-C4 alkyl;
• R6 is C1-C8 alkyl, C3-C8 cycloalkyl, phenyl, or phenyl(C1-C4 alkylene) optionally substituted on the alkylene chain with C1-C4 alkoxycarbonyl;
• X and X′ are independently hydrogen, C1-C6 alkyl, 2-(trimethylsilyl)ethyl, C1-C4 alkyl ω-substituted with C1-C4 alkoxy, Y, (optionally substituted C1-C4 alkylene)-Y, or (optionally substituted C2-C4 alkylene)-NR7R8;
• Y is phenyl, optionally substituted phenyl, diphenylmethyl, C3-C6 cycloalkyl, naphthyl, tetrahydronaphthyl, indanyl, fluorenyl, pyrrolyl, 1-(C1-C4 alkyl)pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, furyl, benzodioxanyl, tetrahydrofuryl, pyrrolidinyl, 1-(C1-C4 alkyl)pyrrolidinyl, 1-benzylpyrrolidinyl, piperidinyl, 1-benzylpiperidin-4-yl, or quinuclidinyl;
• R7 is hydrogen, or C1-C4 alkyl;
• R8 is C1-C4 alkyl, phenyl, or pyridinyl optionally substituted with nitro;
• R7 and R8 taken together with the nitrogen atom to which they are attached form morpholinyl, optionally substituted piperazinyl, or pyrrolidinyl;
• R5 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(C1-C4 alkylene);
• piperidinyl mono- or disubstituted with methyl;
• piperazinyl optionally substituted at the 4-position with C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, phenyl(C1-C4 alkylene), α-methylbenzyl, N-(C1-C4 alkyl)acetamid-2-yl, or C1-C4 alkoxycarbonyl;
• 1,2,3,4-tetrahydroisoquinolin-2-yl;
• or
• homopiperazinyl substituted in the 4-position with C1-C4 alkyl;
• R2, Q, and X taken together with the bridging carbon atoms to which they are attached form the lactone
• R10 is C1-C6 alkyl, C3-C6 cycloalkyl, phenyl(C1-C4 alkylene) where the phenyl is optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or halo, naphthyl, thienyl, furyl, benzothienyl, benzofuryl, or phenyl optionally monosubstituted with C1-C4 alkyl, C1-C4 alkoxy or halo;
• R11 is C1-C4 alkyl, C3-C7 cycloalkyl, phenyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkylsulfonylamino, and nitro, naphthyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, and nitro, or C1-C4 alkoxycarbonyl;
• R12 is:
• C1-C4 alkyl optionally monosubstituted with a substituent selected from the group consisting of hydroxy, protected carboxy, carbamoyl, thiobenzyl and C1-C4 thioalkyl;
• phenyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkylsulfonylamino, and nitro;
• naphthyl optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, and nitro;
• or
• C1-C4 alkoxycarbonyl;
• R13 is:
• C1-C4 alkoxycarbonyl;
• benzyloxycarbonyl where the phenyl group is optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, nitro, amino, carbamoyl, hydroxy, mono(C1-C4 alkyl)amino, and di(C1-C4 alkyl)amino;
• benzoyl where the phenyl group is optionally substituted with one or two substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkylsulfonylamino, and nitro;
• and
• R14 and R15 are:
• C1-C5 alkanoyloxy;
• benzoyloxy optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, nitro, amino and C1-C4 alkoxycarbonyl;
• benzyloxy;
• diphenylmethoxy;
• or
• triphenylmethoxy;
• or
• one of R14 and R15 is hydrogen and the other is:
• C1-C5 alkanoyloxy;
• benzoyloxy optionally substituted with one or two substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen, cyano, nitro, amino and C1-C4 alkoxycarbonyl;
• benzyloxy;
• diphenylmethoxy;
• or
• triphenylmethoxy;
• providing that R2 may be other than hydrogen only when R1 is hydroxy substituted C1-C5 alkyl;
• and hydrates, solvates and pharmaceutically acceptable acid addition salts thereof.