{Beta}-Lactamyl vasopression V1a antagonists and methods of use

Abstract

Novel 2-(azetidin-2-on-1-yl) alkanedioic acid derivatives and 2-(azetidin-2-on-1-yl) alkoxyalkanoic acid derivatives are described for use in the treatment of disease states responsive to antagonism of the vasopressin V 1a receptor.

1 . A method for treating a disease responsive to antagonism of a vasopressin V 1a  receptor in a mammal in need of such treatment, where the disease is selected from the group consisting of bi-polar disorder, obsessive-compulsive disorder, aggressive disorders, anxiety, depression, psychosis, schizophrenia, dementia, preterm labor, primary dysmenorrhoea, premenstrual dysmenorrhoea dysphoria, pain, inflammatory bowel disease, congestive heart failure, thrombosis, emesis, and combinations thereof; the method comprising the step of administering to the mammal a pharmaceutically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein: 
 n is an integer from 0 to 2;  
 A is XNH—, or R 5 XN—;  
 A′ is X′NH—, or R 5′ X′N—;  
 R 2  is hydrogen or C 1 -C 6  alkyl;  
 R 3  is a structure selected from the group consisting of  
                     
 R 4  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 3 -C 9  cycloalkenyl, limonenyl, pinenyl, C 1 -C 3  alkanoyl, optionally-substituted aryl, optionally-substituted aryl(C 1 -C 4  alkyl), optionally-substituted aryl(halo C 1 -C 4  alkyl), optionally-substituted aryl(alkoxy C 1 -C 4  alkyl), optionally-substituted aryl(C 2 -C 4  alkenyl), optionally-substituted aryl(halo C 2 -C 4  alkenyl), or optionally-substituted aryl(C 2 -C 4  alkynyl);  
 X is selected from the group consisting of C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, (C 1 -C 4  alkoxy)-(C 1 -C 4  alkyl), optionally-substituted aryl, optionally-substituted aryl(C 1 -C 4  alkyl), optionally-substituted aryl(C 3 -C 7  cycloalkyl), optionally-substituted indan-1-yl, optionally-substituted indan-2-yl, optionally-substituted 1,2,3,4-tetrahydronaphth-1-yl, optionally-substituted 1,2,3,4-tetrahydronaphth-2-yl, the heterocycle Y, Y—(C 1 -C 4  alkyl), R 7 R 8 N—, and R 7 R 8 N—(C 2 -C 4  alkyl); and  
 R 5  is selected from the group consisting of hydroxy, C 1 -C 6  alkyl, C 1 -C 4  alkoxycarbonyl, and benzyl; or R 5  and X are taken together with the attached nitrogen atom to form an optionally substituted heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, and homopiperazinyl, where said heterocycle is optionally substituted with R 10 , R 12 , R 7 R 8 N—, or R 7 R 8 N—(C 1 -C 4  alkyl);  
 X′ is selected from the group consisting of C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, (C 1 -C 4  alkoxy)-(C 1 -C 4  alkyl), optionally-substituted aryl, optionally-substituted aryl(C 1 -C 4  alkyl), optionally-substituted aryl(C 3 -C 7  cycloalkyl), optionally-substituted indan-1-yl, optionally-substituted indan-2-yl, optionally-substituted 1,2,3,4-tetrahydronaphth-1-yl, optionally-substituted 1,2,3,4-tetrahydronaphth-2-yl, the heterocycle Y′, Y′—(C 1 -C 4  alkyl), R 7′  R 8′ N—, and R 7′  R 8′  N—(C 2 -C 4  alkyl); and  
 R 5′  is selected from the group consisting of hydroxy, C 1 -C 6  alkyl, C 1 -C 4  alkoxycarbonyl, and benzyl; or R 5′  and X′ are taken together with the attached nitrogen atom to form an optionally substituted heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, and homopiperazinyl, where said heterocycle is optionally substituted with R 10 , R 12′ , R 7′  R 8 N—, or R 7′  R 8 N—(C 1 -C 4  alkyl);  
 where the heterocycle Y and the heterocycle Y′ are each independently selected from the group consisting of tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally  N -substituted with C 1 -C 4  alkyl or optionally-substituted aryl(C 1 -C 4  alkyl);  
 R 7  is hydrogen or C 1 -C 6  alkyl; and R 8  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, optionally-substituted aryl, or optionally-substituted aryl(C 1 -C 4  alkyl); or R 7  and R 8  are taken together with the attached nitrogen atom to form an heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where said piperazinyl or homopiperazinyl is optionally  N -substituted with R 12 ;  
 R 7′  is hydrogen or C 1 -C 6  alkyl; and R 8′  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, optionally-substituted aryl, or optionally-substituted aryl(C 1 -C 4  alkyl); or R 7′ and R 8′ are taken together with the attached nitrogen atom to form an heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where said piperazinyl or homopiperazinyl is optionally  N -substituted with R 12′ ;  
 R 10  and R 11  are each independently chosen from the group consisting of hydrogen, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 4  alkoxycarbonyl, C 1 -C 5  alkanoyloxy, benzyloxy, benzoyloxy, diphenylmethoxy, triphenylmethoxy, optionally-substituted aryl, and optionally-substituted aryl(C 1 -C 4  alkyl); where the C 1 -C 6  alkyl or the C 3 -C 8  cycloalkyl is optionally monosubstituted with a substituent selected from the group consisting of hydroxy, protected carboxy, carbamoyl, thiobenzyl and C 1 -C 4  thioalkyl; and the benzyl of said benzyloxy or said benzoyloxy is optionally substituted with one or two substituents independently selected from the group consisting of C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C 1 -C 4  alkyl)amino, di(C 1 -C 4  alkyl)amino, C 1 -C 4  alkylsulfonylamino, and nitro; and  
 R 12  and R 12′ are each independently selected from the group consisting of hydrogen, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 4  alkoxycarbonyl, optionally-substituted aryloxycarbonyl, optionally-substituted aryl(C 1 -C 4  alkyl), and optionally-substituted aryloyl;  
 providing that when A is XNH— and the integer n is 0, then A′ is not anilinyl, substituted anilinyl, benzylamino, or substituted benzylamino.  
 
     
     
         2 . The method of  claim 1  wherein the disease state is selected from the group consisting of bi-polar disorder, obsessive-compulsive disorder, anxiety, depression, primary dysmenorrhoea, premenstrual dysmenorrhoea dysphoria, and combinations thereof.  
     
     
         3 . The method of  claim 1  wherein the disease is anxiety.  
     
     
         4 . The method of  claim 1  wherein the disease, is depression.  
     
     
         5 . The method of  claim 1  wherein the disease is primary dysmenorrhoea.  
     
     
         6 . The method of  claim 1  wherein the disease is premenstrual dysmenorrhoea dysphoria.  
     
     
         7 . A method for treating a disease responsive to antagonism of a vasopressin V 1a  receptor in a mammal in need of such treatment, where the disease is selected from the group consisting of bi-polar disorder, obsessive-compulsive disorder, aggressive disorders, anxiety, depression, psychosis, schizophrenia, dementia, preterm labor, primary dysmenorrhoea, premenstrual dysmenorrhoea dysphoria, pain, inflammatory bowel disease, congestive heart failure, thrombosis, emesis, and combinations thereof; the method comprising the step of administering to the mammal a pharmaceutically effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein: 
 n′ is an integer from 1 to 3;  
 A is XNH—, or R 5 XN—;  
 R 2  is hydrogen or C 1 -C 6  alkyl;  
 R 3  is a structure selected from the group consisting of  
                     
 R 4  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 3 -C 9  cycloalkenyl, limonenyl, pinenyl, C 1 -C 3  alkanoyl, optionally-substituted aryl, optionally-substituted aryl(C 1 -C 4  alkyl), optionally-substituted aryl(halo C 1 -C 4  alkyl), optionally-substituted aryl(alkoxy C 1 -C 4  alkyl), optionally-substituted aryl(C 2 -C 4  alkenyl), optionally-substituted aryl(halo C 2 -C 4  alkenyl), or optionally-substituted aryl(C 2 -C 4  alkynyl);  
 X is selected from the group consisting of C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, (C 1 -C 4  alkoxy)-(C 1 -C 4  alkyl), optionally-substituted aryl, optionally-substituted aryl(C 1 -C 4  alkyl), optionally-substituted aryl(C 3 -C 7  cycloalkyl), optionally-substituted indan-1-yl, optionally-substituted indan-2-yl, optionally-substituted 1,2,3,4-tetrahydronaphth-1-yl, optionally-substituted 1,2,3,4-tetrahydronaphth-2-yl, the heterocycle Y, Y—(C 1 -C 4  alkyl), R 7 R 8 N—, and R 7 R 8 N—(C 2 -C 4  alkyl); and  
 R 5  is selected from the group consisting of hydroxy, C 1 -C 6  alkyl, C 1 -C 4  alkoxycarbonyl, and benzyl; and where X is selected from the group consisting of C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, (C 1 -C 4  alkoxy)-(C 1 -C 4  alkyl), optionally-substituted aryl, optionally-substituted aryl(C 1 -C 4  alkyl), optionally-substituted aryl(C 3 -C 7  cycloalkyl), optionally-substituted indan-1-yl, optionally-substituted indan-2-yl, optionally-substituted 1,2,3,4-tetrahydronaphth-1-yl, optionally-substituted 1,2,3,4-tetrahydronaphth-2-yl, the heterocycle Y, Y—(C 1 -C 4  alkyl), R 7 R 8 N—, and R 7 R 8 N—(C 2 -C 4  alkyl); or R 5  and X are taken together with the attached nitrogen atom to form an optionally substituted heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, and homopiperazinyl, where said heterocycle is optionally substituted with R 10 , R 12 , R 7 R 8 N—, or R 7 R 8 N—(C 1 -C 4  alkyl);  
 R 6′  is selected from the group consisting of C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, (C 1 -C 4  alkoxy)-(C 1 -C 4  alkyl), optionally-substituted aryl(C 1 -C 4  alkyl), Y′—(C 1 -C 4  alkyl), and R 7′  R 8′ N—(C 2 -C 4  alkyl);  
 where the heterocycle Y and the heterocycle Y′ are each independently selected from the group consisting of tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl is optionally  N -substituted with C 1 -C 4  alkyl or optionally-substituted aryl(C 1 -C 4  alkyl);  
 R 7  is hydrogen or C 1 -C 6  alkyl; and R 8  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, optionally-substituted aryl, or optionally-substituted aryl(C 1 -C 4  alkyl); or R 7  and R 8  are taken together with the attached nitrogen atom to form an heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where said piperazinyl or homopiperazinyl is optionally  N -substituted with R 12 ;  
 R 7′ is hydrogen or C 1 -C 6  alkyl; and R 8′ is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, optionally-substituted aryl, or optionally-substituted aryl(C 1 -C 4  alkyl); or R 7′  and R 8′  are taken together with the attached nitrogen atom to form an heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; where said piperazinyl or homopiperazinyl is optionally  N -substituted with R 12′ ;  
 R 10  and R 11  are each independently chosen from the group consisting of hydrogen, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 4  alkoxycarbonyl, C 1 -C 5  alkanoyloxy, benzyloxy, benzoyloxy, diphenylmethoxy, triphenylmethoxy, optionally-substituted aryl, and optionally-substituted aryl(C 1 -C 4  alkyl); where the C 1 -C 6  alkyl or the C 3 -C 8  cycloalkyl is optionally monosubstituted with a substituent selected from the group consisting of hydroxy, protected carboxy, carbamoyl, thiobenzyl and C 1 -C 4  thioalkyl; and where the benzyl of said benzyloxy or said benzoyloxy is optionally substituted with one or two substituents independently selected from the group consisting of C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halogen, hydroxy, cyano, carbamoyl, amino, mono(C 1 -C 4  alkyl)amino, di(C 1 -C 4  alkyl)amino, C 1 -C 4  alkylsulfonylamino, and nitro; and  
 R 12  and R 12′  are each independently selected from the group consisting of hydrogen, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 4  alkoxycarbonyl, optionally-substituted aryloxycarbonyl, optionally-substituted aryl(C 1 -C 4  alkyl), and optionally-substituted aryloyl.  
 
     
     
         8 . The method of  claim 7  wherein the disease is selected from the group consisting of bi-polar disorder, obsessive-compulsive disorder, anxiety, depression, primary dysmenorrhoea, and premenstrual dysmenorrhoea dysphoria, and combinations thereof.  
     
     
         9 . The method of  claim 7  wherein the disease state is anxiety.  
     
     
         10 . The method of  claim 7  wherein the disease state is depression.  
     
     
         11 . The method of  claim 7  wherein the disease state is primary dysmenorrhoea.  
     
     
         12 . The method of  claim 7  wherein the disease state is premenstrual dysmenorrhoea dysphoria.