Beta-LACTAMYL VASOPRESSIN V1a ANTAGONISTS

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 in a mammal in need of such treatment, where the disease is selected from the group consisting of bi-polar disorder, obsessive-compulsive disorder, anxiety, depression, and co-morbid combinations thereof; the method comprising the step of administering to the mammal a pharmaceutically effective amount of a compound, or a composition comprising the pharmaceutically effective amount of the compound, and a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof, where the compound is 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 is anxiety. 
     
     
         3 . The method of  claim 1  wherein the disease is depression. 
     
     
         4 . The method of  claim 1  wherein the compound is of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein
 R 5  is H or C 1 -C 6  alkyl; and X is optionally substituted aryl(C 1 -C 4  alkyl); and 
 R 5′  and X′ are taken together with the attached nitrogen to form a heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, and homopiperazinyl, where the heterocycle is substituted with R 10 , R 12 , R 7′ R 8′ N—, or R 7′ R 8′ N—(C 1 -C 4  alkyl). 
 
     
     
         5 . The method of  claim 4  wherein the compound is of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or solvate thereof. 
     
     
         6 . The method of  claim 5  wherein R 5  is H. 
     
     
         7 . The method of  claim 5  wherein X is aryl(C 1 -C 4  alkyl). 
     
     
         8 . The method of  claim 5  wherein X is pheneth-1-yl. 
     
     
         9 . The method of  claim 5  wherein the compound is of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or solvate thereof. 
     
     
         10 . The method of  claim 5  wherein R 5  is C 1 -C 6  alkyl. 
     
     
         11 . The method of  claim 5  wherein R 5  is methyl. 
     
     
         12 . The method of  claim 5  wherein X is substituted benzyl. 
     
     
         13 . The method of  claim 5  wherein R 5  is CH 3 ; and X is 3-trifluoromethylbenzyl. 
     
     
         14 . 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, anxiety, depression, and co-morbid combinations thereof; the method comprising the step of administering to the mammal a pharmaceutically effective amount of a compound, or a composition comprising the pharmaceutically effective amount of the compound, and a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof, where the compound is 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 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. 
       
     
     
         15 . The method of  claim 14  wherein the disease is anxiety. 
     
     
         16 . The method of  claim 14  wherein the disease is depression. 
     
     
         17 . The method of  claim 14  wherein the compound is of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein
 R 5  and X are taken together with the attached nitrogen atom to form a heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, and homopiperazinyl, where said heterocycle is substituted with R 10 , R 12 , R 7 R 8 N—, or R 7 R 8 N—(C 1 -C 4  alkyl); and 
 R 6′  is optionally substituted aryl(C 1 -C 4  alkyl). 
 
     
     
         18 . The method of  claim 17  wherein R 5  and X are taken together with the attached nitrogen atom to form 4-[2-(piperidin-1-yl)ethyl]piperidin-1-yl. 
     
     
         19 . The method of  claim 17  wherein R 6′  is optionally substituted benzyl. 
     
     
         20 . The method of  claim 17  wherein R 5  and X are taken together with the attached nitrogen atom to form 4-[2-(piperidin-1-yl)ethyl]piperidin-1-yl; and R 6′  is benzyl.