Non-peptidic npy y2 receptor inhibitors

Abstract

The invention provides novel non-peptidic NPY Y2 receptor inhibitors useful in treating or preventing: anxiolytic disorders or depression; injured mammalian nerve tissue; conditions responsive to treatment through administration of a neurotrophic factor; neurological disorders; bone loss; substance related disorders; obesity; or an obesity-related disorder. Compounds of the invention are also useful in modulating endocrine functions, particularly endocrine functions controlled by the pituitary and hypothalamic glands, and are therefore useful in the treatment or prevention of inovulation and infertility.

1 - 10 . (canceled) 
     
     
         11 . A method for the treatment or prevention of disease states mediated by NPY Y2 receptor activity comprising the step of administering to a mammal suffering there from a therapeutically effective amount of compound having NPY Y2 receptor activity of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 the fused pyrrolidine ring optionally contains a single carbon-carbon double bond or a single carbon ring member adjacent to the nitrogen is optionally ═O substituted; 
 n is 1 or 2; 
 m is 0, 1, or 2; 
 Y 1  is a C 0-5  alkylene, C 0-5  alkenylene, C 0-5  alkynylene, C 0-5 acylene; —CH(CONR f R g )— (where R f  and R g  are independently H or C 1-4 alkyl), or —CH(CO 2 C 1-4 alkyl)-; 
 Y 2  is H, phenyl, C 4-8  cycloalkyl or C 4-8  cycloalkenyl, each ring optionally substituted with R q ; 
 Y 3  is —CH 2 —, carbonyl or sulfone; 
 Y 4  is a substituted or unsubstituted C 2-7  alkyl, C 2-7  alkenyl, C 2-7  alkynyl or C 3-7 cycloalkyl; 
 Y 5  is phenyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, naphthalenyl, quinolonyl, purinyl, indolyl, benzofuranyl, or benzothiophenyl, each optionally mono-, di- or tri-substituted with R q ; 
 R 1  is H or is 
 
       
         
           
           
               
               
           
         
         where R a  is H, a substituted or unsubstituted C 1-5  alkyl, C 1-5  alkenyl, C 1-5  alkynyl or C 1-5  acyl, where the substituent is C 1-4 alkoxy or one or more fluoro; 
         R 2  and R 3  are independently selected from H, a substituted or unsubstituted C 1-5  alkyl, C 1-5  alkenyl, or C 1-5  alkynyl, or R 2  and R 3  may be taken together with the nitrogen of R 3  attachment to form piperidine or pyrrolidine or azepanyl; and 
         R q  is selected from the group consisting of —OH, —C 1-6  alkyl, —OC 1-6  alkyl, Ph-, —OPh, benzyl, —Obenzyl, —C 3-6  cycloalkyl, —OC 3-6  cycloalkyl, —CN, —NO 2 , —N(R y )R z  (wherein R y  and R z  are independently selected from H, C 1-6  alkyl, C 1-6  alkenyl, or R y  and R z  may be taken together with the nitrogen of attachment to form an otherwise aliphatic hydrocarbon ring, said ring having 4 to 7 members, optionally having one carbon replaced with 0, ═N—, NH or N(C 1-4 alkyl), optionally having one carbon substituted with —OH, and optionally having one or two unsaturated bonds in the ring), —(C═O)N(R y )R z , —(N—R t )COR t , —(N—R t )SO 2 C 1-6 alkyl (wherein R t  is H or C 1-6 alkyl or two R t  in the same substituent may be taken together with the amide of attachment to form an otherwise aliphatic hydrocarbon ring, said ring having 4 to 6 members), —(C═O)C 1-6 alkyl, —(S═(O) n )—C 1-6 alkyl (wherein n is selected from 0, 1 or 2), —SO 2 N(R y )R z , —SCF 3 , halo, —CF 3 , —OCF 3 , —COOH and —COOC 1-6  alkyl; 
       
       and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof. 
     
     
         12 . A method of  claim 11  for treatment of an anxiolytic disorder or depression comprising administering to a subject suffering there from a therapeutically effective amount of a compound of claim  1  or enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof. 
     
     
         13 . A method of  claim 11  for treatment of injured mammalian nerve tissue comprising administering to a subject suffering there from a therapeutically effective amount of a compound of claim  1  or enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof. 
     
     
         14 . A method of  claim 11  comprising administering to a subject suffering from a condition amenable to treatment through administration of a neurotrophic factor a therapeutically effective amount of a compound of claim  1  or enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof. 
     
     
         15 . A method of  claim 11  for treatment of a neurological disorder comprising administering to a subject suffering there from a therapeutically effective amount of a compound of claim  1  or enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof. 
     
     
         16 . A method of  claim 11  for treatment of bone loss comprising administering to a subject suffering there from a therapeutically effective amount of a compound of claim  1  or enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof. 
     
     
         17 . A method of  claim 11  for treatment of obesity or an obesity-related disorder comprising administering to a subject suffering there from a therapeutically effective amount of a compound of claim  1  or enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof. 
     
     
         18 . A method of  claim 11  for treatment of infertility comprising administering to an infertile subject a therapeutically effective amount of a compound of claim  1  or enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof. 
     
     
         19 . A method of  claim 11  for treatment of an endocrine disorder comprising administering to a subject suffering there from a therapeutically effective amount of a compound of claim  1  or enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof. 
     
     
         20 . A method of  claim 11  for treatment of substance related disorders comprising administering to a subject suffering there from a therapeutically effective amount of a compound of claim  1  or enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof.