Neuropeptide Y antagonists

Abstract

Compounds of the formula are neuropeptide Y antagonists and are effective in treating feeding disorders, cardiovascular diseases and other physiological disorders related to an excess of neuropeptide Y.

1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       Wherein: A is —CH═; X is:  
       
         
           
           
               
               
           
         
         R 1  is phenyl, thienyl or pyridyl each optionally substituted with one to three substituents selected from halogen, —OCF 3 , NO 2 , CN, hydroxy, alkylalkoxy, COOH, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, aryl, heteroaryl, alkoxy, acyloxy, NR 7 R 8 , C 1 -C 4 alkylthio, mono-, di-, or trihaloalkyl; or  
         
           
             
             
                 
                 
             
           
         
         wherein;  
         R is phenyl, substituted phenyl, heteroaryl, C 1 -C 6 alkyl, hydrogen, OH, or alkoxy;  
         R 2  is hydrogen or (C 1 -C 3 alkyl) 2 ;  
         R 3  and R 4  are independently hydrogen, hydroxyl, -N(C 1 -C 3 alkyl) 2 , nitro, cyano, alkylalkoxy, or aryloxy;  
         Y is hydrogen, C 1 -C 6  alkyl, or pyridyl; n is 1 to 3; and m is 1 to 3; R 7  and R 8  are C 1 -C 6  alkyl;  
         and with the proviso that if R 1  is phenyl, R 2  is hydrogen and Y is methyl; X must not be 1-pyrrolidine.  
       
     
     
         2 . A compound of  claim 1  wherein: 
 A is —CH═;  
 n is 2or 3;  
 R 3  is —H or —CH 3 ;  
 R 4  is —H;  
 Y is methyl;  
 R 2  is hydrogen; and  
 R 1  is 3-chlorophenyl, 4-chlorophenyl or thienyl.  
 
     
     
         3 . A compound of  claim 1  wherein: 
 A is —CH═;  
 n is 2;  
 R 3  is H or methyl;  
 R 4  is H;  
 Y is methyl;  
 R 1  is phenyl, halogenated phenyl, or trifluoro methoxyphenyl.  
 
     
     
         4 . A compound selected from the group consisting of: 
 7-Azetidin-1-yl-5-methyl-2-phenyl-pyrazolo[1,5-a]pyrimidine;    2-Phenyl-5-pyridin-2-yl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine;    5-Methyl-7-pyrrolidin-1-yl-2-thiophen-2-yl-pyrazolo[1,5-a]pyrimidine;    2-(3-Chloro-phenyl)-5-methyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine;    2-(4-Chloro-phenyl)-5-methyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine;    5-Methyl-7-pyrrolidin-1-yl-2-(4-trifluoromethoxy-phenyl)-pyrazolo[1,5-a]pyrimidine;    Dimethyl-(8-phenyl-6-pyrrolidin-1-yl-7H-purin-2-yl)-amine;    [4-(5-Methyl-7-pyrrolidin- 1-yl-pyrazolo[1,5-a]pyrimidin-2-yl)-phenyl]-methanol;    2-(4-Chloro-phenyl)-5-methyl-7-(2-methyl-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidine;    2-(4-Chloro-phenyl)-5-methyl-7-piperidin-1-yl-pyrazolo[1,5-a]pyrimidine;    {1(S)-[2-(4-Chloro-phenyl)-5-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-pyrrolidin-3-yl}-dimethyl-amine;    {1(R)-[2-(4-Chloro-phenyl)-5-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-pyrrolidin-3-yl}-dimethyl-amine;    2-(4-Chloro-phenyl)-5-methyl-7-(2-methyl-piperidin-1-yl)-pyrazolo[1,5-a]pyrimidine;    1-[2-(4-Chloro-phenyl)-5-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-pyrrolidin-3-ol;    2-[4-(4-Ethyl-piperazin-1-ylmethyl)-phenyl]-5-methyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine;    Benzyl-[4-(5-methyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidin-2-yl)-benzyl]-amine; and    5-Methyl-2-pyridin-4-yl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine.    
     
     
         5 . A method of inhibiting or alleviating a pathological condition in a mammal characterized by an excess of neuropeptide Y which comprises administering to a mammal in need of such treatment a neuropeptide Y inhibiting amount of the compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein; 
 A is —N or —CR 1 ; 
 X is NR 4 R 5  where R 4  and R 5  are selected independently from C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 8  cycloalkenyl, C 2 -C 8  alkynyl, C 2 -C 8  alkylalkoxy, alkylaryl, alkylheteroaryl, SO 2 R 7 , or SO 2 NR 7 R 8 ; each optionally substituted with 1-2 substituents independently selected from R 6 ; or R 4  and R 5 are taken together to be C 3 -C 8  cycloalkyl, optionally substituted with 1-2 substituents independently selected from R 6 ; C 5 -C 8  cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R 6 ; or a heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR 7 —, and —S(O)m— optionally substituted with 1-3 substituents independently selected from R 6 ; when R 4  and R 5  are taken together to be C 3 -C 8  cycloalkyl, C 5 -C 8  cycloalkenyl, or a heterocyclic ring as described above then said ring system may be further substituted to form an additional 3-8 membered ring optionally containing up to two heteroatoms selected from the group consisting of —O—, —NR 7 —, and —S(O)m—; R 5  may be selected from NR 7 R 8 ;  
 R 6  is selected independently from hydrogen; halogen, nitro, cyano, hydroxy, alkylalkoxy, COOH, C 1 -C 6  alkyl; C 1 -C 6  hydroxyalkyl, C 1 -C 6  aminoalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, alkoxy; acyloxy, NR 7 NR 8 , C 1 -C 4  alkylthio, mono-, di-, or trihaloalkyl;  
 R 7  and R 8  are independently selected from H, C 1 -C 6  alkyl; C 2 -C 6  alkenyl, alkylalkoxy, C 2 -C 6  alkynyl, aryl, or heteroaryl; and may be joined to form a carbocyclic or heterocyclic ring;  
 R 1  is selected from H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 8  cycloalkenyl, or C 2 -C 8  alkynyl, or alkylalkoxy, or R 1  and X may be joined together to form a 5-8 membered nitrogen-containing ring optionally containing an additional heteroatom selected from the group consisting of —O—, —NR 7 —, and —S(O)m— (m=0-2), and said 5-8 membered ring optionally substituted with 1-2 substituents chosen from R 6 ; said 5-8 membered ring may also contain a carbonyl group; R 1  and Y may be joined together to form a 5-8 membered ring optionally containing a heteroatom selected from the group consisting of —O—, —NR 7 —, and —S(O)m— and said 5-8 membered ring optionally substituted with 1-2 substituents chosen from R 6 , as well as said 5-8 membered ring containing a carbonyl group;  
 Y is selected from C 1 -C 6  alkyl; alkoxyalkyl, C 2 -C 6 -alkenyl; C 2 -C 6 -alkynyl, alkoxy, aryl, or heteroaryl, or NR 4 R 5  as defined for X;  
 R 2  is H;  
 R 3  is selected from aryl or heteroaryl optionally substituted with 1-3 substituents chosen from R 6 .  
 
 
     
     
         6 . The method of  claim 5  wherein said pathological condition is obesity or bulimia.  
     
     
         7 . The method of  claim 5  wherein said pathological condition is selected from the group consisting of: disorders or diseases pertaining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure; 
 conditions related to increased sympathetic nerve activity for example, during or after coronary artery surgery, and operations and surgery in the gastrointestinal tract;  
 cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemorrhage, depression, anxiety, schizophrenia, and dementia;  
 conditions related to pain or nociception;  
 diseases related to abnormal gastrointenstinal motility and secretion, such as different forms of ileus, urinary incontinence, and Crohn's disease;  
 abnormal drink and food intake disorders, such as anorexia and metabolic disorders;  
 diseases related to sexual dysfunction and reproductive disorders;  
 conditions or disorders associated with inflammation;  
 respiratory diseases, such as asthma and conditions related to asthma and bronchoconstriction; and diseases related to abnormal hormone release, such as leutinizing hormone, growth hormone, insulin, and prolactin.  
 
     
     
         8 . A pharmaceutical composition for inhibiting or alleviating a pathological condition or physiological disorder in a mammal characterized by or associated with an excess of neuropeptide Y, which comprises a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
     
     
         9 . A compound of Formula I wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature; including  2 H,  3 H,  13 C,  14 C,  15 N, 18O, 17O,  31 P,  32 P,  35 S,  18 F, and  36 Cl.  
     
     
         10 . The compound which is 7-Pyrrolidin-1-yl-5-methyl-2-phenyl-pyrazolo[1,5a]pyrimidine.  
     
     
         11 . The compound which is 5-Isopropyl-2-phenyl-7-pyrrolidin-1-yl-pyrazolo[1,5a]pyrimidine.  
     
     
         12 . The compound which is 5-Ethyl-2-phenyl-7-pyrrolidin-1-yl-pyrazolo[1,5 a]pyrimidine.  
     
     
         13 . The compound which is 2,5-Diphenyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine.  
     
     
         14 . The method of  claim 5  wherein said mammal is a dog or cat.