2,7-substituted octahydro-1H-pyrido[1,2-A]pyrazine derivatives as ligands for serotonin receptors

Abstract

Substituted pyrido[1,2-a]pyrazines of general formula I; wherein Ar and Ar 1 represent various carbocyclic and heterocyclic aromatic rings; A represents O, S, SO, SO 2 , CHOH, C═O, or —(CR 3 R 4 ); and n is 0-2, as well as precursors thereto, are ligands for dopamine receptor subtypes and serotonin (5HT) within the body and are therefore useful in the treatment of disorders of the dopamine and serotonin systems:

1 . A method of treatment of a disease or condition which is caused by a disorder of the serotonin system which comprises administering to a mammal in need of such treatment a compound of the formula  
       
         
           
           
               
               
           
         
         wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, benzoxazolyl;  
         Ar 1  is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl;  
         A is O, S, SO, SO 2 , C═O, CHOH, or —(CR 3 R 4 )—;  
         n is 0, 1 or 2;  
         each of Ar and Ar 1  may be independently and optionally substituted with one to four substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, thiocyano, —SR, —SOR, —SO 2 R, —NHSO 2 R, -(C 1 -C 6 )alkoxy, —NRR, —NRCOR 1 , —CONR 1 R 2 , Ph, —COR, COOR, —(C 1 -C 6 )alkyl, trifluoromethoxy, and -(C 1 -C 6 )alkyl substituted with one to six halogens, -(C 3 -C 6 )cycloalkyl, or trifluoromethoxy;  
         each and every R, R 1 , and R 2  is independently selected from the group consisting of hydrogen, -(C 1 -C 6 )alkyl, -(C 1 -C 6 )alkyl substituted with one to thirteen halogens selected from fluorine, chlorine, bromine and iodine, phenyl, benzyl, -(C 2 -C 6 )alkenyl, -(C 3 -C 6 )cycloalkyl, and -(C 1  -C 6 )alkoxy;  
         each and every R 3  and R 4  is independently selected from a group consisting of hydrogen, methyl, ethyl, n-propyl, and i-propyl; or a  
         diastereomeric or optical isomers thereof; or a  
         pharmaceutically acceptable salt thereof.  
       
     
     
         2 . A method of  claim 1  wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, or quinolyl; Ar 1  is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; A is O, S, or CH 2 ; n is 0 or 1; and wherein Ar and Ar 1  are independently and optionally substituted with up to three substituents independently selected from the group consisting of fluoro, chloro, nitro, cyano, —NRR, -(CC 6 )alkoxy, —COOR, —CONR 1 R 2 , and -(C 1 -C 6 )alkyl.  
     
     
         3 . A method of  claim 2  wherein Ar is optionally substituted phenyl; Ar 1  is optionally substituted and is selected from phenyl, pyridinyl, and pyrimidinyl; A is O; and n is 1.  
     
     
         4 . A method of  claim 3  wherein Ar 1  is 5-fluoro-pyrimidin-2-yl or pyrimidin-2-yl.  
     
     
         5 . A method of  claim 1  wherein the compound of formula I is selected from: 
 (7S,9aS)-7-((3-Methyl-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl )-2,3,4,6, 7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;  
 (7S,9aS)-7-(3-carbomethoxy-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;  
 (7S,9aS)-7-(3-nitro-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1 ,2-a]pyrazine;  
 (7S,9aS)-7-(3-cyano-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro- 1H-pyrido[1 ,2-a]pyrazine;  
 (7S,9aS)-7-(3-methoxy-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;  
 (7S,9aS)-7-(3-acetamido-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;  
 (7S,9aS)-7-(3-(1, 1 -dimethyl)ethyl-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         6 . A method of treatment of a disease or condition which is caused by a disorder of the serotonin system or a disorder of the dopamine system which comprises administering to a mammal in need of such treatment a compound of the formula  
       
         
           
           
               
               
           
         
         wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, benzoxazolyl;  
         Ar 1  is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl;  
         A is O, S, SO, SO 2 , C═O, CHOH, or —(CR 3 R 4 )—;  
         n is 0, 1 or 2;  
         each of Ar and Ar 1  may be independently and optionally substituted with one to four substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, thiocyano, —SR, —SOR, —SO 2 R, —NHSO 2 R, -(C 1 -C 6 )alkoxy, —NRR , —NRCOR 1 —CONR 1 R 2 , Ph, —COR, COOR, -(C 1 -C 6 )alkyl, trifluoromethoxy, and -(C 1 -C 6 )alkyl substituted with one to six halogens, -(C 3 -C 6 )cycloalkyl, or trifluoromethoxy;  
         each and every R, R 1 , and R 2  is independently selected from the group consisting of hydrogen, -(C 1 -C 6 )alkyl, -(C 1 -C 6 )alkyl substituted with one to thirteen halogens selected from fluorine, chlorine, bromine and iodine, phenyl, benzyl, -(C 2- C 6 )alkenyl, -(C 3 -C 6 )cycloalkyl, and -(C 1  -C 6 )alkoxy;  
         each and every R 3  and R 4  is independently selected from a group consisting of hydrogen, methyl, ethyl, n-propyl, and i-propyl; or a  
         diastereomeric or optical isomers thereof; or a  
         pharmaceutically acceptable salt thereof; in an amount effective to treat said disease or condition.  
       
     
     
         7 . A method of  claim 6  wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, or quinolyl; Ar 1  is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; A is O, S, or CH 2 ; n is 0 or 1; and wherein Ar and Ar 1  are independently and optionally substituted with up to three substituents independently selected from the group consisting of fluoro, chloro, nitro, cyano, —NR 1 R 2 , -(C 1 C 6 )alkoxy, —COOR, —CONR 1 R 2 , and -(C 1 -C 6 )alkyl.  
     
     
         8 . A method of  claim 7  wherein Ar is optionally substituted phenyl; Ar 1  is optionally substituted and is selected from phenyl, pyridinyl, and pyrimidinyl; A is O; and n is 1.  
     
     
         9 . A method of  claim 8  wherein Ar 1  is 5-fluoro-pyrimidin-2-yl or pyrimidin-2-yl.  
     
     
         10 . A method of  claim 6  wherein the compound of formula I is selected from: 
 (7S,9aS)-7-((3-Methyl-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;  
 (7S,9aS)-7-(3-carbomethoxy-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;  
 (7S,9aS)-7-(3-n itro-phenoxy)methyl-2-(5-fluoropyrim idin-2-yl )-2 ,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;  
 (7S,9aS)-7-(3-cyano-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro- 1H-pyrido[1,2-a]pyrazine;  
 (7S,9aS)-7-(3-methoxy-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;  
 (7S,9aS)-7-(3-acetamido-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro- 1H-pyrido[1,2-a]pyrazine;  
 (7S,9aS)-7-(3-(1, 1 -dimethyl)ethyl-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         11 . A method of treating a disorder or condition selected from the group consisting of migraine, headache, cluster headache, anxiety, depression, dysthymia, major depressive disorder, panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, avoidant personality disorder, borderline personality disorder, phobia, a disorder of cognition, a memory disorder, a learning disorder (including age related memory disorder), a neurodegenerative disease (including Alzheimer's disease), anxiety and/or depression associated with senile dementia or Alzheimer's disease, cancer (including prostate cancer), cerebral infarct (including that caused by stroke, ischemia or traumatic head injury), a sexual disorder, dizziness, an eating disorder, pain, chemical dependency or addiction, peptic ulcer, and attention deficit hyperactivity disorder in a mammal, comprising administering to said mammal an amount of a compound of the formula  
       
         
           
           
               
               
           
         
         wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, benzoxazolyl;  
         Ar 1  is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl;  
         A is O, S, SO, SO 2 , C═O, CHOH, or —(CR 3 R 4 )—;  
         n is 0, 1 or 2;  
         each of Ar and Ar 1  may be independently and optionally substituted with one to four substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, thiocyano, —SR, —SOR, —SO 2 R, —NHSO 2 R, -(C 1 -C 6 )alkoxy, —NR 1 R 2 , —NRCOR 1 , —CONR 1 R 2 , Ph, —COR, COOR, -(C 1 -C 6 )alkyl, trifluoromethoxy, and -(C 1 -C 6 )alkyl substituted with one to six halogens, -(C 3 -C 6 )cycloalkyl, or trifluoromethoxy;  
         each and every R, R 1 , and R 2  is independently selected from the group consisting of hydrogen, -(C 1 -C 6 )alkyl, -(C 1 -C 6 )alkyl substituted with one to thirteen halogens selected from fluorine, chlorine, bromine and iodine, phenyl, benzyl, -(C 2 -C 6 )alkenyl, -(C 3 -C 6 )cycloalkyl, and -(C 1  -C 6 )alkoxy;  
         each and every R 3  and R 4  is independently selected from a group consisting of hydrogen, methyl, ethyl, n-propyl, and i-propyl; or a  
         diastereomeric or optical isomers thereof; or a  
         pharmaceutically acceptable salt thereof; effective to treat said disorder or condition.  
       
     
     
         12 . A method of  claim 11  wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, or quinolyl; Ar 1  is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; A is O, S, or CH 2 ; n is 0 or 1; and wherein Ar and Ar 1  are independently and optionally substituted with up to three substituents independently selected from the group consisting of fluoro, chloro, nitro, cyano, -NRLR. -(C, C 8 )alkoxy, —COOR, —CONR 1 R 2 , and -(C 1 -C 6 )alkyl.  
     
     
         13 . A method of  claim 12  wherein Ar is optionally substituted phenyl; Ar 1  is optionally substituted and is selected from phenyl, pyridinyl, and pyrimidinyl; A is O; and n is 1.  
     
     
         14 . A method of  claim 13  wherein Ar 1  is 5-fluoro-pyrimidin-2-yl or pyrimidin-2-yl.  
     
     
         15 . A method of  claim 11  wherein the compound of formula I is selected from: 
 (7S,9aS)-7-((3-Methyl-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;  
 (7S,9aS)-7-(3-carbomethoxy-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;  
 (7S,9aS)-7-(3-nitro-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;  
 (7S,9aS)-7-(3-cyano-phenoxy)methyl-2-(5-fl uoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine;  
 (7S,9aS)-7-(3-methoxy-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1 ,2-a]pyrazine;  
 (7S,9aS)-7-(3-acetamido-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro- 1H-pyrido[1 ,2-a]pyrazine;  
 (7S,9aS)-7-(3-(1,1-dimethyl)ethyl-phenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1 ,2-a]pyrazine;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         16 . A method according to  claim 11  wherein the disorder or condition being treated is migraine, headache, or cluster headache.  
     
     
         17 . A method according to  claim 11  wherein the disorder or condition being treated is anxiety, depression, dysthymia, major depressive disorder, panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, avoidant personality disorder, borderline personality disorder, or phobia.  
     
     
         18 . A method according to  claim 11  wherein the disorder or condition being treated is a disorder of cognition, a memory disorder, a learning disorder (including age related memory disorder), or a neurodgenerative disease (including Alzheimer's disease).  
     
     
         19 . A method according to  claim 11  wherein the disorder or condition being treated is anxiety and/or depression associated with senile dementia or Alzheimer's disease.  
     
     
         20 . A method according to  claim 11  wherein the disorder or condition being treated is cancer (including prostate cancer).  
     
     
         21 . A method according to  claim 11  wherein the disorder or condition being treated is cerebral infarct (including that caused by stroke, ischemia or traumatic head injury).  
     
     
         22 . A method according to  claim 21 , wherein the compound of formula I is administered in combination with a 5HT 2  antagonist.  
     
     
         23 . A method according to  claim 11  wherein the disorder or condition being treated is a sexual disorder.  
     
     
         24 . A method according to  claim 11  wherein the disorder or condition being treated is dizziness.  
     
     
         25 . A method according to  claim 11  wherein the disorder or condition being treated is an eating disorder.  
     
     
         26 . A method according to  claim 11  wherein the disorder or condition being treated is pain.  
     
     
         27 . A method according to  claim 11  wherein the disorder or condition being treated is chemical dependency or addiction.  
     
     
         28 . A method according to  claim 11  wherein the disorder or condition being treated is attention deficit hyperactivity disorder.  
     
     
         29 . A method according to  claim 11  wherein the disorder or condition being treated is peptic ulcer.  
     
     
         30 . A method according to  claim 1 , wherein the compound of formula I is administered in combination with a serotonin reuptake inhibitor.  
     
     
         31 . A method according to  claim 6 , wherein the compound of formula I is administered in combination with a serotonin reuptake inhibitor.  
     
     
         32 . A method according to  claim 11 , wherein the compound of formula I is administered in combination with a serotonin reuptake inhibitor.  
     
     
         33 . A method according to  claim 17 , wherein the compound of formula I is administered in combination with a serotonin reuptake inhibitor.  
     
     
         34 . A method according to  claim 27 , wherein the compound of formula I is administered in combination with a serotonin reuptake inhibitor.  
     
     
         35 . A method of imaging an organ in a mammal, comprising administering to said mammal a radioactive form of a compound of the formula  
       
         
           
           
               
               
           
         
         wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, benzoxazolyl;  
         Ar 1  is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl;  
         A is O, S, SO, SO 2 , C═O, CHOH, or —(CR 3 R 4 )—;  
         n is 0, 1 or 2;  
         each of Ar and Ar 1  may be independently and optionally substituted with one to four substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, thiocyano, —SR, —SOR, —SO 2 R, —NHSO 2 R, -(C 1 -C 6 )alkoxy, —NR 1 R 2 , —NRCOR 1 , —CONR 1 R 2 , Ph, —COR, COOR, -(C 1 -C 6 )alkyl, trifluoromethoxy, and -(C 1 -C 6 )alkyl substituted with one to six halogens, -(C 3 -C 6 )cycloalkyl, or trifluoromethoxy;  
         each and every R, R 1 , and R 2  is independently selected from the group consisting of hydrogen, -(C 1 -C 6 )alkyl, -(C 1 -C 6 )alkyl substituted with one to thirteen halogens selected from fluorine, chlorine, bromine and iodine, phenyl, benzyl, -(C 2 -C 6 )alkenyl, -(C 3 -C 6 )cycloalkyl, and -(C 1 -C 6 )alkoxy;  
         each and every R 3  and R 4  is independently selected from a group consisting of hydrogen, methyl, ethyl, n-propyl, and i-propyl; or a  
         diastereomeric or optical isomers thereof; or a  
         pharmaceutically acceptable salt thereof;  
         and detecting the emissions of the radioactive compound.  
       
     
     
         36 . A method of imaging an organ in a mammal, comprising administering to said mammal a compound of the formula  
       
         
           
           
               
               
           
         
         wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, benzoxazolyl;  
         Ar 1  is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl;  
         A is O, S, SO, SO 2 , C═O, CHOH, or —(CR 3 R 4 )—;  
         n is 0, 1 or 2;  
         each of Ar and Ar 1  may be independently and optionally substituted with one to four substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, thiocyano, —SR, —SOR, —SO 2 R, —NHSO 2 R, -(C 1 -C 6 )alkoxy, —NR 1 R 2 , —NRCOR 1 , —CONR 1 R 2 , Ph, —COR, COOR, -(C 1 -C 6 )alkyl, trifluoromethoxy, and -(C 1 -C 6 )alkyl substituted with one to six halogens, -(C 3 -C 6 )cycloalkyl, or trifluoromethoxy;  
         each and every R, R 1 , and R 2  is independently selected from the group consisting of hydrogen, -(C 1 -C 6 )alkyl, -(C 1 -C 6 )alkyl substituted with one to thirteen halogens selected from fluorine, chlorine, bromine and iodine, phenyl, benzyl, -(C 2 -C )alkenyl, -(C 3 -C 6 )cycloalkyl, and -(C 1 -C 6 )alkoxy;  
         each and every R 3  and R 4  is independently selected from a group consisting of hydrogen, methyl, ethyl, n-propyl, and i-propyl; or a  
         diastereomeric or optical isomers thereof; or a  
         pharmaceutically acceptable salt thereof;  
         in combination with a radioactive agent, and detecting the emissions of the radioactive agent.