Arylvinylazacycloalkane compounds and methods of preparation and use thereof

Abstract

Novel vinylazacycloalkane compounds of Formula (I) are disclosed. The compounds are ligands of various nAChRs. The compounds and their pharmaceutically acceptable salts can be used to prepare pharmaceutical compositions and/or medicaments intended to prevent or treat disorders associated with dysfunction of nAChRs, especially within the central nervous system or the gastrointestinal system. Examples of types of disorders that can be treated include neurodegenerative disorders, including central nervous system disorders such as Alzheimer's disease, cognitive disorders, motor disorders such as Parkinson's disease, drug addiction, behavioral disorders and inflammatory disorders within the gastrointestinal system. The compounds can also serve as analgesics in the treatment of acute, chronic or recurrent pain.

1 - 10 . (canceled)  
   
   
       11 . A method of treating neurodegenerative disorders comprising administering to a patient in need thereof an effective amount of a compound of the formula:  
     
       
         
         
             
             
         
       
       wherein:  
       the wavy line represents variable geometry (E or Z) about the double bond;  
       X is nitrogen or C—R 2 ;  
       R 1  is hydrogen, C 1-6 -alkyl, halogen, —OR 4 , —NR 4 R 5 , or —SR 4  when X is C—R 2  and hydrogen, C 1-6 alkyl, —OR 4 , or —NR 4 R 5  when X is nitrogen;  
       R 2  is hydrogen, C 1-6 -alkyl, aryl-C 1-6 -alkyl, C 1-6 -alkyl-aryl, heteroaryl, heteroaryl C 1-6 -heterocyclyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, polycycloalkyl, —NR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , each of which can optionally be substituted with 1 or more substituents selected from halogen, —CN, —NO 2 , —NH 2 , —OH, —OR 6 , —COOH, —C(O)OR 6 , —O—C(O)R 6 , —NR 6 R 7 , —NHO(O)R 6 , —C(O)NR 6 R 7 , —SR 6 , —S(O)R 6 , —SO s R 6 , —NHSO 2 R 6 , —SO 2 NR 6 R 6 , —C(S)NR 6 R 6 , —NHC(S)R 6 , —O—SO 2 R 6 , aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy and C 1-6 alkyl;  
       R 1  is hydrogen, C 1-6 -alkyl-C 1-6 -alkyl, —C 1-6 -ylalkyl, cycloalkyl;  
       m is between 1 and 4;  
       n is between 1 and 3;  
       R 4  and R 5  are, independently, hydrogen or C 1-6 -alkyl;  
       R 6  and R 7  are, independently, hydrogen, C 1-6 -alkyl (including cycloalkyl containing alkyl), aryl, aryl C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or polycycloalkyl, each of which can optionally be substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, —CN, —NO 2 , —NH 2 , —OH, —COOH, —COO—C 1-6 alkyl, —CONH 2 , formyl, trifluoromethyl and trifluoromethoxy,  
       wherein the C 1-6 -alkyl, heterocyclyl, heteroaryl and aryl groups can be substituted with from 1-6 substituents selected from the group consisting of F, Cl, Br, I, R 8 , —NR 8 R 9 , —CF 1 , —CN, —NO 3 , —C 1 R 8 , —N 3 , —SO 2 CH 3 , —OR 8 , —SR 8 , —C(═O)NR 8 R 9 , —NR 8 C(—O)R 8 , —C(—O)R 8 , —C(—O)OR 8 , —(CH 2 ) 4 OR 8 , —OC(═O)R 8 , —OC(—O)NR 8 R 9  and —NR 8 C(—O)OR 8 ,  
       where R 8  and R 9  are individually hydrogen, C 1 -C 6  alkyl, pyridyl, substituted pyridyl, quinolinyl, substituted quinolinyl, pyrimidinyl, substituted pyrimidinyl, phenyl, substituted phenyl, benzyl, or substituted benzyl (substituted with one or more of the above substituents), and where either R 6  and R 7  or R 8  and R 9  can form a C 1-10  cycloalkyl functionality,  
       and isomers, mixtures, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts thereof.  
     
   
   
       12 . The method of  claim 11 , wherein R 1  is hydrogen.  
   
   
       13 . The method of  claim 11 , where R 2  is X is N.  
   
   
       14 . (canceled)  
   
   
       15 . The method of  claim 11 , wherein n—1.  
   
   
       16 . The method of  claim 11 , wherein m—2.  
   
   
       17 . The method of  claim 11 , wherein R 6  is alkyl, including cycloalkyl-containing alkyl.  
   
   
       18 . The method of  claim 11 , where R 6  is a heterocycle.  
   
   
       19 . The method of  claim 18 , wherein the heterocycle is selected from the group consisting of piperidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isothiazolidinyl, thiazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, tetrahydropyranyl and tetrahydrofuranyl.  
   
   
       20 . The method of  claim 11 , wherein the neurodegenerative disorder results from in appropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors.  
   
   
       21 . The method of  claim 20 , wherein the disorder results from a deficiency of acetylcholine, dopamine, norepinephrine and/or scrotonin.  
   
   
       22 . The method of  claim 11 , wherein the disorder is selected from the group consisting of pre-senile dementia (early-onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), premature amnesic and cognitive disorders which are age-related or a consequence of alcoholism, micro-infaret dementia and vascular dementia, AIDS-related dementia, Creutzfeld-Jakob disease, Pick's disease, Parkinson's disease, Lewy body dementia, progressive supranuclear palsy, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, epilepsy, attention deficit disorder, anxiety, dyslexia, schizophrenia, depression, obsessive-compulsive disorders, Tourette's syndrome, amyotrophic lateral sclerosis, multiple sclerosis, peripheral neurotrophies, cerebral or spinal traumas, and drug addiction.  
   
   
       23 . A method of providing analgesia and/or treating inflammatory gastrointestinal disorders comprising administering to a patient in need thereof an effective amount of a compound of the formula:  
     
       
         
         
             
             
         
       
       wherein:  
       the wavy line represents variable geometry (E or Z) about the double bond;  
       X is nitrogen or C—R 2 ;  
       R 1  is hydrogen, C 1-6 -alkyl, halogen, —OR 4 , —NR 4 R 5 , or —SR 4  when X is C—R 2  and hydrogen, C 1-6 alkyl, —OR 4 , or —NR 4 R 5  when X is nitrogen  
       R 2  is hydrogen, C 1-6 -alkyl, aryl, aryl C 1-6 -alkyl, C 1-6 -alkyl-aryl, heteroaryl, heteroaryl C 1-6 -alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, polycycloalkyl, —OR 6 , —NR 6 R 7 , —SR 6 , —SOR 6 , or —SO 2 R 6 , each of which can optionally be substituted with 1 or more substituents selected from halogen, —CN, —NO 2 , —NH 2 , —OH, OR 6 , —COOH, —C(O)OR 6 , —O—C(O)R 6 , —NR 6 R 7 , —NHC(O)R 6 , —C(O)NR 6 R 7 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —NHSO 2 R 6 , —SO 2 NR 6 R 6 , —C(S)NR 6 R 6 , —NHC(S)R 6 , —O—SO 2 R 6 , aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy and C 1-6 alkyl;  
       R 3  is hydrogen,  
       m is between 1 and 4;  
       n is between 1 and 3;  
       R 4  and R 5  are, independently, hydrogen, or C 1-6 -alkyl;  
       R 6  and R 7  are, independently, hydrogen, C 1-6 -alkyl (including cycloalkyl containing alkyl), aryl, aryl C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or polycycloalkyl, each of which can optionally be substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, —CN, —NO 2 , —NH 2 , —OH, —COOH, —COO—C 1-6 alkyl, —CONH 2 , formyl, trifluoromethyl and trifluoromethoxy,  
       wherein the C 1-6 -alkyl, heterocyclyl, heteroaryl and aryl groups can be substituted with from 1-6 substituents selected from the group consisting of F, Cl, Br, I, R 8 , —NR 8 R 9 , —CF 3 , —CN, —NO 2 , —C 2 R 8 , —N 3 , —SO 2 CH 3 , —OR 8 , —SR 8 , —C(—O)NR 8 R 9 , —NR 8 C(═O)R 8 , —C(—O)R 8 , —C(═O)OR 8 , —(CH 2 ) 4 OR 8 , —OC(═)R 8 , —OC(—O)NR 8 R 9  and —NR 8 C(—O)OR 8 ,  
       where R 8  and R 9  are individually hydrogen, C 1 -C 6  alkyl, pyridyl, substituted pyridyl, quinolinyl, substituted quinolinyl, pyrimidinyl, substituted pyrimidinyl, phenyl, substituted phenyl, benzyl, or substituted benzyl (substituted with one or more of the above substituents), and where either R 6  and R 7  or R 8  and R 9  can form a C 1-10  cycloalkyl functionality,  
       and isomers, mixtures, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts thereof.  
     
   
   
       24 . The method of  claim 23 , where R 1  is hydrogen.  
   
   
       25 . The method of  claim 23 , wherein R 6  X is N.  
   
   
       26 . (canceled)  
   
   
       27 . The method of  claim 23 , wherein n—1.  
   
   
       28 . The method of  claim 23 , wherein n—2.  
   
   
       29 . The method of  claim 23 , wherein R 6  is alkyl (including cycloalkyl containing alkyl).  
   
   
       30 . The method of  claim 23 , wherein R 6  is a heterocycle.  
   
   
       31 . The method of  claim 30 , wherein heterocycle is selected from the group consisting of piperidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isothiazolidinyl, thiazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, tetrahydropyranyl and tetrahydrofuranyl.  
   
   
       32 . The method of  claim 23 , wherein the inflammatory disorder is selected from the group consisting of diarrhea, Crohn's disease, irritable bowel syndrome and ulcerous colitis.  
   
   
       33 . A method of treating a neurodegenerative disorder or providing analgosia and/or treating inflammatory disorders comprising, administering to a patient in need thereof an effective, anti-inflammatory amount of a compound selected from the group consisting of (R)— and (S)-3-((E)-2-pyrrolidin-3-ylvinyl)-5-(tetrahydropyran-4-yloxy)pyridine (R)— and (S)-5-((E)-2pyrrolidin-3-ylvinyl)pyrimidine (R)— and (S)-2-chloro-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine (R)— and (S)-3-isopropoxy-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine (R)— and (S)-3-cyclopropylmethoxy-5-((E)-2-pyrrolidin-3-ylvinyl)pyridine (R)— and (S)-5((E)ethylpyrrolidin-3-yl)vinyidine (R)— and (S)-3-propylme-5-((E)-2-(pyrrolinyl) (R)— and (S)-5-((E)-2-piperidin-3-ylvinyl)pyrimidine (R)— and (S)-5-((E)ethylpip)vinyl)idiine (R)— and (S)-2-chloro-5-((E)-2-piperidin-3-ylvinyl)pyridine (R)— and  loro-5-((ethylpi-3-yl)viny (R)— and (S)-3-cyclopropylmethoxy-5-((E)-2-piperidin-3-ylvinyl)pyridine 5-((E)-2-piperidin-4-ylvinyl)pyrimidine 5-(1-methylpiperidinyl)vinyl) 2-chloro-5-((E)-2-piperidin-4-ylvinyl)pyridine  ((E)-2-piperidin-4-pyridine 3-cyclopropylmethoxy-5-((E)-2-piperidin-4-ylvinyl)pyridine 5-((E)-2-azetidin-3-ylvinyl)pyrimidine 5-((E)-2-azetidin-3-ylvinyl)-2-chloropyridine ((E)-2-(1-methylazotidyl)vinyloro 3-((E)-2-azetidin-3-ylvinyl)-5-cyclopropylmethoxypyridine (R)— and (S)-3-phenoxy-5-((E)-2-piperidin-3-ylvinyl)pyridine 3-phenoxy-5((E)-2-piperidin-4-ylvinyl)pyridine 3-phen(E)-2-(piperidin-4-yl)vinyl) 3-phenoxy-5-((E)-2-azetidin-3-ylvinyl)pyridine 5- ethylyl)pyridine geometric isomers thereof, mixtures thereof, including racemic mixtures, enantiomers, and tautomers thereof, and pharmaceutically acceptable salts thereof, 
 to a patient in need of treatment thereof.    
   
   
       34 . A method of preparing compounds of the formula:  
     
       
         
         
             
             
         
       
       wherein:  
       the wavy line represents variable geometry (E or Z) about the double bond;  
       X is nitrogen or C—R 2 ;  
       R 1  is hydrogen, C 1-6 -alkyl, halogen, —OR 4 , —NR 4 R 5 , or —SR 4  when X is C—R 2  and hydrogen, C 1-6 alkyl, —OR 4 , or —NR 4 R   when X is nitrogen;  
       R 2  is hydrogen, C 1-6 -alkyl, aryl, aryl C 1-6 -alkyl, C 1-6 -alkyl-aryl, heteroaryl, heteroaryl C 1-6 -alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, polycycloalkyl, OR 6 , NR 6 R 7 , SR 6 , SOR 6 , or SO 2 R 6 , each of which can optionally be substituted with 1 or more substituents selected from halogen, —CN, —NO 2 , —NH 2 , —OH, —OR 6 , —COOH, —C(O)OR 6 , —O—C(O)R 6 , —NR 6 R 7 , —NHC(O)R 6 , —C(O)NR 6 R 7 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —NHSO 2 R 6 , —SO 2 NR 6 R 6 , —C(S)NR 6 R 6 , —NHC(S)R 6 , —O—SO 2 R 6 , aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy and C 1-6 alkyl;  
       R   is hydrogen,  alkyl 1-6 -alkyl 1-6 -alky 1-6 ;  
       m is between 1 and 4;  
       n is between 1 and 3;  
       R 4  and R 5  are, independently, hydrogen or C 1-6 -alkyl;  
       R 6  and R 5  are, independently, hydrogen, C 1-6 -alkyl (including cycloalkyl containing alkyl), aryl, aryl C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heterocyclyl, heterocycloalkyl, cycloalkyl or polycycloalkyl, each of which can optionally be substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, —CN, —NO 2 , —NH 2 , —OH, —COOH, —COO—C 1-6 alkyl, —CONH 2 , formyl, trifluoromethyl and trifluoromethoxy,  
       wherein the C 1-6 -alkyl, heterocyclyl, heteroaryl and aryl groups can be substituted with from 1-6 substituents selected from the group consisting of F, Cl, Br, I, R 8 , —NR 8 R 9 , —CF 3 , —CN, —NO 2 , —C 2 R 8 , —N 3 , —SO 2 CH 3 , —OR 8 , —SR 8 , —C(═O)NR 8 R 9 , —NR 8 C( O)R 8 , —C( O)R 8 , —C( O)OR 8 , —C(—O)OR 8 , —(CH 2 )   OR 8 , —OC(—O)R 8 , —OC(—O)NR 8 R 9  and —NR 8 C(—O)OR 8 ,  
       where R 8  and R 9  are individually hydrogen, C 1 -C 6  alkyl, pyridyl, substituted pyridyl, quinolinyl, substituted quinolinyl, pyrimidinyl, substituted pyrimidinyl, phenyl, substituted phenyl, benzyl, or substituted benzyl (substituted with one or more of the above substituents), and where either R 6  and R 7  or R 8  and R 9  can form a C 1-10  cycloalkyl functionality, and  
       and isomers, mixtures, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts thereof,  
       comprising:  
       a) reacting an aldehyde of formula:  
       
         
           
           
               
               
           
         
       
       where m is between 1 and 4 and n is between 1 and 3;  
       with a phosphorane ylide of the formula  
         PPh 3 ═CH 2    
       to yield a vinylazacycloalkane of the formula  
       
         
           
           
               
               
           
         
       
       b) reacting the resulting vinylazacycloalkane with a heteroaryl halide of the formula:  
       
         
           
           
               
               
           
         
       
       where X and R 1  are as defined above and Y is a halogen, and  
       c) removing any remaining protecting groups.  
     
   
   
       35 . A method of treating neurodegenerative disorders comprising administering to a patient in need thereof an effective amount of a compound of the formula:  
     
       
         
         
             
             
         
       
       wherein:  
       the wavy line represents variable geometry (E or Z) about the double bond;  
       X is nitrogen or C—R 2 ;  
       R 1  is hydrogen, C 1-6 -alkyl, halogen, —OR 4 , —NR 4 R 5 , or —SR 4  when X is C—R 2  and hydrogen, C 1-6 alkyl, where R 1  is just —OR 4 , or —NR 4 R 5  when X is nitrogen;  
       R 2  is hydrogen, C 1 -alkyl, aryl, aryl-C 1-6 -alkyl, C 1 -alkyl-aryl, heteroaryl, heteroaryl C 1 alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, polycycloalkyl, —OR 6 , —NR 6 R 7 , —SR 6 , —SOR 6 , or —SO 2 R 6 , each of which can optionally be substituted with 1 or more substituents selected from halogen, —CN, —NO 2 , —NH 2 , —OH, —OR 6 , —COOH, —C(O)OR 6 , —O—C(O)R 6 , —NR 6 R 7 , —NHC(O)R 6 , —C(O)NR 6 R 7 , —SR 6 , —S(O)R 6 , —SO   R   , —NHSO 2 R 6 , —SO 2 NR 6 R 6 , —C(S)NR 6 R 6 , —NHC(S)R 6 , —O—SO 2 R 6 , aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy and C 1-6 alkyl;  
       R 3  is hydrogen, C 1-6 -alkyl, aryl-C 1-6 -alkyl, heteroaryl-C 1-6 -alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or polycycloalkyl;  
       m is between 1 and 4;  
       n is between 1 and 3;  
       R 4  and R   are, independently, hydrogen or C 1-6 -alkyl;  
       R 6  and R   are independently, hydrogen, C 1-6 -alkyl (including cycloalkyl containing alkyl), aryl, aryl C   -alkyl, heteroaryl, heteroaryl-C   -alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or polycycloalkyl, each of which can optionally be substituted with one or more substituents selected from halogen, C -6 alkyl, C 1-6 alkoxy, —CN, —NO 2 , —NH 2 , —OH, —COOH, —COO—C 1-6 alkyl, —CONH 2 , formyl, trifluoromethyl and trifluoromethoxy,  
       wherein the C 1-6  alkyl, heterocyclyl, heteroaryl and aryl groups can be substituted with from 1-6 substituents selected from the group consisting of F, Cl, Br, I, R 8 , —NR 8 R 9 , —CF   , —CN, —NO 2 , —C 2 R   , —N 3 , —SO 2 CH   , —OR 8 , —SR 8 , —C(—O)NR 8 R 9 , —NR 8 C(═O)R 8 , —C( O)R 8 , —C( O)OR 8 , —(CH 2 )   OR 8 , —OC(—O)R 8 , —OC(—O)NR 8 R 9  and —NR 8 C(—O)OR 8 ,  
       where R 8  and R 9  are individually hydrogen, C 1 -C 6 alkyl, pyridyl, substituted pyridyl, quinolinyl, substituted quinolinyl, pyrimidinyl, substituted pyrimidinyl, phenyl, substituted phenyl, benzyl, or substituted benzyl (substituted with one or more of the above substituents), and where either R 6  and R 7  or R 8  and R 9  can form a C 1-10 cycloalkyl functionality,  
       and isomers mixtures, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts thereof.  
     
   
   
       36 . A method of treating a neurodegenerative disorder or providing analgesia and/or treating inflammatory gastrointestinal disorders comprising administering, to a patient in need thereof an effective amount of a compound of the formula:  
     
       
         
         
             
             
         
       
       wherein:  
       the wavy line represents variable geometry (E or Z) about the double bond;  
       X is C—R 2 ;  
       R 1  is hydrogen, C 1-6 -alkyl, halogen, —OR 4 , —NR 4 R 5 , or —SR 4  when X is C—R 2  and hydrogen, C 1-6 alkyl, —OR 4 , or —NR 4 R 5  when X is nitrogen;  
       R 2  is —OR 6 ,  
       R 3  is hydrogen, C 1-6 -alkyl, aryl-C 1-6 alkyl, heteroaryl-C 1-6 -alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or polycycloalkyl;  
       m is between 1 and 4;  
       n is between 1 and 3;  
       R 4  and R 5  are, independently, hydrogen or C 1-6 -alkyl;  
       R 6  and R 7  are, independently, hydrogen, C 1-6 -alkyl (including cycloalkyl containing alkyl), aryl, aryl C 1-6 alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or polycycloalkyl, each of which can optionally be substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, —CN, —NO 2 , —NH 2 , —OH, —COOH, —COO—C 1-6 alkyl, —CONH 2 , formyl, trifluoromethyl and trifluoromethoxy,  
       wherein the C 1-6 -alkyl, heterocyclyl, heteroaryl and aryl groups can be substituted with from 1-6 substituents selected from the group consisting of F, Cl, Br, I, R 8 , —NR 8 R 9 , —CF   , —CN, —NO 2 , —C 2 R 8 , —N 3 , —SO 2 CH 3 , —OR 8 , —SR 8 , —C(—O)NR 8 R 9 , —NR 8 C(—O)R 8 , —C(—O)R 8 , —C(—O)OR 8 , —(CH 2 )   OR 8 , —OC(—O)R 8 , —OC(—O)NR 8 R 9  and —NR 8 C(—O)OR 8 ,  
       where R 8  and R 9  are individually hydrogen, C 1 -C 6  alkyl, pyridyl, substituted pyridyl, quinolinyl, substituted quinolinyl, pyrimidinyl, substituted pyrimidinyl, phenyl, substituted phenyl, benzyl, or substituted benzyl (substituted with one or more of the above substituents), and where either R 6  and R 7  or R 8  and R 9  can form a C 1-10  cycloalkyl functionality,  
       and isomers, mixtures, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts thereof.