NK1 receptor antagonists

Abstract

Non-peptide acetamide derivatives of Formula I are specific NK 1 antagonists, where R is aryl, R 1 and R 2 are H or alkyl, m, n and q are integers from 0 to 4, X is NR 8 or NHCONH, R 3 and R 9 are H or alkyl, R 4 is naphthyl or indolyl, R 5 and R 2 are H or alkyl, and R 6 is aryl. The compounds are useful agents for treating inflammatory and allergic disorders, pain, anxiety, depression, schizophrenia and emesis.

We claim:  
     
         1 . A compound of Formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 ▪, , and and ▴ indicate all stereoisomers,  
 R is: 
 pyridyl,  
 thienyl,  
 furyl,  
 pyrrolyl,  
 pyrazolyl,  
 quinolyl,  
 isoquinolyl,  
 naphthyl,  
 indolyl,  
 benzofuryl,  
 benzothiophenyl,  
 benzimidazolyl, and  
 benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by 
 alkyl,  
 hydroxy,  
 alkoxy,  
 halogen,  
 —CF 3 ,  
 carboxy,  
 sulfonamide, or  
 nitro;  
 
 
 R can also be:  
                     
 R 1  and R 2  are each independently H or C 1 -C 4  alkyl;  
 m is an integer from 0 to 3;  
 X is NHCONH, or NR 8  where R 8  is H or C 1 -C 4  alkyl;  
 R 3  is hydrogen or C 1 -C 4  alkyl;  
 n is an integer from 1 to 2;  
 R 4  is naphthyl or indolyl, wherein said groups are unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy or formyl;  
 R 9  is hydrogen or C 1 -C 4  alkyl;  
 R 5  and R 7  are each independently hydrogen or (CH 2 ) p R 10  where: 
 p is an integer of 1 to 3, and  
 R 10  is H, CH 3 , CN, OH, OCH 3 , CO 2 CH 3 , NH 2 , NHCH 3 , or N(CH 3 ) 2 ;  
 
 q is an integer of 0 to 4;  
 R 6  is 
 phenyl,  
 pyridyl,  
 thienyl,  
 furyl,  
 pyrrolyl,  
 pyrazolyl,  
 imidazolyl,  
 quinolyl,  
 isoquinolyl,  
 naphthyl,  
 indolyl,  
 benzofuryl,  
 benzothiophenyl,  
 benzimidazolyl, or  
 benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by 
 alkyl,  
 hydroxy,  
 alkoxy,  
 halogen,  
 CF 3 ,  
 NO 2 ,  
 N(CH 3 ) 2 ,  
 OCF 3 ,  
 SONH 2 ,  
 NH 2 ,  
 CONH 2 ,  
 CO 2 CH 3 , or  
 CO 2 H,  
 
 
 or R 6  is: 
 straight alkyl of from 1 to 3 carbons,  
 branched alkyl of from 3 to 8 carbons,  
 cycloalkyl of from 5 to 8 carbons, or  
 heterocycloalkyl,  
 each of which can be substituted with up to one or two substituents selected from 
 OH,  
 CO 2 H,  
 N(CH 3 ) 2 ,  
 NHCH 3  and  
 CH 3 ; and  
 
 
 R 5  and R 6 , when joined by a bond, can form a ring;  
 R 6  is also  
                     
 where X 1  represents the rest of the molecule.  
 
     
     
         2 . A compound of claim I wherein R is selected from: 
 pyridyl,    thienyl,    furyl,    quinolyl    isoquinolyl    naphthyl,    indolyl,    benzofuryl,    benzothiophenyl,    benzimidazolyl,    benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, or CF 3 ,                          m is an integer from 1 to 3;    R 6  is 
 phenyl  
 pyridyl,  
 thienyl,  
 furyl,  
 pyrrolyl,  
 quinolyl,  
 isoquinolyl,  
 naphthyl,  
 indolyl,  
 benzofuryl,  
 benzothiophenyl,  
 benzimidazolyl, or  
 benzoxazolyl,  
 wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by 
 alkyl,  
 hydroxy,  
 alkoxy,  
 halogen,  
 CF 3 ,  
 NO 2    
 N(CH 3 ) 2 ,  
 OCF 3 ,  
 SONH 2 ,  
 NH 2 ,  
 CONH 2 ,  
 CO 2 CH 3 , or  
 CO 2 H,  
 
 cycloalkyl of from 5 to 6 carbons or heterocycloalkyl, with up to one or two substituents selected from 
 OH,  
 CO 2 H,  
 N(CH 3 ) 2 ,  
 NHCH 3  and  
 CH 3 ; and  
 
   R 5  and R 6  when joined by a bond can form a ring.    
     
     
         3 . A compound according to  claim 2  wherein R 1  and R 2  each are hydrogen.  
     
     
         4 . A compound according to  claim 3  wherein X is NR 8 .  
     
     
         5 . A compound according to  claim 4  wherein 
 R is 
 pyridyl,  
 thienyl,  
 furyl,  
 quinolyl,  
 naphthyl,  
 benzofuryl,  
 benzothiophenyl,  
 benzimidazolyl, or  
 benzoxazolyl, where each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, or —CF 3 ,  
                     
 
 R 1  and R 2  are each H;  
 m is an integer from 1 to 3;  
 X is NR 8  or NHCONH, where R 8  is H or methyl;  
 R 9  is hydrogen or alkyl of 1 to 3 carbon atoms;  
 R 6  is 
 phenyl,  
 pyridyl,  
 thienyl,  
 furyl,  
 pyrrolyl,  
 benzimidazolyl, where each of the foregoing is unsubstituted, mono-, di- or trisubstituted by 
 alkyl,  
 hydroxy,  
 alkoxy,  
 halogen,  
 CF 3 ,  
 NO 2 , or  
 N(CH 3 ) 2 ;  
 
 cyclohexyl or heterocycloalkyl, with up to one or two substituents selected from 
 OH,  
 CO 2 H,  
 N(CH 3 ) 2 ,  
 NHCH 3  and  
 CH 3 ; and  
 
 
 R 5  and R 6 , when joined by a bond, can form a ring.  
 
     
     
         6 . A compound of the Formula II  
       
         
           
           
               
               
           
         
       
       wherein: 
 R is 
 benzofuryl,  
 benzoxazolyl,  
 3-cyanophenyl,  
 3-nitrophenyl, or  
 3-trifluoromethylphenyl;  
 
 R 3  is hydrogen or methyl;  
 X is NH or NHCONH;  
 R 5  and R 7  independently are hydrogen or CH 2 R 10 , where R 10  is H, CH 3  or OH;  
 R 6  is 
 phenyl,  
 substituted phenyl,  
 pyridyl, or,  
 cyclohexyl;  
 and the pharmaceutically acceptable salts thereof.  
 
 
     
     
         7 . A compound of  claim 6  selected from: 
 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)] 
 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-4-yl-ethyl)-propionamide, [R—(R*,S*)] 
 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-[1-(4-nitro-phenyl)-ethyl]-propionamide, [R—(R*,R*)] 
 2-[(Benzofuran-2-ylmethyl)-amino]-N-(2-hydroxy-1-phenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide, [R—(R*,R*)] 
 [R—(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-N-(1-cyclohexyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide  
 [R—(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-p-tolyl-ethyl)-propionamide  
 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-p-tolyl-ethyl)-propionamide, [R—(R*,S*)] 
 2-(3-Cyano-benzylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)] 
 3-(1H-Indol-3-yl)-2-(3-nitro-benzylamino)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)] 
 3-(1H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-(3-trifluoromethoxy-benzylamino)-propionamide, [R—(R*,S*)] 
 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-pyridin-4-yl-ethyl)-propionamide, [R—(R*,S*)] 
 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)] 
 2-[(Benzooxazol-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide  
 2-(2-Benzofuran-2-yl-ethylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)] and  
 2-(3-Benzofuran-2-ylmethyl-ureido)-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)].  
 
     
     
         8 . A pharmaceutical formulation comprising a compound of claim I admixed with a pharmaceutically acceptable diluent, carrier or excipient.  
     
     
         9 . A formulation according to  claim 8  employing a compound of Formula II  
       
         
           
           
               
               
           
         
       
       wherein: 
 R is 
 benzofuryl,  
 benzoxazolyl,  
 3-cyanophenyl,  
 3-nitrophenyl, or  
 3-trifluoromethylphenyl;  
 
 R 3  is hydrogen or methyl;  
 X is NH or NHCONH;  
 R 5  and R 7  independently are hydrogen or CH 2 R 10 , where R 10  is H, CH 3  or OH;  
 R 6  is 
 phenyl,  
 substituted phenyl,  
 pyridyl, or,  
 cyclohexyl;  
 or a pharmaceutically acceptable salts thereof.  
 
 
     
     
         10 . A formulation according to  claim 9  employing a compound selected from: 
 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)] 
 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-4-yl-ethyl)-propionamide, [R—(R*,S*)] 
 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-[1-(4-nitro-phenyl)-ethyl]-propionamide, [R—(R*,R*)] 
 2-[(Benzofuran-2-ylmethyl)-amino]-N-(2-hydroxy-1-phenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide, [R—(R*,R*)] 
 [R—(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-N-(1-cyclohexyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide  
 [R—(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-p-tolyl-ethyl)-propionamide  
 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-p-tolyl-ethyl)-propionamide, [R—(R*,S*)] 
 2-(3-Cyano-benzylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)] 
 3-(1H-Indol-3-yl)-2-(3-nitro-benzylamino)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)] 
 3-(1H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-(3-trifluoromethoxy-benzylamino)-propionamide, [R—(R*,S*)] 
 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-pyridin-4-yl-ethyl)-propionamide, [R—(R*,S*)] 
 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)] 
 2-[(Benzooxazol-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide  
 2-(2-Benzofuran-2-yl-ethylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)] and  
 2-(3-Benzofuran-2-ylmethyl-ureido)-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)].  
 
     
     
         11 . A method for antagonizing the NK 1  receptor in a mammal comprising administering a compound of  claim 1 .  
     
     
         12 . A method for treating a CNS disorder in a mammal in need of treatment comprising administering an effective amount of a compound of  claim 1 .  
     
     
         13 . A method according to  claim 12  wherein the CNS disorder is selected from pain, anxiety, depression or schizophrenia.  
     
     
         14 . A method according to  claim 12  wherein the CNS disorder is selected from neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders, obesity, and addiction disorders.  
     
     
         15 . A method for treating an allergic or inflammatory disorder in a mammal in need of treatment comprising administering an effective amount of a compound of  claim 1 .  
     
     
         16 . A method according to  claim 15  wherein the allergic or inflammatory disorder is selected from arthritis, asthma, bronchitis, psoriasis, eczema, rhinitis, colitis or Crohn's disease.  
     
     
         17 . A method for treating a neuropathological disorder in a mammal in need of treatment comprising administering an effective amount of a compound of  claim 1 .  
     
     
         18 . A method according to  claim 17  wherein the neuropathological disorder is selected from scleroderma or emesis.