Pharmaceutical combination

Abstract

The present invention relates to a pharmaceutical combination for the treatment of schizophrenia and acute manic episodes associated with bipolar disorders, which comprises a compound which is active on a trace amine-associated receptor 1 (TAAR1 agonist) and an antipsychotic drug. This combination can reduce metabolic side effects which appear if using an antipsychotic drug alone.

1 . (canceled) 
     
     
         2 . A combination comprising a therapeutically effective amount of each of olanzapine and a TAAR1 agonist I
 comprising a compound of formula II   
       
         
           
           
               
               
           
         
         wherein 
         R is hydrogen or lower alkyl; 
         R 1  is —(CH 2 ) n —(O) o -heterocycloalkyl, optionally substituted by lower alkyl, hydroxy, halogen, or by —(CH 2 ) p -aryl; 
         n is 0, 1 or 2; 
         o is 0 or 1; 
         p is 0, 1 or 2; 
         R 2  is cycloalkyl, heterocycloalkyl, or is aryl or heteroaryl, wherein the aromatic rings are optionally substituted by one or two substituents, selected from lower alkyl, halogen, heteroaryl, CF 3 , OCF 3 , OCH 2 CF 3 , lower alkoxy, CH 2 -lower alkoxy, lower alkynyl or cyano; 
         X is a bond, —NR′—, —CH 2 NH—, —CHR″—, —(CH 2 ) q —O— or —(CH 2 ) 2 —; 
         R′ is hydrogen or lower alkyl, 
         R″ is hydrogen, lower alkyl, lower alkoxy, and 
         q is 0, 1 or 2; 
         or a pharmaceutically suitable acid addition salt thereof. 
       
     
     
         3 . (canceled) 
     
     
         4 . The combination of  claim 2 , comprising olanzapine and a TAAR1 agonist selected from the group consisting of
 5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl)-amide;   4-chloro-N-(4-pyrrolidin-3-yl-phenyl)-benzamide; and   1-(5-chloro-pyridin-2-yl)-3-(4-pyrrolidin-3-yl-phenyl)urea.   
     
     
         5 . The combination of  claim 2 , comprising olanzapine and a TAAR1 agonist selected from the group consisting of
 5-chloro-pyrimidine-2-carboxylic acid {4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-amide;   N-{4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-4-chloro-benzamide;   (R)-2-chloro-6-methyl-N-(4-(morpholin-2-yl)phenyl)isonicotinamide;   (S)—N-(4-(morpholin-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)nicotinamide;   (S)—N-(4-(morpholin-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide;   (S)-1-(4-fluorobenzyl)-3-(4-(morpholin-2-yl)phenyl)urea;   (S)-1-(3-cyanophenyl)-3-(4-(morpholin-2-yl)phenyl)urea; and   (S)-6-chloro-N-(4-(morpholin-2-yl)phenyl)nicotinamide.   
     
     
         6 . (canceled) 
     
     
         7 . A method for treating schizophrenia and manic episodes associated with bipolar disorders with reduced incidence of metabolic syndrome, comprising administering to a human in need thereof an effective amount of a combination comprising a therapeutically effective amount of each of olanzapine and a TAAR1 agonist comprising a compound of formula II 
       
         
           
           
               
               
           
         
         wherein 
         R is hydrogen or lower alkyl; 
         R 1  is —(CH 2 ) n —(O) o -heterocycloalkyl, optionally substituted by lower alkyl, hydroxy, halogen, or by —(CH 2 ) p -aryl; 
         n is 0, 1 or 2; 
         o is 0 or 1; 
         p is 0, 1 or 2; 
         R 2  is cycloalkyl, heterocycloalkyl, or is aryl or heteroaryl, wherein the aromatic rings are optionally substituted by one or two substituents, selected from lower alkyl, halogen, heteroaryl, CF 3 , OCF 3 , OCH 2 CF 3 , lower alkoxy, CH 2 -lower alkoxy, lower alkynyl or cyano; 
         X is a bond, —NR′—, —CH 2 NH—, —CHR″—, —(CH 2 ) q —O— or —(CH 2 ) 2 —; 
         R′ is hydrogen or lower alkyl, 
         R″ is hydrogen, lower alkyl, lower alkoxy, and 
         q is 0, 1 or 2; 
         or a pharmaceutically suitable acid addition salt thereof. 
       
     
     
         8 . The method of  claim 7 , wherein the reduced incidence of metabolic syndrome results from antidiabetic efficacy with lowering blood glucose excursion fat mass and body weight. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 7 , wherein the TAAR1 agonist is selected from the group consisting of
 5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl)-amide;   4-chloro-N-(4-pyrrolidin-3-yl-phenyl)-benzamide; and   1-(5-chloro-pyridin-2-yl)-3-(4-pyrrolidin-3-yl-phenyl)urea.   
     
     
         12 . The method of  claim 7 , wherein the TAAR1 agonist is selected from the group consisting of
 5-chloro-pyrimidine-2-carboxylic acid {4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-amide;   N-{4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-4-chloro-benzamide;   (R)-2-chloro-6-methyl-N-(4-(morpholin-2-yl)phenyl)isonicotinamide;   (S)—N-(4-(morpholin-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)nicotinamide;   (S)—N-(4-(morpholin-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide;   (S)-1-(4-fluorobenzyl)-3-(4-(morpholin-2-yl)phenyl)urea;   (S)-1-(3-cyanophenyl)-3-(4-(morpholin-2-yl)phenyl)urea; and   (S)-6-chloro-N-(4-(morpholin-2-yl)phenyl)nicotinamide.   
     
     
         13 . A pharmaceutical composition comprising a combination of olanzapine and a TAAR1 agonist
 comprising a compound of formula II   
       
         
           
           
               
               
           
         
         wherein 
         R is hydrogen or lower alkyl; 
         R 1  is —(CH 2 ) n —(O) o -heterocycloalkyl, optionally substituted by lower alkyl, hydroxy, halogen, or by —(CH 2 ) p -aryl; 
         n is 0, 1 or 2; 
         o is 0 or 1; 
         p is 0, 1 or 2; 
         R 2  is cycloalkyl, heterocycloalkyl, or is aryl or heteroaryl, wherein the aromatic rings are optionally substituted by one or two substituents, selected from lower alkyl, halogen, heteroaryl, CF 3 , OCF 3 , OCH 2 CF 3 , lower alkoxy, CH 2 -lower alkoxy, lower alkynyl or cyano; 
         X is a bond, —NR′—, —CH 2 NH—, —CHR″—, —(CH 2 ) q —O— or —(CH 2 ) 2 —; 
         R′ is hydrogen or lower alkyl, 
         R″ is hydrogen, lower alkyl, lower alkoxy, and 
         q is 0, 1 or 2; 
         or a pharmaceutically suitable acid addition salt thereof and one or more pharmaceutically acceptable excipients. 
       
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The pharmaceutical composition of  claim 13 , wherein the TAAR1 agonist is selected from the group consisting of
 5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl)-amide;   4-chloro-N-(4-pyrrolidin-3-yl-phenyl)-benzamide; and   1-(5-chloro-pyridin-2-yl)-3-(4-pyrrolidin-3-yl-phenyl)urea.   
     
     
         17 . The pharmaceutical composition of  claim 13 , wherein the TAAR1 agonist is selected from the group consisting of
 5-chloro-pyrimidine-2-carboxylic acid {4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-amide;   N-{4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-4-chloro-benzamide;   (R)-2-chloro-6-methyl-N-(4-(morpholin-2-yl)phenyl)isonicotinamide;   (S)—N-(4-(morpholin-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)nicotinamide;   (S)—N-(4-(morpholin-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide;   (S)-1-(4-fluorobenzyl)-3-(4-(morpholin-2-yl)phenyl)urea;   (S)-1-(3-cyanophenyl)-3-(4-(morpholin-2-yl)phenyl)urea; and   (S)-6-chloro-N-(4-(morpholin-2-yl)phenyl)nicotinamide.   
     
     
         18 . A compound of  claim 5 , which is (S)—N-(4-(morpholin-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide. 
     
     
         19 . The method of  claim 12 , wherein the TAAR1 agonist is (S)—N-(4-(morpholin-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide. 
     
     
         20 . The pharmaceutical composition of  claim 17 , wherein the TAAR1 agonist is (S)—N-(4-(morpholin-2-ylphenyl)-2-(trifluoromethyl)isonicotinamide.