Sigma receptor inhibitors

Abstract

The invention relates to compounds of formula I having pharmacological activity towards the sigma receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use for the treatment and or prophylaxis of a disease in which the sigma receptor is involved.

1 - 17 . (canceled) 
     
     
         18 . A method of treating or preventing a sigma receptor mediated disease or condition, said method comprising administering to a patient in need of such a treatment a therapeutically effective amount of a compound of the formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group formed by hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkenyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR 8 , —C(O)OR 8 , —C(O)NR 8 R 9  —C═NR 8 , —CN, —OR 8 , —OC(O)R 8 , —S(O) t —R 8  , —NR 8 R 9 , —NR 8 C(O)R 9 , —NO 2 , —N═CR 8 R 9 , or halogen; 
 R 2  is selected from the group formed by hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR 8 , —C(O)OR 8 , —C(O)NR 8 R 9 —C═NR 8 , —CN, —OR 8 , —OC(O)R 8 , —S(O) t —R 8 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NO 2 , —N═CR 8 R 9 , or halogen; 
 Y is selected from substituted or unsubstituted, branched or linear C 1-6 -alkyl; substituted or unsubstituted C 3-8 -cycloalkyl; 
 R 5  and R 6  are independently selected from the group formed by hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR 8 , —C(O)OR 8 , —C(O)NR 8 R 9  —C═NR 8 , —CN, —OR 8 , —OC(O)R 8 , —S(O) t —R 8  , —NR 8 R 9 , —NR 8 C(O)R 9 , —NO 2 , —N═CR 8 R 9 , or halogen; 
 together form, with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group; 
 n is selected from 1, 2, 3, 4, 5, 6, 7 or 8; 
 t is 1,2 or 3; 
 R 8  and R 9  are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or halogen; 
 
       optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. 
     
     
         19 . A method according to  claim 18 , wherein the compound is a compound of the formula IB: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group formed by hydrogen; substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR 8 , —C(O)OR 8 , —C(O)NR 8 R 9  —C═NR 8 , —CN, —OR 8 , —OC(O)R 8 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NO2, —N═CR 8 R 9  or halogen, 
 R 2  is selected from the group formed by hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR S , —C(O)OR 8 , —C(O)NR 8 R 9 —C═NR 8 , —CN, —OR 8 , —OC(O)R 8 , —S(O) t -R 8  , —NR 8 R 9 , —NR 8 C(O)R 9 , —NO 2 , —N═CR 8 R 9 , or halogen; 
 R 5  and R 6  are independently selected from the group formed by hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR 8 , —C(O)OR 8 , —C(O)NR 8 R 9  —C═NR 8 , —CN, —OR 8 , —OC(O)R 8 , —S(O) t —R 8  , —NR 8 R 9 , —NR 8 C(O)R 9 , —NO 2 , —N═CR 8 R 9 , or halogen; 
 together form, with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group; 
 n is selected from 1, 2, 3, 4, 5, 6, 7 or 8; 
 t is 1, 2 or 3; 
 R 8  and R 9  are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or halogen; 
 
       optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. 
     
     
         20 . A method according to  claim 18 , wherein the compound is a compound of the formula IC: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group formed by hydrogen; substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR 8 , —C(O)OR 8 , —C(O)NR 8 R 9  —C═NR 8 , —CN, —OR 8 , —OC(O)R 8 , —NR 8 R 9 , —NR 8 C(O)R 9 , —NO2, —N═CR 8 R 9  or halogen, 
 R 2  is selected from the group formed by hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR 8 , —C(O)OR 8 , —C(O)NR 8 R 9  —C═NR 8 , —CN, —OR 8 , —OC(O)R 8 , —S(O) t —R 8  , —NR 8 R 9 , —NR 8 C(O)R 9 , —NO 2 , —N═CR 8 R 9 , or halogen; 
 R 5  and R 6  are independently selected from the group formed by hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, —COR 8 , —C(O)OR 8 , —C(O)NR 8 R 9 —C═NR 8 , —CN, —OR 8 , —OC(O)R 8 , —S(O) t —R 8  , —NR 8 R 9 , —NR 8 C(O)R 9 , —NO 2 , —N═CR 8 R 9 , or halogen; 
 together form, with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group; 
 n is selected from 1, 2, 3, 4, 5, 6, 7 or 8; 
 t is 1, 2 or 3; 
 R 8  and R 9  are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or halogen; 
 
       optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. 
     
     
         21 . A method according to  claim 18 , wherein the compound is characterized in that R 1  selected from H, halogen, —COR S , or substituted or unsubstituted alkyl, preferably it is selected from H, Cl, methyl or acetyl. 
     
     
         22 . A method according to  claim 18 , wherein the compound is characterized in that R 1  is hydrogen. 
     
     
         23 . A method according to  claim 18 , wherein the compound is characterized in that R 2  is H, aryl, C(O)OR 8  or alkyl, preferably methyl, iso-propyl, phenyl, C(O)O—C 2 H 5  or H. 
     
     
         24 . A method according to  claim 18 , wherein the compound is characterized in that n is selected from 2, 3, 4, preferably 2. 
     
     
         25 . A method according to  claim 18 , wherein the compound is characterized in that R 5  and R 6  are selected from hydrogen or substituted or unsubstituted alkyl, preferably hydrogen, methyl, ethyl, propyl or butyl. 
     
     
         26 . A method according to  claim 18 , wherein the compound is characterized in that R 5  and R 6  together form, with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group,
 preferably form a substituted or unsubstituted heterocyclyl having 5 or 6 atoms in the ring, with optionally 1 C-atom in the ring being replaced by an heteroatom selected from N, S or O,   more preferably form a substituted or unsubstituted piperidine, pyrrolidine, piperazine or morpholine, especially unsubstituted piperidine, pyrrolidine, or morpholine.   
     
     
         27 . A method according to  claim 18 , wherein the compound is selected from the group consisting of:
 1-[2-(1-tert-butyl-1H-pyrazol-3-yloxy)ethyl]piperidine;   4-[2-(1-tert-butyl-1H-pyrazol-3-yloxy)ethyl]morpholine;   2-(1-tert-butyl-1H-pyrazol-3-yloxy)-N,N-diethylethanamine;   1-tert-butyl-3[2-(pyrrolidin-1-ypethoxy]-1H-pyrazole;   4-(2-(1-cyclohexyl-1H-pyrazol-3-yloxy)ethyl)morpholine;   1-(2-(1-cyclohexyl-1H-pyrazol-3-yloxy)ethyl)piperidine;   2-(1-cyclohexyl-1H-pyrazol-3-yloxy)-N,N-diethylethanamine;   1-Cyclohexyl-3-(2-(pyrro lidin-1-yl)etho xy)-1H-pyrazole;   4-(2-(1-Cyclohexyl-1H-pyrazol-3-yloxy)ethyl)-2,6-dimethylmorpholine;   1-(4-(2-(1-Cyclohexyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone;   1-(2-(1-Cyclohexyl-1H-pyrazol-3-yloxy)ethyl)-4-phenylpiperidine;   2-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)-N,N-diethylethanamine;   1-Cyclohexyl-5-methyl-3-(2-(pyrrolidin-1-yl)ethoxy)-1H-pyrazole;   1-(2-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperidine;   4-(2-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholine;   4-(2-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)ethyl)-2,6-dimethylmorpholine;   1-(4-(2-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone;   4-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)-N,N-diethylbutan-1-amine ;   4-(1-Cyclohexyl-1H-pyrazol-3-yloxy)-N,N-diethylbutan-1-amine;   1-Cyclohexyl-5-methyl-3-(4-(pyrrolidin-1-yl)butoxy)-1H-pyrazole;   1-Cyclohexyl-3-(4-(pyrrolidin-1-yl)butoxy)-1H-pyrazole;   1-(4-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)butyl)piperidine;   1-(4-(1-Cyclohexyl-1H-pyrazol-3-yloxy)butyl)piperidine;   4-(4-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)butyl)morpholine;   4-(4-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)butyl)-2,6-dimethylmorpholine;   4-(4-(1-Cyclohexyl-1H-pyrazol-3-yloxy)butyl)morpholine;   4-(4-(1-Cyclohexyl-1H-pyrazol-3-yloxy)butyl)-2,6-dimethylmorpholine;   1-(4-(4-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)butyl)piperazin-1-yl)ethanone;   1-(4-(4-(1-Cyclohexyl-1H-pyrazol-3-yloxy)butyppiperazin-1-yl)ethanone;   1-[2-(1-tert-butyl-1H-pyrazol-3-yloxy)ethyl]piperidine oxalate;   4-[2-(1-tert-butyl-1H-pyrazol-3-yloxy)ethyl]morpholine oxalate;   2-(1-tert-butyl-1H-pyrazol-3-yloxy)-N,N-diethylethanamine oxalate;   1-tert-butyl-3-[2-(pyrrolidin-1-ypethoxy]-1H-pyrazole oxalate;   4-(2-(1-cyclohexyl-1H-pyrazol-3-yloxy)ethyl)morpholine oxalate;   1-(2-(1-cyclohexyl-1H-pyrazol-3-yloxy)ethyl)piperidine oxalate;   2-(1-cyclohexyl-1H-pyrazol-3-yloxy)-N,N-diethylethanamine oxalate;   1-Cyclohexyl-3-(2-(pyrrolidin-1-yl)ethoxy)-1H-pyrazole oxalate;   4-(2-(1-Cyclohexyl-1H-pyrazol-3-yloxy)ethyl)-2,6-dimethylmorpholine oxalate;   1-(4-(2-(1-Cyclohexyl-1H-pyrazol-3-yloxy)ethyl)piperazin-1-yl)ethanone oxalate;   1-(2-(1-Cyclohexyl-1H-pyrazol-3-yloxy)ethyl)-4-phenylpiperidine oxalate;   2-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)-N,N-diethylethanamine oxalate;   1-Cyclohexyl-5-methyl-3-(2-(pyrrolidin-1-yl)ethoxy)-1H-pyrazole oxalate;   1-(2-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)ethyl)piperidine oxalate;   4-(2-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)ethyl)morpholine oxalate;   4-(2-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)ethyl)-2,6-dimethylmorpholine oxalate;   1-(4-(2-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)ethyl) piperazin-1-yl)ethanone oxalate;   4-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)-N,N-diethylbutan-1-amine oxalate;   4-(1-Cyclohexyl-1H-pyrazol-3-yloxy)-N,N-diethylbutan-1-amine oxalate;   1-Cyclohexyl-5-methyl-3-(4-(pyrrolidin-1-yl)butoxy)-1H-pyrazole oxalate;   1-Cyclohexyl-3-(4-(pyrrolidin-1-yl)butoxy)-1H-pyrazoleoxalate;   1-(4-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)butyl)piperidine oxalate;   1-(4-(1-Cyclohexyl-1H-pyrazol-3-yloxy)butyl)piperidine oxalate;   4-(4-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)butyl)morpholine oxalate;   4-(4-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)butyl)-2,6-dimethylmorpholine oxalate;   4-(4-(1-Cyclohexyl-1H-pyrazol-3-yloxy)butyl)morpholine oxalate;   4-(4-(1-Cyclohexyl-1H-pyrazol-3-yloxy)butyl)-2,6-dimethylmorpho line oxalate;   1-(4-(4-(1-Cyclohexyl-5-methyl-1H-pyrazol-3-yloxy)butyl)piperazin-1-yl)ethanone oxalate; and   1-(4-(4-(1-Cyclohexyl-1H-pyrazol-3-yloxy)butyl)piperazin-1-yl) ethanone oxalate;   
       optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or another corresponding salt thereof, or a corresponding solvate thereof. 
     
     
         28 . A method according to  claim 18 , wherein the disease is diarrhoea, lipoprotein disorders, metabolic syndrome, treatment of elevated triglyceride levels, chylomicronemia, hyperlipoproteinemia; hyperlipidemia, especially mixed hyperlipidemia; hypercholesterolemia, dysbetalipoproteinemia, hypertriglyceridemia including both the sporadic and familial disorder (inherited hypertriglyceridemia), migraine, obesity, arthritis, hypertension, arrhythmia, ulcer, learning, memory and attention deficits, cognition disorders, neurodegenerative diseases, demyelinating diseases, addiction to drugs and chemical substances including cocaine, amphetamine, ethanol and nicotine, tardive diskinesia, ischemic stroke, epilepsy, stroke, depression, stress, psychotic condition, schizophrenia; inflammation, autoimmune diseases or cancer; disorders of food ingestion, the regulation of appetite, for the reduction, increase or maintenance of body weight, for the prophylaxis and/or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes, preferably type II diabetes caused by obesity. 
     
     
         29 . A method according to  claim 18 , wherein the disease is pain, especially neuropathic pain, inflammatory pain or other pain conditions, allodynia and/or hyperalgesia, especially mechanical allodynia. 
     
     
         30 . A method according to  claim 18 , wherein the compound is used as a pharmacological tool or as an anxiolytic or immunosuppressant.