New compounds i

Abstract

The present application relates to new compounds of formula (I), to pharmaceutical compositions comprising the compounds, to processes for their preparation, and to the use of the compounds as leptin receptor modulator mimetics in the preparation of medicaments against conditions associated with weight gain, type 2 diabetes and dyslipidemias.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is selected from O, S, N(R 1 ) and CH(R 2a ), provided that the ring containing X is not 3-pyrrolidine; 
         Y is CH 2 , O or N(R 5 ); 
         each R 1  is independently selected from hydrogen, C 1-6 -alkyl which is unsubstituted or optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano and C 1-6 -alkoxy, and C 1-6 -acyl which is unsubstituted or optionally substituted with one or more substituents independently selected from halogen, hydroxy and C 1-6 -alkoxy; 
         each R 2  and each R 3  is independently selected from halogen, hydroxy, C 1-6 -alkyl which is unsubstituted or optionally substituted with one or more substituents independently selected from halogen, hydroxy and C 1-6 -alkoxy, and C 1-6 -alkoxy which is unsubstituted or optionally substituted with one or more substituents independently selected from halogen, hydroxy and C 1-6 -alkoxy; 
         R 2a  is hydrogen or R 2 ; 
         each R 4  is independently selected from halogen, hydroxy, cyano, nitro, CF 3 , C 1-6 -alkyl and C 1-6 -alkoxy; 
         R 5  is hydrogen or C 1-4 -alkyl; 
         a, b and c are each independently 0, 1, 2 or 3; 
         d is 0, 1 or 2; 
         e is 1, 2 or 3; and 
         f and g are each independently 0, 1 or 2. 
       
     
     
         2 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is O. 
     
     
         3 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is O, N(R 1 ) or CH(R 2a ). 
     
     
         4 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is hydrogen, methyl, ethyl or acetyl. 
     
     
         5 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein a and b are each independently 0 or 1. 
     
     
         6 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein c is 0, 1 or 2. 
     
     
         7 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 4  is independently selected from fluoro, chloro, methyl and ethyl. 
     
     
         8 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I′) 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1  and X 2  are each independently selected from O, N(R 1 ) and CH(R 2a ), provided that at least one of X 1 1 and X 2  is N(R 1 ); 
 R 1 , R 2 , R 2a  and R 4  are as defined in  claim 1 ; 
 c is 0, 1, 2 or 3; 
 e is 1 or 2; and 
 g is 0 or 1. 
 
     
     
         9 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from:
 [(3R)-1-methylpiperidin-3-yl]methyl 4-(4-methylphenyl)piperazine-1-carboxylate;   [(3S)-1-methylpiperidin-3-yl]methyl 4-(4-methylphenyl)piperazine-1-carboxylate;   [(2S)-1,4-dimethylpiperazin-2-yl]methyl 4-phenylpiperazine-1-carboxylate;   [(2R)-1,4-dimethylpiperazin-2-yl]methyl 4-phenylpiperazine-1-carboxylate;   [(2S)-1,4-dimethylpiperazin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylate;   [(2R)-1,4-dimethylpiperazin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylate;   4-phenylpiperazine-1-carboxylic acid 2-(1,4-dimethylpiperazin-2-yl)ethyl ester;   [(2S)-1,4-dimethylpiperazin-2-yl]methyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate;   [(2S)-4-methylpiperazin-2-yl]methyl 4-phenylpiperazine-1-carboxylate;   (1,4-dimethylpiperazin-2-yl)methyl 4-benzylpiperazine-1-carboxylate;   morpholin-2-ylmethyl 4-phenylpiperazine-1-carboxylate;   (2S)-morpholin-2-ylmethyl 4-phenylpiperazine-1-carboxylate;   (2R)-morpholin-2-ylmethyl 4-phenylpiperazine-1-carboxylate;   (4-methylmorpholin-2-yl)methyl 4-phenylpiperazine-1-carboxylate;   [(2S)-4-methylmorpholin-2-yl]methyl 4-phenylpiperazine-1-carboxylate;   [(2R)-4-methylmorpholin-2-yl]methyl 4-phenylpiperazine-1-carboxylate;   [(2S)-4-methylmorpholin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylate;   [(2R)-4-methylmorpholin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylate;   [(2S)-4-methylmorpholin-2-yl]methyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate;   [(2R)-4-methylmorpholin-2-yl]methyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate;   morpholin-2-ylmethyl 4-(4-fluorophenyl)piperazine-1-carboxylate;   (2S)-morpholin-2-ylmethyl 4-(4-fluorophenyl)piperazine-1-carboxylate;   (2R)-morpholin-2-ylmethyl 4-(4-fluorophenyl)piperazine-1-carboxylate;   (4-methylmorpholin-2-yl)methyl 4-(4-chlorophenyl)piperazine-1-carboxylate;   (4-methylmorpholin-2-yl)methyl 4-(4-fluorobenzyl)piperazine-1-carboxylate;   (4-acetylmorpholin-2-yl)methyl 4-phenylpiperazine-1-carboxylate;   morpholin-3-ylmethyl 4-(4-fluorophenyl)piperazine-1-carboxylate;   (3S)-morpholin-3-ylmethyl 4-(4-fluorophenyl)piperazine-1-carboxylate;   (3R)-morpholin-3-ylmethyl 4-(4-fluorophenyl)piperazine-1-carboxylate;   (4-methylmorpholin-3-yl)methyl 4-(4-fluorophenyl)piperazine-1-carboxylate;   morpholin-3-ylmethyl 4-phenylpiperazine-1-carboxylate;   morpholin-3-ylmethyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate;   (4-methylmorpholin-3-yl)methyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate;   (2S)-morpholin-2-ylmethyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate; and   (2R)-morpholin-2-ylmethyl 4-(2,4-difluorophenyl)piperazine-1-carboxylate;   
       and pharmaceutically acceptable salts thereof. 
     
     
         10 . A pharmaceutical formulation containing a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, as an active ingredient, in combination with a pharmaceutically acceptable diluent or carrier. 
     
     
         11 . A method for treatment or prevention of conditions or diseases associated with weight gain, which comprises administering to a mammal, including man, in need of such treatment an effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method according to  claim 11 , wherein the condition or disease is obesity, type 2 diabetes, lipodystrophy, insulin resistance, metabolic syndrome, hyperglycemia, hyperinsulinemia, dyslipidemia, hepatic steatosis, hyperphagia, hypertension, hypertriglyceridemia, infertility, a skin disorder associated with weight gain or macular degeneration. 
     
     
         13 . A method for treatment or prevention of severe weight loss, dysmenorrhea, amenorrhea, female infertility or immunodeficiency, or the treatment of wound healing, which comprises administering to a mammal, including man, in need of such treatment an effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         14 . method for treatment or prevention of inflammatory conditions or diseases, low level inflammation associated with obesity and excess plasma leptin, atherosclerosis, macro or micro vascular complications of type 1 or 2 diabetes, retinopathy, nephropathy, autonomic neuropathy, or blood vessel damage caused by ischaemia or atherosclerosis, which comprises administering to a mammal, including man, in need of such treatment an effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         15 . A method for inhibition of angiogenesis, which comprises administering to a mammal, including man, in need of such treatment an effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         16 . A process for the preparation of a compound of  claim 1 , comprising:
 (a) reacting a compound of formula (II):   
       
         
           
           
               
               
           
         
       
       wherein R 3 , R 4 , b, c, f and g are as defined in  claim 1 ,
 with 4-nitrophenyl chloroformate or bis-(4-nitrophenyl)carbonate in the presence of a suitable base (such as DIPEA or NEt 3 ) in a suitable solvent (such as DCM or THF), at −10 to 40° C., to form a compound of formula (III): 
 
       
         
           
           
               
               
           
         
         (b) reacting the compound of formula (III) with a compound of formula (IV): 
       
       
         
           
           
               
               
           
         
       
       wherein X, R 1 , R 2 , a, d and e are as defined in  claim 1 ,
 in the presence of a suitable base, (such as NaH or NMM), in a suitable solvent (such as THF or DCM), at −10 to 40° C., to obtain a compound of formula (I); and 
 (c) optionally, in one or several steps transforming a compound of formula (I) into another compound of formula (I). 
 
     
     
         17 . A process for the preparation of a compound of  claim 1 , comprising:
 (a) reacting a compound of formula (IV):   
       
         
           
           
               
               
           
         
       
       Wherein X, R 1 , R 2 , a, d and e are as defined in  claim 1 ,
 with 4-nitrophenyl chloroformate or bis-(4-nitrophenyl)carbonate in the presence of a suitable base (such as DIPEA or NMM) in a suitable solvent (such as DCM), at −10 to 40° C., to form a compound of formula (V): 
 
       
         
           
           
               
               
           
         
         (b) reacting the compound of formula (V) with a compound of formula (II): 
       
       
         
           
           
               
               
           
         
       
       wherein R 3 , R 4 , b, c, f and g are as defined in  claim 1 ,
 in the presence of a suitable base, (such as DIPEA), in a suitable solvent (such as DCM or DMF), at −10 to 40° C., to obtain a compound of formula (I); and 
 (c) optionally, in one or several steps transforming a compound of formula (I) into another compound of formula (I).