Melanin concentrating hormone antagonist

Abstract

A melanin-concentrating hormone antagonist which comprises a compound of the formula: wherein Ar 1 is a cyclic group which may have substituents; X is a spacer having a main chain of 1 to 6 atoms; Y is a bond or a spacer having a main chain of 1 to 6 atoms; Ar is a monocyclic aromatic ring which may be condensed with a 4 to 8 membered non-aromatic ring, and may have further substituents; R 1 and R 2 are independently hydrogen atom or a hydrocarbon group which may have substituents; R 1 and R 2 , together with the adjacent nitrogen atom, may form a nitrogen-containing hetero ring which may have substituents; R 2 may form a spiro ring together with Ar; or R 2 , together with the adjacent nitrogen atom and Y, may form a nitrogen-containing hetero ring which may have substituents; or a salt thereof; which is useful as an agent for preventing or treating obesity, etc.

1 . A method for preventing or treating diseases caused by a melanin-concentrating hormone in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
         wherein Ar 1  is a cyclic group which may have substituents;  
         X is a spacer having a main chain of 1 to 6 atoms;  
         Y is a bond or a spacer having a main chain of 1 to 6 atoms;  
         Ar is a monocyclic aromatic ring which may be condensed with a 4 to 8 membered non-aromatic ring, and may have further substituents;  
         R 1  and R 2  are independently hydrogen atom or a hydrocarbon group which may have substituents; R 1  and R 2 , together with the adjacent nitrogen atom, may form a nitrogen-containing hetero ring which may have substituents; R 2  may form a spiro ring together with Ar;  
         or R 2 , together with the adjacent nitrogen atom and Y, may form a nitrogen-containing hetero ring which may have substituents; or a salt thereof.  
       
     
     
         2 - 3 . (canceled)  
     
     
         4 . The method according to  claim 1 , wherein Ar 1  is a cyclic group which may have 1 to 5 substituents selected from the group consisting of 
 (1) oxo,    (2) halogen atoms,    (3) C 1-3  alkylenedioxy,    (4) nitro,    (5) cyano,    (6) optionally halogenated C 1-6  alkyl,    (7) hydroxy-C 1-6  alkyl,    (8) carboxy-C 1-6  alkyl,    (9) C 1-6  alkoxy-carbonyl-C 1-6  alkyl,    (10) C 6-14  aryloxy-C 1-6  alkyl,    (11) C 1-6  alkyl-C 6-14  aryl-C 2-6  alkenyl,    (12) optionally halogenated C 3-6  cycloalkyl,    (13) optionally halogenated C 1-6  alkoxy,    (14) optionally halogenated C 1-4  alkylthio,    (15) C 7-9  aralkyl,    (16) hydroxy,    (17) C 6-14  aryloxy,    (18) C 7-19  aralkyloxy,    (19) C 6-14  aryl-carbamoyl,    (20) amino,    (21) amino-C 1-6  alkyl,    (22) mono-C 1  6 alkylamino,    (23) di-C 1-6  alkylamino,    (24) mono-C 1-6  alkylamino-C 1-6  alkyl,    (25) di-C 1-6  alkylamino-C 1-6  alkyl,    (26) 5 to 7 membered saturated cyclic amino,    (27) 5 to 7 membered non-aromatic heterocyclic groups,    (28) acyl,    (29) acylamino,    (30) acyloxy, and    (31) aromatic hetero ring-C 1-6  alkoxy, 
 wherein the above (15), (17), (18) and (19) may have 1 to 5 substituents selected from the group consisting of halogen atom, C 1-3  alkylenedioxy, nitro, cyano, optionally halogenated C 1-6  alkyl, optionally halogenated C 3-6  cycloalkyl, optionally halogenated C 1-6  alkoxy, optionally halogenated C 1-6  alkylthio, hydroxy, amino, mono-C 1-6  alkylamino, di-C 1-6  alkylamino, amino-C 1-6  alkyl, mono-C 1-6  alkylamino-C 1-6  alkyl, di-C 1-6  alkylamino-C 1-6  alkyl, formyl, carboxy, carbamoyl, thiocarbamoyl, optionally halogenated C 1-6  alkyl-carbonyl, C 1-6  alkoxy-carbonyl, mono-C 1-6  alkyl-carbamoyl, di-C 1-6  alkyl-carbamoyl, optionally halogenated C 1-6  alkylsulfonyl, formylamino, optionally halogenated C 1-6  alkyl-carboxamide, C 1-6  alkoxy-carboxamide, C 1-6  alkylsulfonylamino, C 1-6  alkyl-carbonyloxy, C 1-6  alkoxy-carbonyloxy, mono-C 1-6  alkyl-carbamoyloxy and di-C 1-6  alkyl-carbamoyloxy,  
 the above (26) and (27) may have 1 to 5 substituents selected from the group consisting of  
   1) oxo,    2) optionally halogenated C 14  alkyl,    3) optionally halogenated C 1-6  alkyl-carbonyl,    4) optionally halogenated C 1-6 alkylsulfonyl,    5) C 6-14  aryl,    6) C 7-19  aralkyl,    7) C 6-14  aryl-carbonyl,    8) 5 to 10 membered aromatic heterocyclic group which may have 1 to 5 substituents selected from the group consisting of 
 8a) halogen atom,  
 8b) C 1-3  alkylenedioxy,  
 8c) nitro,  
 8d) cyano,  
 8e) optionally halogenated C 1-6  alkyl,  
 8f) C 6-14  aryloxy-C 1-6  alkyl,  
 8g) C 1-6  alkyl-C 6-14  aryl-C 2-6  alkenyl,  
 8h) optionally halogenated C 3-6  cycloalkyl,  
 8i) optionally halogenated C 1-6  alkoxy,  
 8i) optionally halogenated C 1-6  alkylthio,  
 8k) C 7-19  aralkyl,  
 8l) hydroxy,  
 8m) C 6-14  aryloxy,  
 8n) C 7-19  aralkyloxy,  
 8o) amino,  
 8p) amino-C 1-6  alkyl,  
 8q) mono-C 1-6  alkylamino,  
 8r) di-C 1-6  alkylamino,  
 8s) mono-C 1-6  alkylamino-C 1-6  alkyl,  
 8t) di-C 1-6  alkylamino-C 1-6  alkyl,  
 8u) 5 to 7 membered saturated cyclic amino,  
 8v) acyl,  
 8w) acylamino and  
 8x) acyloxy, and  
   9) 5 to 8 membered monocyclic non-aromatic heterocyclic group, 
 wherein the above 5), 6), 7), 8k), 8m) and 8n) may have 1 to 5 substituents selected from the group consisting of halogen atom, C 1-3  alkylenedioxy, nitro, cyano, optionally halogenated C 1-6  alkyl, optionally halogenated C 3-6  cycloalkyl, optionally halogenated C 1-6  alkoxy, optionally halogenated C 1-6  alkylthio, hydroxy, amino, mono-C 1-6  alkylamino, di-C 1-6  alkylamino, amino-C 1-6  alkyl, mono-C 1-6  alkylamino-C 1-6  alkyl, di-C 1-6  alkylamino-C 1-6  alkyl, formyl, carboxy, carbamoyl, thiocarbamoyl, optionally halogenated C 1-6  alkyl-carbonyl, C 1-6  alkoxy-carbonyl, mono-C 1-6  alkyl-carbamoyl, di-C 1-6  alkyl-carbamoyl, optionally halogenated C 1-6  alkylsulfonyl, formylamino, optionally halogenated C 1-6  alkyl-carboxamide, C 1-6  alkoxy-carboxamide, C 1-6  alkylsulfonylamino, C 1-6  alkyl-carbonyloxy, C 1-6  alkoxy-carbonyloxy, mono-C 1-6  alkyl-carbamoyloxy and di-C 1-6  alkyl-carbamoyloxy,  
 provided that when the cyclic group is a non-aromatic cyclic hydrocarbon group or a non-aromatic heterocyclic group, the cyclic group may have 1 to 3 substituents selected from the group consisting of the “C 6-14  aryl which may have substituents” as defined in the above 5), and  
   the “5 to 10 membered aromatic heterocyclic groups which may have substituents” as defined in the above 8).    
     
     
         5 . The method according to  claim 1 , wherein the cyclic group for Ar 1  is a C 6-14  monocyclic or a condensed polycyclic aromatic hydrocarbon group.  
     
     
         6 . The method according to  claim 1 , wherein the cyclic group for Ar 1  is a group formed by removing one hydrogen atom from an aromatic ring assemble in which 2 or 3 C 6-14  monocyclic or condensed polycyclic aromatic hydrocarbon groups are directly bonded by single bonds.  
     
     
         7 . The method according to  claim 1 , wherein the cyclic group for Ar 1  is a group formed by removing one hydrogen atom from an aromatic ring assemble in which C 6-14  monocyclic or condensed polycyclic aromatic hydrocarbon and 5 to 10 membered aromatic hetero ring are directly bonded by a single bond.  
     
     
         8 . The method according to  claim 1 , wherein Ar 1  is phenyl, biphenylyl, phenyl-pyridyl, phenyl-furyl, phenyl-isoxazolyl, diphenyl-oxazolyl, pyridyl-phenyl, phenyl-pyrimidinyl, benzofuranyl-phenyl, furyl-phenyl, terphenyl, thienyl-phenyl, indolyl, naphthyl-oxadiazolyl, benzofuranyl-oxadiazolyl, benzothienyl, benzofuranyl, fluorenyl, pyridyl-pyrrolyl or thioxanthenyl: 
 each of which may have 1 to 3 substituents selected from the group consisting of halogen atom; nitro; C 1-3  alkylenedioxy; optionally halogenated C 1-6  alkyl; hydroxy-C 1-6  alkyl; optionally halogenated C 3-6  cycloalkyl; optionally halogenated C 1-6  alkoxy; optionally halogenated C 1-6  alkythio; hydroxy; C 7-19  aralkyloxy which may have substituents; C 6-14  aryloxy which may have substituents; amino; mono-C 1-6  alkylamino; di-C 1-6  alkylamino; 5 to 7 membered saturated cyclic amino which may have substituents and may be condensed with a benzene ring; 5 to 7 membered non-aromatic heterocyclic groups which may have substituents: formyl; carboxy; C 6-14  aryl-carbonyl which may have substituents; C 6-14  aryl-carbamoyl which may have substituents; aromatic hetero ring-carbamoyl which may have substituents; C 1-6  alkoxy-carbonyl; optionally halogenated C 1-6  alkyl-carboxamide; C 6-14  aryl-carboxamide which may have substituents; C 7-19  aralkyl-carboxamide which may have substituents: aromatic hetero ring-carboxamide which may have substituents; N—(C 6-14  aryl-carbonyl which may have substituents)-N—C 1-6  alkylamino; C 6-14  arylamino-carbonylamino which may have substituents; C 6-14  arylsulfonylamino which may have substituents; C 6-14  aryl-carbonyloxy which may have substituents; oxo; carboxy-C 1-6  alkyl; C 1-6  alkoxy-carbonyl-C 1-6  alkyl; C 7-19  aralkyl which may have substituents; aromatic hetero ring-C 1-6  alkoxy; and cyano.    
     
     
         9 . The method according to  claim 1 , wherein Ar 1  is piperidinyl, piperazinyl, pyrrolidinyl, dihydropyridyl or tetrahydropyridyl; each of which may have 1 or 2 substituents selected from the group consisting of oxo, C 6-14  aryl which may have substituents, hydroxy, C 7-19  aralkyloxy-carbonyl, and C 7-19  aralkyl.  
     
     
         10 . The method according to  claim 1 , wherein said spacer having a main chain of 1 to 6 atoms for X and Y is 
 a bivalent group consisting of 1 to 3 species selected from —O—, —S—, —CO—, —SO—, —SO 2 —, —NR 8 —, 
 wherein R 8  is hydrogen atom, optionally halogenated C 1-6  alkyl, 
 optionally halogenated C 1-6  alkyl-carbonyl, optionally halogenated C 1-6  alkylsulfonyl,  
 
   and a bivalent C 1-6  non-cyclic hydrocarbon group which may have substituents.    
     
     
         11 . The method according to  claim 1 , wherein the spacer having a main chain of 1 to 6 atoms for X and Y is 
 (1) C 1-6  alkylene;    (2) C 2-6  alkenylene:    (3) C 2-6  alkynylene;    (4) —(CH 2 ) w1 O(CH 2 ) w2 —, —(CH 2 ) w1 NR 8 (CH 2 ) w2 —, —(CH 2 ) w1,CO(CH   2 ) w2 —, —(CH 2 ) w1 SO(CH 2 ) w2 —, —(CH 2 ) w1 SO 2 (CH 2 ) w2 —, or —(CH 2 ) w1 NR 8 (CH 2 ), w2 —;    (5) —(CH 2 ) w3 CONR 8 (CH 2 ) w4 —, —(CH 2 ) w3 NR 8 CO(CH 2 ) w4 —, —(CH 2 ) w3 SO 2 NR 8 (CH 2 ) w4 —, —(CH 2 ) w3 NR 8 SO 2 (CH 2 ) w4 —, or —(CH 2 ), w3 COO(CH 2 ) w4 —;    (6) —(CH 2 ) w5 NR 8 CONR 8 (CH 2 ) w6 —; or    (7) —(CH 2 ) w7 CONR 8 —(CH 2 ) w8 —CONR 8b —(CH 2 ) w9 —; —CH═CH-CONR 8 —; or —CH═CH—SO 2 NR 8 —;    wherein R 8  and R 8b are each hydrogen atom, optionally halogenated C 1-6  alkyl, optionally halogenated C 1-6  alkyl-carbonyl, or optionally halogenated C 1-6  alkylsulfonyl; w1 and w2 are each integers of 0 to 5, and w1+w2 is 0 to 5; w3 and w4 are each integers of 0 to 4, and w3+w4 is 0 to 4; w5 and w6 are each integers of 0 to 3, and w5+w6 is 0 to 3; w7, w8 and w9 are each integers of 0 to 2, and w7+w8+w9 is 0 to 2.    
     
     
         12 . The method according to  claim 1 , wherein X is —(CH 2 ) w3 CONR 8 (CH 2 ), w4 — wherein R 8  is hydrogen atom, optionally halogenated C 1-6  alkyl, optionally halogenated C 1-6  alkyl-carbonyl, or optionally halogenated C 1-6  alkylsulfonyl; w3 and w4 are each an integer of 0 to 4, and w3 +w4 is 0 to 4.  
     
     
         13 . The method according to  claim 1 , wherein Y is C 1-3  alkylene, —(CH 2 ) w3 CONH(CH 2 ) w4 — or —(CH 2 ) w3 COO(CH 2 ) w4 — wherein w3 and w4 are each an integer of 0 to 4, and w3 +w4 is 0 to 4.  
     
     
         14 . The method according to  claim 1 , wherein Ar is 
 benzene, pyridine, or rings of the formulae:                          wherein  is a single bond or double bond; each of m and n is an integer of 1 to 4.    
     
     
         15 . The method according to  claim 1 , wherein R 1  and R 2  are hydrogen atom or C 1-6  alkyl which may have substituents; or R 1  and R 2 , together with the adjacent nitrogen atom, form a 3 to 8 membered nitrogen-containing hetero ring.  
     
     
         16 . The method according to  claim 1 , wherein the compound is 
 N-[4-[[[2-(Diethylamino)ethyl]amino]carbonyl]phenyl]4-biphenylylcarboxamide;    4-(4-Biphenylylmethoxy)-N-[2-(isopropylamino)ethyl]benzamide;    2-(N,N-Diethylamino)ethyl4-(4-biphenylylcarbonylamino)benzoate;    N-[4-[[[2-(Dimethylamino)ethtyl]amino]carbonyl]phenyl]4-biphenylylcarboxamide;    N-[4-[[2-(Piperidinoethyl)amino]carbonyl]phenyl]4-biphenylylcarboxamide;    N-[4-[[2-(1-Pyrrolidinyl)ethyl]amino]carbonyl]phenyl]4-biphenylylcarboxamide;    N-[4-[(E)-3-Amino-3-oxo-1-propenyl]phenyl][1,1′-biphenyl]4-carboxyamide;    tert-Butyl 3-[[4-[[(4′-chloro]1,1′-biphenyl]-4-yl)carbonyl]amino]phenyl](hydroxy)methyl]-1-piperidinecarboxylate;    tert-Butyl 3-[4-[([1,1′-biphenyl]4-ylcarbonyl)amino]benzyl]-1-piperidinecarboxylate;    tert-Butyl 3-[4-[[(4′-fluoro]1,1′-biphenyl]4-yl)carbonyl]amino]benzyl]-1-piperidinecarboxylate;    tert-Butyl 3-[4-[[(4′-chloro[1,1′-biphenyl]4-yl)carbonyl]amino]benzyl]-1-piperidinecarboxylate;      4 ′-Chloro-N-[4-(4-piperidinyl)phenyl][1,1′-biphenyl]4-carboxamide;    N-[4-[(E)-2-(4,5-Dihydro-1H-imidazol-2-yl)ethenyl]phenyl][1,1′-biphenyl]-4-carboxamide hydrochloride;    N-[4-[2-(4,5-Dihydro-1H-imidazol-2-yl)ethenyl]phenyl][1,1′-biphenyl]-4-carboxamide hydrochloride;    4′-Chloro-N-[4-(3-piperidinylcarbonyl)phenyl][1,1′-biphenyl]-4-carboxamide hydrochloride;    4′-Chloro-N-[4-[hydroxy(3-piperidinyl)methyl]phenyl][1,1′-biphenyl]-4-carboxamide hydrochloride;    [4-[[(4′-Chloro 1,1′-biphenyl]-4-yl)carbonyl]amino]phenyl](3-piperidinyl)methyl acetate;    N-[4-(3-Piperidinylmethyl)phenyl][1,1′-biphenyl]-4-carboxamide hydrochloride;    4′-Fluoro-N-[4-(3-piperidinylmethyl)phenyl][1,1′-biphenyl]-4-carboxamide hydrochloride;    4′-Chloro-N-[4-(3-piperidinylmethyl)phenyl][1,1′-biphenyl]-4-carboxamide hydrochloride;    4′-Chloro-N-[4-(4-piperidinyl)phenyl][1,1 ′-biphenyl]-4-carboxamide;    4′-Chloro-N-[4-(1-methyl4-piperidinyl)phenyl][1,1 ′-biphenyl]-4-carboxamide;    Benzyl 4-[2-[[2-(dimethylamino)ethyl]amino]-2-oxoethyl]phenylcarbamate;    N-[4-[2-[[2-(Dimethylamino)ethyl]amino]-2-oxoethyl]phenyl][1,1′-biphenyl]-4-carboxamide hydrochloride;    Benzyl 4-[[4-[2-[[2-(dimethylamino)ethyl]amino]-2-oxoethyl]anilino]carbonyl]-1-piperidinecarboxylate;    N-[4-[2-[[2-(Dimethylamino)ethyl]amino]-2-oxoethyl]phenyl]-3-[3-(2-naphthyl)-1,2,4-oxadiazol-5-yl]propanamide;    N-[4-[2-[[2-(Dimethylamino)ethyl]amino]-2-oxoethyl]phenyl]-2-(4-nitrophenyl)acetamide;    (E)-N-[4-[2-[[2-(Dimethylamino)ethyl]amino]-2-oxoethyl]phenyl]-3-[4-(4-methoxyphenoxy)phenyl]-2-propanamide;    4-[3-(1-Benzofuran-2-yl)-1,2,4-oxadiazol-5-yl]-N-[4-[2-[[2-(dimethylamino)ethyl]amino]-2-oxoethyl]phenyl]butanamide;    N-[4-[2-[[2-(Dimethylamino)ethyl]amino]-2-oxoethyl]phenyl]-3-methoxy4-(2-quinolinylmethoxy)benzamide;    3-[1-(2,4-Dichlorobenzyl)-1H-indol-3-yl]-N-[4-[2-[[2-(dimethylamino)ethyl]amino]-2-oxoethyl]phenyl]propanamide;    N-[4-[2-[[2-(Dimethylamino)ethyl]amino]-2-oxoethyl]phenyl]-1-benzothiophen-2-carboxamide;    2-(2-Benzylphenyl)-N-[4-[2-[[2-(dimethylamino)ethyl]aminol-2-oxoethyl]phenyl]acetamide;    2-(3,4-dimethoxyphenyl)-N-[4-[2-[[2-(dimethylamino)ethyl]amino]-2-oxoethyl]phenyl]acetamide;    N-[4-[2-[[2-(Dimethylamino)ethyl]amino]l-2-oxoethyl]phenyl]-2-(5-methoxy-2-methyl-1H -indol-3-yl)acetamide;    N-[4-[2-[[2-(Dimethylamino)ethyl]aminol-2-oxoethyl]phenyl]-4-(1H-indol-3-yl)butanamide;    N-[4-[2-[[2-(Dimethylamino)ethyl]aminol-2-oxoethyl]phenyl]furo[2,3-f][1,3]benzodioxol-6-carboxamide;    4-([1,1′-Biphenyl]-4-ylmethoxy)-N-[4-[2-[[2-(dimethylamino)ethyl]amino]-2- oxoethyl]phenyl]benzamide;    4-(Benzoylamino)-N-[4-[2-[[2-(dimethylamino)ethyl]amino]-2-oxoethyl]phenyl]benzamide;    N-[4-[2-[[2-(Dimethylamino)ethyl]amino]-2-oxoethyl]phenyl]-4′-methoxy[1,1′-biphenyl]-4-carboxamide;    N-[4-[2-[[2-(Dimethylamino)ethyl]amino]-2-oxoethyl]phenyl]-9,10,10-trioxo-9,10-dihydro-10λ 6 -thioxanten-3-carboxamide;    4-(Benzyloxy)-N-[4-[2-[[2-(dimethylamino)ethyl]amino]-2-oxoethyl]phenyl]benzamide;    4-Benzoyl-N-[4-[2-[[2-(dimethylamino)ethyl]amino]-2-oxoethyl]phenyl]benzamide;    N-[4-[2-[[2-(Dimethylamino)ethyl]amino]-2-oxoethyl]phenyl]-5-methyl-3-(4-pyridinyl)-1H -pyyrole-2-carboxamide; or    1-(3,4-Dichlorobenzyl)-N-[4-[2-[[2-(dimethylamino)ethyl]amino]-2-oxoethyl]phenyl]-4-piperidinecarboxamide.    
     
     
         17 - 38 . (canceled)  
     
     
         39 . A method for preventing or treating obesity in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of the formula;  
       
         
           
           
               
               
           
         
         wherein Ar 1  is a cyclic group which may have substituents;  
         X is a spacer having a main chain of 1 to 6 atoms;  
         Y is a bond or a spacer having a main chain of 1 to 6 atoms;  
         Ar is a monocyclic aromatic ring which may be condensed with a 4 to 8 membered non-aromatic ring, and may have further substituents; 
 R 1  and R 2  are independently hydrogen atom or a hydrocarbon group which may have substituents; R 1  and R 2 , together with the adjacent nitrogen atom, may form a nitrogen-containing hetero ring which may have substituents; R 2  may form a spiro ring together with Ar; or R 2 , together with the adjacent nitrogen atom and Y, may form a nitrogen-containing hetero ring which may have substituents; or a salt thereof.  
 
       
     
     
         40 . A method for antagonizing a melanin-concentrating hormone receptor in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of the formula;  
       
         
           
           
               
               
           
         
         wherein Ar 1  is a cyclic group which may have substituents;  
         X is a spacer having a main chain of 1 to 6 atoms;  
         Y is a bond or a spacer having a main chain of 1 to 6 atoms;  
         Ar is a monocyclic aromatic ring which may be condensed with a 4 to 8 membered non-aromatic ring, and may have further substituents;  
         R 1  and R 2  are independently hydrogen atom or a hydrocarbon group which may have substituents; R 1  and R 2 , together with the adjacent nitrogen atom, may form a nitrogen-containing hetero ring which may have substituents; R 2  may form a spiro ring together with Ar; or R 2 , together with the adjacent nitrogen atom and Y, may form a nitrogen-containing hetero ring which may have substituents; or a salt thereof.