| abstract |
A compound of structural formula (1) or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: m is a number from 0 to 3; n is a number from 0 to 3; m and n can be the same or different; X1 is CH, N, or C-C 1-3 alkyl; X2 is N-R5, CH2, O, S, SO, SO2, CH- (C1-6 alkyl), or CH- (CH2-O-C1-3 alkyl); X3 is O or N-R6: X4 is a single bond, O, N, NH, N-R7, or when X4 is N, R2 and R4 can join to form a heterocycloalkyl group such as piperidine, pyrrolidine, morpholine, piperazine, thiomorpholine, or formulas (2), (3) wherein the N of X4 is the heteroatom of said heterocycloalkyl group, wherein said heterocycloalkyl groups may be optionally substituted with one or more alkyl, aryl, aralkyl, or cycloalkylalkyl; Ar is an arylene or heteroarylene group; R is R4-phenyl, R4-pyridyl, R4-pyridyl-N-oxide, R4-pyrazyl, or R4-pyrimidyl; R1 is hydrogen, or C1-3 alkyl; R2 is alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, cycloalkylalkyl, R8-phenyl, R8-pyridyl, R8-pyridyl-N-oxide; R3 is hydrogen, OH, -O-C1-3alkyl, or unsubstituted or halosubstituted C1-3alkyl; R4 and R8 can be the same or different, they can be number 0 to 3; each independently being selected from the group consisting of hydrogen, -C1-6 alkyl, -C3-7 cycloalkyl, halo, -CN, C1-6 alkoxy, -CF3, -OCF3, -CONH2, -CONH C1-6 alkyl , -CON C1-6 alkyl C1-6 alkyl, -NH2, -NHC (O) C1-6 alkyl, -NHC (O) NH C1-6 alkyl, -NHC (O) N (C1-6 alkyl) (alkyl C1-6), -NHSO2 C1-6 alkyl, -S C1-6 alkyl, -SO C1-6 alkyl, -SO2 C1-6 alkyl, -SO2-NH C1-6 alkyl, -O C1-3 alkylene O- and NO2, or two adjacent R4 groups or two adjacent R8 groups together can form a methylenedioxy, propylenedioxy or ethylenedioxy group; R5 is hydrogen, unsubstituted or halosubstituted C1-6 alkyl, unsubstituted or halosubstituted C3-7 cycloalkyl, C3-7 cycloalkyl unsubstituted or halosubstituted C1-6 alkyl, C1-6 substituted or halosubstituted C1-6 alkylene, alkoxycarbonyl unsubstituted or halosubstituted, unsubstituted or halosubstituted aryl, unsubstituted or halosubstituted heterocycloalkyl, unsubstituted or halosubstituted heteroaryl, unsubstituted or halosubstituted aralkyl, C1-6 unsubstituted or halosubstituted alkylbenzimidazole, unsubstituted or halosubstituted NHC heteroaryl or alkyl (halosubstituted) C1-3 N (R9) 2 unsubstituted or halosubstituted, -SO2 C1-6 alkyl, or wherein R5 is independently selected from -SO2NH2, -SO2NH alkyl, -SO2N alkyl2, formulas (4) and (5); R6 and R7 may be the same or different, each being independently selected from hydrogen, unsubstituted or halo substituted C1-3 alkyl; or R6 and R7 can join to form a 4 to 7 member ring; and R9 is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkylmethyl, aralkyl or heteroaralkyl, or the -N (R9) 2 portion may represent a pyrrolidine, piperazine or piperidine wherein the N of N (R9) 2 is the N of said pyrrolidine, piperazine or piperidine, which are new antagonists for the melanin concentrating hormone (MCH), as well as methods for the preparation of said compounds. In another embodiment, pharmaceutical compositions comprising said MCH antagonists are described, as well as the use of compounds and compositions to prepare medicaments for the treatment of obesity, metabolic disorders, eating disorders such as hyperphagia and diabetes. |