Patent NZ-333728-A (NZ)
Title: Substituted 6,6-hetero-bicyclic derivatives as corticotropin releasing factor (hormone) CRF (CRH) antagonists
Inventor: CHEN YUHPYNG LIANG
IPC: C07D475/02
Filed: 1997-07-21
Abstract: A compound of formula (I) wherein:   the dashed lines represent optional double bonds;  A is nitrogen or CR7;  B is -NRR,-CRRR10,-C(=CRR11)R,-NHCRRR10,-OCRRR10,-SCRRR10, -CRR10NHR,-CRR10OR, -CR2R'0SRl or COR2;  G is nitrogen or CR4 and is single bonded to all atoms to which it is attached, or G is carbon and is double bonded to K;  K is nitrogen or CR6 when double bonded to G or E, or K is oxygen, sulfur, C=O, C=S, CR6R12 or NR8 when single bonded to both adjacent ring atoms, or K is a two atom spacer, wherein one of the two ring atoms of the spacer is oxygen, nitrogen, sulfur, C=O, C=S, CR6R12, NR6 or CR6, and the other is CR6R12 or CR9;  D and E are each, independently, C=O, C=S, sulfur, oxygen, CR4R6 or NR8 when single bonded to both adjacent ring atoms, or nitrogen or CR4 when it is double bonded to an adjacent ring atom; the 6- or 7-membered ring that contains D, E, K and G may contain from one to three double bonds, from zero to two heteroatoms selected from oxygen, nitrogen and sulfur, and from zero to two 0=0 or O=S groups, wherein the carbon atoms of such groups are part of the ring and the oxygen and sulfur atoms are substituents on the ring;  R' is alkyl optionally substituted with from one or two substituents independently selected from hydroxy, fluoro, chloro, bromo, iodo, alkoxy, CF3, -C(=O)alkyl, -C(=O)-O-alkyl,-OC(=O)alkyl, -OC(=O)N(alkyl)2, -NHCOalkyl, -COOH, -COOalkyl, -CONHalkyl, -C O N(alkyl)2,  -Salkyl, -CN, -NO2, -SOalkyl, -SO2alkyl, -SO2NHalkyl and -SO2N(alkyl)2, wherein alkyl group may optionally contain one or two double or triple bonds;  R2 is alkyl which may optionally contain from one to three double or triple bonds, aryl or alkylenearyl, wherein said aryl and the aryl moiety is selected from phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidinyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl and benzoxazolyl; cycloalkyl or alkyleneC3-C8 cycloalkyl, wherein one or two of the carbon atoms of said cycloalkyl and the 5 to 8 membered cycloalkyl moieties of said alkylenecycloalkyl may optionally and independently be replaced by an oxygen or sulfur atom or by NZ wherein Z is hydrogen, alkyl or benzyl, and wherein each of the foregoing R2 groups may optionally be substituted with from one to three substituents independently selected from chloro, fluoro, hydroxy and alkyl, or with one substituent selected from C, alkoxy, -OC(=O) alkyl, -OC(=O)N(alkyl)2 -S alkyl, amino1 -NHalkyl, -N(alkyl)2, -Nalkyl-CO-alkyl, -NHCOalkyl, -COOH, -COOalkyl, -CONHalkyl,  -CON(alkyl)2, -SH, -CN, -NO2, -SOalkyl, -SO2alkyl, -SO2NHalkyl and -SO2N(alkyl)2;  -NR1R2 or CR'R2R'0 may form a ring selected from saturated 3 to 8 membered rings, the 5 to 8 membered rings of which may optionally contain one or two double bonds, and wherein one or two of the ring carbon atoms of such 5 to 8 membered rings may optionally and independently be replaced by an oxygen or sulfur atom or by NZ wherein Z is hydrogen, benzyl or alkyl;  R3 is hydrogen, alkyl, -Oalkyl, chloro, fluoro, bromo, iodo, -Salkyl or-SO2alkyl  each R8, R9 and R12 is selected, independently, from hydrogen and C1-C2 alkyl;  each R4 and R3 that is attached to a carbon atom is selected, independently, from hydrogen and alkyl, fluoro, chloro, bromo, iodo, hydroxy, hydroxy-alkyl, trifluoromethyl-, cyano, amino, nitro, -Oalkyl, -N(alkyl)2, CH2SCH3, -Salkyl, -COalkyl, -C(=O)H or-C(=O)Oalkyl, wherein each of the C,-C2 alkyl moieties in the foregoing R4 and R6 groups may optionally contain one double or triple bond; and R6, when attached to a nitrogen atom, is selected from hydrogen and C,-C4 alkyl;  R5 is substituted phenyl, naphthyl, pyridyl or pyrimidyl, wherein each of the foregoing R5 groups is substituted with from two to four substituents R'3, wherein up to three of said substituents may be selected, independently, from chloro, alkyl, -Oalkyl and - alkylene-O-C1-C6alkyl, and wherein one of said substituents may be selected, independently from bromo, iodo, formyl, cyano, trifluoromethyl, nitro, amino, -NHalkyl, -N(alkyl)2, -C(=O)Oalkyl, -C(=O)alkyl, -COOH, -SO2NHalkyl, -SO2N(alkyl)2, -SO2NH2, -NHSO2alkyl, -(C0-C1alkylene)-S-alkyl, -(C0-C1alkylene) -SO-alkyl, -(C0-C1alkylene)-SO2-alkyl and -alkylene-OH, and wherein each of the alkyl moieties in the foregoing R6 groups may optionally be substituted with one or two substituents independently selected from fluoro, hydroxy, amino, methylamino, dimethylamino and acetyl;  R7 is hydrogen, methyl, halo (e.g., chloro, fluoro, iodo or bromo), hydroxy, methoxy, -C(=O)(C1-C2 alkyl), -C(=O)O(C1-C2 alkyl), hydroxymethyl, trifluoromethyl or formyl;  R10 is hydrogen, hydroxy, methoxy or fluoro; and R11 is hydrogen or Cl-C4 alkyl;  with the proviso that in the ring containing D, E, K and G of formula I, there can not be two double bonds adjacent to each other; and the pharmaceutically acceptable salt of such compound.