MXPA99001309A - Substituted pyrido- or pyrimido-containing 6,6- or 6,7-bicyclic derivatives - Google Patents

Abstract

This invention relates to compounds of formula (I), wherein A, B, D, E, K, G, Z, R3 and R5 are defined as in the specification, and to the pharmaceutically acceptable salts of such compounds. Compounds (I) are corticotropin releasing factor (hormone) CRF (CRH) antagonists.

Description

DERIVATIVES 6.6- OR 6.7-SUBSTITUTE BICYCLICS THAT CONTAIN PIRIDO OR PIRIMIDO BACKGROUND OF THE INVENTION This invention relates to certain substituted 6,6- or 6,7-bicyclic substituted pyrimido or pyrimido-substituted pharmaceutically active derivatives, to pharmaceutical compositions containing them and to methods of administering them to subjects who require their antagonist activity of the factor of release of corticotropin. The substituted heterocyclic derivatives claimed in this case exhibit activity as corticotropin releasing factor (CRF) (hormone) (CRH) antagonists. CRF antagonists are cited in U.S. Patents 4,605,642 and 5,063,245, which refer, respectively, to peptides and pyrazolinones. These are also cited in the following documents: PCT patent application PCT / IB95 / 00439, which designates the United States and was filed on June 6, 1995 and published on December 14, 1995; PCT patent application PCT / IB95 / 00373, which designates the United States and was filed on May 18, 1995 and published on December 21, 1995; United States patent application 08 / 448,539, which was filed as PCT on November 12, 1993 and filed in the United States national phase on June 14, 1995; PCT patent application WO 95/10506, which was filed on October 12, 1993 and published on April 20, 1995 and United States patent application 08 / 481,413, which was filed as PCT on November 26 of 1993 and presented in the national phase of the United States on July 24, 1995; U.S. Patent Application 08 / 254,820, filed April 19, 1995; U.S. Provisional Patent Application 60 / 008,396, which was filed on December 8, 1995; and U.S. Provisional Patent Application 60 / 006,333, filed November 8, 1995. The above patents and patent applications are all incorporated herein by reference in their entirety. The importance of CRF antagonists is described in the literature, for example, P. Black, Scientific American SCIENCE & MEDICINE, 1995, pages 16 to 25; T. Lovenberg, et al., Current Pharmaceutical Design, 1995, 1, 305-316; and U.S. Patent 5,063,245, which has been cited above. In M. J. Owens et al., Pharm. Rev., Vol. 43, pages 425 to 473 (1991), incorporated herein by reference, there is a recent profile of the different activities possessed by CRF antagonists. Based on the investigations described in these and other references, CRF antagonists are effective in the treatment of a wide range of stress-related diseases, mood disorders such as depression, major depressive disorder, isolated episodes of depression, depression recurrent, depression induced by child abuse, postpartum depression, dystemia, bipolar disorders and cyclothymia; Chronic Fatigue Syndrome; eating disorders such as anorexia and bulimia nervosa; generalized anxiety disorder; panic disorder; phobias; obsessive-compulsive disorder, post-traumatic stress syndrome, pain perception as fibromyalgia; headaches; gastrointestinal diseases; hemorrhagic stress; ulcers; psychotic episodes induced by stress; fever; diarrhea; postoperative ileus; hypersensitivity in the colon; irritable bowel syndrome; Crohn's disease; spastic colon; inflammatory disorders such as rheumatoid arthritis and osteoarthritis; pain; asthma; psoriasis; allergies; osteoporosis; premature birth; hypertension, congestive heart failure; sleep disorders; neurodegenerative diseases such as Alzheimer's disease, senile dementia of the Alzheimer type, multi-infarct dementia, Parkinson's disease and Huntington's disease; cranial trauma; Ischemic neuronal injury; excitotoxic neuronal injury; epilepsy; cerebrovascular accident spinal cord trauma; psychosocial dwarfism; euthyroid patient syndrome; inadequate antidiarrheal hormone syndrome; obesity; dependencies and chemical addictions; symptoms of drug and alcohol withdrawal syndrome; sterility, cancer; muscle spasms; urinary incontinence; hypoglycaemia and immune dysfunctions including immune dysfunction induced by stress, immunosuppression and human immunodeficiency virus infections; and stress-induced infections in humans and animals. It is also believed that the compounds of this invention are inhibitors of the CRH binding protein and, therefore, are useful in the treatment of disorders whose treatment can be carried out or be favored by the inhibition of said protein. Examples of such disorders are Alzheimer's disease and obesity.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of formula: in which dashed lines represent optional double links; A is nitrogen or CR7; B is -NR! R2, -CR ^ R10, -C (rCR2Rn) R -NHCR ^ R10, -OCR ^ R10, -SCR ^ R10, -CR2R10NHRI, -CR2R10OR1, -CR ^ SR1 or -COR2, and is linked by a simple link to D; or B is -CR! R2 and is linked by a double bond to D, and D is carbon; D is nitrogen or CR4 and is linked by a single bond to all the atoms to which it is attached, or D is carbon and is linked by a double bond to E or by a double bond to B; E is oxygen, nitrogen, sulfur, C = O, C = S, CR6R12, NR6 or CR6; E is a separator of two atoms, in which one of the atoms is oxygen, nitrogen, sulfur, C = O, OS, CR6R12, NR6 or CR6, and the other is CR6R12 or CR9; K and G are each, independently, C = O, C = S, sulfur, oxygen, oo CHR or NR, when they are attached by simple bonds to the adjacent atoms of the ring, or nitrogen or CR8 when they are joined by means of a double bond to an adjacent atom of the ring; the 6 or 7 link ring containing D, E, K and G can contain one to three double bonds, zero to two heteroatoms selected from oxygen, nitrogen and sulfur, and zero to two groups C = O or C = S, in which the carbon atoms of such groups are part of the ring and the oxygen and sulfur atoms are ring substituents; R1 is -C1 alkyl, optionally substituted with one to two substituents independently selected from hydroxy, fluoro, chloro, bromo, iodo, alkoxy -Gi, CF3, -C (= O) (C4-alkyl), -C (= O) -O- (C? -C4 alkyl), -OC- (= O) (C4 alkyl), -OC (= O) N (d-C4 alkyl) (C! -C2 alkyl), -NHCO ( C4 alkyl), -COOH, -COO (Q-C4 alkyl), -CONH- (C4 alkyl), -CON (C1-C4 alkyl) (C! -C2 alkyl), -S- (C4 alkyl) , -CN, -NO2, -SO (C4-alkyl), -SO2 (C4-alkyl), -SO2NH (C4-C4 alkyl) and -SO2N (-C4-alkyl) (-C2-alkyl), wherein each alkyl group C1-C4 of the above R1 groups may optionally contain one or two double or triple bonds; R2 is C? -C12 alkyl which may optionally contain one to three double or triple bonds, aryl or (C? -C4 alkylene) aryl, wherein said aryl and the aryl radical of said (C1-C4 alkylene) aryl are selects from phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidinyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl and benzoxazolyl; C3-C8 cycloalkyl or (C3-C8 alkylene) (C3-C8 cycloalkyl), in which one or two of the carbon atoms of said cycloalkyl and the cycloalkyl radicals of 5 to 8 links of said (alkylene-CO) (C3 cycloalkyl) -C8) can, optionally and independently, be replaced by an oxygen or sulfur atom, in which each of the above R groups can optionally be substituted with, from one to three substituents independently selected from chlorine, fluoro , hydroxy and C 1 -C 4 alkyl, or with a substituent selected from C 1 -C 6 alkoxy, -OC (= O) - (alkyl C? -C6), -OC (= O) -N- (C1-C4 alkyl) (C1-C2 alkyl), -S (C? -C6 alkyl), amino, -NH (C-C2 alkyl), -N (C 1 -C 2 alkyl) (C 4 alkyl), -N (C 1 -C 4 alkyl) -CO- (C 1 -C 4 alkyl), -NHCO (C 1 -C 4 alkyl), -COOH, -COO (C 1 -C 4 alkyl) C4), -CONH- (C4 alkyl), -CON- (C4 alkyl) (C? -C2 alkyl), -SH, -CN, -N02, -SO (C1.C4 alkyl), -SO2 (C1 alkyl) -C4), -SO2NH- (d-C4 alkyl) and -SO2N (C1-C4 alkyl) (C1-C2 alkyl); -NR'R2 OR CR ^ R10 can form a ring selected from 3 to 8 link sautered rings , the rings of 5 to 8 links can optionally contain one or two double bonds, and in which one or two of the ring carbon atoms of such rings of 5 to 8 links can, optionally and independently, be replaced by an oxygen or sulfur atom or by NZ, wherein Z is hydrogen or C4 alkyl, R3 is hydrogen, C1-C4 alkyl, -O (C1-C4 alkyl), chloro, fluoro, bromo, iodo, -S (C1-C4 alkyl) or -SO2 (C1-C4 alkyl); R 4 is hydrogen, C 1 -C 2 alkyl, hydroxy or fluoro; each R6, R8 and R9 which is bonded to a carbon atom is independently selected from hydrogen and CrC2 alkyl, fluoro, chloro, bromo, iodo, hydroxy, hydroxymethyl, formyl, trifluoromethyl, cyano, amino, nitro, - O (C1-C2 alkyl), - N (d-C2 alkyl) (C1-C2 alkyl), -S (C? -C2 alkyl), -CO (C1-C2 alkyl), -C (= O) H or -C (= O) -O- (C? -C2 alkyl), wherein each of the C? -C2 alkyl radicals of the above R, R and R groups may optionally contain a double or triple bond; and each of the groups R6, R8 and R9 which is attached to a nitrogen atom is independently selected from hydrogen and C1-C4 alkyl; R5 is substituted phenyl, naphthyl, pyridyl or pyrimidyl, wherein each of the above R5 groups is substituted with two to four R15 substituents, in which one to three substituents can be selected independently from chloro, Ci-alkyl; Cß, -O (C? -C6 alkyl) and - (C1-C6 alkylene) -O- (C? -C6 alkyl), and wherein one of said substituents can be independently selected from bromine, iodine , formyl, cyano, trifluoromethyl, nitro, amino, -NH (C 1 -C 4 alkyl), -N- (C 1 -C 2 alkyl) (C 1 -C 4 alkyl), -C (= O) -O- (C 1 -C 4 alkyl) ), -C (= O) (d-C4 alkyl), -COOH, -SO2NH (d-C4 alkyl), -SO2N- (C2 alkyl) (C1-C4 alkyl), -SO2NH2, -NHSO2 (C1 alkyl) -C4), -S (Ci-Cß alkyl) and SO 2 (C?-C6 alkyl), and wherein each of the C 1 -C 4 alkyl and d-C 6 alkyl radicals of the above R 5 groups can be optionally substituted with one or two substituents selected, independently, from fluoro, hydroxy, amino, methylamino, dimethylamino and acetyl; R is hydrogen, methyl, halogen (e.g., chloro, fluoro, iodo or bromo), hydroxy, methoxy, -C (= O) (C 1 -C 2 alkyl), -C (= O) O (d-C 2 alkyl) ), trifluoromethoxy, hydroxymethyl, trifluoromethyl or formyl; R10 is hydrogen, hydroxy, methoxy or fluoro; and Ru is hydrogen or C1-C4 alkyl; R 12 is hydrogen or methyl; and Z is NH, oxygen, sulfur, -N (d-C4 alkyl) or CR13R14, wherein R13 and R14 are independently selected from hydrogen and methyl, with the exception that one of R13 and R14 may optionally be cyano; provided that: (a) in the rings of six or seven links of the structures of formula I, there can not be two adjacent double bonds; and (b) when D is carbon and is linked by a double bond to B, then B is CR! R2; and the pharmaceutically acceptable salts of said compounds. The following examples are more specific embodiments of formula I, wherein (R) n represents from zero to two substituents, each of substituents being as defined above in the definition of formula I. n More specific embodiments of the invention include compounds of formula I wherein B is -CHR! R2, -NR] R2 and R1 is d-C6 alkyl, which may be optionally substituted with a hydroxy, fluoro, trifluoromethyl, or C1-alkoxy group -C4, and may optionally contain a double or triple bond; and R 2 is benzyl or d-C 6 alkyl, which may optionally contain a double or triple bond, wherein said C 1 -C 6 alkyl and the phenyl radical of said benzyl may be optionally substituted by a fluoro, dd alkyl, C 1 alkoxy group -C2 or chlorine. Other more specific embodiments of the invention include compounds of formula I wherein R 3 is methyl, ethyl, chloro or methoxy; R6, R8 and R9 are independently selected from hydrogen and methyl; and R5 is phenyl, pyridyl or di- or trisubstituted pyrimidyl, wherein up to three of the substituents can be selected, independently, from alkyl dd, -O- (C1-C4 alkyl) and - (alkylene d-C2) -O- (alkyl d-C4), and in which one of the substituents can be selected, independently, between trifluoromethyl, trifluoromethoxy, -CHO, (d-C4 alkyl) -OH, cyano, chloro, fluoro, bromo , iodine and nitro, and wherein each of the d-above alkyl groups may optionally contain a double or triple bond; and Z is oxygen or NH. Other more preferred embodiments of the invention include compounds of formula I wherein A is nitrogen or CH. Examples of preferred compounds of the invention are: 1- (1-ethyl-o-ropil) -4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-pyrido [3,4-b] pyrazin-3 -one; l- (1-ethyl-propyl) -4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-pyrido [3,4-b] pyrazin-3-one; l- (1-ethyl-propyl) -4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -1,2,3,4-tetrahydro-pyrido [3,4-b] pyrazine; l- (1-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazine; Methyl ester of l- (l-ethyl-propyl) -7-methyl-2-oxo-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro- [l .6 Naphyridin-3-carboxylic acid; Isopropyl ester of l- (l-ethyl-propyl) -7-methyl-2-oxo-5- (2,4,6-trimethyl-phenoxy) -1,2,3,4-tetrahydro- [1,6] nafiiridin -3-carboxylic; l- (1-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -3,4-dihydro-1H- [1, 6] naphyridin-2-one; l- (l-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro [l. 6] naphyridine; l- (1-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene; l- (1-ethyl-propyl) -4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene; l- (1-ethyl-propyl) -3,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -3,4-dihydro-1H-3-oxa- [1, 6] -naphyridin-2 ona; and l- (1-ethyl-propyl) -3,3,6-trimethyl-4- (2,4,6-trimethyl-phenoxy) -2,3-dihydro-1H-pyrrolo [3,2-c] pyridine. Other compounds of formula I include the following: 1- (1-ethyl-propyl) -4,7-dimethyl-5- (4-bromo-2,6-dimethyl-phenoxy) -1,4-dihydro-2H-pyrido [3,4-b] pyrazin-3-one; 1- (1-ethyl-propyl) -4,7-dimethyl-5- (4-bromo-2,6-dimethyl-phenoxy) -1,4-dihydro-2H-pyrido [3,4-b] pyrazin-3- ona; 1- (1-ethyl-propyl) -4,7-dimethyl-5- (4-bromo-2,6-dimethyl-phenoxy) -1,2,3,4-tetrahydro-pyrido [3,4-b] pyrazine; l- (1-ethyl-propyl) -7-methyl-5- (4-bromo-2,6-dimethyl-phenoxy) -l, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazine; Methyl ester of l- (l-ethyl-propyl) -7-methyl-2-oxo-5- (4-bromo-2,6-dimethyl-phenoxy) -l, 2,3,4-tetrahydro- [1.6 ] nañiridin-3-carboxylic acid; Isopropyl ester of l- (l-ethyl-propyl) -7-methyl-2-oxo-5- (4-bromo-2,6-dimethyl-phenoxy) -l, 2,3,4-tetrahydro- [1.6 ] nañiridin-3-carboxylic acid; l- (1-ethyl-propyl) -7-methyl-5- (4-bromo-2,6-dimethyl-phenoxy) -3,4-dihydro-1H- [1.6 -naphthyridin-2-one; l- (1-ethyl-propyl) -7-methyl-5- (4-bromo-2,6-dimethyl-phenoxy) -l, 2,3,4-tetrahydro- [1,6] naphthyridine; 1- (1-ethyl-propyl) -7-methyl-5- (4-bromo-2,6-dimethyl-phenoxy) -1,4-dihydro-2H-3-oxa-1,6-diaza-naalene; 1- (1-ethyl-propyl) -4,7-dimethyl-5- (4-bromo-2,6-dimethyl-phenoxy) -1,4-dihydro-2H-3-oxa-1, 6-diaza- nafialene; l- (1-ethyl-propyl) -3,7-dimethyl-5- (4-bromo-2,6-dimethyl-phenoxy) -3,4-dihydro-1H-3-oxa [1.6] -naphyridin- 2-one; l- (1-ethyl-propyl) -3,3,6-trimethyl-4- (4-bromo-2,6-dimethyl-phenoxy) -2,3-dihydro-1H-pyrrolo [3,2-c] pyridine; l- (1-ethyl-propyl) -4,7-dimethyl-5- (4-chloro-2,6-dimethyl-phenoxy) -1,4-dihydro-2H-pyrido [3,4-b] pyraz-3 ~ ona; l- (1-ethyl-propyl) -4,7-dimethyl-5- (4-chloro-2,6-dimethyl-phenoxy) -1,4-dihydro-2H-pyrido [3,4-b] pyrazin-3 - ona; l- (1-ethyl-propyl) -4,7-dimethyl-5- (4-chloro-2,6-dimethyl-phenoxy) -l, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazine; l- (1-ethyl-propyl) -7-methyl-5- (4-chloro-2,6-dimethyl-phenoxy) -l, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazine; Methyl ester of l- (l-ethyl-propyl) -7-methyl-2-oxo-5- (4-chloro-2,6-dimethyl-phenoxy) -l, 2,3,4-tetrahydro- [1.6 Naphyridin-3-carboxylic acid; Isopropyl ester of l- (l-ethyl-propyl) -7-methyl-2-oxo-5- (4-chloro-2,6-dimethyl-phenoxy) -1, 2,3,4-tetrahydro- [1.6 Naphthyridine-3-carboxylic acid; l- (L-ethyl-pro? il) -7-methyl-5- (4-chloro-2,6-dimethyl-phenoxy) -3,4-dihydro-lH- [1,6] naphthyridin-2-one; l- (1-ethyl-propyl) -7-methyl-5- (4-chloro-2,6-dimethyl-phenoxy) -l, 2,3,4-tetrahydro- [1,6] nañiridine; l- (1-ethyl-propyl) -7-methyl-5- (4-chloro-2,6-dimethyl-phenoxy) -1,4-dihydro-2H-3-oxa-1,6-diaza-naalene; l- (1-ethyl-propyl) -4,7-dimethyl-5- (4-chloro-2,6-dimethyl-phenoxy) -1,4-dihydro-2H-3-oxa-1, 6-diaza- naphthalene; l- (1-ethyl-propyl) -3,7-dimethyl-5- (4-chloro-2,6-dimethyl-phenoxy) -3,4-dihydro-1 H-3 -oxa- [1,6] -nafiiridin -2-ona; l- (1-ethyl-propyl) -3,3,6-trimethyl-4- (4-chloro-2,6-dimethyl-phenoxy) -2,3-dihydro-1H-pyrrolo [3,2-c] pyridine; l- (1-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-pyrimido [4,5-d] [1.3] oxazine; [1- (1-ethyl-propyl) -7-methyl-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalen-5-yl] - (2,4,6-trimethyl-phenyl) )-amine; [1 - (1-ethyl-pro? Il) -7-methyl-1,4-dihydro-2H-? Irimido [4,5-d] [1,3] oxazin-5-yl] - (2,4,6-trimethyl) phenyl) -amine; 3- [7-methyl-5- (2,4,6-trimethyl-phenoxy) -4 H -3-oxa-l, 6-diaza-naphialen-1-yl] pentan-1-ol; 2- [7-methyl-5- (2,4,6-trimethyl-phenoxy) -4 H -3-oxa-1,6-diaza-naphialen-1-yl] -butan-1-ol; l- (1-ethyl-butyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-3-oxa-1, 6-diaza-naalene; 7-methyl-1- (1-propyl-butyl) -5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene; l- (1-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenylamino) -1,4-dihydro-2H-pyrido [3,4-b] pyrazin-3-one; 8- (1-ethyl-propyl) -2-methyl-4- (2,4,6-trimethyl-phenylamino) -7,8-dihydro-5H-pteridin-6-one; 8- (1-ethyl-propyl) -2-methyl-4- (2,4,6-trimethyl-phenoxy) -7,8-dihydro-5H-pteridin-6-one; 8- (1-ethyl-propyl) -2-methyl-4- (2,4,6-trimethyl-phenoxy) -5,6,7,8-tetrahydro-pteridine; [8- (1-ethyl-propyl) -2-methyl-5,6,7,8-tetrahydro-pteridin-4-yl] - (2,4,6-trimethyl-phenyl) -amine; [1 - (1-ethyl-propyl) -7-methyl-1, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazin-5-yl] - (2,4,6-trimethyl-phenyl) - amine; l- (1-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydropyrido [3,4-b] pyrazine; 8- (1-ethyl-propyl) -2-methyl-4- (2,4,6-trimethyl-phenoxy) -5,6,7,8-tetrahydro-pteridine; [8- (L-ethyl-pro? Il) -2-methyl-5,6,7,8-tetrahydro-tertidin-4-yl] - (2,4,6-trimethyl-phenyl) -amine; [1- (1-ethyl-propyl) -7-methyl-1, 2,3,4-tetrahydro- [1,6] nañiridin-5-yl] - (2,4,6-trimethyl-phenyl) -amine; 8- (1-ethyl-propyl) -2-methyl-4- (2,4,6-trimethyl-phenoxy) -5,6,7,8-tetrahydro-pyrido [2,3-d] pyrimidine; [8- (1-ethyl-propyl) -2-methyl-5,6,7,8-tetrahydro-pyrido- [2,3-d] pyrimidin-4-yl] - (2,4,6-trimethyl-phenyl) -amine; l- (l-Ethyl-propyl) -4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -l, 4-dihydro-2H-pyrimido [4,5-d] [l .3] oxazine; [1- (1-ethyl-propyl) -4,7-dimethyl-1,4-dihydro-2H-pyrimido [4,5-d] [1,3] oxazin-5-yl] - (2,4,6-trimethyl- phenyl) -amine; [1 - (1-ethyl-propyl) -4,7-dimethyl-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalen-5-yl] - (2,4,6-trimethyl) phenyl) -amine; l- (1-hydroxymethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-pyrido [3,4-b] pyrazin-3-one; l- (1-hydroxymethyl-propyl) -4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-pyrido [3,4-b] pyrazin-3-one; 2- [4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -3,4-dihydro-2 H -pyrido [3,4-b] pyrazin-1-yl] -butan-1-ol; 2- [7-methyl-5- (2,4,6-trimethyl-phenoxy) -3,4-dihydro-2H-pyrido [3,4-b] pyrazin-1-yl] -butan-1-ol; 2- [7-methyl-5- (2,4,6-trimethyl-phenoxy) -3,4-dihydro-2H- [1.6] nañiridin-1-yl] -butan-1-ol; 2- [4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -4 H -3-oxa-l, 6-diaza-naphialen-1-yl] -butan-1-ol; 5- (1-ethyl-propyl) -3-methyl-1- (2,4,6-trimethyl-phenoxy) -isoquinoline; diethyl- [3-methyl-1- (2, 4,6-trimethyl-phenoxy) -isoquinolin-5-yl] -amine; [5- (1-ethyl-propyl) -3-methyl-isoquinolin-1-yl] - (2,4,6-trimethyl-phenyl) -amine; N-5-butyl-N-5-ethyl-3-methyl-N- 1 - (2,4,6-trimethyl-phenyl) -isoquinolin-1,5-diamine; 5- (1-ethyl-propyl) -3-methyl-1- (2,4,6-trimethyl-phenoxy) - [2,6] naphthyridine; 5- (1-ethyl-propyl) -3-methyl-1- (2,4,6-trimethyl-phenoxy) - [2,7] naphthyridine; 4- (1-ethyl-propyl) -6-methyl-8- (2,4,6-trimethyl-phenoxy) - [1.7] nañiridine; [5- (1-ethyl-propyl) -3-methyl- [2,6] naphyridin-1-yl] - (2,4,6-trimethyl-phenyl) -amine; l- (1-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenylamino) -lH- [1,6] naphyridin-2-one; 4- (1-ethyl-propyl) -6-methyl-8- (2,4,6-trimethyl-phenoxy) -lH- [1.7] naphyridin-2-one; 4-diethylamino-6-methyl-8- (2,4,6-trimethyl-phenoxy) -lH- [1.7] naphyridin-2-one; l- (1-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazine; l- (1-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -2,3-dihydro-1H-4-oxa-1,6-diaza-naphthalene; 1- (1-Ethyl-ro-pyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -2,3-dihydro-1H-4-thia-l, 6-diaza-naphthalene; [1 - (1-ethyl-propyl) -7-methyl-1, 2,3,4-tetrahydro- [1,6] naphthyridin-5-yl] - (2,4,6-trimethyl-phenyl) -amine; [1 - (1-ethyl-propyl) -7-methyl-2,3-dihydro-1 H-4-oxa-1,6-diaza-nañalen-5-yl] - (2,4,6-trimethyl- phenyl) -amine; [l- (l-ethyl-propyl) -7-methyl-2,3-dihydro-lH-4-thia-l, 6-diaza-naphialen-5-yl] - (2,4,6-trimethyl-phenyl) )-amine; [1- (1-ethyl-propyl) -7-methyl-1, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazin-5-yl] - (2,4,6-trimethyl-phenyl) - amine; [1 - (1-ethyl-propyl) -7-methyl-1, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazin-5-yl] - (2,4,6-trimethyl-phenyl) - amine; 1- (1-Ethyl-ro-pyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-3-thia-l, 6-diaza-naphthalene; 1- (1-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -1,2,3,4-tetrahydro-pyrido [4.3-d] pyrimidine; l- (1-ethyl-propyl) -3,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro-pyrido [4,3-d] pyrimidine; l- (1-ethyl-propyl) -4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro- [1,6] naphyridin-tetrahydro-pyrido [4.3 -d] pyrimidine; l- (1-ethyl-propyl) -4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-3-thia-1,6-diaza-naphthalene; l- (l-ethyl-propyl) -4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro-pyrido [4.3 -d] pyrimidine; 4- (1-ethyl-propyl) -6-methyl-8- (2,4,6-trimethyl-phenoxy) -pirano [2,3-c] pyridin-2-one; 1 -sec-butyl-7-methyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-pyrido [3,4-b] pyrazin-3-one; l-sec-butyl-7-methyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro- [1,6] -3-nañyridine; l-sec-butyl-7-methyl-5- (2,4,6-trimethyl-phenoxy) -l, 4-dihydro-2H-3-oxa-l, 6-diaza-naphialene; l-sec-butyl-7-methyl-5- [2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazine; 1 -sec-butyl-4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene; 1 -sec-butyl-4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -1,2,3,4-tetrahydro-pyrido [3,4-b] pyrazine; 7-methyl-1- (1-propyl-butyl) -5- (2,4,6-trimethyl-phenoxy) -1,3,3,4-tetrahydro- [1,6] nañiridine; 5-sec-butyl-3-methyl-1- (2,4,6-trimethyl-phenoxy) -isoquinoline; diethyl- [3-methyl-1- (2,4,6-trimethyl-phenoxy) -isoquinolin-5-yl] -amine; [5-sec-butyl-3-methyl-isoquinolin-1-yl] - (2,4,6-trimethyl-phenyl) -amine; N-5-butyl-N-5-ethyl-3-methyl-N-l- (2,4,6-trimethyl-phenyl) -isoquinoline-1,5-diamine; 5-sec-butyl-3-methyl-1- (2,4,6-trimethyl-phenoxy) - [2,6] naphyridine; 5-sec-butyl-3-methyl-1- (2,4,6-trimethyl-phenoxy) - [2,7] naphyridine; 4-sec-butyl-6-methyl-8- (2,4,6-trimethyl-phenoxy) - [1.7] naphyridine; [5-sec-butyl-3-methyl- [2,6] naphlyridin-1-yl] - (2,4,6-trimethyl-phenyl) -amine; l-sec-butyl-7-methyl-5- (2,4,6-trimethyl-phenylamino) -lH- [1,6] naphyridin-2-one; 4-sec-butyl-6-methyl-8- (2,4,6-trimethyl-phenoxy) -lH- [1.7] naphthyridin-2-one; 4-diethylamino-6-methyl-8- (2,4,6-trimethyl-phenoxy) -lH- [1.7] naphyridin-2-one; 1 -sec-butyl-7-methyl-5- (2,4,6-trimethyl-phenoxy) -1,2,3,4-tetrahydro-pyrido [3.4-b] p: irazma; l-sec-butyl-7-methyl-5- (2,4,6-trimethyl-phenoxy) -2,3-dihydro-lH-4-oxa-l, 6-diaza-naphialene; l-sec-butyl-7-methyl-5- (2,4,6-trimethyl-phenoxy) -2,3-dihydro-lH-4-thia-l, 6-diaza-naphialene; [l-sec-butyl-7-methyl-l, 2,3,4-tetrahydro- [1,6] naphyridin-5-yl] - (2,4,6-trimethyl-phenyl) -amine; [1 -sec-butyl-7-methyl-2,3-dihydro-1 H-4-oxa-1,6-diaza-naphialen-5-yl] - (2,4,6-trimethyl-phenyl) -amine; [l-sec-butyl-7-methyl-2,3-dihydro-lH-4-thia-l, 6-diaza-naphthalen-5-yl] - (2,4,6-trimethyl-phenyl) -amine; [l-sec-butyl-7-methyl-l, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazin-5-yl] - (2,4,6-trimethyl-phenyl) -amine; [l-sec-butyl-7-methyl-l, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazin-5-yl] - (2,4,6-trimethyl-phenyl) -amine; l-sec-butyl-7-methyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-3-thia-l, 6-diaza-naalene; l-sec-butyl-7-methyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro-pyrido- [4,3-d] pyrimidine; l-sec-butyl-3,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -1,2,3,4-tetrahydro-pyrido- [4,3-d] pyrimidine; l-sec-butyl-4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro- [1,6] -nafiiridin-tetrahydro-pyrido [4.3-d] pyrimidine; l-sec-butyl-4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-3-thia-l, 6-diaza-naphthalene; l-sec-butyl-4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro-pyrido- [4,3-d] pyrimidine; and 4-sec-butyl-6-methyl-8- (2,4,6-trimethyl-phenoxy) -pirano [2,3-c] pyridin-2-one. Unless indicated otherwise, the alkyl groups recited herein, as well as the alkyl radicals of other groups mentioned herein (eg, alkoxy), may be linear or branched, and these may be cyclic (eg. example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or be linear or branched and contain cyclic radicals.

The invention also relates to a pharmaceutical composition for the treatment, prevention or inhibition of (a) a disorder whose treatment can be carried out or favored by the antagonism of CRF, which includes but is not limited to disorders induced or favored by CRF; or (b) a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder, panic; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; perception of pain as fibromyalgia; mood disorders such as depression, including major depression, isolated episodes of depression, recurrent depression, depression induced by child abuse, mood disorders associated with premenstrual syndrome and postpartum depression; dystemia; bipolar disorders; cyclothymia; Chronic Fatigue Syndrome; stress induced headaches; Cancer; Irritable bowel syndrome, Crohn's disease; spastic colon; postoperative ileus; ulcer; diarrhea; stress-induced fever; infections by the human immunodeficiency virus (HIV); neurodegenerative diseases such as Alzheimer's disease; Parkinson's disease and Huntington's disease; gastrointestinal diseases; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; dependencies and chemical addictions (for example, dependence on alcohol, nicotine, cocaine, heroin, benzodiazepines or other drugs); symptoms of drug and alcohol withdrawal syndrome; psychotic episodes induced by stress; euthyroid patient syndrome; inadequate antidiarrheal hormone syndrome (ADH); obesity; sterility; head trauma; spinal cord injuries; ischemic neuronal injury (eg, cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal injury; epilepsy; cerebrovascular accident immune dysfunctions including stress-induced immune dysfunction (eg, porcine stress syndrome, bovine hemorrhagic septicemia, paroxysmal equine fibrillation and confinement-induced dysfunctions in chickens, stress in sheep by shearing or stress induced by human-animal interaction in dogs ); muscle spasms; urinary incontinence; senile dementia of the Alzheimer type; multi-infarct dementia; Amyotrophic Lateral Sclerosis; hypertension; tachycardia; congestive heart failure; osteoporosis; premature birth; and hypoglycemia in a mammal, including a human, comprising an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, which is effective in the treatment of said disorder, and a pharmaceutically acceptable carrier. The invention further relates to a method for the treatment, prevention or inhibition of (a) a disorder whose treatment can be carried out or favored by antagonizing CRF, including but not limited to disorders induced or favored by CRF; or (b) xm disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; perception of pain as fibromyalgia; mood disorders such as depression, including major depression, isolated episodes of depression, recurrent depression, depression induced by child abuse, mood disorders associated with premenstrual syndrome and postpartum depression; dystemia; bipolar disorders; cyclothymia; Chronic Fatigue Syndrome; stress induced headaches; Cancer; Irritable bowel syndrome, Crohn's disease; spastic colon; postoperative ileus; ulcer; diarrhea; stress-induced fever; infections by the human immunodeficiency virus (HIV); neurodegenerative diseases such as Alzheimer's disease, Parkinson's and Huntington's disease; gastrointestinal diseases; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; psychotic episodes induced by stress; euthyroid patient syndrome; inadequate antidiarrheal hormone syndrome (ADH); obesity; sterility; head trauma; spinal cord injuries; ischemic neuronal injury (eg, cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal injury; epilepsy; cerebrovascular accident Immune dysfunctions including stress-induced irimothyroid dysfunctions (eg, porcine stress syndrome, bovine hemorrhagic septicemia, equine paroxysmal fibrillation and confinement-induced dysfunctions in chickens, stress in sheep by shear or stress induced by human-animal interaction in dogs ); muscle spasms; urinary incontinence; senile dementia of the Alzheimer type; multi-infarct dementia; Amyotrophic Lateral Sclerosis; dependencies and chemical addictions (for example, dependence on alcohol, nicotine, cocaine, heroin, benzodiazepines or other drugs); symptoms of drug and alcohol withdrawal syndrome; hypertension; tachycardia, congestive heart failure; osteoporosis; premature birth; and hypoglycemia in a mammal, including a human, which comprises administering to a subject in need of such treatment an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, which is effective in the treatment of said disorder.

This invention further relates to a method for treating or preventing disorder or condition, the treatment or prevention of which can be effected or promoted by the inhibition of the CRH binding protein, in a mammal, including a human being, which comprises administering to said mammal an inhibitory amount of the CRH binding protein of a compound of formula I, or a pharmaceutically acceptable salt thereof. This invention further relates to a pharmaceutical composition for treating- or preventing a disorder or condition, the treatment or prevention of which may be effected or promoted by the inhibition of the CRH binding protein, in a mammal, including a human , which comprises an inhibitory amount of the CRH binding protein of xm compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention further includes intermediate compounds of formulas wherein T is chloro, bromo, iodo or -OSO2CF3; when D is II III carbon, U is CN, -COO (alkyl d-d), chlorine, bromine, iodine, -OSO2CF3, hydroxy or amino and when D is nitrogen, U is hydrogen. This invention includes all optical isomers and other stereoisomers of the compounds of formula I. When such compounds contain one or more asymmetric centers, it will be understood that the invention includes the racemic mixtures, as well as the individual enantiomers and diastereomers of such compounds, and the mixtures thereof. The compounds of this invention include compounds identical to those described above, except for the fact that one or more hydrogen, nitrogen or carbon atoms are replaced by isotopes thereof (eg, tritium, or carbon 14 isotopes). Such compounds are useful as a research and diagnostic tool in pharmacokinetic studies of metabolism and in binding assays.

DETAILED DESCRIPTION OF THE INVENTION The following compounds having the formulas II, III and IV are useful as intermediates in the synthesis of the compounds of formula I.

II III In the above compounds of formulas II to IV, M is chlorine, bromine, iodine or -OSO2CF3 or ZR5; P is NH, CHCN or CHCOO (alkyl d-C4); Q is amino, (d-C2 alkyl) CH [COO (d-C4 alkyl)] 2, (C2-C3 alkyl) -CN, hydroxy or mercapto and A, B, D, E, K and G are as they have been defined above. The procedures for preparing the compounds and compositions of this invention are described below. Unless indicated in gold mode, in the following description and reaction schemes, R1 to R14, R12, A, B, D, E, K, G, Z, T, M, P, Q and U, dashed lines and structural formulas I, II, III and IV, are as defined above.

SCHEME 1 rv-a IV-b Y = o, s or NR8 n = 1, 2 1-d SCHEME 2 The compounds of formula I can be prepared by reacting x compound of formula II with the corresponding compound of formula R5ZH. This reaction is generally carried out with or without a solvent, in the presence of a base, at a temperature ranging from about 0 ° C to about 270 ° C, at a pressure of about 9.6 x 104 Pa to about 2.1 x 106 Pa. Suitable solvents include organic solvents such as tetrahydrofrank (THF), acetonitrile, N, N-dimethylformamide (DMF), dimethisulfoxide (DMSO), acetone, C2 to C15 alcohols, chloroform, dioxane, chlorobenzene, benzene, toluene, xylene, sulfolane, pyridine, quinoline, 2,4,6-trimethylpyridine, acetamide, di (d-C2 alkyl) acetamide and l-methyl-2-pyrrolidinone (NMP). When Z is NH, an excess of R5ZH can be used, either as reagent or as a base. Examples of bases other than R5ZH that may be used include potassium carbonate, sodium hydride, potassium hydride, sodium C1-C4 alkoxides, d- potassium alkoxides, sodium, sodium amide, tri - [(C 1 -C 6 alkyl)] amines, organometallic lithium or sodium compounds such as n-butyl lithium, s-butyl lithium, t-butyl lithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium diisopropylamide or sodium bis (trimethylsilyl) amide, and organometallic bases as Grignard reagents. This reaction is usually carried out in a suitable solvent (for example, THF, dioxane, sulfolane, DMSO, toluene, DMF or NMP, with or without an additional catalyst such as copper halide, oxide or sulfate (for example, , CuBr, Cu2O, CuCl, CuSO4, Cul2, CuBr2, CuCl2 or Cu (O)), a salt of Pd (O) as Pd (PPH3) 4, xma salt of Pd (II) as Pd (OAc) 2 (in which OAc is acetate) with (R) - or (S) -2,2-bis (diphenylphosphino) -l, 1-binaphthyl (BINAP) or racemic, at a temperature ranging from about room temperature to about 270 ° C. When Z is oxygen or sulfur, a base can be used which can deprotonate R5ZH, such as potassium carbonate, sodium carbonate, sodium, sodium amide, xm alkali metal hydride such as sodium or potassium hydride, a (C1-C4 alkoxide) of sodium, xm (alkoxide dd) of potassium, sodium amide, a tri - [(C 1 -C 6 alkyl)] amine or an organometallic base such as n-butyl lithium, s-butyl lithium, t-butyl lithium, diisopropylamide lithium, bis (trimethylsilyl) amide of lithium, sodium diisopropylamide or sodium bis (trimethylsilyl) amide. The reaction temperature may vary from about 0 ° C to about 180 ° C and preferably from about 50 ° C to about 140 ° C. Suitable solvents include DMSO, THF, sulfolane, dioxane and NMP. When Z is CHCN or CHCOO (alkyl dd), a base which can deprotonate R5ZH, such as an alkali metal hydride (eg, sodium or potassium hydride), a sodium (C1-C4 alkoxide) or an organometallic base can be used. such as n-butyl lithium, s-butyl lithium, t-butyl lithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium diisopropylamide or sodium bis (trimethylsilyl) amide, in a suitable solvent, for example, THF, DMSO, dioxane, methylene chloride, chloroform, toluene, xylene, benzene or a d-C6 alkanol. When Z is CR CN, the compounds of formula I can be prepared by reacting the corresponding compounds wherein Z is CHCN, first with a base such as alkali metal hydride such as sodium or potassium hydride, n-butyl lithium, s- butyl lithium, t-butyl lithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide or sodium diisopropylamide and then with a compound of formula R13L, in which L is a leaving group such as iodine, chlorine, bromine, mesylate (Oms) or tosylate (Ots). The compounds of formula I in which Z is CHR13 can be prepared by acid hydrolysis (using, for example, 85% phosphoric acid) of the corresponding compounds in which Z is CR13CN, followed by decarboxylation upon heating in an oil bath at a temperature of about 120 ° C to about 180 ° C. A subsequent alkylation in the presence of base and a compound of formula R14L, wherein L is as defined above, will provide the corresponding compounds of formula I, wherein Z is CR13R14.

When Z is N (alkyl dd), the compounds of formula I can be prepared by reacting the corresponding compounds wherein Z is NH, first, with a base and then with a compound of formula (d-C4 alkyl) - L, in which L is defined as above. Bases such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide or sodium diisopropylamide can be used. Suitable solvents include THF, methylene chloride (CH2C12), DMSO, DMP, NMP and dioxane. The reaction temperature may vary from about 20 ° C to about 150 ° C, and preferably from about room temperature to about 100 ° C. The compounds of formula I in which D is carbon and B is -NR! R2, - OCIRR2 OR -SCHR'R2 can be prepared by reacting the corresponding compounds of formula III, wherein U is chlorine, bromine or iodine , with a compound of formula BH in the presence of xma base, using procedures analogous to those described above for the conversion of compounds of formula II into compounds of formula I. The compounds of formula I wherein D is carbon and B is -CR1R2R10 , -C (= CR2R11) R1, -CR2R10NHR1, -CR ^ OR1, -CR2R10SR1 or -COR2 can be prepared by reacting the corresponding compounds of formula III, in which U is cyano, with a Grignard reagent containing the group R2 desired, forming a compound of formula I wherein B is COR2. Subsequent reaction of this compound with a Grignard reagent containing the desired R 1 group will provide the compound of formula I wherein B is -C-R 1 R 2 (OH).

Compounds of formula I wherein B is -CR ^ R11, or -C (OCR ^^ R1 can be prepared using conventional procedures well known to those skilled in the art, for example, the reaction of compounds of formula I in the that B is -C (OH) R1R2 with an acid such as concentrated sulfuric acid in acetic acid, or an internal Burgess salt (such as the methyl ester of hydroxyl (carboxysulfamoyl) triethylammonium) will provide a compound of formula I wherein B is 9 1 1 1 - C (= CR R) R. Hydrogenation of a compound of formula I wherein B is -C (= CR2R11) R1 using Pd / C (palladium on carbon) or platinum oxide catalyst, using conventional procedures well known in the art, will provide xm compound of formula I where B is -CHR'R2. The reaction of compounds of formula I wherein B is -CR R (OH) with diethylaminosulfur trifluoride or triphenylphosphine / carbon tetrachloride will provide a compound of formula I wherein B is -C-R ^ F or -CR1R2C1, respectively. The reduction of compounds of formula I wherein B is -COR2 with sodium borohydride in an inert reaction solvent such as an alcohol dd, THF or dioxane, preferably methanol, at a temperature from about room temperature to about 100 ° C, preferably from about room temperature to about 60 ° C, will provide a compound of formula I in which B is -CHR 2 OH. Alkylation of the -CHR2OH group with an alkyl halide (such as alkyl iodide) in the presence of a base (such as sodium hydride, potassium hydride, or sodium, or lithium bis (trimethylsilyl) amide) at about room temperature will provide the compound corresponding to formula I wherein B is -CHR2OR1. Compounds of formula I wherein B is -CR2R10NHR1 can also be prepared by a conventional procedure well known in the art, such a reductive amination of the corresponding compounds of formula I wherein B is -COR2 with an amine and an agent suitable reducing agents (for example, sodium cyanoborohydride or sodium triacetoxyborohydride) in an appropriate solvent (for example, a lower alkanol or acetic acid). The compounds of formula III in which U is CN can be prepared by reacting the corresponding compounds of formula III in which U is chlorine, bromine, iodine or -OCOCF3 with potassium cyanide or copper cyanide in dimethisulfoxide, THF, methylene chloride, toluene or DMF, with or without a Pd (0) or Pd (JJ) catalyst, at a temperature from about room temperature to about 180 ° C, preferably at about the reflux temperature. The compounds of formula III in which U is chloro, bromo, iodo or -COCOF3 can be prepared from the corresponding compounds of formula III in which U is hydroxy or amino. Compounds of formula III in which U is halo or -COCOF3 may be prepared by reacting a compound of formula III in which U is amino with a compound of formula (C1-C5 alkyl) -ON = O and a copper halide (II) in a suitable solvent such as acetonitrile, acetone, toluene, methylene chloride or dichloroethane, at a temperature from about room temperature to about the reflux temperature. This reaction is preferably carried out in acetonitrile at the reflux temperature. The compounds of formula III in which U is chloro or bromo can be prepared by reacting the corresponding compounds of formula DI wherein U is hydroxy with a compound of formula POX3, wherein X is chloro or bromo, with or without di (C 1 -C 4 alkyl) aniline. This reaction can be carried out only with the compounds or in a solvent such as dimethylformamide, dichloroethane or methylene chloride, at a temperature of from about 100 ° C to about 180 ° C. Compounds of formula III in which U is -OTf (where Tf is triflate) can be prepared by reacting the corresponding compounds of formula III wherein U is OH with Tf2O in the presence of a base such as tri- (d-alkyl). -C4) amine or pyridine or a suitable pyridine derivative (eg, dimethylaminopyridine) in suitable solvent such as methylene chloride, DMF, DMSO, chloroform or THF. The reaction of the compounds of formula III in which U is OTf, with a compound of formula KX, NaX or CuX (in which X is chlorine, bromine or iodine) in a suitable solvent such as DMF, dimethylacetamide, N-methylpyrrolidone ( NMP) or DMSO at x temperature from about room temperature to about 180 ° C will provide compounds of formula III in which U is chlorine, bromine or iodine. The compounds of formula I, II and III wherein Z and R5 are as defined above for formula I and R3 is -O- (alkyl dd) or -S- (alkyl dd) (hereinafter R) is they can be prepared by reacting the corresponding compounds of formula I, wherein R is chloro, bromo, OTs or iodo, with a nucleophile of formula R20H, wherein R20H is a d-C6 alkanol or a (C? -C6 alkane) thiol, optionally in the presence of an organic or inorganic base. Suitable bases include sodium, sodium hydride, potassium hydride, lithium diisopropylamide, lithium bis (trimethylsilyl) amide and sodium diisopropylamide. The compounds of formula I in which R is fluoro can be prepared by reacting the corresponding compounds in which R3 is chloro, bromo, iodo, -OCO-CF3 or -OSO2CF3 with tetrabutylammonium fluoride, potassium fluoride or other suitable fluoride, using conventional procedures well known to those skilled in the art. The compounds of formula I in which G is O, S or NR8 can be prepared from the compounds of formula IV-a, as illustrated in scheme 1. With reference to scheme 1, the compounds of formula IV- b can be prepared by reacting the appropriate compound of formula IV-a wherein B is -CR ^ R10, -C (= CR2R11) R1, CR'R ^ OR1, CR ^ SR1 or COR2; And it is O, S, NR8; and A is CR7 or N, with an acyl halide such as L- (CH2) n-COX (wherein X is chlorine, bromine, iodine, mesylate, tosylate, triflate or OCOCF3) and L is chlorine, bromine, iodine, hydroxy, mesylate, tosylate, triflate or OCOCF3), or an anhydride such as [(alkyl Cl-d) CO] 2?) in the presence of a base such as tri (alkyl d-omin, pyridine or a substituted pyridine, in a suitable solvent such as methylene chloride, chloroform, THF, DMSO, dioxane, ether, dimethoxyethane at a temperature from about 0 ° C to about 180 ° C, preferably from about room temperature to about 60 ° C. The compounds of formula Ia can be prepared by reacting the corresponding compounds of formula IV-a with a base Suitable bases for use in this reaction include sodium, sodium hydride, potassium hydride, lithium diisopropylamide, butyl lithium, lithium bis (trimethylsilyl) amide, sodium diisopropylamide or carbonate sodium or potassium, the alkylation of the compounds of formula Ia with a base, followed by inactivation of the reaction with an alkyl halide in a suitable solvent such as ether, THF, methylene chloride, dioxane, benzene, toluene or dimethoxyethane (DME) with or without hexamethylphosphoramide (HMPA) , at a temperature of about -78 ° C at about room temperature, will provide the corresponding compounds of formula Ic. Suitable bases for use in this reaction include lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium diisopropylamide and butyl lithium. The reduction of the compounds of formulas I-a or Ic with xm reducing agent such as dimethyl sulfur-borane complex (BH3 »DMS), borane (BH3), THF-borane complex (BH3« THF), diisobutylaluminium hydride or lithium aluminum hydride will provide the corresponding compounds of formulas Ib or Id, respectively. The compounds of formula I in which G is carbon can be prepared from the compounds of formula IV-c, as illustrated in scheme 2. With reference to scheme 2, the compounds of formula 1-e can be prepared cyclizing the compounds of formula IV-c wherein Q is (alkyl d-C2) CR4 (COOalkyl dd)) 2, (C?-C2 alkyl) CR4 (COO (C?-C4 alkyl)), (C C alkyl) -C2) CR4 (CN) 2, (alkyl d-C2) CR4 (CN) or (alkyl dd) CR4COOH, using conventional methods for the formation of amides which are well known in the literature. Such procedures include acid cyclization (such as: (a) heating in 40-85% phosphoric acid at a temperature of about 100 ° C to about 150 ° C, (b) heating in aqueous acetic acid / hydrochloric acid, or (c) basic hydrolysis followed by decarboxylation and then cilation of the amide). The compounds of formula I-f can be obtained by reducing the corresponding compounds of formula I-e using methods analogous to those described above for the conversion of compounds of formula I-a to those of formula I-b. Compounds of formula IV-c, wherein Q is (d-C2 alkyl) CR4 (COO (d-C4 alkyl)) or (d-C2 alkyl) CR4 (CN) 2 can be prepared by the reaction of a compound of formula Na-, K- or Li-CR4 (COO (C? -) alkyl) 2 or Na-, Ko Li-CR4 (CN) 2 with a compound of formula IV-c wherein Q is CHR8X or CHR8CHR4X (wherein X is chlorine, bromine or iodine), at a temperature from about 0 ° C to about 150 ° C, preferably from about 10 ° C to about 60 ° C, in a suitable solvent such as THF, DMSO, DMF, a (d-C5 alkyl) -alcohol, acetonitrile, acetone, toluene, NMP or dimethyl acetamide. The preferred solvent is DMSO. Other compounds of formula IV can be prepared by procedures analogous to those described in the international patent application WO 95/33750, which designates the United States and was published on May 18, 1995. This application is incorporated herein by reference in its entirety. The compounds of formula I wherein E is CR, G is CR8, D is nitrogen and K is oxygen can be prepared by reacting the compounds of formula IV-c, wherein Q is CHR8OH with aqueous formaldehyde or R6CHO in a solvent suitable as benzene, toluene, xylene, a (C 1 -C 5 alkyl) alcohol or acetonitrile, in the presence of acid catalyst such as p-TsOH, H 2 SO 4 or HCl, at a temperature from about LS room temperature to about 160 ° C, preferably at approximately the reflux temperature. The preferred solvent is toluene or benzene. The compounds of formula IV-c can be prepared by the methods described in the international patent application WO 95/33750, which designates the United States and was published on May 18, 1995. The acid addition salts of the compounds of formula I can be prepared in a conventional manner by treating a solution or suspension of the corresponding free base with a chemical equivalent of a pharmaceutically acceptable acid.

Conventional concentration or crystallization techniques can be used to isolate the salts. Examples of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulphamic, sulfonic, methanesulfonic, benzenesulfonic, p-toluenesulfonic acid and similar acids. The compounds of formula I and their pharmaceutically acceptable salts (hereinafter collectively referred to as "the active compounds of this invention") can be administered alone or in combination with pharmaceutically acceptable carriers., in single or divided doses. Pharmaceutically acceptable carriers include diluents or inert solid fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by the combination of the novel formula I compounds and the pharmaceutically acceptable carriers can be easily administered in various dosage forms such as tablets, powders, tablets, syrups, injectable solutions and the like. These pharmaceutical compositions may, if desired, contain additional ingredients such as flavors, binders, excipients and the like. Thus, for the purpose of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be used, together with various disintegrants such as starch, hypromellose, alginic acid and certain complex silicates, together with binding agents. such as polyvinyl pyrrolidone, sucrose, gelatin and gum arabic. In addition, for the preparation of tablets, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are very useful. Solid compositions of a similar type can also be employed as fillers in hard and soft filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient thereof may be combined with various sweetening or flavoring agents, coloring materials or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerol and combinations thereof. For parenteral administration, solutions containing an active compound of this invention or a pharmaceutically acceptable salt thereof in sesame or peanut oil, aqueous propylene glycol or in sterile aqueous solution may be employed. Such aqueous solutions should be suitably buffered if necessary and first of all made isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media used can be obtained easily by conventional techniques known to those skilled in the art. Effective dosages of the active compounds of this invention will depend on the desired route of administration and factors such as the age and weight of the patient, as is generally known to a physician. The dosages will also depend on the particular disease being treated. For example, the daily dose for stress-induced diseases, inflammatory disorders, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress and withdrawal symptoms of drugs and alcohol will vary, in general, from about 0.1 to about 50 mg / kg of weight of the patient in question.

The methods that can be used to determine the CRF antagonist activity of the active compounds of this invention and their pharmaceutically acceptable salts are described in Endocrinologv, 116, 1653-1659 (1985) and Peptides, 10, 179-188, (1985). The binding activities for compounds of formula I, expressed as IC 50 values, vary, in general, from about 0.5 nanomolar to about 10 micromolar. The methods that can be used to determine the inhibition activity of CRF binding proteins of the compounds of formula I are described in Brain Research. (1977), 745 (1.2), 248-255. The present invention is illustrated by the following examples. It will be understood, however, that the invention is not limited to the specific details of these examples. The melting points are uncorrected. The proton nuclear magnetic resonance (NMR) spectra and 13 C nuclear magnetic resonance spectra (13 C NMR) were measured for solutions in deuterochloroform (CDCI3) and the peak positions are expressed in parts per million ( ppm) downfield relative to tetramethylsilane (TMS). The shapes of the peaks are represented as follows: s, smglete; d, doublet; t, triplet; q, quartet; m, multiplet; b wide. In the examples the following abbreviations are used: Ph = phenyl; iPr = isopropyl; HRMS = high resolution mass spectrum.

EXAMPLE 1 l- (1-Ethyl-propyl) -7-methyl-5- (2,4,6-trimethy1-phenoxy) -1,4-dihydro-2H-pyrido [3,4-blpyrazin-3-one] A solution of lithium bis (trimethylsilyl) amide IN in THF (0.84 ml, 0.84 mmol) was added at -78 ° C to a solution of 2-chloro-N- [4- (l-ethyl-propylamino) -6- methyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-3-yl] acetamide (170 mg, 0.42 mmol) in 2 ml of dry THF. The mixture was gradually warmed to room temperature and stirred at room temperature for 2 hours. An additional 0.42 ml of lithium bis (trimethylsilyl) amide was added in THF at -78 ° C and the resulting mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness, yielding 160 mg of yellow solid. The yellow solid residue. The solid residue was purified on a chromatography column on silica gel using 15% ethyl acetate (EtOAc) in hexane as eluent, affording 91 mg (59%) of the title compound as white crystals. 1 H NMR (CDC13) d 7.84 (s, 1H), 6.88 (s, 2H), 6.22 (s, 1H), 3.82 (s, 2H), 3.58 (m, 1H), 2.30 (s, 3H), 2.18 (s, 3H), 2.08 (s, 6H), 1.63 (m, 4H), 0.95 (m, 6H) ppm.

EXAMPLE 2 l- (l-Ethyl-propyl) -4-dimethyl-5- (2,4,6-trimethyl-phenoxy) -l, 4-dihydro-2H-pyrido [3,4-blpyrazin-3-one] Xma lithium bis (trimethylsilyl) amide solution in THF (0.14 ml) was added at -78 ° C to a solution of l- (1-ethyl-propyl) -7-methyl-5- (2,4,6 -trimethyl-phenoxy) -l, 4-dihydro-2H-pyrido [3,4-b] pyrazin-3-one (50 mg, 0.136 mmol) in 2 ml of dry THF and the mixture was stirred at that temperature for 20 minutes. The mixture was added at said temperature for 20 minutes. An excess of methyl iodide was added at -78 ° C and the resulting mixture was stirred at that temperature for 20 minutes, then gradually warmed to room temperature and stirred for another 2 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 61 mg of pale yellow solid. The solid was purified on a chromatography column on silica gel using 10% ethyl acetate in hexane as eluent, affording 28 mg of the title compound as white crystals, melting point (mp) 112-114 ° C, NMR 1H (CDC13) d 6.89 (s, 2H), 6.29 (s, 1H), 3.63 (s, 2H), 3.59 (s, 3H), 3.48 (m, 1H), 2.31 (s, 3H), 2.18 (s) , 3H), 2.10 (s, 6H), 1.60 (m, 4H), 0.94 (t, 6H) ppm.

EXAMPLE 3 l- (l-Ethyl-propip-4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro-pyridof3.4-b, pyrazine A mixture of 1- (1-ethyl-propyl) -4 was heated at reflux for 3 hours., 7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -l, 4-dihydro-2H-pyrido [3,4-b] pyrazin-3-one (21 mg, 0.055 mmol) and sulfur complex dimethyl borane 2M (BH3 * DMS) (0.07 ml, 0.14 mmol) in 2 ml dry THF. The mixture was cooled to 0 ° C and quenched with 0.2 ml of MeOH and 0.2 ml of concentrated hydrochloric acid (HCl). The resulting mixture was stirred at room temperature for 2 hours and concentrated to dryness. The residue was quenched with water and extracted with chloroform. The organic layer was dried and concentrated to provide 19 mg of a clear oil which was purified by column chromatography on silica gel using 10% ethyl acetate in hexane as eluent, yielding 11 mg of the title compound as white crystals, m.p. 78-80 ° C; 1 H NMR (CDC13) d 6.85 (s, 2 H), 6.28 (s, 1 H), 3.73 (m, 1 H), 3.12 (m, 4 H), 2.85 (s, 3 H), 2.29 (s, 3 H), 2.13 (s, 3H), 2.11 (s, 6H), 1.61 (m, 4H), 0.90 (t, 6H) ppm.

EXAMPLE 4 1 - (1-Ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro-pyrido [3,4-py pyrazine] The title compound was prepared as brown crystals, m.p. 138-140 ° C, by a procedure analogous to that of Example 3 starting from l- (l-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -l, 4-dihydro- 2H-pyrido [3,4-b] pyrazin-3-one. NMR of H (CDC13) d 6.87 (s, 2H), 6.17 (s, 1H), 3.62 (m, 1H), 3.39 (m, 2H), 3.32 (m, 2H), 2.29 (s, 3H), 2.13 (s, 3H), 2.11 (s, 6H), 1.59 (m, 4H), 0.91 (t, 6H) ppm.

EXAMPLE 5 L- (1-Ethyl-propyl) -7-methyl-2-oxo-5- (2,4,6-trimethyl-phenoxy) -1,2,4,4-tetrahydro-fl-methyl ester. 61naphyridine-3-carboxylic acid Dimethyl acid ester was heated at 130 ° C for hours 2- [4- (1-ethyl-propylamino) -6-methyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-3-ylmethyl] -mononic acid (22 mg, 0.048 mmol) and 2 ml of acid acetic and bubbled through HCL (g). The reaction was cooled and concentrated to dryness. The residue was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 7 mg of the title compound. 1 H NMR (CDC13) d 6.89 (s, 2H), 6.59 (s, 1H), 4.4 (m, 1H), 3.72 (s, 3H), 3.6-3.8 (m, 1H), 3.4-3.6 ( m, 1H), 3.1-3.2 (dd, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.06 (s, 6H), 1.8-2.2 (m, 4H), 0.92 (t, 6H) ppm.

EXAMPLE 6 Isopropyl ester of l- (1-ethyl-propyl) -7-methyl-2-oxo-5- (2,4,6-trimethi-phenoxy) -1,2,3,4-tetrahydro-fl. 61-naphthyridine-3-carboxylic acid The title compound was prepared by a procedure analogous to that of Example 5, starting from the diisopropyl ester of 2- [4- (1-ethyl-propylamino) -6-methyl-2- (2,4,6-trimethyl- phenoxy) -pyridin-3-ylmethyl] malonic acid. 1 H NMR (CDC13) d 6.88 (s, 2 H), 6.57 (s, 1 H), 5.00 (m, 1 H), 3.4-3.6 (m, 2 H), 3.15 (dd, 1 H), 2.30 (s, 3 H) , 2.24 (s, 3H), 2.05 (s, 6H), 2.0-2.3 (m, 3H), 1.75-1.95 (m, 2H), 1.22 (d, 3H), 1.14 (d, 3H), 0.93 (t , 6H) ppm.

EXAMPLE 7 1- (1-Ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -3,4-dihydro-1H-r 61-naphthyridin-2-one It was heated at 73 ° C overnight, and then a mixture of the 2- [4- (1-ethyl-propylamino) -6-methyl-2- (2-diisopropyl) 2- (2-diisopropyl) ester was heated at 133 ° C for 1 hour. , 4,6-trimethyl-phenoxy) -pyridin-3-ylmethyl] malonic acid (40 mg, 0.078 mmol) and 85% phosphoric acid. The reaction mixture was cooled, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give a brown oil. The oily residue was purified by column chromatography on silica gel using 3% ethyl acetate in hexane as eluent, yielding 28 mg (98%) of the title compound. 1 H NMR (CDC13) d 6.89 (s, 2 H), 6.56 (s, 1 H), 4.4 (m, 1 H), 3.00 (m, 2 H), 2.67 (m, 2 H), 2.31 (s, 3 H), 2.25 (s, 3H), 2. 07 (s, 6H), 1.86 (m, 4H), 0.90 (t, 6H) ppm.

EXAMPLE 8 1 - (1-Ethyl-propin-7-methyl-5- (2,4,6-trimethyl-phenoxy) -l .2.3.4-tetrahydro- [1.61 naphthyridine The title compound was prepared as a white solid by a procedure analogous to that of Example 3, starting with l- (1-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) - 3,4-dihydro-lH- [1.6] naphyridin-2-one. 1 H NMR (CDC13) d 6.83 (s, 2 H), 6.14 (s, 1 H), 3.63 (m, 1 H), 3.08 (m, 2 H), 2.75 (m, 2 H), 2.26 (s, 3 H), 2.10 (s, 3H), 2.07 (s, 6H), 1.90 (m, 2H), 1.54 (m, 4H), 0.87 (t, 6H) ppm.

EXAMPLE 9 l- (1-Ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-3-oxa-1, 6-diazanephthalene A mixture of [1- (1-ethyl-propylamino) -6-methyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-3 was refluxed in a Dean-Stark trap for 15 hours. il] methanol (42 mg, 0.122 mmol) and 37% formaldehyde (0.05 ml) and p-toluenesulfonic acid (p-TsOH) (35 mg) in 3.5 ml of toluene. The mixture was quenched with water, saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried and concentrated to give 52 mg of crude product in light green solid fopna. The crude material was purified by column chromatography on silica gel using hexane / CHCl 3 1: 1 as eluent, yielding 34 mg (86%) of the title compound as white crystals, m.p. 112-114 ° C. 1 H NMR (CDC13) d 6.86 (s, 2 H), 6.25 (s, 1 H), 4.92 (s, 2H), 4.68 (s, 2H), 3.54 (m, 1H), 2.29 (s, 3H), 2.17 (s, 3H), 2.07 (s, 6H), 1.5-1.7 (m, 4H), 0.95 (t, 6H) ppm.

EXAMPLE 10 l- (1-Ethyl-propyl) -4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-3-oxa-1, 6-diaza- naphthalene The title compound was prepared as a white solid by a procedure analogous to that described in Example 9, starting with l- [4- (l-ethyl-propylamino) -6-methyl-2- (2,4,6- trimethyl-phenoxy) -pyridin-3-yl] ethanol. 1H-NMR (CDC13) d 6.87 (s, 2H), 6.26 (s, 1H), 5.16 (q, 1H), 4.7 (Abq, 2H), 3.63 (m, 1H), 2.29 (s, 3H), 2.15 (s, 3H), 2.08 (s, 6H), 1.65 (d, 3H), 1.5-1.8 (m, 4H), 0.96 (m, 6H) ppm.

EXAMPLE 11 l- (l-Ethyl-propyl) -3,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -3,4-dihydro-lH-3-oxa- [1.61-naphthyridin-2- ona A mixture of 2- [4- (1-ethyl-propylamino) -6-methyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-3-ylmethyl acid dimethyl ester was refluxed for 16 hours. ] -2-methyl malonic acid (130 mg) and 85% phosphoric acid (4 ml) and water (4 ml). The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium bicarbonate and brine, dried and concentrated to give 80 mg of clear oil. The oil was purified by column chromatography on silica gel using hexane to 10% ethyl acetate in hexane as eluent, providing 67 mg (64%) of the title compound as a white solid. 1 H NMR (CDC13) d 6.87 (s, 2 H), 6.53 (s, 1 H), 4.3 (m, 1 H), 3.14 (m, 1 H), 2.69 (m, 2 H), 2.29 (s, 3 H), 2.22 (s, 3H), 2. 05 (s, 6H), 1.83 (m, 4H), 1.25 (d, 3H), 0.86 (t, 6H) ppm.

EXAMPLE 12 l- (1-Ethyl-propyn-3,3,6-trimethyl-4- (2,4,6-trimethy1-phenoxy) -2,3-dihydro-1H-pyrrolor3.2-pyridine A solution of l- (l-ethyl-propyl) -3,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -3,4-dihydro-lH-3-oxa- [1.6] was treated. Naphyridin-2-one (56 mg) in 4 ml of dry THF with a dimethyl-borane sulfur complex 2. 0 M in THF (0.3 ml) and refluxed for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 50 mg of the title compound as a colorless oil. The oil was purified by column chromatography on silica gel using 10% ethyl acetate in hexane as eluent, providing 22 mg of the title compound as a white solid, 1 H NMR (CDC13) d 6.83 (s, 2H), 6.15 (s, 1H), 3.65 (m, 1H), 3.12 (m, 1H), 2.98 (m, 1H), 2.62 (m, 1H), 2.26 (s, 3H), 2.23 (m, 1H), 2.12 (s, 3H), 2.06 (s, 6H), 1.95 (m, 1H), 1.57 (m, 4H), 1.07 (d, 3H), 0.87 (t, 6H) ppm.

EXAMPLE 13 p- (1-Ethyl-propyl) -7-methyl-1, 4-dil-idro-2H-3-oxa-1, 6-diaza-naphthalene-5-yl- (2,4,6-trimethyl) -feniD-amine It was heated to reflux using a Dean-Stark trickle for 3 hours a mixture of [4- (1-ethyl-propylammo) -6-methyl-2- (2,4,6-trimethyl-phenylamino) -pyridin-3-. il] -methanol (280 mg, 0.82 mmol), 37% aqueous formaldehyde (0.35 ml) and pTsOH (78 mg, 0.41 mmol) in 10 ml of toluene. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give 280 mg of a green oil. The oil was purified by column chromatography on silica gel using EtOAc as eluent to provide the title compound as a brown oil. 1 H NMR (CDC13) d 6.89 (s, 2H), 6.09 (s, 1H), 4.51 (s, 2H), 4.19 (s, 2H), 3.53 (m, 1H), 2.25 (s, 6H), 2.15 (s, 6H), 1.55 (m, 4H), 0.90 (t, 6H) ppm.

EXAMPLE 14 l- (1-Ethyl-propyl) -7-methyl-5- (2,4., 6-trimethyl-phenylamino) -3,4-dihydro-1 H- [1.61 naphthyridin-2-one A mixture of 2- [4- (1-ethyl-propylamino) -6-methyl-2- (2,4,6-trimethyl-phenylamino) -pyridin-3-ylmethyl acid dimethyl ester was refluxed for 2 hours. ] malonic (100 mg, 0.219 mmol), 85% phosphoric acid (3 ml) and water (3 ml).

The reaction mixture was cooled to room temperature, diluted with water and neutralized to pH 6 with dilute NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4, filtered and concentrated to dryness, yielding 61 mg of a yellow foam. The oil was purified by column chromatography on silica gel using 10% EtOAc in hexane as eluent, affording 41 mg of the title compound as a tan solid, m.p. 44-46 ° C. NMR of! C (CDC13) d 6.87 (s, 2H), 6.36 (s, 1H), 5.64 (width s, 1H), 4.21 (m, 1H), 2.51 (m, 2H), 2.37 (m, 2H), 2.29 (s, 3H), 2.27 (s, 3H), 2.11 (s, 6H), 2. 02 (m, 2H), 1.76 (m, 2H), 0.86 (t, 6H) ppm.

EXAMPLE 15 l- (l-Ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -3,4-dihydro-lH-pyrido4.3-dl pyrimidin-2-one Triphosgene (34 mg, 0.114 mmol) was added at 0 ° C to a mixture of [3-aminomethyl-6-methyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-4-yl] - (l) ethyl-propyl) amine (100 mg, 0.292 mmol) in dry THF. The reaction mixture was allowed to warm gradually to room temperature and was stirred for 2 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness, yielding 130 mg of a clear oil. The solid was purified by column chromatography on silica gel using 10% EtOAc in hexane as eluent, affording 89 mg (82.4%) of the title compound as a white crystalline solid, m.p. 197-199 ° C. 1 H NMR (CDC13) d 6.86 (s, 2 H), 6.44 (s, 1 H), 5.14 (broad s, 1 H), 4.49 (s, 2 H), 4.20 (m, 1 H), 2.28 (s, 3 H), 2.22 (s, 3H), 2.04 (s, 6H), 1.6 (m, 4H), 0.94 (t, 6H) ppm.

PREPARATION A 2-Chloro-N- [4- (l-ethyl-propylamine) -6-methyl-2- (2,4,6-trimethyl-phenoxy) pyridin-3-yl-acetamide It was treated with chloroacetyl chloride (0.06 ml, 0.76 mmole) at 0 ° C xma mixture of 2- (2,4,6-trimethyl-phenoxy) -N-4- (1-ethyl-propyl) -6-methyl- pyridine-3,4-diamine (250 mg, 0.76 mmol) and triethylamine (0.11 ml, 0.76 mmol) in 5 ml of dry THF. The resulting mixture was stirred at room temperature for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 310 mg of green crystals which were purified by column chromatography on silica gel using 10% ethyl acetate in hexane as eluent to give 280 mg (90%) of the title compound as crystals. chestnut color, mp 152-154 ° C. 1H-NMR (CDC13) d 8.07 (s, 1H), 6.88 (s, 2H), 6.16 (s, 1H), 4.75 (s, 1H), 4.25 (s, 2H), 3.33 (m, 1H), 2.30 (s, 3H), 2.18 (s, 3H), 2.08 (s, 6H), 1.4-1.8 (m, 4H), 0.97 (t, 6H) PREPARATION B 2-f4- (l-Ethyl-propylamino) -6-methyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-3-ylmethin-2-methyl-malonic acid dimethyl ester A mixture of methyl dimethylmalonate (260 mg) and 60% sodium hydride in oil (70 mg) in 4 ml of DMSO was stirred at room temperature for 10 minutes. A solution of 3-chloromethyl-6-methyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-4-yl- (1-ethyl-propyl) -amine (200 mg) in 2 ml of DMSO. The mixture was stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give the crude material which was purified by silica gel using hexane to 10% ethyl acetate in hexane as eluent, affording 137 mg of the 2- [4- (l-ethyl) dimethyl ester. -propylamino) -6-methyl-2- (2,4,6-trimethyl-phenoxy) -pyridin-3-ylmethyl] -2-methyl malonic acid as a white solid xm. 1 H NMR (CDC13) d 6.83 (s, 2 H), 6.01 (s, 1 H), 5.00 (m, 1 H), 3.70 (s, 6 H), 3.40 (s, 2 H), 3.25 (m, 1 H), 2.27 (s, 3H), 2.12 (s, 3H), 2.05 (s, 6H), 1.5-1.7 (m, 4H), 1.48 (s, 3H), 0.94 (t, 6H) ppm.

Claims (26)

Having described the invention as an antecedent, it is declared as property it contended in the following NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula: in which the dashed lines represent optional double links; A is nitrogen or CR7; B is -NR] R2, -CR ^ R10, -C (= CR2R11) R1, -NHCR R10, -OCR ^ R10, -SCR ^ R10, -CR2R10NHR1, -CR W, -CR2R10SR! or -COR2, and is linked by xm single bond to D; or B is -CR * R2 and is x by a double bond to D, and D is carbon, D is nitrogen or CR and is bonded to a single bond to all the atoms to which it is bound, or D is carbon and is linked by a double bond to E or by a double bond to B; E is oxygen, nitrogen, sulfur C = O, C = S, CR6R12, NR6 or CR6; or E is xm separator of two atoms, in which one of the atoms is oxygen, nitrogen, sulfur, C = O, C = S, CR6R12, NR6 or CR6, and the other is CR6R12 or CR9; K and G are each, independently, C = O, C = S, sulfur, oxygen, CHR8 or NR8, when they are attached by simple bonds to the adjacent atoms of the ring, or estrogen or CR when bound by means of a double bond to an adjacent atom of the ring; the 6 or 7 link ring containing D, E, K and G can contain from one to three double bonds, from zero to two heteroatoms selected from oxygen, nitrogen and sulfur, and from zero to two groups C = O or C = S, in which the carbon atoms of such groups are part of the ring and the oxygen and sulfur atoms are ring substituents; R1 is C? -C6 alkyl, optionally substituted with one to two substituents independently selected from hydroxy, fluoro, chloro, bromo, iodo, C? -C4 alkoxy, CF3, -C (= O) (C4 alkyl), -C (= O) -O- (C 1 -C 4 alkyl), -OC - (= O) (C 1 -C 4 alkyl), -OC (= O) N (C 4 alkyl) (C 2 -C 2 alkyl), -NHCO (d-C4 alkyl), -COOH, -COO (d-C4 alkyl), -CONH- (d-C4 alkyl), -CON (d-C4 alkyl) (d-C2 alkyl), -S- ( alkyl d-C4), -CN, -NO2, -SO (d-C4 alkyl), -SO2 (d-C4 alkyl), -SO2NH (d-C4 alkyl) and -SO2N (C1-C4 alkyl) (C-alkyl) ? -C2), wherein each C1-C4 alkyl group of the above R1 groups may optionally contain one or two double or triple bonds; R2 is alkyl dCi2 which may optionally contain from one to three double or triple bonds, aryl or (d-C4 alkylene) aryl, wherein said aryl and the aryl radical of said (alkylene d-C4) aryl is selected from phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidinyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl and benzoxazolyl; cycloalkyl -Q or (d-C6 alkylene) (C3-Cs cycloalkyl), in which one or two of the carbon atoms of said cycloalkyl and cycloalkyl radicals and cycloalkyl radicals of 5 to 8 links of said (alkylene C? -C6) (C3-C8 cycloalkyl) can, optionally and independently, be replaced by an oxygen or sulfur atom, in which each of the above R2 groups can optionally be substituted with one to three substituents, selected from independently between chloro, fluoro, hydroxy and dd alkyl, or with a substituent selected from C 1 -C 6 alkoxy, -OC (= O) - (d-C6 alkyl), -OC (= O) -N- (C1 alkyl) -C4) (C2 alkyl), -S (Ci-C3 alkyl), amino, -NH (d-C2 alkyl), -N (d-C2 alkyl) (C? -C4 alkyl), -N (d-C4 alkyl) -CO- (CrC4 alkyl), -NHCO (alkyl) C1-C4), -COOH, -COO (d-C4 alkyl), -CONH- (C1-C4 alkyl), -CON- (d-C4 alkyl) (alkyl C? -C2), -SH, -CN, -NO2, -SO (alkyl d-C4), -SO2 (alkyl d-C4), -SO2NH- (C1-C4 alkyl) and -SO2N (alkyl d) -C4) (C1-C2 alkyl); -NR * R2 or CR ^ R10 may form a ring selected from rings of 3 to 8 links, the rings may contain from 5 to 8 links optionally one or two double bonds, and in which one or two of the carbon atoms of the ring of such rings of 5 to 8 links can, optionally and independently, be replaced by an oxygen or sulfur atom or by NZ3, in which Z3 is hydrogen or dd alkyl; R 3 is hydrogen, C 1 -C 4 alkyl, -O (C 1 -C 4 alkyl), chloro, fluoro, bromo, iodo, -S (C 1 -C 4 alkyl) or -S 2 (C 1 -C 4 alkyl); R 4 is hydrogen, C 1 -C 2 alkyl, hydroxy or fluoro; each R6, R8 and R9 which is bonded to a carbon atom is independently selected from hydrogen and d-C2 alkyl, fluoro, chloro, bromo, iodo, hydroxy, hydroxymethyl, formyl, trifluoromethyl, cyano, amino, nitro , -O (alkyl d-C2), -N (alkyl d-C2) (C2 alkyl), -S (alkyl d-C2), -CO (alkyl -d), -C (= O) H or - C (= O) -O- (alkyl dd), wherein each of the alkyl radicals dd of the groups R6, R8 and R9 above may optionally contain a double or triple bond; and each of the groups R6, R8 and R9 which is attached to a nitrogen atom is independently selected from hydrogen and alkyl d-d; R5 is phenyl, naphthyl, pyridyl or substituted pyrimidyl, wherein each of the above R5 groups is substituted with two to four R15 substituents, in which one to three substituents can be independently selected from chloro, dd alkyl, -O (alkyl dd) y- (C? -C6 alkylene) -O- (Ci-d alkyl), and wherein one of said substituents can be selected, independently, between bromine, iodine, formyl, cyano trifluoromethyl , nitro, amino, -NH (alkyl dd), -N- (alkyl d-C2) (alkyl d-C6), -C (= O) -O- (alkyl) C1-C4), -C (= O) (alkyl d-C4), -COOH, -SO2NH (C1-C4 alkyl), -SO2N- (C1-C2 alkyl) (C 1 -C 4 alkyl), -SO

2 NH 2, -NHSO 2 (C 1 -C 4 alkyl), -S (d 6 alkyl) and -SO 2 (d 6 alkyl), and wherein each of the alkyl radicals d- and C6 alkyl of the above R5 groups may be optionally substituted with one or two substituents independently selected from fluoro, hydroxy, amino, methylamino, dimethylamino and acetyl; R7 is hydrogen, methyl, halogen (for example, chloro, fluoro, iodo or bromo), hydroxy, methoxy, -C (= O) (alkyl d-C2), -C (= O) O (alkyl d-C2) , trifluoromethoxy, hydroxymethyl, trifluoromethyl or formyl; R10 is hydrogen, hydroxy, methoxy or fluoro; and R11 is hydrogen or C1-C4 alkyl; R 12 is hydrogen or methyl; and Z is NH, oxygen, sulfur, -N (C1-C4 alkyl) or CR13R14, wherein R13 and R14 are independently selected from hydrogen and methyl, with the exception that one of R13 and R14 may optionally be cyano; provided that: (a) in the rings of six or seven links of the structures of formula I, there can not be two adjacent double bonds; and (b) when D is carbon and is linked by a double bond to B, then B is CR'R2; O xma pharmaceutically acceptable salt of said compound.

1. A compound according to claim 1, wherein B is -CHR R or -NR! R2, and R1 is alkyl dd which may be optionally substituted with a hydroxy, fluoro, trifluoromethyl or d-C4 alkoxy group and it may optionally contain a double or triple bond; and R 2 is benzyl or d-C 6 alkyl and may optionally contain a double or triple bond, and wherein said d-C 6 alkyl and the phenyl radical of said benzyl may be optionally substituted with a fluoro group, C 1 -C 2 alkyl, alkoxy C? -C2 or chlorine.

3. A compound according to claim 1, wherein R3 is methyl, ethyl, chloro or methoxy; R6, R8 and R9 are independently selected from hydrogen and methyl; R5 is phenyl, pyridyl or di- or trisubstituted pyrimidyl, in which up to three of the substituents can be selected independently from alkyl dd, -O- (C 1 -C 4 alkyl) and - (C 1 -C 2 alkylene) -O- (alkyl d-C4), and in which one of the substituents can be selected, independently, between trifluoromethyl, trifluoromethoxy, -CHO, (C 1 -C 4 alkyl) -OH, cyano, chloro, fluoro, bromine, iodine and nitro, and wherein each of the above dC alkyl groups may optionally contain a double or triple bond; and Z is oxygen or NH.

4. A compound according to claim 1, wherein A is N or CH.

5. A compound according to claim 1, wherein D is nitrogen, EK is CH2CH2, CH2-C = O, (C = O) -CH2, and G is CH2, CHCH3 or C (CH3) 2.

6. A compound according to claim 1, wherein D is nitrogen, EK is CH2CH2, CH = CH, CH2-C = O, (C = O) -CH2 or CH2-O, and G is NH or NCH3.

7. A compound according to claim 1, which is selected from: 1- (1-ethyl-propyl) -4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -l, 4-dihydro -2H-pyrido [3,4-b] pyrazin-3-one; l- (1-ethyl-propyl) -4,7-dimethyl-5- (24,6-trimethyl-phenoxy) -1,4-dihydro-2H-pyrido [3,4- b] pyrazin-3-one; 1- (1-ethyl-propyl) -4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazine; l- (1-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro-pyrido [3,4-b] pyrazine; methyl ester of l- (l-ethyl-propyl) -7-methyl-2-oxo-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro- [1,6] naphthyridine -3-carboxylic acid; isopropyl ester of l- (l-ethyl-propyl) -7-methyl-2-oxo-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro- [1,6] nafiiridin -3-carboxylic acid; l- (1-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -3,4-dihydro-1H- [1 .6] naphyridin-2-one; 1- (1-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -l, 2,3,4-tetrahydro [1.6] naphthyridine; l- (1-ethyl-propyl) -7-methyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene; 1- (1-ethyl-propyl) -4,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene; l- (1-ethyl-propyl) -3,7-dimethyl-5- (2,4,6-trimethyl-phenoxy) -3,4-dihydro-1 H-3 -oxa- [1,6] -naphyridin-2 -one; and 1- (1-ethyl-propyl) -3,3, 3-trimethyl-4- (2,4,6-trimethyl-phenoxy) -2,3-dihydro-lH-pyrrolo [3,2-c] pyridine.

8. A pharmaceutical composition for the treatment, prevention or inhibition of (a) a disorder whose treatment can be carried out or favored by the antagonism of CRF, which includes but is not limited to, disorders induced or favored by CRF; or (b) a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; perception of pain as fibromyalgia; mood disorders such as depression, including major depression, isolated episodes of depression, recurrent depression, depression induced by child abuse, mood disorders associated with premenstrual syndrome and postpartum depression; dystemia; bipolar disorders; cyclothymia; Chronic Fatigue Syndrome; stress induced headaches; Cancer; Irritable bowel syndrome, Crohn's disease; spastic colon; postoperative ileus; ulcer; diarrhea; stress-induced fever; infections by the human immunodeficiency virus (HIV); neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; dependencies and chemical addictions (for example, dependence on alcohol, cocaine, heroin, benzodiazepines or other drugs); symptoms of drug and alcohol withdrawal syndrome; psychotic episodes induced by stress; euthyroid patient syndrome; inadequate antidiarrheal hormone syndrome (ADH); obesity; sterility; head trauma; spinal cord injuries; ischemic neuronal injury (eg, cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal injury; epilepsy; cerebrovascular accident immune dysfunctions including stress-induced immune dysfunctions (eg, porcine stress syndrome, bovine hemorrhagic septicemia, paroxysmal equine fibrillation and confinement-induced dysfunctions in chickens, stress in sheep by shearing or stress induced by human-animal interaction in dogs ); muscle spasms; urinary incontinence; senile dementia of the Alzheimer type; multi-infarct dementia; Amyotrophic Lateral Sclerosis; hypertension; tachycardia; congestive heart failure; osteoporosis; premature birth; and hypoglycemia in a mammal, comprising an amount of a compound according to claim 1 which is effective in the treatment of said disorder, and pharmaceutically acceptable vehicle.

9. The use of the compound according to claim 1, for the manufacture of a medicament for the treatment, prevention or inhibition of (a) a disorder whose treatment can be carried out or be favored by the antagonization of CRF, which includes but is not is limited to, disorders induced or favored by CRF; or (b) a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; perception of pain as fibromyalgia; mood disorders of depression, including major depression, isolated episodes of depression, recurrent depression, depression induced by child abuse, mood disorders associated with premenstrual syndrome and postpartum depression; dystemia; bipolar disorders; cyclothymia; Chronic Fatigue Syndrome; stress induced headaches; Cancer; Irritable bowel syndrome, Crohn's disease; spastic colon; postoperative ileus; úclera; diarrhea; stress-induced fever; infections by the human immunodeficiency virus (HIV); neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; dependencies and chemical addictions (for example, dependence on alcohol, cocaine, heroin, benzodiazepines or other drugs); symptoms of drug and alcohol withdrawal syndrome; psychotic episodes induced by stress; euthyroid patient syndrome; inadequate antidiarrheal hormone syndrome (ADH); obesity; sterility; head trauma; spinal cord injuries; ischemic neuronal injury (eg, cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal injury; epilepsy; cerebrovascular accident immune dysfunctions including stress-induced immune dysfunctions (eg, porcine stress syndrome, bovine hemorrhagic septicemia, equine paroxysmal fibrillation and confinement-induced dysfunctions in chickens, stress in sheep by shear or stress induced by human-animal interaction in dogs ); muscle spasms; urinary incontinence; senile dementia of the Alzheimer type; multi-infarct dementia; Amyotrophic Lateral Sclerosis; hypertension; tachycardia, congestive heart failure; osteoporosis; premature birth; and hypoglycemia in a mammal, comprising administering to a subject in need of such treatment an amount of a compound according to claim 1, which is effective in the treatment of said disorder.

10. The use of an amount of CRH binding protein inhibition of xm compound according to claim 1, for the manufacture of xm drug for the treatment or prevention of a disorder or condition, whose treatment or prevention can be carried out or seen favored by the inhibition of the CRH binding protein in a mammal, including a human, which comprises administering to said mammal an inhibitory amount of the CRH binding protein of a compound according to claim 1.

11.- A composition pharmaceutical for the treatment or prevention of a disorder or condition, whose treatment or prevention can be carried out or be favored by the inhibition of the CRH binding protein in a mammal, including a human, comprising an inhibitory amount of the CRM binding protein of xm compound according to claim 1 and a pharmaceutically acceptable carrier.

12. - A compound according to claim 2, wherein B is CHR! R2.

13. A compound according to claim 2, wherein B is NR! R2.

14. A compound according to claim 12, wherein R3 is methyl, ethyl, chloro or methoxy.

15. A compound according to claim 13, wherein R is methyl, ethyl, chloro or methoxy.

16. A compound according to claim 14, wherein A is N or CH.

17. A compound according to claim 15, wherein A is N or CH.

18. A compound according to claim 16, wherein D is N; E-K-G is CR6 = CH-C (= O), CR6R12CHR8, CR6 = CR8-NH, CR6 = CR8NCH3, CR6R12C (= O) -NH, CR6R12C (= O) -NCH3, CR6R12-CHR8-CHR8, C (= O) -CR8 = CR8, CR6R12-CHR8-O, CR6R12-CHR8-S, CR6 = CR8-S, C (= O) -CHR8-S, C (= O) -CHR8NH, C (= O ) -CHR8-NCH3, CR6R12-O-CHR8, CR6R12-S-CHR8, C (= O) -CHR8-O, C (= O) -C (= O) -NH, C (= O) -C ( = O) -CH3, CR6R12-N-CHR8.

19. A compound according to claim 18, wherein CR6R12 is CH2 and CR6 is CH.

20. A compound according to claim 18, wherein CHR8 is CH2 and CR8 is CH.

21. A compound according to claim 18, wherein CR6R12 is CH2, CR6 is CH, CHR8 is CH2 and CR8 is CH.

22. A compound according to claim 21, wherein R5 is phenyl, pyridyl or di- or trisubstituted pyrimidyl, wherein the two or three substituents are independently selected from C?-C4 alkyl, O- (C1-alkyl) -C4), (C? -C2 alkylene) -O- (C? -C4 alkyl), trifluoromethyl, trifluoromethoxy, CH (= O), (C? -d) alkyl, chloro, fluoro, bromo, iodo and nitro, and wherein each of the above alkyl-d groups may optionally contain a double or triple bond. 1 9

23. A compound according to claim 2, wherein B is NR R or CHR R; and the ring containing D, E, K and G is a ring of benzene, pyrido or pyrimido.

24. A compound according to claim 2, wherein B is NR * R2, CHR'R2; and D ^ EKG is C = CH-C (= O) -NH, C = CH-C (= O) -NMe, C = CH-C (= O) -O or C = CH-C (= O) -S.

25. A compound according to claim 23, wherein R5 is di- or trisubstituted phenyl, wherein the two or three substituents are independently selected from C1-C4 alkyl, O- (C1-C4 alkyl), ( alkylene d-C2) -O- (C 1 -C 4 alkyl), trifluoromethyl, trifluoromethoxy, CH (= O), (C 1 -d) -OH alkyl, chloro, fluoro, bromo, iodo and nitro, and wherein each one of the d-above alkyl groups may optionally contain a double or triple bond.

26. A compound according to claim 24, wherein R5 is di- or trisubstituted phenyl, wherein the two or three substituents are independently selected from C1-C4 alkyl, O- (C? -C4 alkyl), (C? -C2 alkylene) -O- (C? -C alkyl), trifluoromethyl, trifluoromethoxy, CH (= O), (C? -C) alkyl -OH, chloro, fluoro, bromo, iodo and nitro, and that each of the above d-C4 alkyl groups may optionally contain a double or triple bond.