This invention relates to certain pharmaceutically active substituted pyrido- or pyrimido-containing 6,6- or 6,7-bicyclic derivatives, pharmaceutical compositions containing them and methods of administering them to subjects in need of their corticotropin releasing factor antagonist activity.
The substituted heterocyclic derivatives claimed in this case exhibit activity as corticotropin releasing factor (hormone) CRF (CRH) antagonists.
CRF antagonists are mentioned in U.S. Pat. Nos. 4,605,642 and 5,063,245 referring to peptides and pyrazolinones, respectively. They are also referred to in the following: PCT Patent Application PCT/IB95/00439, which designates the United States and was filed on Jun. 6, 1995 and published on Dec. 14, 1995; PCT patent application PCT/IB95/00373, which designates the United States and was filed on May 18, 1995 and published on Dec. 21, 1995; U.S. patent application Ser. No. 08/448,539, which was filed in the PCT on Nov. 12, 1993 and entered the U.S. national phase on Jun. 14, 1995; PCT patent application WO 95/10506, which was filed on Oct. 12, 1993 and published on Apr. 20, 1995, and U.S. patent application 08/481,413, which was filed in the PCT on Nov. 26, 1993 and entered the U.S. national phase on Jul. 24, 1995; U.S. patent application Ser. No. 08/254,820, which was filed on Apr. 19, 1995; Provisional U.S. patent application Ser. No. 60/008,396, which was filed on Dec. 8, 1995; and Provisional U.S. patent application Ser. No. 60/006,333, which was filed on Nov. 8, 1995. All the foregoing patent applications are incorporated herein by reference in their entireties.
The importance of CRF antagonists is set out in the literature, e.g., P. Black, Scientific American SCIENCE and MEDICINE, 1995, p. 16-25; T. Lovenberg, et al., Current Pharmaceutical Design, 1995, 1, 305-316; and U.S. Pat. No. 5,063,245, which is referred to above. A recent outline of the different activities possessed by CRF antagonists is found in M. J. Owens et al., Pharm. Rev., Vol. 43, pages 425 to 473 (1991), also incorporated herein by reference. Based on the research described in these two and other references, CRF antagonists are effective in the treatment of a wide range of stress-related Illnesses, mood disorders such as depression, major depressive disorder, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, dysthemia, 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 disorder, pain perception such as fibromyalgia; headache; gastrointestinal diseases; hemorrhagic stress; ulcers; stress-induced psychotic episodes; fever; diarrhea; post-operative ileus, colonic hypersensitivity; 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 Alzheimers disease, senile dementia of the Alzheimer""s type, multiinfarct dementia, Parkinson""s disease, and Huntington""s disease; head trauma; ischemic neuronal damage; excitotoxic neuronal damage; epilepsy; stroke; spinal cord trauma; psychosocial dwarfism; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone; obesity; chemical dependencies and addictions; drug and alcohol withdrawal symptoms; infertility, cancer; infertility; muscular spasms; urinary incontinence; hypoglycemia and immune dysfunctions including stress induced immune dysfunctions, immune suppression and human immunodeficiency virus infections; and stress-induced infections in humans and animals.
The compounds of this invention are also believed to be inhibitors of CRH binding protein and therefore useful in the treatment of disorders the treatment of which can be effected or facilitated by inhibiting such protein. Example of such disorders are Alheimer""s disease and obesity.
The present invention relates to compounds of the formula 
the dashed lines represent optional double bonds;
A is nitrogen or CR7:
B is xe2x80x94NR1R2, xe2x80x94CR1R2R10, xe2x80x94C(xe2x95x90CR2R11)R1, xe2x80x94NHCR1R2R10, xe2x80x94OCR1R2R10, xe2x80x94SCR1R2R10, xe2x80x94CR2R10NHR1, xe2x80x94CR2R10OR1, xe2x80x94CR2R10SR1 or xe2x80x94COR2, and is single bonded to D; or B is xe2x80x94CR1R2, and is double bonded to D and D is carbon;
D is nitrogen or CR4 and is single bonded to all atoms to which it is attached, or D is carbon and is double bonded to E or double bonded to B;
E is oxygen, nitrogen, sulfur, Cxe2x95x90O, Cxe2x95x90S, CR6R12, NR6 or CR6; or E is a two atom spacer, wherein one of the atoms is oxygen, nitrogen, sulfur, Cxe2x95x90O, Cxe2x95x90S, CR6R12, NR6 or CR6, and the other is CR6R12 or CR9;
K and G are each, independently, Cxe2x95x90O, Cxe2x95x90S, sulfur, oxygen, CHR8 or NR8 when single bonded to both adjacent ring atoms, or nitrogen or CR8 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 Cxe2x95x90O or Cxe2x95x90S groups, wherein the carbon atoms of such groups are part of the ring and the oxygen and sulfur atoms are substituents on the ring;
R1 is C1-C6 alkyl optionally substituted with from one or two substituents independently selected from hydroxy, fluoro, chloro, bromo, iodo, C1-C4 alkoxy, CF3, xe2x80x94C(xe2x95x90O)(C1-C4alkyl), xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94(C1-C4)alkyl, xe2x80x94OC(xe2x95x90O)(C1-C4 alkyl), xe2x80x94OC(xe2x95x90O)N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94NHCO(C1-C4 alkyl), xe2x80x94COOH, xe2x80x94COO(C1-C4 alkyl), xe2x80x94CONH(C1-C4 alkyl), xe2x80x94CON(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94S(C1-C4 alkyl), xe2x80x94CN, xe2x80x94NO2, xe2x80x94SO(C1-C4 alkyl), xe2x80x94SO2(C4 alkyl), xe2x80x94SO2NH(C1-C4 alkyl) and xe2x80x94SO2N(C1-C4 alkyl)(C1-C2 alkyl), wherein each of the C1-C4 alkyl groups in the foregoing R1 groups may optionally contain one or two double or triple bonds;
R2 is C1-C12 alkyl which may optionally contain from one to three double or triple bonds, aryl or (C1-C4 alkylene)aryl, wherein said aryl and the aryl moiety of said (C1-C4 alkylene)aryl is selected 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 (C1-C6 alkylene)(C3-C8 cycloalkyl), wherein one or two of the carbon atoms of said cycloalkyl and the 5 to 8 membered cycloalkyl moieties of said (C1-C6 alkylene)(C3-C8 cycloalkyl may optionally and independently be replaced by an oxygen or sulfur 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 C1-C4 alkyl, or with one substituent selected from C1-C6 alkoxy, xe2x80x94OC(xe2x95x90O)(C1-C6 alkyl), xe2x80x94OC(xe2x95x90O)N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94S(C1-C6 alkyl), amino, xe2x80x94NH(C1-C2 alkyl), xe2x80x94N(C1-C2 alkyl)(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)xe2x80x94COxe2x80x94(C1-C4 alkyl), xe2x80x94NHCO(C1-C4 alkyl), xe2x80x94COOH, xe2x80x94COO(C1-C4 alkyl), xe2x80x94CONH(C1-C4 alkyl), xe2x80x94CON(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94SH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94SO(C1-C4 alkyl), xe2x80x94SO2(C1-C4 alkyl), xe2x80x94SO2NH(C1-C4 alkyl) and xe2x80x94SO2N(C1-C4 alkyl)(C1-C2 alkyl);
xe2x80x94NR1R2 or CR1R2R10 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 NZ3 wherein Z3 is hydrogen or C1-C4 alkyl;
R3 is hydrogen, C1-C4 alkyl, xe2x80x94O(C1-C4 alkyl), chloro, fluoro, bromo, iodo, xe2x80x94S(C1-C4 alkyl) or xe2x80x94SO2(C1-C4 alkyl)
R4 is hydrogen, C1-C2 alkyl, hydroxy or fluoro;
each R6, R8 and R9 that is attached to a carbon atom is selected, independently, from hydrogen, C1-C2 alkyl, fluoro, chloro, bromo, iodo, hydroxy, hydroxymethyl, formyl, trifluoromethyl, cyano, amino, nitro, xe2x80x94O(C1-C2 alkyl), xe2x80x94N(C1-C2 alkyl)(C1-C2 alkyl), xe2x80x94S(C1-C2 alkyl), xe2x80x94CO(C1-C2 alkyl), xe2x80x94C(xe2x95x90O)H or xe2x80x94C(xe2x95x90O)O(C1-C2 alkyl), wherein each of the C1-C2 alkyl moieties in the foregoing R6, R8, and R9 groups may optionally contain one double or triple bond; and each R6, R8, and R9 that is attached to a nitrogen atom is selected, independently, from hydrogen and C1-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 R15, wherein from one to three of said substituents may be selected, independently, from chloro, C1-C6 alkyl, xe2x80x94O(C1-C6 alkyl) and xe2x80x94(C1-C6 alkylene)O(C1-C6 alkyl), and wherein one of said substituents may be selected, independently, from bromo, iodo, formyl, cyano, trifluoromethyl, nitro, amino, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C2 alkyl)(C1-C5 alkyl), xe2x80x94C(xe2x95x90O)O(C1-C4 alkyl), xe2x80x94C(xe2x95x90O)(C1-C4 alkyl), xe2x80x94COOH, xe2x80x94SO2NH(C1-C4 alkyl), xe2x80x94SO2N(C1-C2 alkyl)(C1-C4 alkyl), xe2x80x94SO2NH2, xe2x80x94NHSO2(C1-C4 alkyl), xe2x80x94S(C1-C6 alkyl) and xe2x80x94SO2(C1-C6 alkyl), and wherein each of the C1-C4 alkyl and C1-C6 alkyl moieties in the foregoing R5 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, lodo or bromo), hydroxy, methoxy, xe2x80x94C(xe2x95x90O)(C1-C2 alkyl), xe2x80x94C(xe2x95x90O)O(C1-C2 alkyl), trifluoromethoxy, hydroxymethyl, trifluoromethyl, or formyl;
R10 is hydrogen, hydroxy, methoxy or fluoro;
R11 is hydrogen or C1-C4 alkyl;
R12 is hydrogen or methyl; and
Z is NH, oxygen, sulfur, xe2x80x94N(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;
with the proviso that: (a) in the six or seven membered rings of structures in formula I, there can not be two double bonds adjacent to each other; and (b) when D is carbon and is double bonded to B, then B is CR1R2;
and the pharmaceutically acceptable salts of such compounds.
Examples of more specific embodiments of formula I are the following, wherein (R)n represents from zero to two substituents, wherein such substitutents are as defined above in the definition of formula 1. 
More specific embodiments of this invention include compounds of the formula I wherein B is xe2x80x94CHR1R2 or xe2x80x94NR1R2, and R1 is C1-C6 alkyl which may optionally be substituted with one hydroxy, fluoro, trifluoromethyl or C1-C4 alkoxy group and may optionally contain one double or triple bond; and R2 is benzyl or C1-C6 alkyl which may optionally contain one double or triple bond, and wherein said C1-C6 alkyl and the phenyl moiety of said benzyl may optionally be substituted with one fluoro, C1-C2 alkyl, C1-C2 alkoxy or chloro group.
Other more specific embodiments of the invention include compounds of formula I wherein R3 is methyl, ethyl, chloro or methoxy; R6, R8 and R9 are selected, independently, from hydrogen and methyl; R5 is di- or tri-substituted phenyl, pyridyl, or pyrimidyl, in which up to three of the substitutents can be independently selected from C-C4 alkyl, xe2x80x94Oxe2x80x94(C1-C4 alkyl) and (C1-C2 alkylene)xe2x80x94Oxe2x80x94(C1-C4 alkyl), and wherein one of the substituents can be independently selected from trifluoromethyl, trifluoromethoxy, xe2x80x94CHO, (C1-C4 alkyl)xe2x80x94OH, cyano, chloro, fluoro, bromo, iodo and nitro, and wherein each of the foregoing (C1-C4) alkyl groups may optionally contain one double or triple bond; and Z is oxygen or NH.
Other more specific embodiments of the invention include compounds of the formula I wherein A is nitrogen or CH.
Examples of preferred compounds of the invention are:
1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-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)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(2,4,6trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylic acid methyl ester;
1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylic acid isopropyl ester;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine;
1-(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;
1-(1-ethyl-propyl)-3,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-1H-3-oxa-[1,6]-naphthyridin-2-one; and
1-(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 the 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-one;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-(1-ethyl-propyl)-7-methyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido [3,4-b]pyrazine;
1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(4-bromo-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylic acid methyl ester;
1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(4-bromo-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylic acid isopropyl ester;
1-(1-ethyl-propyl)-7-methyl-5-(4-bromo-2,6-dimethyl-phenoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;
1-(1-ethyl-propyl)-7-methyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine;
1-(1-ethyl-propyl)-7-methyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6diaza-naphthalene;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;
1-(1-ethyl-propyl)-3,7-dimethyl-5-(4-bromo-2,6-dimethyl-phenoxy)-3,4-dihydro-1H-3-oxa-[1,6]-naphthyridin-2-one;
1-(1-ethyl-propyl)-3,3,6-trimethyl-4-(4-bromo-2,6-dimethyl-phenoxy)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-pyrido [3,4-b]pyrazin-3-one;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-(1-ethyl-propyl)-7-methyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(4-chloro-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylic acid methyl ester;
1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(4-chloro-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylic acid isopropyl ester;
1-(1-ethyl-propyl)-7-methyl-5-(4-chloro-2,6-dimethyl-phenoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;
1-(1-ethyl-propyl)-7-methyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,2,3,4-.tetrahydro[1,6]naphthyridine;
1-(1-ethyl-propyl)-7-methyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;
1-(1-ethyl-propyl)-3,7-dimethyl-5-(4-chloro-2,6-dimethyl-phenoxy)-3,4-dihydro-1H-3-oxa-[1,6-naphthyridin-2-one;
1-(1-ethyl-propyl)-3,3,6-trimethyl-4-(4-chloro-2,6-dimethyl-phenoxy)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine;
1-(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-propyl)-7-methyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5-y-(2,4,6-trimethyl-phenyl)-amine;
3-[7-methyl-5-(2,4,6-trimethyl-phenoxy)-4H-3-oxa-1,6-diaza-naphthalen-1-yl]-pentan-1-ol; 2-[7-methyl-5-(2,4,6-trimethyl-phenoxy)-4H-3-oxa-1,6-diaza-naphthalen-1-yl]-butan-1-ol;
1-(1-ethyl-butyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;
7-methyl-1-(1-propyl-butyl)-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;
1-(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-methyl4-(2,4,6-trimethyl-phenylamino)-7,8-dihydro-5H-pyridin-6-one;
8-(1-ethyl-propyl)-2-methyl-4-(2,4,6trimethyl-phenoxy)-7,8-dihydro-5H-pyridin-6-one;
8-(1-ethyl-propyl)-2-methyl-4-(2,4,6-trimethyl-phenoxy)-5,6,7,8-tetrahydro-pyridine;
[8-(1-ethyl-propyl)-2-methyl-5,6,7,8-tetrahydro-pyridin-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;
[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-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine; 8-(1-ethyl-propyl)-2-methyl-4-(2,4,6-trimethyl-phenoxy)-5,6,7,8-tetrahydro-pyridine;
[8-(1-ethyl-propyl)-2-methyl-5,6,7,8-tetrahydro-pyridin-4-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-(1-ethyl-propyl)-7-methyl-1,2,3,4-tetrahydro-[1,6]naphthyridin in-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(2,3d]pyrimidine;
[8-(1-ethyl-propyl)-2-methyl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4yl]-(2,4,6-trimethyl-phenyl)-amine;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]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;
1-(1-hydroxymethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;
1-(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-2H-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]naphthyridin-1-yl]-butan-1-ol;
2-[4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)4H-3-oxa-1,6-diaza-naphthalen-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-N1-(2,4,6-trimethyl- phenyl)-isoquinoline-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-tnimethyl-phenoxy)-[2,7]naphthyridine;
4-(1-ethyl-propyl)-6-methyl-8-(2,4,6-trimethyl-phenoxy)-[1,7]naphthyridine;
[5-(1-ethyl-propyl)-3-methyl-[2,6]naphthyridin-1-yl]-(2,4,6-trimethyl-phenyl)-amine;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenylamino-1H-[1,6]naphthyridin-2-one;
4-(1-ethyl-propyl)-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;
4-diethylamino-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;
4-diethylamino-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-4-oxa-1,6-diaza-naphthalene;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-4-thia-1,6-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-1H-4-oxa-1,6-diaza-naphthalen-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-(1-ethyl-propyl)-7-methyl-2,3-dihydro-1H4-thia-1,6-diaza-naphthalen-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-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-thia-1,6-diaza-naphthalene;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[4,3-d]pyrimidine;
1-(1-ethyl-propyl)-3,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[4,3-d]pyrimidine;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine tetrahydro-pyrido[4,3-d]pyrimidine;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-thia-1,6-diaza-naphthalene;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[4,3-d]pyrimidine;
4-(1-ethyl-propyl)-6-methyl-8-(2,4-trimethyl-phenoxy)-pyrano[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;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]3naphthyridine;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-sec-butyl-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4dihydro-2H-3-ixa-1,6-diaza-napthalene;
1-sec-butyl4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-]pyrazine;
7-methyl-1-(1-propyl-butyl)-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine;
5-sec-butyl-3-methyl-1-(2,4,6trimethyi-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-ethyl-3methyl-N1-(2,4,6-trimethyl-phenyl)-isoquinoline-1,5diamine;
5-sec-butyl-3-methyl-1-(2,4,6-trimethyl-phenoxy)-[2,61naphthyeidine;
5-sec-butyl-3-methyl-1-(2,4,6-trimethyl-phenoxy)-[2,7]naphthyridine;
4-sec-butyl-6-methyl-8-(2,4,6-trimethyl-phenoxy)-[1,7]naphthyridine;
[5-sec-butyl-3-methyl-[2,6]naphthyridin-1-yl]-(2,4,6trimethyl-phenyl)-amine;
1-sec-butyl-7-methyl-5-(2,4,6tnimethyl-phenylamino)-1H-[1,6]naphthyridin-2-one;
4-sec-butyl-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;
4-diethylamino-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;
4-diethylamino-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-4-oxa-1,6-diaza-naphthalene;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-4-thia-1,6-diaza-naphthalene;
[1-sec-butyl-7-methyl-1,2,3,4-tetrahydro-[1,6]naphthyridin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-sec-butyl-7-methyl-2,3-dihydro-1H-4-oxa-1,6-diaza-naphthalen-5-yl]-(2,4,6trimethyl-phenyl)-amine;
[1-sec-butyl-7-methyl-2,3-dihydro-1H-4-thia-1,6-diaza-naphthalen-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-sec-butyl-7-methyl-1,2,3,4-tetrahydro-pyrido [3,4-b]pyrazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-sec-butyl-7-methyl-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-thia-1,6-diaza-naphthalene;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido-[4,3-d]pyrimidine;
1-sec-butyl-3,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido-[4,-d]pyrimidine;
1-sec-butyl-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]-naphthyridine tetrahydro-pyrido[4,3-d]pyrimidine;
1-sec-butyl-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-thia-1,6-diaza-naphthalene;
1-sec-butyl-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4tetrahydro-pyrido-[4,3-d]pyrimidine; and
4-sec-butyl-6-methyl-8-(2,4,6-trimethyl-phenoxy)-pyrano[2,3-c]pyridin-2-one.
Unless otherwise indicated, the alkyl groups referred to herein, as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy), may be linear or branched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linear or branched and contain cyclic moieties.
The invention also relates to a pharmaceutical composition for the treatment, prevention or inhibition of (a) a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated 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; pain perception such as fibromyalgia;
mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, mood disorders associated with premenstrual syndrome, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; chronic fatigue syndrome; stress-induced headache; cancer; irritable bowel syndrome, Crohn""s disease; spastic colon; post operative ileus; ulcer; diarrhea; stress-induced fever; human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimers disease, Parkinson""s disease and
Huntington""s disease; gastrointestinal diseases; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; chemical dependencies and addictions (e.g., dependencies on alcohol, nicotine, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer""s type; multiinfarct 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 the formula I or a pharmaceutically acceptable salt thereof, that is effective in the treatment of such disorder, and a pharmaceutically acceptable carrier.
The invention also relates to a method for the treatment, prevention or inhibition of (a) a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitator 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; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, mood disorders associated with premenstrual syndrome, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; chronic fatigue syndrome; stress-induced headache; cancer; irritable bowel syndrome; Crohn""s disease; spastic colon; post operative ileus; ulcer; diarrhea; stress-induced fever; human immunodeficiency virus (HIV) infections; 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; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimers type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g., dependencies on alcohol, nicotine, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; hypertension; tachycardia; congestive heart failure; osteoporosis; premature birth; and hypoglycemia in a mammal, including a human, comprising administering to a subject in need of said treatment an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder.
This invention also relates to a method of treating or preventing a disorder or condition, the treatment or prevention of which can be effected or facilitated by inhibiting CRH binding protein in a mammal, including a human, comprising administering to said mammal a CRH binding protein inhibiting amount of a compound of the formula I or a pharmaceutically acceptable salt thereof.
This invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition, the treatment or prevention of which can be effected or facilitated by inhibiting CRH binding protein in a mammal, including a human, comprising a CRH binding protein inhibiting amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention further includes intermediate compounds of formulas 
a wherein T is chloro, bromo, iodo, or xe2x80x94OSO2CF3; U is CN, xe2x80x94COO(C1-C4 alkyl), chloro, bromo, iodo, xe2x80x94OSO2CF3, hydroxy or amino when D is carbon, and U is hydrogen when D is nitrogen.
This invention includes all optical isomers and other stereoisomers of compounds of the formula I. When such compounds contain one or more chiral centers, it is understood that the invention includes the racemic mixtures as well as all individual enantiomers and diastereomers of such compounds, and mixtures thereof.
The compounds of this invention include compounds identical to those described above but for the fact that one or more hydrogen, nitrogen or carbon atoms are replaced by isotopes thereof (e.g., tritium or carbon-14 isotopes). Such compounds are useful as research and diagnostic tools in metabolism pharmokinetic studies and in binding assays.
The following compounds having the formulas II, III, and IV are useful as intermediates in the synthesis of compounds of the formula I. 
In the above compounds of formulas II to IV, M is chloro, bromo, iodo, xe2x80x94OSO2CF3 or ZR5; P is NH, CHCN or CHCOO(C1-C4 alkyl); Q is amino, xe2x80x94(C1-C2 alkyl)CH[COO(C1-c4alkyl)]2, (C2-C3 alkyl)-CN, hydroxy or mercapto, and A, B, D, E, K and G are defined as above.
Methods of preparing the compounds and compositions of this invention are described below. In the discussion and reaction schemes that follow, R1 through R14, R12, A, B, D, E, K, G. Z, T, M, P, Q, and U, the dashed lines and structural formulas I, II, III, and IV, unless otherwise indicated, are defined as above. 
Compounds of the formula I may be prepared by reacting a compound of the formula 11 with the corresponding compound of the formula R5ZH. This reaction is generally carried out with or without a solvent, in the presence of a base, at a temperature from about 0xc2x0 C. to about 270xc2x0 C., at a pressure from about 14 psi to about 300 psi. Suitable solvents include organic solvents such as tetrahydrofuran (THF), acetonitrile, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMS0), acetone, C2-C15 alcohols, chloroform, dioxane, chlorobenzene, benzene, toluene, xylene, sulfolane, pyridine, quinoline, 2,4,6-trimethylpyridine, acetamide, di-(C1-C2)alkylacetamide, and 1-methyl-2-pyrrolidinone (NMP).
When Z is NH, an excess of R5ZH, may be used both as the reagent and as the base. Examples of bases other than R5ZH that may be used include potassium carbonate, sodium hydride, potassium hydride, sodium (C1-C4) alkoxides, potassium (C1-C4) alkoxides, sodium, sodium amide, tri-[(C1-C4) alkyllamines, organolithium or organosodium compounds such as n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylimide, lithium bis(trimethylsilyl)amide, sodium diisopropylamide or sodium bis(trimethylsilyl)amide, and organometallic bases such as Grignard reagents. This reaction is generally carried out in an appropriate solvent (e.g., THF, dioxane, sulfolane, DMSO, toluene, DMF or NMP, with or without an additional catalyst such as a copper halide, oxide or sulfate e.g., Cul, CuBr, Cu2O, CuCl, CuSO4 Cu2. CuBr2, CuCl2 or Cu(O)), a Pd(O) salt such as Pd(PPH3)4, a Pd(II) salt such as Pd(OAc)2 (wherein OAc is acetate) with racemic or (R)xe2x80x94 or (S)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (BINAP), at temperature from about room temperature to about 270xc2x0 C.
When Z is oxygen or sulfur, a base that is capable of deprotonating R5ZH may be used, such as potassium carbonate, sodium carbonate, sodium, sodium amide, an alkali metal hydride such as sodium or potassium hydride, a sodium (C1-C4 alkoxide), a potassium (C1-C4 alkoxide), sodium amide, a tri-[(C1-C6)alkyl]amide or an organometallic base such as n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium diisopropylamide or sodium bis(trimethylsilyl)amide. The reaction temperature can range from about 0xc2x0 C. to about 180xc2x0 C. and is preferably from about 50xc2x0 C. to about 140xc2x0 C. Suitable solvents include DMSO, THF, sulfolane, dioxane and NMP.
When Z is CHCN or CHCOO(C1-C4 alkyl), a base that is capable of deprotonating R5ZH may be used, such as an alkali metal hydride (e.g., sodium or potassium hydride), a sodium (C1-C4 alkoxide) or an organometallic base such as n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium diisopropylamide or sodium bis(trimethylsilyl)amide, in an appropriate solvent, e.g., THF, DMSO, dioxane, methylene chloride, chloroform, toluene, xylene, benzene or a C1-C6 alkanol.
When Z is CR13CN, compounds of formula I may be prepared by reacting the corresponding compounds wherein Z is CHCN first with a base such as an alkali metal hydride such as sodium or potassium hydride, n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide or sodium diisopropylamide, and then with a compound of the formula R13L wherein L is a leaving group such as iodo, chloro, bromo, mesylate (OMs) or tosylate (OTs).
Compounds of the formula I wherein Z is CHR13 may be prepared by acid hydrolysis (using, e.g., 85% phosphoric acid) of the corresponding compounds wherein Z is CR13CN, followed by decarboxylation upon heating in an oil bath at a temperature from. about 120xc2x0 C. to about 180xc2x0 C. Further alkylation in the presence of base and a compound of the formula and R14L, wherein L is defined as above, will provide the corresponding compounds of formula I wherein Z is CR13R14.
When Z is N(C1-C4 alkyl), compounds of the formula I may be prepared by reacting the corresponding compounds wherein Z is NH first with a base and then with a compound of the formula (C1-C4 alkyl)-L, wherein L is defined as above. Bases such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium diisopropylamide may be used. Suitable solvents include THF, methylene chloride (CH2Cl2), DMSO, DMP, NMP and dioxane. The reaction temperature may range from about 20xc2x0 C. to about 150xc2x0 C., and is preferably from about room temperature to about 100xc2x0 C.
Compounds of formula I wherein D is carbon and B is xe2x80x94NR1R2, xe2x80x94OCHR1R2 or xe2x80x94SCHR1R2 may be prepared by reacting the corresponding compounds of formula III, wherein U is chloro, bromo or iodo, with a compound of the formula BH in the presence of a base, using methods analogous to those described above for the conversion of compounds of the formula II into compounds of the formula I.
Compounds of formula I wherein D is carbon and B is xe2x80x94CR1R2R10, xe2x80x94C(xe2x95x90CR2R11)R1, xe2x80x94CR2R10NHR1, xe2x80x94CR2R10OR1, xe2x80x94CR2R10SR1 or xe2x80x94COR2 may be prepared by reacting the corresponding compounds of formula III, wherein U is cyano, with a Grignard reagent containing the desired R2 group to form a compound of the formula I wherein B is COR2. Further reaction of this compound with a Grignard reagent containing the desired R1 group will yield the compound of formula I wherein B is xe2x80x94CR1 R2(OH).
Compounds of the formula I wherein B is xe2x80x94CR1R2R11, or xe2x80x94C(Cxe2x95x90CR2R11)R1 may be prepared using conventional methods well known to those skilled in the art. For example, reaction of compounds of the formula I wherein B is xe2x80x94C(OH)R1 R2 with an acid such as concentrated sulfuric acid in acetic acid, or a Burgess inner salt (such as (carboxysulfamoyl)triethylammonium hydroxide methyl ester) will yield a compound of the formula I wherein B is xe2x80x94C(xe2x95x90CR2R11)R1. Hydrogenation of a compound of the formula I wherein B is xe2x80x94C(xe2x95x90CR2R11)R1 using a Pd/C (palladium on carbon) or platinum oxide catalyst, using standard methods well known in the art, will yield a compound of formula I wherein B is xe2x80x94CHR1R2. Reaction of compounds in formula I wherein B is xe2x80x94CR1R2(OH) with diethylaminosulfur trifluoride or triphenylphosphine/carbon tetrachloride will afford a compound of formula I wherein B is xe2x80x94CR1R2F or xe2x80x94CR1R2Cl, respectively.
Reduction of compounds of the formula I wherein B is xe2x80x94COR2 with sodium borohydride in a reaction inert solvent such as a (C1-C4 alcohol), THF or dioxane, preferably methanol, at a temperature from about room temperature to about 100xc2x0 C, preferably from about room temperature to about 60xc2x0 C., will yield a compound of the formula I wherein B is xe2x80x94CHR2OH. Alkylation of the xe2x80x94CHR2OH group with an alkyl halide (such as an 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 afford the corresponding compound of formula I wherein B is xe2x80x94CHR2OR1. Compounds of formula I wherein B is xe2x80x94CR2R10NHR1 may also be prepared by a conventional methods well known in the art, such as reductive amination of the corresponding compounds of formula I wherein B is xe2x80x94COR2 with an appropriate amine and reducing agent (e.g., sodium cyanoborohydride or sodium triacetoxylborohydride) in an appropriate solvent (e.g., a lower alkanol or acetic acid).
Compounds of the formula ill wherein U is CN may be prepared by reacting the corresponding compounds of the formula lIl wherein U is chloro, bromo, iodo, or xe2x80x94OCOCF3 with potassium cyanide or copper cyanide in dimethylsulfoxide, THF, methylene chloride, toluene or DMF, with or without a Pd(0) or Pd(II) catalyst, at a temperature from about room temperature to about 180xc2x0 C., preferably at about the reflux temperature.
Compounds of the formula Ill wherein U is chloro, bromo, iodo, or xe2x80x94OCOCF3 may be prepared from the corresponding compounds of the formula III wherein U is hydroxy or amino. Compounds of the formula III wherein U is halo, or xe2x80x94OCOCF3 may be prepared by reacting a compound of the formula III wherein U is amino with a compound of the formula (C1-C5 alkyl)-O-Nxe2x95x90O and a copper (II) halide in an appropriate 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.
Compounds of formula III wherein U is chloro or bromo may be prepared by reacting the corresponding compounds of the formula III wherein U is hydroxy with a compound of the formula POX3, wherein X is chloro or bromo, with or without di-(C1-C4alkyl)aniline. This reaction may be conducted neat or in a solvent such as dimethylformamide, dichloroethane or methylene chloride, at a temperature from about 100xc2x0 C. to about 180xc2x0 C. Compounds of formula III wherein U is xe2x80x94OTf (wherein Tf is triflate) may be prepared by reacting the corresponding compounds of the formula III wherein U is OH with Tf2O in the presence of a base such as tri-(C1-C4 alkyl) amine or pyridine or an appropriate pyridine derivative (e.g., dimethylaminopyridine) in an appropriate solvent such as methylene chloride, DMF, DMSO, chloroform, or THF. Reaction of compounds of formula III wherein U is OTf with a compound of the formula KX, NaX or CuX (wherein X is chloro, bromo or iodo) in an appropriate solvent such as DMF, dimethylacetamide, N-methyl-pyrrolidone (NMP), or DMSO at temperature between about room temperature and about 180xc2x0 C. will yield compounds of the formula III wherein U is chloro, bromo or iodo.
Compounds of formula I, II, and III, wherein Z and R5 are defined as above for formula I and R3 is xe2x80x94O-(C1-C4) alkyl or xe2x80x94S-(C1-C4) alkyl (hereinafter R20) may be prepared by reacting the corresponding compounds of the formula I, wherein R3 is chloro, bromo, OTs or iodo, with a nucleophile of the formula R20H, wherein R20H is a (C1-C6)alkanol or a (C1-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. Compounds of the formula I wherein R3 is fluoro may be prepared by reacting the corresponding compounds wherein R3 is chloro, bromo, iodo, xe2x80x94OCOCF3, or xe2x80x94OSO2CF3 with tetrabutylammonium fluoride, potassium fluoride or another suitable fluoride agent, using standard methods well known to those skilled in the art.
Compounds of formula I wherein G is O, S, or NR8 may be prepared from compounds of formula IV-a, as illustrated in Scheme 1. Referring to Scheme 1, compounds of the formula IV-b may be prepared by reacting the appropriate compound of the formula IV-a, wherein B is xe2x80x94CR1R2R10, xe2x80x94C(xe2x95x90CR2R11)R1, CR1R10OR1, CR2R10SR1 or COR2; Y is O, S, NR8; and A is CR7 or N, with an acyl halide such as L-(CH2)nxe2x80x94COX (wherein X is chloro, bromo, iodo, mesylate, tosylate, triflate or OCOCF3; and L is chloro, bromo, iodo, hydroxy, mesylate, tosylate, triflate or OCOCF3), or an anhydride (such as [C1-C4alkyl)CO]2O) in the presence of a base such as a tri-(C1-C4 alkyl)amine, pyridine or a substituted pyridine, in an appropriate solvent such as methylene chloride, chloroform, THF, DMSO, dioxane, ether, dimethoxyethane, at a temperature from about 0xc2x0 C. to about 180xc2x0 C., preferably from about room temperature and about 60xc2x0 C.
Compounds of formula la may be prepared by reacting the corresponding compounds of the formula IV-b 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 sodium or potassium carbonate. Alkylation of the resulting compounds of the formula Ia with a base, followed by quenching with alkyl halide in an appropriate solvent such as ether, THF, methylene chloride, dioxane, benzene, toluene, or dimethoxyethane (DME), with or without hexamethylphosphoramide (HMPA), at temperature from about xe2x88x9278xc2x0 C. to about room temperature, will afford the corresponding compounds of the formula Ic. Suitable bases for use in this reaction include lithium diisopropyilnide, lithium bis(trimethylsilyl)amide, sodium diisopropylamide, and butyl lithium. Reduction of compounds of the formula I-a or I-c with a reducing agent such as borane methyl sulfide complex (BH3xe2x80xa2DMS), borane (BH3), borane THF complex (BH3xe2x80xa2DMS), diisobutylaluminum hydride or lithium aluminum hydride will yield the corresponding compounds of the formula I-b or I-d, respectively.
Compounds of formula I wherein G is carbon may be prepared from compounds of formula IV-c, as illustrated in Scheme 2. Referring to scheme 2, compounds of formula 1-e may be prepared by cyclization of compounds of formula IV-c wherein Q is (C1-C2 alkyl)CR4(COOC1-C4 alkyl)2, (C1-C2 alkyl)CR4(COOC1-C4 alky), (C1-C2 alkyl)CR4(CN)2, (C1-C2 alkyl)CR4(CN) or (C1-C2 alkyl)CR4COOH using standard methods for amide formation that are well known in the literature. Such methods include acid cyclization (such as: (a) heating in 40-85% phosphoric acid at a temperature from about 100xc2x0 C. to about 150xc2x0 C.; (b) heating in aqueous acetic acid/hydrochloric acid; or (c) base hydrolysis; followed by decarboxylation and then amide cyclization). Compounds of formula I-f may be obtained by reduction of the corresponding compounds of the formula I-e using the methods analogous to those described above for conversion of compounds of the formula I-a into those of the formula I-b.
Compounds of formula IV-c wherein Q is (C1-C2 alkyl)CR4(COOC1-C4 alkyl)2 or (C1-C2 alkyl)CR4(CN)2 can be prepared by reaction of a compound of the formula Naxe2x80x94, Kxe2x80x94 or Lixe2x80x94CR4(COOC1xe2x80x94C4 alkyl)2 or Naxe2x80x94, Kxe2x80x94 or Lixe2x80x94CR4(CN)2 with a compound in formula IV-c wherein Q is CHR8X or CHR8CHR4X (wherein X is chloro, bromo or iodo), at a temperature between about 0xc2x0 C. and about 150xc2x0 C., preferably between about 10xc2x0 C. to about 60xc2x0 C., in an appropriate solvent such as THF, DMSO, DMF, a (C1-C5 alkyl)-alcohol, acetonitrile, acetone, toluene, NMP or dimethyl acetamide. The preferred solvent is DMSO. Other compounds of formula IV may be prepared by methods analogous to those described in World Patent Application WO 95/33750, which designates the United States and which was published on May 18, 1995. This application is incorporated herein by reference in its entirety.
Compounds of formula I wherein E is CR6, G is CR8, D is nitrogen and K is oxygen may be prepared by reacting compounds of the formula IV-c wherein Q is CHR8OH with aqueous formaldehyde or R6CHO in an appropriate solvent such as benzene, toluene, xylene, a C1-C5 alkyl alcohol or acetonitrile, in the presence of acid catalyst such as p-TsOH, H2SO4 or HCl, at a temperature from about room temperature to about 160xc2x0 C., preferably at about the reflux temperature. Toluene or benzene is preferred solvent.
Compounds of formula IV-c may be prepared by the methods described in World Patent Application WO 95/33750, which designates the United States and was published on May 18,1995.
The acid addition salts of compounds of the formula can be prepared in a conventional manner by treating a solution or suspension of the corresponding free base with one chemical equivalent of a pharmaceutically acceptable acid. Conventional concentration or crystallization techniques can be employed to isolate the salts. Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzene sulfonic, p-toluenesulfonic, and related acids.
The compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to, collectively, as xe2x80x9cthe active compounds of this inventionxe2x80x9d) may be administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents The pharmaceutical compositions formed by combining the novel compounds of formula I and pharmaceutically acceptable carriers can then be readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, methylcellulose, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard 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 therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin 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 the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
The effective dosages for the active compounds of this invention will depend on the intended route of administration and factors such as the age and weight of the patient, as generally known to a physician. The dosages will also depend on the particular illness to be treated. For instance, the daily dosage for stress-induced illnesses, inflammatory disorders, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress and drug and alcohol withdrawal symptoms will generally range from about 0.1 to about 50 mg/kg body weight of the patient to be treated.
Methods that may be used to determine the CRF antagonist activity of the active compounds of this invention and their pharmaceutically acceptable salts are described in Endocrinology, 116, 1653-1659 (1985) and Peptides, 10, 179-188 (1985). The binding activities for compounds of the formula I, expressed as IC50 values, generally range from about 0.5 nanomolar to about 10 micromolar. Methods that can be used to determine the CRF binding protein inhibiting activity of compounds of the formula I can be determined using the method described in Brain Research, (1997), 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. Melting points are uncorrected. Proton nuclear magnetic resonance spectra (1H NMR) and C13 nuclear magnetic resonance spectra (C13 NMR) were measured for solutions in deuterochloroform (CDCl3) and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane (TMS). The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad.