MXPA98007869A - Pyridines and pyrimidines fused with ariloxy yariltio, and derived from the mis - Google Patents

Abstract

Novel compounds and pharmaceutical compositions thereof are provided, and methods for using same for treating anxiety, depression and other psychiatric and neurological disorders. The novel compounds provided by this invention are those of formulas (I), (II), wherein r1, R3, X, Y, Z, G and Q are as defined in the present

Description

AND FUSED PYRIMIDINES • PiRiPiras WITH ARILOX1 AND RI TTO. AND DERIVED FROM THEMSELVES CaMPO OF THE INVENTION This invention relates to novel compounds and pharmaceutical compositions, and to methods for using same in the treatment of psychiatric disorders and neurological diseases, including major depression, anxiety-related disorders,. Post-traumatic stress disorders, supranuclear palsy and eating disorders.

ANÍ? DENTS OF THE INVENTION 15 The corticotropin releasing factor (hereinafter referred to as CRF), a peptide of 41 % amino acids, is the main physiological regulator of the secretion of the peptide derived from proopiomelanocortin (POMC) of the anterior pituitary or pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80: 4851 (1983); W. Vale et al., Science 213: 1394 (1981)]. In addition to its endocrine role in the pituitary gland, the immunohistochemical localization of CRF has shown that the hormone has a broad extra-hypothalamic distribution in the system REF. 28317% central nervous system and produces a broad spectrum of autonomous, electrophysiological and behavioral effects consistent with a neurotransmitter or with the role of a neuromodulator in the brain [W. Vale et al., Rec. Prcg. 5 Horm. Res. 39: 245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., "Neurosci., 5: 3189 (1985).] There is also evidence that CRF plays an important role in the integration of the response of the immune system to physiological, psychological, and other stressors. immunological [J. E. Blalock, Physiological Reviews 69: 1 (1989); J. E. Morley, Life Sci. 41: 527 (1987)]. Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, disorders related to anxiety and eating disorders. A role of CRF in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Hungtinton's disease, progressive supranuclear palsy and ameotrophic lateral sclerosis has also been postulated. relate to the dysfunction of CRF neurons in the central nervous system [for a review see E.B. De Souza, Hosp. Practice 23:59 (1988)]. In affective disorders, or major depression, the concentration of CRF increases significantly in the cerebrospinal fluid (CSF) of individuals free of • medicines [C. B. Nemeroff et al. , Sience 226: 1342 (1984); C.M. Banki et al., Am. J. Psuchiatry 14: 8 '3 (1987); R.D. France et al., Biol. Psychiatry 28: 86 (1988); M. Arato et al., Biol. Psychiatry 25: 355 (1989)]. In addition, the 5"density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF. [CB Nemeroff et al., Arch. Gen. Psychiatry 45: 577 (1988)] In addition, there is a suppressed adrenocorticotropin response (ACTH) to CRF (administered via i.v.) observed in depressed patients [P ,. . Gold et al., Am J. Psychiatry 141: 619 (1984); F. Holsboer et al. , Psychoneuroendocrinology 9: 147 (1984); p. . Gold et al., New Eng. J. Med. 314: 1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms observed in human depression [R.M. Sapolsky, Arch. Gen. Psychiatry 46: 1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and therefore modulate the amounts of CRF receptor in brain iGrigoriadis et al., Neuropsychopharmacology 2 -.53 (1989)]. A role for CRF has also been postulated in the etiology of disorders related to anxiety. CRF produces anxiogenic effects in animals and interactions between benzodiazepine / non-benzodiazepine anxiolytics and CRF have been demonstrated in various behavioral models with anxiety [D.R. Britton et al., Life Sci. 31: 363 (1982); C.W. Berridge and A.J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist, an a-helical ovine CRF (9-41) in a variety of behavioral paradigms shows that the antagonist produces effects "similar to anxiolytics11 that are qualitatively similar to those of benzodiazepines [ CW Berridge and AJ Dunn Horm. Behav. 21: 393 (1987), Brain Research Reviews 15: 71 (1990).] Neurochemical, endocrine and receptor binding studies have shown, all, interactions between CRF and benzodiazepine anxiolytics providing Additional evidence of the relationship of CRF in these disorders Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both conflict tests [KT Britton et al., Psychopharmacology 86: 170 (1985), KT Britton et al., Psychopharmacology 94: 306 (1988)] and in acoustic stress tests [NR Swerdlow et al., Psychopharmacology 88: 147 (1986)] in rats. The benzodiazepine receptor antagonist (Rol5-1788), which is found to have no behavioral activity alone in operant conflict tests, reverses the effects of CRF in a dose-dependent manner while the inverse benzodiazepine agonist (FG7142) increases the actions of CRF [KT Britton et al., Psychopharmacology 94: 306 (1988)]. The mechanisms and sites of action through which standard anxiolytics and antidepressants produce their therapeutic effects are still to be elucidated. However, it has been hypothesized that they are involved in the suppression of CRF hypersecretion observed in these disorders. It is of particular interest that preliminary studies examine the effects of a CRF receptor antagonist (CRF9.41 a-helical) in various behavioral paradigms that the CRF antagonist has been shown to produce "anxiolytic-like" effects qualitatively similar to those of benzodiazepines [for a review see GF Kood and K.T. Britton, En: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E.B. De Souza and C.B. Nemeroff eds., CRC Press p221 (1990)]. The PCT application of DuPont Merck US94 / 11050 describes corticotropin releasing factor antagonist compounds of the formula: And its use to treat psychiatric disorders and neurological diseases. Included in the description are pyridines and fused pyrimidines of the formula: where: Z is CR2 or N; A is CR30 or N; D is CR28 or N; and R3 may be aryloxy or arylthio. Pfizer WO 95/33750 discloses corticotropin releasing factor antagonist compounds useful in the treatment of CNS and stress disorders. The description includes compounds of the formulas: where A is CR7 or N; B is OCHR ^ or SCHR ^; R1 is substituted or unsubstituted alkyl; R2 is alkyl, aryl or heteroaryl, substituted or unsubstituted; R3 is methyl, halo, cyano, methoxy, etc .; R 4 is H, alkyl, substituted or unsubstituted, halo, amino, nitro, etc .; R5 is aryl or Heteroaryl, substituted or unsubstituted; R6 is H or alkyl is H, methyl, halo, cyano, etc .; R16 and R17 taken together form an oxo group (= 0); and G is = 0, = S, = NH, = NCH3, hydrogen, methyl, methoxy, etc. Pfizex WO 95/34563 discloses corticotropin releasing factor antagonist compounds which include compounds of the formula: wherein A, B and the R groups have definitions similar to those of WO 95/33750. Pfizer WO 95/33727 describes corticotropin releasing factor antagonist compounds of the formula: twenty Wherein A is CH2 and Z can be a heteroaryl portion. Ganguly et al., US Pat. No. 4,076,711 describes triazolo [4,5-d] pyrimidines of the formula wherein X is halo, -NRXR or alkoxy, with R1 and R each being H or alkyl; Y is alkyl, cycloalkyl, hydroxycycloalkyl, phenyl, bicycloalkyl or phenylalkyl or bicycloalkylalkyl; and Q is H or Y. The patent states that the compounds are useful in the treatment of psoriasis. Tanji et al., Chem. Pharm. Bull. 39 (11) 3037-3040 (1991), describes triazolo [4,5-d] pyrimidines of the formula: wherein halo is I, Br or Cl, Ph is phenyl and Me is methyl. Utility for the compounds is not described. Settimo et al., II Drug, Ed. Se, 35 (4), 308-323 (1980) describes 8-azaadenines (Triazolo [4,5-d] pyrimidines of the formula: wherein R 1 is H or benzyl and R 2 is p-methylphenyl. Biagi et al., Drug II, 49 (3), 183-186 (1994), describes N (6) -substituted 2-n-butyl-9-benzyl-8-azaadenines of the formula: - li wherein R2 can be alkyl, phenyl or benzyl. The document states that the compounds have affinity for adenosine receptors. Thompson et al., J. Med. Chem., 1991, 34, 2877-2882, describes N6, 9-disubstituted adenines of the formula: wherein Ph is phenyl or (when C-2 is unsubstituted) 2-fluorophenyl. The document states that the compounds have selective affinity for the adenosine receptor Ax. Kelley et al., J. Med. Chem. 1990, 31, 606-612 describes the compound wherein R6 is NHC6H5 and R9 is CH2C6HS, and reports that the compound is active when tested for anticonvulsant activity. The document reports that various 6- (alkylamino) -9-benzyl-9H-purine analogs of the above compound show anticonvulsant activity. Kelley et al., J. Med. Chem. 1990, 33, 1360-1363, describe 6-anilino-9-benzyl-2-chloro-9H-purines of the formula: wherein Bz is benzyl or (when R4 is H) p-methylbenzyl and R 4 is H or alkyl, alkoxy, halo, cyano, nitro, etc. Compound tests for antirhinoviral activity are reported. Kelley et al., J. Heterocyclic Chem., 28, 1099 (1991), describe 6-substituted-9- (3-formamidobenzyl) -9H-purines of the formula: wherein R1 is NH2 or NHCHO. The compound wherein R 1 is NHCHO is tested for benzodiazepine receptor binding and is inactive, although several analogs were active. Khairy et al., J. Heterocyclic Chem., 22, 853 (1985), describe the synthesis of certain 9-aryl-9H-purin-6-amines of the formula wherein, the R groups are H, methyl, ethyl, isopropyl, chloro or fluoro. Hoechst EP 298467 (1989) describes azapurine derivatives, which include compounds of the structure wherein Q is O, S, SO, S02 or NH2; X is O, S, SO or S02; Z is H, halogen, CF3, alkoxy of 1 to 3 carbon atoms or * 10 alkylthio; R2 is alkyl or alkoxy; R3 is OR. These compounds are claimed to be useful for the treatment of viral diseases, autoimmune diseases and cancers. SS Pharmaceutical Co. Jp 59062595 (1984) and Jp 56131587 (1981) describe triazolopyrimidine derivatives which include compounds of the structure: where Q is 0, S, S02; R is amino or substituted amino, alkoxy, benzyloxy, halogen or phenylhydrazino. It is stated that these compounds are useful as anticancer agents. Fuji Jp 60194443 (1985) describes aza-indenos, which include compounds of the structure: where Q is O, S; R1, R2 and R3 are H, alkyl, aryl, aralkyl, amino, hydroxyl, alkoxy, carbamoyl, aryloxy, Alkoxycarbonyl, cyano, halogen, alkylthio, arylthio, carboxyl or mercapto, with the proviso that at least one of the substituents is mercapto. It is stated that these compounds are useful as light sensitizing agents, providing high photographic speed and contrast to silver halide emulsions.

BRIEF DESCRIPTION OF THE INVENTION This invention is a class of novel compounds which are antagonists of CRF receptors and r by formula I or formula (II): or a salt in the form of pharmaceutically acceptable prodrug thereof, wherein: X is N or CR1; 15 And it is N or CR2; Z is NR3, O or S (0) n; G is O or S; Q is O or S (0) n Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl or optionally substituted with 1 to 4 R5 groups; R1 is independently each time H, C1-C4 alkyl, C2-C4 alkenyl, C1-CJ alkynyl, halo, CN, haloalkyl occur. of ^ d, -NR9R10, NR9COR10, -OR11, SH or -S (0) nR12; R2 is H, d-alkyl, cycloalkyl of d-Cg, halo, CN, -NR6R7, NR9COR10, haloalkyl of Cx-C4, -OR7, SH or -S (0) nR12; R 3 is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 8 cycloalkyl or C 12 -C 12 cycloalkylalkyl each optionally substituted with 1 to 3 substituents which are independently selected each time which occur of alkyl of d-Cs, cycloalkyl of C3-C6, halo, haloalkyl of C ^ d, cyano, -0R7, SH, -S (0) nR13, -COR7, -C02R7, -OC (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13, -NR6R7, -CONRsR7, aryl, heteroaryl and heterocyclyl, wherein Aryl, heteroaryl or heterocyclyl are optionally substituted with 1 to 3 substituents which are independently selected, each time they occur, from C3-C6 cycloalkyl, halo, haloalkyl of C ^ d, cyano, -OR7, SH, - S (0) nR13, -COR7, -C02R7, -OC (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13, -NR6R7 and -CONReR7; R5 is independently, each time C¿-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, -N02, halo, -CN, haloalkyl are present. from 0.-0-4, -NR6R7, NR8C0R7, NR8C02R7, -COR7 ,. -OR7, -C0NR6R7, -CO (NOR9) R7, C02R7 or -S (0) nR7, wherein C? -C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and cycloalkylalkyl of C4-C12 are optionally substituted with 1 to 3 substituents that are independently selected each time they occur from 0-C4 alkyl, -N02, halo, -CN, -NR6R7, -NRSR7, NR8COR7, -COR7M -OR7, - CONR6R7, C02R7, -CO (ÑOR9) R7 or -S (0) nR7; R6 and R7 are independently, each time they occur, H, Cx-C4 alkyl, Cx-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, C1- arylalkyl C4, heteroaryl or heteroarylalkyl of C1-C4; or NR6R7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; each time it occurs, H, or 0-C4 alkyl; R9 and R1 are independently, each time they occur, selected from H, C1-C4 alkyl or C3-C6 cycloalkyl; R1 is H, alkyl of 0-C4, haloalkyl of Cx-C4 or cycloalkyl of C3-C6; R1 is 0-C4 alkyl or 0-C4 haloalkyl; P R13 is 0-C4 alkyl, C1-C4 haloalkyl, Alkoxyalkyl of C2-CB, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, arylalkyl of 0-C4, heteroaryl or heteroarylalkyl of 0-C4; aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents which independently select, each time they occur, 0-C3 alkyl, C3-C6 cycloalkyl, halo, haloalkyl 0-C4, cyano, -OR7, SH, -S (0) nR13, -COR7, -C02R7 , -OC (0) R13, -NR8COR7, -N (C0R7) 2, -NR8CONR6R7, -NR8C02R13, -NR6R7, and twenty - . 20 -CONRsR7; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, Benzothiazolyl, isoxazolyl or pyrazolyl optionally substituted with 1 to 3 substituents which are independently selected, each time they occur, from 0-C5 alkyl, C3-C6 cycloalkyl, halo, haloalkyl 0-C4, cyano, OR7, SH , -S (0) nR13, -COR7, -C02R7, -OC (0) R13, -NR8C0R \ -N (C0R7) 2, -NR8C0NR6R7, -NR8C02R13, -NR6R7, and -CONRsR7; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents that are independently selected each time they occur from 0-C6 alkyl, C3-C6 cycloalkyl, halo, haloalkyl 0-C4, cyano, OR7, SH , -S (0) nR13, - COR7, -C02R7, -OC (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13, -NR6R7, and -CONR6R7; n is independently each time 0, 1 or 2 is presented; with the proviso that in formula I, when X and Z are each N and Y is CR2, then R1 and R2 can not be mercapto groups. Included in this invention is the method for treating affective disorders, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other eating disorders, symptoms e suppresses alcohol or drug measures, addition to drugs, inflammatory disorders or fertility problems in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I or II. Also included in this invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of any of the compounds described herein. previous. The compounds provided by this invention (and especially the labeled compounds of this invention) are also useful as standards or reagents for determining the ability of a potential drug substance to bind to the CRF receptor.

Many compounds of this invention have one or more asymmetric centers or planes. Unless indicated otherwise, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric isomers of olefins, C = N double bonds and the like may also be present in the compounds, and all such stable isomers are contemplated in the present invention. The compounds can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as resolution of racemic forms or by synthesis of optically active materials. All chiral (enantiomeric and diastereomeric) and racemic forms, and all isomeric geometric forms of the structure are contemplated, unless the specific stereochemistry of the isomer form is specifically indicated. The term "alkyl" includes both branched and straight chain alkyl having the specified number of carbon atoms. "Alkenyl" includes hydrocarbon chains of straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur at any stable point along the chain, such as ethenyl, propenyl, and the like. "Alkynyl" includes hydrocarbon chains of straight or branched configuration and one or more triple carbon-carbon bonds which may occur at any stable point along the chain, such as ethynyl, propynyl and the like. "Haloalkyl" is intended to include both branched and straight chain alkyl having the specified number of carbon atoms, substituted with one or more halogen atoms; "alkoxy" represents a carbon alkyl group linked through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, including monocyclic, bicyclic or polycyclic ring systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so forth. "Halo" or "halogen" includes fluoro, chloro, bromo and iodo. The term "substituted", as used herein, means that one or more hydrogens of the atom Designated are substituted with a selection of the indicated type, with the proviso that the normal valence of the designated atom is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (ie, = 0), then 2 hydrogen atoms are substituted.

Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently strong to survive the isolation in a useful degree of purity from a reaction mixture, and its formulation into an effective therapeutic agent. The term "pharmaceutically acceptable salts" includes acid or base salts of the compounds of the formulas (I) and (II). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts or basic residues such as amines; alkaline or organic salts of acidic residues such as carboxylic acids; and similar. The pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture thereof. two; Generally, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred. The lists of suitable salts are found in Remington's Pharmaceutical Sciences. 17th ed. , Mack Publishing Company, Easton, PA, 1985, P. 1418, the description of which is incorporated herein by reference. The "prodrugs" are considered to be any covalently bonded carrier which can release the original active drug of formula (I) or (II) in vivo when such a prodrug is administered to a mammalian subject. The prodrugs of the compounds of formula (I) and (II) are prepared by modifying functional groups present in the compounds in such a way that the modifications are separated, either by usual manipulation or in vivo, to obtain the original compounds.

"The prodrugs include compounds wherein the hydroxy, amine or sulfhydryl groups bind to any group which, when administered to a mammalian subject, is separated to form a free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrug include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formulas (I) and (II); and similar. The term "therapeutically effective amount" of a compound of this invention means an amount effective to antagonize an abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.

Synthesis The novel substituted fused pyrimidines of the present invention are prepared by one of the general schemes indicated below, wherein Ar, Q, G, X, Y, Z, Rj, R2, R3 and R13 are as indicated in above and L represents a suitable leaving group such as halo, methanesulfonate, p-toluenesulfonate or triflate.

• Scheme 1 II III 10 20 25 VII VIII ipo III (Scheme 1) are prepared by condensing alkali metal salts of compounds of type I, where Q = 0 or S, with compounds of type II manufactured according to the procedures of the literature [Ashley and Harris, J Chem Soc., 677 (1944); Albert et al., J. Chem Soc., 3832 (1954)] in solvents such as acetonitrile at temperatures between 0 and 50 ° C. Compounds of type IV are obtained from compounds of type III by treatment with primary amines such as 4-aminoheptane in solvents such as dioxane at temperatures between 25 and 100 ° C. These amino adducts are converted to type V compounds by reduction with hydrogen in the presence of catalysts such as platinum in carbon at atmospheric or elevated pressure, or by reducing agents such as sodium dithionite, or iron in acetic acid. Compounds of type VI are prepared from compounds of type V through diazotization and cyclization with an alkali metal nitrite in the presence of of an acid in water with or without an organic cosolvent such as cyclic ethers or aromatic hydrocarbons. Compounds of type VII are prepared by the condensation of type V compounds with phosgene, thiophosphate, carbonyldiimidazole, thiocarbonyldiimidazole, urea, Thiourea, guanidine and the like, in the presence or absence of solvents such as ethers with high boiling point or aromatic hydrocarbons, and at temperatures between 100-200 °.

Scheme 2 XIII XII Compounds of type VIII are prepared by condensation of compounds of type V with reagents such as acids, acid chlorides, anhydrides, amides or orthoesters in the presence or absence of solvents such as at temperatures between 0 to 200 ° C. Compounds of type VII, wherein R13 = H, are alkylated with reagents such as alkyl and similar halides, in the presence or absence of bases such as sodium hydroxide, in solvents such as tetrahydrofuran or DMF and at temperatures between 0 and 100 ° C to provide compounds of type VIII. * Alternatively, compounds of type VII are prepare from compounds of type X (Scheme 2). These diaminopyrimidines, X are manufactured from dichloroaminopyrimidines of type IX which are synthesized from compounds of type II by treatment with reducing agents such as, but not limited to sodium, iron or zinc dithionite in the presence of acid or catalytic hydrogenation (see: LaRock, Comprehensive Organic Transformations, VCH Publishers, NY, 1989, 411). Diamine compounds, X are converted to compounds of type XII using the same procedure to that described for the preparation of the compounds of type VII from the compounds of type V, and then condensing the compounds of type XII with salts of the compounds of type I in solvents such as DMF or 2-ethoxyethanol at temperatures between 25 and 25. and 200 ° C.

Alternatively, compounds of type VII are prepared from type X compounds by first converting them to compounds of type XIII using the same method as that described for the preparation of compounds of type VIII from compounds of type V, and then condensing the compounds of the type XIII obtained in this manner with salts of the compounds of type I under the conditions described for the conversion of the compounds of type I and compounds of type II. Alternatively, compounds of type VI are prepared from compounds of type X by diazotization and cyclization, as previously described for compounds of compounds of type V to compounds of type VI to give compounds of type XI. Subsequent treatment with the salts of type I compounds with compounds of type XI, as previously described, provides these triazole adducts of type VI. The compounds of the present invention and their synthesis are further illustrated by the following examples and preparations.

Example 1 3 - . 3-bromo-4-hydroxy-5-methoxyacetophenone Bromine (9.62 g) in 30 ml of chloroform is added dropwise to a solution of acetovainillone (10.0 g) and 150 ml of chlorine, so it is maintained at 0-5 ° C , so that the temperature does not increase above 5 ° C. After the addition is complete, the mixture is stirred at 0-5 ° C for 4 hours. The residue is treated with water. The organic layer is dried over MgSO 4 and distilled off from the solvent under reduced pressure to give a pinkish powder which is titrated with ether and filtered to provide the title compound, m.p. 148-152 ° C.

Example 2 3-bromo-4-hydroxy-5-methoxy-g.ff-dimethylbenzenemethanol Methylmagnesium bromide (3M in diethyl ether, 11.42 ml) is added dropwise to a solution of 5-bromo-4-hydroxy-3-methoxyacetophenone (3.0 g) in anhydrous tetrahydrofuran (60 ml) which is maintained at 0-5 ° C. under N2 gas, so that the temperature does not increase above 5 ° C. After the addition is complete, the solution is stirred at room temperature for 2 hours. Unsaturated ammonium chloride is added dropwise until the effervescence ceases. The mixture is treated with an excess of organic chlorine on MgSO4 and is distilled off from the solvent under reduced pressure to give the title compound as a viscous oil which solidifies after a period of time, m.p. 107-112 ° C.

Example 3 3-bromo-5-methoxy-tt.a-dimethyl-4-? r6-chloro-2-methyl-5-nitro-10 4-pyrimidinyl oxyl benzene-methanol Dissolve 3-bromo-4-hydroxy-5-methoxy-a, a-dimethylbenzenemethanol (1.16 g) in 10% NaOH (1.78 g) and 5 ml of water. The solvent is distilled off under pressure reduced. The salt is taken up in 50 ml of acetonitrile and is added dropwise by means of a pipette to an already cooled solution (0-5 ° C) of 4,6-dichloro-2-methyl-5-nitro-l, 3-pyrimidine ( 0.92 g) in 80 ml of acetonitrile. The mixture is stirred at 0 ° -5 ° C for 3 hours. The solvent is removed under The pressure is reduced and the residue is extracted with methylene chloride. The extracts are combined and evaporated under reduced pressure to provide the title compound.

EXAMPLE 4 3-Bromo-5-methoxy- ". Tt-dimethyl-4-r r 2 -methyl-5-nitro-6-f- (1-propylbutyl) aminol 4-pyrimidinyl oxyl benzenemet A solution of 3-bromo-5-methoxy-a, a-dimethyl-4- [[6-chloro-2-methyl-5-nitro-4-pyrimidinyl] oxy] benzenemethanol (1.88 g) in 1,4-dioxane anhydrous (50 ml) with 0.50 g of potassium carbonate, 4-ethylamine (1.00 ml) is added and the solution is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue is taken up in water and extracted with methylene chloride. The extracts are combined and dried over MgSO4. The solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel using a 1: 1 mixture of ethyl acetate and hexane to provide the title compound, m.p. 138 ° C. Prepared by the same procedure 3-bromo-5-methoxy-a, a-dimethyl-4- [(6- (1-methoxypropyl) amino-2-methyl-5-nitro) -4-pyrimidinyl] oxybenzenemethanol, m.p. 119-120 ° C.

Example 5 3-bromo-5-methoxy-a. a-dimethyl-4-f5-amino-2-methyl-6- (1- propylbutyl) aminol -4-pyrimidinyl oxyl benzenemethanol Platinum black (5%, 0.25 g) is added to a solution of 3-bromo- 5-methoxy-a, a-dimethyl-4- [[2-methyl-5-nitro-6- [(1-propylbutyl) amino] -4-pyrimidinyl] oxy] benzenemethanol (0.80 g) in 50 ml of ethanol. The mixture is hydrogenated at a pressure of 2.9 kg / cm2 (41 psi) for 18 hours. The mixture is filtered through celite and the filtrate is distilled off under reduced pressure. The residue is taken up in 1N NaOH and extracted with methylene chloride. The combined methylene chloride extracts are dried over MgSO4 and the filtrate is distilled off under reduced pressure to provide the title compound, m.p. 114-116 ° C.

Example 6 3-bromo-5-methoxy-a. a-dimethyl-4- T (5-methyl-3- (1-propylbutyl) -3h-1, 2, 3-triazolo [4, -dl pyrimidin-7-yl) oxyl benzenemethanol To a solution of 3-bromo-5-methoxy-a, a-dimethyl-4- [[5-amino-2-methyl-6- [(1-propylbutyl) amino] -4-pyrimidinyl] -oxy] benzenemethanol (0.70 g) in 35 ml of glacial acetic acid, 0.10 g of sodium nitrite is added in drops 1 ml of water The mixture is stirred at room temperature for 20 minutes and then diluted with water, made basic with INN NaOH and extracted three times with ethyl acetate. The combined extracts are dried over MgSO4 and are distilled off from the solvent under reduced pressure to provide the title compound as a viscous liquid.

Example 7 7- \ 2-bromo-6-methoxy-4- (1-methylethhenyl) phenoxy-5-methyl-3- (1-propylbutyl) -3H-1,2,3-triazolo [4,5-dl pyrimidine] To a solution of 3-bromo-5-methoxy-a, a-dimethyl-4- [(5-methyl-3- (1-propylbutyl) -3H-1, 2,3-triazolo [4,5-d] - pyrimidin-7-yl) -oxi] benzenemethanol (0.59 g) in 35 ml of benzene, a small amount of p-toluenesulfonic acid is added. The solution is refluxed under azeotropic conditions for 1.5 hours. Once cooled to room temperature, the solution is washed with saturated NaHCO 3, followed by water. The organic phase is dried over MgSO 4 and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel using a 1: 1 mixture of ethyl acetate and hexane to give the title compound as a colorless solid, m.p. 110-115 ° C. 7- \ 2-bromo-6-methoxy-4- (1-methylethyl) phenoxy-5-methyl-3- (1-propylbutyl) -3H-1,2,3-triazolo-4,5-di-pyrimidine Platinum black, 5% (0.19 g) is added to a solution of 7- [2-bromo-6-methoxy-4- (1-methylethyl) phenoxy] -5-methyl-3- (1-propylbutyl) -3H -1, 2, 3-triazolo [4,5-d] pyrimidine (0.17 g) in 50 ml of ethanol. The mixture is hydrogenated to a * 10 pressure of 2.8 kg / cm2 (40 psi) for 18 hours and filtered through celite. The filtrate is distilled off from the solvent under reduced pressure and the residue is recrystallized from hexane to give the title compound as a colorless crystalline solid, p.f. 129-131 ° C. ' Example 9 3- (1-ethylpropyl) -5-methyl-7- (2,4,6-trimethylphenoxy) -3H-20 1,2, 3-triazolo f4, 5-dl pyrimidine 2, 4, 6-Trimethylphenol (0.114) is added to a solution of sodium methoxide (0.334 g) methanol (10 ml) and the resulting solution is evaporated to dryness under pressure reduced. The salt obtained in this manner is taken up in 10 ml of acetonitrile and added dropwise to a cold solution (0-5 ° C) of 7-chloro-3- (1-ethylpropyl) -5-methyl-3H-1. , 2, 3-triazolo [4, 5-d] pyrimidine in 35 ml of acetonitrile, so that the temperature does not increase above 5 5 ° C. The mixture is stirred at 0-5 ° C for three hours. The solvent is subsequently removed from the mixture under reduced pressure and the residue is treated with water and extracted three times with methylene chloride. The combined extracts are dried over MgSO4 and are distilled off from the solvent under reduced pressure. The material is purified on silica gel using a solution of 1% methanol in methylene chloride to provide the title compound as a colorless powder, m.p. 92 ° C.

Example 10 6- (1-methoxypropyl) amino-2-methyl-5-nitro-4- (2-bromo-6-methoxy-4- (1-methyleteni) phenoxy pyrimidine Some crystals of 4-toluenesulfonic acid are added to a solution of 3-bromo-5-methoxy-a, a-dimethyl-4- [[6- (1-methoxypropyl) amino-2-methyl-5-nitro] - pyrimidinyl]] oxybenzenemethanol (1.70 g) in benzene (30 ml) and the resulting mixture is heated overnight reflux using a Dean-Stark trap. It is then cooled diluted with benzene (70 ml), washed successively with 1N aqueous NaOH and water. Dry over magnesium sulfate and evaporate to dryness under reduced pressure to provide a semi-solid which, by trituration with ether and filtration gives a yellow solid. Recrystallization from ethanol gives the title compound as a light yellow yellow solid, m.p. 136-137 ° C.

Example 11 2-amino-6- (1-methoxypropyl) amino-2-methyl-4-? (2-bromo-6-methoxy-4- (1-methylethyl) phenoxy] pyrimidine Platinum black (5%, 250 mg) to a solution of 6- (1-methoxypropyl) amino-2-methyl-5-nitro-4- [(2-bromo-6-methoxy-4- (1-methylethyl) phenoxy] pyrimidine (550 mg) in ethyl acetate (100 ml) and the resulting mixture is hydrogenated at 2.1 kg / cm2 (30 p.s.i.) overnight. The mixture is then filtered and evaporated to dryness under reduced pressure to provide the title compound as a highly viscous liquid.

Example 12 7- r 2 -bromo-6-methoxy-3- (1-methoxypropyl) -5-methyl-4- (1-methylethyl) phenoxy-3 H-1,2,3-triazolo T 4, 5-dl pyrimidine A solution of sodium nitrite (42 mg) in water (1 ml) is added dropwise to a solution of 2-amino-6- (1-methoxypropyl) -amino-2-methyl-4- [(2-bromo) 6-methoxy-4- (1-methylethyl) -phenoxy] pyrimidine (270 mg) in acetic acid (10 ml) with stirring at room temperature. After the addition is complete, the mixture is stirred overnight at room temperature and most of the acetic acid is distilled off under reduced pressure. The residue is treated with aqueous IN NaOH and extracted with ethyl acetate (2X). The ethyl acetate extract is washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give a semi-solid which is chromatographed on silica using 1: 1 ethyl acetate: hexane as the eluent to supply the title compound, mp 149-150 ° C.

Utility CRF-R1 Receptor Binding Assay for the Evaluation of Biological Activity ^? H- The following is a description of the isolation of cell membranes containing human CRF-R1 receptors cloned for use in the standard binding assay as well as a description of the assay same. 5 Human hippocampal messenger RNA was isolated. He MRNA was subjected to reverse transcription using oligo (dt) 12-18 and the coding region was amplified by PCR from the start codons to the stop codons. The resulting PCR fragment was cloned into the EcoRV site of pGEMV, from where the insert was purchased again using Xhol + Xbal and cloned into the Xhol + Xbal sites of the pm3ar vector (which contains a CMV promoter, the SV40"t" junction and the early poly A signals, a origin of viral replication of Epstein-Barr and a marker selectable hygromycin). The resulting expression vector, called phchCRFR, was transfected into 293EBNA cells and cells that retain the episome in the presence of 400 μM hygromycin were selected. The cells that survived four weeks of selection in hygromycin were harvested, adapted for growth in suspension and used to generate membranes for the binding assay described below. Subsequently, the individual aliquots containing approximately 1 x 108 of the suspended cells were centrifuged to form a sediment and they were frozen.

For the binding assay, the frozen pellet described above containing 293EBNA cells was transfected with hCRFR1 receptors and homogenized in 10 ml of ice-cooled tissue buffer (50 mM HEPES buffer, pH 7.0, containing 10 mM MgCl 2, 2 mM EGTA, 1 μg / 1 aprotinin, 1 μg / ml leupeptin and 1 μg / ml pepstatin). The homogenate was centrifuged at 40,000 x g for 12 minutes and the resulting pellet was homogenized in 10 ml of tissue buffer. After further centrifugation at 40,000 x g for 12 minutes, the pellet was resuspended to a protein concentration of 360 μg / ml to be used in the assay. The binding assays were performed in 96-well plates; each well had a capacity of 300 μl. To each well was added 50 μl of the dilutions of the test drug (the final concentration of the drugs varies from 10"10 to 10" 5), 100 μl of 125I- ovino-CRF (125I-o-CRF) (concentration final, 150 pM) and 150 μl of the cell homogenate described above. The plates were then allowed to incubate at room temperature for two hours before entering the incubation on GF / F filters (pre-wetted with 0.3% polyethylenimine) using an appropriate cell harvester. The filters are moistened twice with ice-cooled assay buffer before removing the individual filters and determining them for radioactivity in a gamma counter. The curves of the binding inhibition of 125I-o-CRFa cell membranes at various dilutions of test drug are analyzed by the iterative curve fitting program LIGAND [P.J. Munson and D. Rodbard, Anal. Biochem. 170: 220 (1980), which provides Ki values for inhibition which are then used to determine biological activity. A compound is considered to be active if it has a Kx value of less than about 10,000 nM for the inhibition of CRF to its receptor.

Inhibition of adenylate cyclase activity stimulated by CRF An examination of the inhibition of adenylate cyclase activity stimulated by CRF was performed as described by G. Battaglia et al. Synapse 1: 572 (1987). Briefly, tests were carried out at 37 ° C for 10 minutes on 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37 ° C), 10 mM MgCl 2, 0.4 mM EGTA, 0.1% BSA, isobutylmethylxanthine ( IBMX) 1 mM, 250 units / ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine triphosphate, 100 nM oCRF, antagonist peptides (concentration range, 10"9 al?" 6m) and 0.8 mg of original wet weight tissue (approximately 40-60 mg of protein). The reactions were initiated by the addition of 1 mM ATP / [32 P] ATP (approximately 2-4 mCi / tube) and finalized by the addition of 100 ml of 50 mM Tris-HCl, 45 mM ATP and 2% sodium dodecyl sulfate. . In order to monitor cAMP recovery, 1 μl of [3 H] cAMP (approximately 40,000 dpm) was added to each tube before separation. The separation of [32 P] cAMP from [32 P] ATP was performed by sequence sequencing on Dowex and alumina columns. The recovery was consistently greater than 80%. Some compounds of this invention were tested in this assay and found to be active.

Biological test in vivo The in vivo activity of the compounds of the present invention can be determined using any of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startle test, the Stair climbing test and the chronic administration test. These and other useful models for testing compounds of the present invention have been delineated in C.W. Berridge and A.J. Dunn Brain Research Reviene 15:71 (1990).

The compounds can be tested in any of the species of rodents or small mammals. The description of the assays herein is not intended to limit the ability of the invention. The compounds of this invention have utility in the treatment of imbalances associated with abnormal levels of corticotropin releasing factor in patients suffering from depression, affective disorders and / or anxiety. The compounds of this invention can be administered to treat these abnormalities by means of that which brings about contact of the active agent with the site of action of the agent in the body of a mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceutical substances either with an individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The dosage administered will vary based on the use of known factors such as the pharmacodynamic nature of the particular agent and its mode and route of administration; the age, weight and health of the recipient; the nature and degree of the symptoms; the class of concurrent treatment; the frequency of treatment and the desired effect. For use in the treatment of such diseases or conditions, the compounds of this invention can be administered orally daily at a dosage of the active ingredient from 0.002 to 200 mg / kg of body weight. Usually, a dose of 0.01 to 10 mg / kg in divided doses of 1 to 4 times a day, or in a sustained release formulation will be effective to obtain the desired pharmacological effect. Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. These pharmaceutical compositions, the active ingredient will usually be present in an amount from about 0.5 to 95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups and / or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dose formulations. Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as, but not limited to, lactose, starch, magnesium stearate, stearic acid or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both the tablets and the capsules can be manufactured as sustained release products to provide continuous release of the medication over a period of time. The compressed tablets may be sugar coated or film coated to mask any unpleasant taste, or they may be used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract. Liquid dosage forms for oral administration may contain coloring or flavoring agents to increase patient acceptance. In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar and solutions and glycols such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Preferably, solutions for parenteral administration contain a water-soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, shortening substances. Antioxidant agents, such as sodium bisulfite, sodium sulfite, either alone or in combination, are suitable stabilizing agents. It also uses citric acid and its salts, and EDTA. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methylparaben or propylparaben and chlorobutanol. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences," A. Osol, a standard reference in the art. The pharmaceutical dosage forms useful for administration of the compounds of this invention can be illustrated as follows: Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 100 mg of magnesium stearate.

Soft gelatin capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by positive displacement means * and pumped into gelatin to form soft gelatine capsules containing 100 mg of the active ingredient. The capsules are washed and dried.

Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg of * 10 colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. The appropriate coatings can be applied to increase the pleasantness or for delayed adsorption. The compounds of this invention can also be used as reagents or standards in the biochemical study of neurological function, dysfunction and diseases. It is noted that in relation to this date, the The best method known by the applicant to carry out the aforementioned invention is conventional for the manufacture of the objects to which it refers. Having described the invention as above, property is claimed as contained in the following:

Claims (6)

1. An antagonist compound of CRF (corticotropin releasing factor) characterized in that it is of formula I or formula II II 15 or a pharmaceutically acceptable salt or prodrug form thereof, wherein X is N or CR1; And it is N or CR2; Z is NR3, O or S (0) n; 20 G is O or S; Q is O or S (0) n Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl or pyrazolyl, each optionally substituted with 1 to 4 R5 groups; R1 is independently each time H is present, C1-C4 alkyl, C2-C4 alkenyl, 0-C4 alkynyl, halo, CN, haloalkyl of -O., -NR9R10, NR9COR10, -OR11, SH or - S (0) nR12; R2 is H, 0-C4 alkyl, O-Cg cycloalkyl, halo, CN, -NRSR7, NR9COR10, C1-C4 haloalkyl, -OR7, SH O -S (0) nR12; R3 is H, O-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl or C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents which are independently selected each time occur of 0-C6 alkyl, C3-C6 cycloalkyl, halo, haloalkyl of 0-C4, cyano, -OR7, SH, -S (0) nR13, -COR7, -C02R7, -OC (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13, -NRSR7, -CONR6R7, aryl, heteroaryl and heterocyclyl, wherein aryl, heteroaryl or heterocyclyl are optionally substituted with 1 to 3 substituents which are independently selected, each time which occur, of 0-C6 alkyl, C3-C6 cycloalkyl, halo, Cx-C4 haloalkyl, cyano, -OR7, SH, 2R7, -OC (0) R13, -NR8COR7, -N (COR7) 2 , -NR8CONR6R7, -NR8C02R13, -NR6R7 and -CONR6R7; R5 is independently, each time O-O0 alkyl, C2-C10 alkenyl, alkynyl of ~ O0, cycloalkyl of C3-C6, cycloalkylalkyl of C4-C12, -N02, halo, -CN, haloalkyl of 0- C4, -NR6R7, NR8COR7, NR8C02R7, -COR7, -OR7, -C0NR6R7, -CO (NOR9) R7, C02R7 or -S (0) nR7, wherein alkyl of O-C10, C2-C10 alkenyl, alkynyl of C2-C10, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents which are independently selected each time they occur from alkyl of 0-C4, -N02, halo, -CN, -NRSR7, -NR6R7, NR8COR7, NR8C02R7, -COR7 -OR7, -C0NR6R7, C02R7, -CO (NOR9) R7 or -S (0) nR7; R6 and R7 are independently, each time they occur, H, CX-C4 alkyl, 0-C4 haloalkyl, C2-C8 alkoxyalkyl, cycloalkyl C3-C6, C4-C12 cycloalkylalkyl, aryl, 0-C4 arylalkyl, heteroaryl or 0-C4 heteroarylalkyl; or NRdR7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; whenever it occurs, H, or 0-C4 alkyl; R9 and R10 are independently, each time they occur, selected from H, 0_0 alkyl or C3-C5 cycloalkyl; R11 is H, CX-C4 alkyl, haloalkyl of O-O ° C3-C6 cycloalkyl; R12 is 0-0 alkyl or 0-C4 haloalkyl; R13 is 0-C4 alkyl, 0-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, 0-C4 arylalkyl, heteroaryl or C1-C4 heteroarylalkyl; aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents which 15 independently select, each time they occur, from 0-C6 alkyl, C3-C3 cycloalkyl, halo, haloalkyl 0-C4, cyano, -OR7, SH, -S (0) nR13, -COR7, -C02R7 , -OC (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13, -NR6R7, and twenty - . 20 -CONR6R7; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinol ini lo, i soquinol ini lo, tieno lo, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, Benzothiazolyl, isoxazolyl or pyrazolyl * optionally substituted with 1 to 3 substituents which are independently selected, each time they occur, from 0-C3 alkyl, C3-C6 cycloalkyl, halo, haloalkyl 0-C4, cyano, OR7, SH, -S (0) nR13, -COR7, -C02R7, -OC (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13, -NR6R7, and -CONRsR7; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 10 substituents which are independently selected each time they occur of 0-C6 alkyl, C3-C6 cycloalkyl, halo, haloalkyl of 0-C4, cyano, OR7, SH, -S (0) nR13, - COR7, -C02R7 , -OC (0) R13, -NR8COR7, -N (COR7) 2, fifteen - . 15-NR8CONR5R7, -NR8C02R13, -NR6R7, and -CONR6R7; n is independently each time 0, 1 or 2 is presented; with the proviso that in formula I, when X and Z are each N and Y is CR2, then R1 and R2 can not be mercapto groups.

2. The compound according to claim 1, characterized in that it is selected from the group consisting of: a) 3-bromo-5-methoxy-a, a-dimethyl-4- [[6-chloro-2-methyl-5- Nitro-4-pyrimidinyl] oxy] benzenemethanol b) 3-bromo-5-methoxy-a, -dimethyl-4- [[2-methyl-5-nitro-6- [(1-propylbutyl) amino] -4-pyrimidinyl ] oxy] benzenemethanol c) 3-bromo-5-methoxy-a, a-dimethyl-4- [[5-amino-2-methyl-6- [(1-propylbutyl) amino] -4-pyrimidinyl] oxy] benzenemethanol d) 3-bromo-5-methoxy-a, a-dimethyl-4- [(5-methyl-3- (1-propylbutyl) -3H-1, 2,3-triazolo [4,5-d] pyrimidine- 7-yl) -oxi] benzenemethanol e) 7- [2-bromo-6-methoxy-4- (1-methylethyl) phenoxy] -5-methyl-3- (1-propylbutyl) -3H-1, 2, 3 -triazolo [4, 5-d] pyrimidine f) 7- [2-bromo-6-methoxy-4- (1-methylethyl) phenoxy] -5-methyl-3- (1-propylbutyl) -3H-1, 2 , 3-triazolo [4,5-d] pyrimidine g) 3- (1-ethylpropyl) -5-methyl-7- (2,4,6-trimethylphenoxy) -3H-1, 2,3-triazolo [4, 5-d] irimidine h) 6- (1-methoxypropyl) amino-2-methyl-5-nitro-4- [(2-bromo-6-methox i-4- (1-methylethyl) phenoxy] pyrimidine i) 2-amino-6- (1-methoxypropyl) amino-2-methyl-4- [(2-bromo-6-methoxy-4- (1-methylethyl)) phenoxy] pyrimidine j) 7- [2-bromo-6-methoxy-3- (1-methoxypropyl) -5-methyl-4- (1-methylethyl) phenoxy] -3H-1, 2, 3-triazolo [4, 5-d] pyrimidine k) 3-bromo-5-methoxy-a, a-dimethyl-4 - [(6 - (1-methoxypropyl) amino-2-methyl-5-nitro) -4-pyrimidinyl ] oxy-benzenemethanol.

The method comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1.

4. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 2. * 5. A method for treating an affective disorder, anxiety, depression, irritable bowel syndrome, tension disorder post-traumatic, supranuclear palsy, immune suppression, Alzheimer's disease, 15 gastrointestinal disease, anorexia nervosa or other eating disorder, symptoms of drug or alcohol suppression, drug involvement, inflammatory disorders or fertility problems in a mammal, characterized in that it comprises administering to the mammal a

The therapeutically effective amount of a CRF antagonist compound of formula I or II: 25 II # 10 or a pharmaceutically acceptable salt or form of prodrug thereof, wherein X is N or CR1; And it is N or CR2; Z is NR3, O or S (0) n; 15 G is O or S; Q is O or S (0) n Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinoline 1, isoquinolinyl, thienyl, imidazolyl, thiazolyl, Indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl or. pyrazolyl, each optionally substituted with 1 to 4 R5 groups; R1 is independently every time H is presented, 0-C4 alkyl, C2-C4 alkenyl, 0-C4 alkynyl, halo, CN, Cx-C4 haloalkyl, -NR9R10, NR9COR10, -OR11, SH or -S (0) nR12; R 2 is H, 0-0 alkyl / 0-C6 cycloalkyl, halo, CN, -NR6R7, NR9COR10, haloalkyl of 0-C4, -OR7, SH or -S (0) nR12; R3 is H, O-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl or C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents which are independently selected each time occur of 0-C6 alkyl, C3-C6 cycloalkyl, halo, haloalkyl of 0-C4, cyano, -OR7, SH, -S (0) nR13, -COR7, -C02R7, -OC (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13, -NR6R7, -CONR6R7, aryl, heteroaryl and heterocyclyl, wherein aryl, heteroaryl or heterocyclyl are optionally substituted with 1 to 3 substituents which are independently selected, each time which occur, of alkyl of 0-C6, cycloalkyl of C3-C6, halo, haloalkyl of 0-C4, cyano, -OR7, SH, -S (0) nR13, -COR7, -C02R7, -OC (0) R13, -NR8COR7,. -N (COR7) 2, -NR8CONRsR7, -NR8C02R13, -NRSR7 and -CONR5R7; R5 is independently, each time there is O-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C3 cycloalkyl, cycloalkylalkyl of O-O2 / -N02, halo, -CN, haloalkyl of Cx -C4, -NR6R7, NR8COR7, NR8C02R7, -COR7, -OR7, -CONR6R7, -CO (NOR9) R7, C02R7 or -S (0) nR7, wherein O-C10 alkyl, C2-C10 alkenyl, alkynyl of C2-C10, C3-C6 cycloalkyl and 0-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents which are independently selected each time they occur from 0-C4 alkyl, -N02, halo, -CN, -NR6R7 , -NRSR7, % 10 NR8COR7, NR8C02R7, -COR7 -OR7, -CONR6R7, C02R7, -CO (NOR9) R7 or -S (0) nR7; R6 and R7 are independently, each time they occur, H, C1-C4 alkyl, haloalkyl O-O, alkoxyalkyl C2-C8, cycloalkyl C3-C6, C4-C12 cycloalkylalkyl, aryl, 0-C4 arylalkyl, heteroaryl or 0-C4 heteroarylalkyl; or NR6R7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; R8 is independently, whenever it occurs, H, or 0-C4 alkyl; R9 and R1 are independently, each time they occur, selected from H, 0-C4 alkyl or C3-C6 cycloalkyl; R11 is H, CX-C4 alkyl, haloalkyl of 0-C4 C3-C3 cycloalkyl; R: 12 is 0-C4 alkyl or Cx-C4 haloalkyl; R13 is 0-0 alkyl, 0-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, 0-C4 arylalkyl, heteroaryl or Cx-C4 heteroarylalkyl; aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents which are independently selected, each time they occur, from 0-C6 alkyl, C3-C6 cycloalkyl, halo, haloalkyl 0-C4, cyano, - OR7, SH, -S (0) nR13, -COR7, -C02R7, -OC (0) R13, -NR8COR7, -N (C0R7) 2, -NR8CONR6R7, -NR8C02R1 -NR6R7 -CONRsR7; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl or pyrazolyl optionally substituted with 1 to 3 substituents which are independently selected, each time they occur, of alkyl of 0-C3, cycloalkyl of C3-C6, halo, haloalkyl of 0-C4, cyano, OR7, SH, -S (0) nR13, -COR7, -C02R7, -OC (0) R13, -NR8COR7, -N (COR7) 2, -NR8C0NR6R7, -NR8C02R13, -NR6R7, and -CONRdR7; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents which are independently selected each time they occur from 0-C6 alkyl, C3-C6 cycloalkyl, halo, haloalkyl 0-C4, cyano, OR7, SH, % -S (0) pR13, -COR7, -C02R7, -OC (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13, -NR5R7, and -C0NR6R7; n is independently every time 0, 1 or 2 is presented.

6. A method for treating an affective disorder, 15 anxiety or depression in a mammal, characterized in that it comprises administering to the mammal a therapeutically effective amount of a CRF antagonist compound, in accordance with claim 2.