MXPA98009730A - Tetrahidropteridinas and piridil piperazinas for the treatment of neurologic disorders - Google Patents

Abstract

The present invention relates to antagonists of corticotropin releasing factor (CRF) of Formula (I) and its use in the treatment of anxiety, depression and other psychiatric and neurological disorders.

Description

TETRAHIDROPTERIDINS AND PYRIDYLPIPERAZINES FOR THE TREATMENT OF NEUROLOGICAL DISORDERS FIELD OF THE INVENTION The present invention relates to 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 and supranuclear palsy and eating disorders. BACKGROUND OF THE INVENTION Corticotropin releasing factor (hereinafter referred to as CRF), which is a 41 amino acid peptide, is the primary physiological regulator of propiomelanocortin (POMC) - peptide derived from secretory 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 function in the pituitary gland, the immunohistochemical localization of CRF has shown that the hormone has a wide extrahypothalamic distribution in the central nervous system and produces u? broad spectrum of autonomic, electrophysiological and behavioral effects, consistent with the function of a neurotransmitter or neuromodulator [W. Vale et al. , Rec. Prog. Horm. Res. 39: 245 (1983); G.F. Koob, REF. 28885 Persp. Behav. Med. 2:39 (1985); IN. De Souza et al. , J. Neurosci. 5: 3189 (1985)]. There is also evidence that CRF plays a significant role in the integration of the immune system response against physiological, psychological and immunological stressors [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, anxiety-related disorders, and eating disorders. A function of CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis, since they are related to the dysfunction of CRF neurons in the central nervous system. [for more information see EB De Souza, Hosp. Practice 23:59 (1989)]. In affective disorders or major depression, the concentration of CRF is significantly increased in the cerebrospinal fluid (CSF) in drug-free individuals [C.B. Nemeroff et al. , Science 226: 1342 (1984); C.M. Banki et al. , Am. J. Psychiatry 144: 873 (1987); R.D. France et al. , Biol. Psychiatry 28:86 (1988); M. Arato et al. , Biol. Psychiatry 25: 355 (1989)]. In addition, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, which is consistent with a hypersecretion of CRF [C.B. Nemeroff et al. , Arch. Gen. Psychiatry 45: 577 (1988)]. In addition, there is a clear response of adrenocorticotropin (ACTH) to CRF (administered intravenously) observed in patients with depression [P.W. 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 thus modulate the number of CRF receptors in the brain [Grigoriadis et al. , Neuropsychopharmacology 2:53 (1989)]. A role of CRF in the etiology of anxiety-related disorders has also been postulated. CRF produces anxiogenic effects in animals and interactions between benzodiazepine / non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D.R. Britton et al. , Life Sci. 31: 363 (1982); C.W.

Berridge and A.J. Dunn Regul. Peptides 6:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist, which is an a-helical ovine CRF (9-41) in a variety of behavioral paradigms, demonstrated that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to those of benzodiazepines [C.W. Berridge and A.J. Dunn Horm. Behav. 21: 393 (1987), Brain Research Reviews 15:71 (1900)]. Neurochemical, endocrine and receptor-binding studies have demonstrated interactions between CRF and benzodiazepine anxiolytics, which provide additional evidence of the involvement of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both conflict tests [K.T. Britton et al., Psychopharmacology 86: 170 (1985); K.T. Britton et al. , Psychopharmacology 94: 306 (1988)] as in the acoustic startle test [N.R. Swerdlow et al. , Psychopharmacology 88: 147 (1986) in rats. The benzodiazepine receptor antagonist (Rol5-1788), which had no activity on behavior alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner, whereas the benzodiazepine inverse agonist (FG7142 ) intensified the actions of the CRF [KT Brittos et al. , Psychopharmacology 94: 306 (1988)].

The mechanisms and action sites through which anxiolytics and standard antidepressants produce their therapeutic effects, still remain to be clarified. However, there is a hypothesis that they are involved in the suppression of hypersecretion of CRF that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (a-helical CRF9-41) in a variety of behavioral paradigms have shown that the CRF antagonist produces "anxiolytic-like" effects qualitatively similar to those of the benzodiazepines [For more information see G.F. Koob and K.T. Britton, in: Corticotropin-Releasing Factor: Basic and Clinical? Studies of a Neuropeptide, E.B. De Souza and C.B. Nemeroff eds., CRC Press p221 (1990)]. Several published patent applications describe antagonists of corticotropin releasing factor. Among these is the PCT application US94 / 11050 from DuPont Merck, WO 95/33750 from Pfizer, WO 95/34563 from Pfizer and WO 95/33727 from Pfizer. U.S. Patent No. 5,424,311 describes the antiviral use of azaquinoxalines of the formula: wherein V, W, Y and Z are radicals CH, CR, or N; 2 X can be an oxygen or sulfur atom or an NR radical; R may be an alkenyl, alkoxy, thioalkyl, alkylsulfinyl, alkylsulfonyl or alkylamino radical; R 2, R3, R4 and R can be a hydrogen atom, an alkyl, aryl or heteroaryl radical. U.S. Patent No. 5,283,244 describes glutamate receptor antagonist activity of fused pyrazine derivatives of the Formula: wherein Z represents a C or N atom; R represents a diazo or triazole substituent; and the other R groups represent a hydrogen atom or several substituents such as alkenyl, phenyl or heterocycles.

BRIEF DESCRIPTION OF THE INVENTION The present invention is a method for the treatment of an affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immunosuppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other disorders. of feeding, symptoms caused by the withdrawal of drugs or alcohol, addiction to drugs or inflammatory disorders in a mammal, comprising administering to the mammal a therapeutically effective amount of a CRF antagonist compound of Formula I: .-. or a pharmaceutically acceptable salt or prodrug thereof, wherein: A is an N atom or a C-R 11 radical; X is an atom of H, a radical OR1, SÍOJnR1, NR1! ** 2, CR 1R2R3, phenyl (optionally substituted with 1 to 4 groups which are independently selected from halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 atoms carbon or phenyl) or heteroaryl, (optionally substituted at one or all positions permitted by its valence with groups that are independently selected from halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms , carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon or phenyl atoms); n is 0, 1 or 2; R is an alkyl radical of 1 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl from 2 to 12 carbon atoms, aryl- (alkyl of 1 to 12 carbon atoms), dialkylaminoalkyl of 3 to 12 carbon atoms, cyanoalkyl of 2 to 13 carbon atoms, carboalkoxy of 2 to 5 carbon atoms- (alkyl of 1 to 12 carbon atoms), phenyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms carbon, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl), or heteroaryl (optionally substituted in one at all positions permitted by its valence, with groups which are independently selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl from 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms carbon, dialkylamino of 2 to 8 carbon atoms or feni lo); R3 are independently selected from the group consisting of H atoms, alkyl radicals of 1 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms. carbon, cycloalkylalkyl of 4 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, aryl- (alkyl of 1 to 12 carbon atoms), dialkylaminoalkyl of 3 to 12 carbon atoms , cyanoalkyl of 2 to 13 carbon atoms, carboalkoxy of 1 to 4 carbon atoms, carboalkoxyalkyl of 2 to 12 carbon atoms, C (= 0) CH3, phenyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl), or heteroaryl (optionally substituted in one at all positions permitted by its valence, with groups that are selected independently of the group that with system of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl from 1 to 4 carbon atoms, H2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl); R 4 is an H atom, an alkyl radical of 1 to 12 carbon atoms, allyl, propargyl or benzyl (optionally substituted with 1 to 4 groups independently selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms) carbon, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl); R 1 and R 4 can also optionally be considered together with the other four interconnected atoms, to form a ring of 5 to 9 total atoms, wherein the structural sequence between the group X and the ring nitrogen atom consists of the group (CH 2) pW (CH2) q; p and q are independently 0, 1 6 2; W is a radical CH2, C (CH3) 2. C (= 0), 0, S or NCH3; c R * or R, R, R and R are independently selected from the group consisting of H atoms, radicals alkyl of 1 to 4 carbon atoms, allyl, propargyl, phenyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 1 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl) or benzyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms , carboalkoxy of 1 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon or phenyl atoms; R 4, R 5 and R 6 can also be considered in conjunction with the two interconnected atoms, to construct either an imidazole ring, or a tetrazole ring, wherein the imidazole ring is optionally substituted with 1 to 2 groups that are independently selected from the group consisting of alkyl radicals of 1 to 4 carbon atoms or phenyl; R and R can also be considered together as an O, S atom or a NR 12 radical; R9 is a phenyl radical (optionally substituted with 1 to 4 groups which are selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano) , pyridyl (optionally substituted with 1 to 4 groups which are selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkoxy from 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano), or pyrimidyl (optionally substituted with 1 to 4 groups which are selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano); R, 10"is an atom of H, an alkyl radical of 1 to 4 carbon atoms or cyano, R 11 is an atom of H, an alkyl radical of 1 to 4 carbon atoms or halogen; R 12 is a hydrogen atom; H, an alkyl radical of 1 to 4 carbon atoms or phenyl, aryl is phenyl, biphenyl or naphthyl, and heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl or pyrazolyl The compounds of Formula I differ from those in which R and R are taken together and are O, S or NR 12, are novel. The present invention includes the novel compounds of the Formula. and the compositions pharmaceuticals that contain them. Preferred compounds for use in the method of the present invention are the compounds of Formula (I) wherein: X is a radical OR1, NR ^ 2, CRXR2R3 or phenyl (optionally substituted at the position with CF3, nitro, halogen or cyano; R is an alkenyl radical of 1 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl- (alkyl of 1 to 12 carbon atoms), dialkylaminoalkyl of 3 to 12 carbon atoms or phenyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of halogen, haloalkyl, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl) R is an H atom or an alkyl radical of 1 to 4 carbon atoms; R and R are either an H atom or an alkyl radical of 1 to 4 carbon atoms; R, R and R can also be considered in conjunction with the two interconnected atoms, to constitute a tetrazole ring; R is a phenyl radical (optionally substituted with 1 to 4 groups which are selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano), 3-pyridyl (optionally substituted with 1 to 4 to groups which are selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano) , or 5-pyrimidyl (optionally substituted with 1 to 4 groups which are selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano); R > ? * 1 * or "is a CH3 radical, and R is an H atom. The most preferred compounds of the present invention are those of Formula (I) wherein: A is N; X is N ^ 2 or CR ^ R 3: R is alkyl of 1 to 6 carbon atoms or alkoxyalkyl of 2 to 8 carbon atoms, R 2 and R 3 are independently an H atom, an alkyl radical of 1 to 6 carbon atoms or alkoxyalkyl of 2 to 8 atoms carbon; R is an atom of H; R and R are H atoms; * 7 8 R and R are independently H atoms or radicals CH3; and R is a phenyl radical (optionally substituted with 1 to 4 groups which are selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms carbon, alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano ). The following compounds are specifically preferred due to their biological activity: 8- (2-bromo-4-isopropylphenyl) -4- (ethylbutylamino) -2-methyl-5, 6, 7, 8-tetrahydropteridine; 8- (2-Chloro-4,6-dimethoxyphenyl) -4- (ethylbutylamino) -2-methyl-5,6,7,8-tetrahydropteridine; 4- (ethylbutylamino) -2-methyl-8- (2,4,6-trimethylphenyl) -5,6,7,8-tetrahydropheridine); and 4- (l-methoxy-2-butyl) amino-2-methyl-8- (2,4,6-trimethylphenyl) -5,6,7,8-tetrahydropteridine. DETAILED DESCRIPTION OF THE INVENTION Many compounds of the present invention have one or more centers or asymmetric planes. Unless otherwise indicated, all chiral forms (enantiomeric and diastereomeric) and racemic forms they 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 by resolution of racemic forms or by synthesis from optically active raw materials. All chiral forms (enantiomeric and diastereoisomeric) and racemic forms and all geometric isomeric forms of a structure are included, unless the stereochemistry or specific isomeric form is specifically indicated. The term "alkyl" includes both branched and straight chain alkyl radicals having the specified number of carbon atoms. The term "alkenyl" includes straight chain or branched chain hydrocarbon chains and one or more unsaturated carbon-carbon bonds that may occur at any stable point along the chain, such as ethyl, propenyl groups and the like. The term "alkynyl" includes hydrocarbon chains of straight or branched configuration and having one or more triple carbon-carbon bonds that may occur at any stable point along the chain, such as ethynyl, propynyl groups and the like. The term "haloalkyl" includes straight or branched alkyl chains having the specified number of carbon atoms, substituted with one or more halogen radicals; the term "alkoxy" represents an alkyl group of the indicated number of carbon atoms, linked through an oxygen bridge; the term "cycloalkyl" is intended to include saturated ring groups, including monocyclic, bicyclic or polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and others. The term "halo" or "halogen" includes fluoro, chloro, bromo and iodo radicals. The term "substituted", as used herein, means that one or more hydrogens of the designated atom are replaced by a selection of the indicated group, provided that the normal valence of the designated atom is not exceeded and that the substitution as a result a stable compound. When a substituent is keto (ie, = 0), then 2 hydrogens on the atom are replaced. Substitutant and / or variable combinations are permissible only if such combinations result in stable compounds. The term "compound "stable" or "stable structure" means a compound that is strong enough to withstand its isolation to a useful degree of purity from the reaction mixture and that can be formulated into an effective therapeutic agent. "suitable" means any group known in the art of organic synthesis that serves for the protection of amine and carboxylic acid groups, Such amine protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley &Sons , New York (1991) and "The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1981), the description of which is incorporated herein by reference.Any known amine protecting group can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) of acyl type such as formyl, trifluoroacetyl, phthalyl and p-toluenesulfonyl; of the aromatic carbamate type such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1- (p-biphenyl) -1- ethylethoxycarbonyl and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) of aliphatic carbamate type such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl; 4) type cyclic alkyl carbamate such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) of alkyl type such as triphenylmethyl or benzyl; 6) of the trialkylsilane type such as trimethylsilane; and 7) of the thiol-containing type such as phenylthiocarbonyl and dithiosuccinyl. The term "amino acid" as used herein means an organic compound that contains both a basic amino group and an acid carboxyl group. This term includes natural amino acids, modified and unusual amino acids, as well as amino acids that are known to occur biologically in free or combined form, but which normally do not occur in proteins. Included within this term are the modified and unusual amino acids, such as those described in, for example, Roberts and Vellaccio (1983) The Peptides, 5: 342-429, the teachings of which are incorporated herein by reference. Modified or unusual amino acids that can be used for the practice of the present invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an amino acid protected with N-Cbz, ornithine, 2,4-diaminobutyric acid , homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, β-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N- Methyl-norleucine, 3,4-dehydroproline, N, N-dimethylaminoglycine,. N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4- (aminomethyl) -cyclohexanecarboxylic acid, 2-, 3- and 4- (aminomethyl) -benzoic acid, 1-aminociclopentanecarboxylic acid, acid 1-aminocyclopropanecarboxylic acid and 2-benzyl-5-aminopentanoic acid. The term "amino acid residue" as used herein means that portion of an amino acid (such as defined herein) that is present in a peptide. The term "peptide" as used herein means a compound consisting of two or more amino acids (such as those defined herein) that are linked via a peptide bond. The term "peptide" also includes compounds that contain peptide and non-peptide components, such as pseudopeptide residues or mimetic peptides or other amino acid components. Such compounds that contain both peptide and non-peptide components can also be referred to as "peptide analogs". . The term "peptide bond" means a covalent amide bond formed by the loss of a molecule of water between the carboxyl group of an amino acid and the amino group of a second amino acid. The term "pharmaceutically acceptable salts" includes acid or basic salts of the compounds of Formulas (I) and (II). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; organic alkali salts of acidic residues such as carboxylic acids; and similar. The pharmaceutically acceptable salts of the compounds of the present invention can be prepared by reacting the free acid or basic form of these compounds with a stoichiometric amount of the appropriate acid or base in water or in an organic solvent, or in a mixture of both of them; in general, being a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, 1985, p. 1418, the description of which is incorporated herein by reference. A "prodrug" is considered to be any covalently linked vehicle that releases the active drug of Formula (I) or (II) in vivo when said prodrug is administered to a mammalian subject. The prodrugs of the compounds of the formulas (I) and (II) they are prepared by modifying the functional groups present in the compounds in such a way that the modifications can be broken, either in the routine manipulation, or in vivo, to obtain the progenitor compounds. Prodrugs include compounds wherein hydroxy, amine or sulfhydryl groups are linked to any group that, when administered to a mammalian subject, breaks down to form a free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate 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 the present invention means an amount effective to antagonize abnormal levels of CRF or to treat symptoms of affective disorder, anxiety or depression in a host. Synthesis The synthesis of the compounds of the Formula (I) wherein A = N can be initiated with amidine compounds of the Formula (II) (Scheme I) which are commercially available or are synthesized from the heating of a compound nitrile and an ammonium salt. The compound (II), then, can be condensed with a malonate ester (using conditions such as sodium in ethanol, to obtain a dihydroxypyrimidine compound of the Formula (III). The nitration at position 5 can be carried out through the use of conditions such as concentrated nitric acid with or without the presence of another acid, such as concentrated sulfuric acid or glacial acetic acid. The hydroxy groups of the nitrated compound of the formula (IV), subsequently, can be transformed into leaving groups (Y), which include chloro, bromo, toluenesulfonate or methanesulfonate groups. The dichloro compound (Formula (V), Y = Cl), can be prepared from the dihydroxy compound by a reagent such as phosphorus oxychloride, with or without the assistance of a catalyst such as diethylaniline. The bis (toluenesulfonate) compound (Formula (V), Y = OSO2C6HCH3), can be prepared from the dihydroxy compound by a treatment with a reagent such as toluene sulfonic anhydride. The careful addition of an equivalent of a suitable form of a compound XH to the compound of the formula (V), results in the replacement of one of the groups Y by X. This is of particular utility when the group X represents a nucleophilic atom , such as nitrogen, sulfur or oxygen. Conditions that will facilitate this transformation include the optional presence of bases such as sodium hydride, triethylamine, diisopropylethylamine or potassium carbonate, in solvents such as tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, methylene chloride, acetonitrile or ethanol, at appropriate temperatures.

Alternatively, in the case where X represents a group without a corresponding nucleophilic compound XH available, a compound of Formula (II) can be condensed with an appropriately substituted ketoester (using conditions similar to those for condensation with malonate), to obtain a compound of Formula (VII). Then, nitration conditions similar to those described above can be used to prepare in compound nitro of the Formula (VIII). The transformation of the pyrimidone group into the desired Y group, subsequently, can be carried out using the same conditions as described above for the transformation of the compound of the Formula (IV) into the compound of the Formula (V) A third alternative involves the treatment of the compound of the Formula (V) with a compound R -NH2.

Conditions can be found for each group Y in such a way that one group Y is replaced by a radical R -NH and the other is hydrolyzed to the pyrimidone group (compound of Formula (IX) For example, for Y = Cl, this transformation can be effected by the slow addition of a dimethylsulfoxide solution of an equivalent Q of R-NH 2 to a dimethylsulfoxide solution of the compound of the Formula ( V), followed by aqueous processing The pyrimidone of Formula (IX) can be transformed into a Y-carrier compound (Formula (X)) using the conditions described above for the transformation of the compound of the Formula (IV) into the compound of the Formula (V). Then, the group Y can be replaced by X in a manner analogous to the transformation of the compound of the formula (V) into the compound of the formula (VI), to obtain a compound of the formula (XI).

Alternatively, the compound of Formula (VI) can be transformed into the compound of Formula (XI) 9 by treatment with compound R-NH2. Suitable conditions for this reaction include treatment with an excess of sodium hydride in refluxing toluene or heating the two compounds together in an alcohol solvent (ethanol, propanol, butanol, ethylene glycol, ethoxyethoxyethanol) or another polar aprotic solvent (such as dimethylformamide). , 1,4-dioxane, dimethoxyethane or diglyme) without a base, to effect the coupling. Scheme II shows the binding of the second ring to the pyrimidine ring. The nitro group of the compound of Formula (XI) can be reduced to an amino group using conditions such as sodium dithionite, catalytic hydrogenation, iron or zinc. The compound of Formula (XII) can be treated with a base such as sodium hydride (in solvents such as dimethylformamide, dimethisulfoxide, 1,4-dioxane, tetrahydrofuran, etc.), followed by a reagent of the 7th General Formula Y-CR R -C02R, where Y is a halogen or a pseudohalogen and the structure of R is only important if the removal of the group is desired before cyclization.

The cyclization of the compound of the Formula (XIV) can be carried out by heating in a solvent such as ethanol, dimethylformamide, etc., at temperatures ranging from room temperature to the boiling point of the solvent. An additive such as an acid source (such as toluene sulfonic acid, aqueous hydrochloric acid, etc.), a base (triethylamine, sodium hydroxide, etc.), or a physical catalyst (such as molecular sieves) can be added in amounts which vary from a catalytic amount to an excess, going through a stoichiometric amount. In practice, cyclization of the compound of Formula (XIII) is often very easy, particularly in the case where R is a lower alkyl group, and will occur spontaneously in the alkylation reaction medium of the compound of Formula (XII). The compound of the cyclic Formula (XIV) may be alkylated with the R group by a first treatment with a base such as sodium hydride in a solvent such as dimethylformamide or dimethisulfoxide, and then an alkylating reagent (such as a halogen-bearing compound). or pseudohalogen), which provides the group R 4, to obtain the compound of the Formula (XV). At this point, the compounds derived from the alkylation with bromoacetate of the compound of the Formula (XII), can be alkylated with an appropriate R * 7 and Rfi by a treatment with a strong base such as sodium hydride, lithium diisopropylamide or sodium hexamethyldisilazide and then adding the alkylating agents carrying the R or R groups, thereby obtaining the compound of the Formula (XV). The compound of Formula (XV) is a key intermediate that can be used to generate variations of Formula (I). For example, the carbonyl group of the compound of Formula (XV) can be reduced with reagents such as lithium aluminum hydride, borane (complexed with tetrahydrofuran or other suitable ligand) or diisobutylaluminum hydride, which will generate a compound of the Formula (XVI). The carbonyl group can be substituted with R and R groups using appropriately substituted organolithium or organomagnesium reagents, to prepare compounds of the Formula (XVII). The carbonyl group of the compound of the Formula (XV) can be converted to a thiocarbonyl by treatment with reagents such as Lawesson's Reagent or phosphorus pentasulfide, in appropriate solvents (toluene, benzene, etc.). The thioamide group of the compound of Formula (XVIII) can be transformed into amidine using the method of Robba et al. , (Tetrahedron Letters 1992, 33, 2803-2804), which involves treatment with an amine of the Formula R-H2 and a catalyst such as a mercury (II) salt. This will result in the synthesis of a compound of Formula (XIX). The compounds of Formula (I) formed by a fused pyridine ring (A = CH) can be prepared using a technology very similar to that presented in Scheme II. However, in this case, the raw material is not of the structure of the Formula (XI), but has the structure of the Formula (XXV) (Scheme III).

This compound can be prepared by starting with a lactone compound of Formula (XX), which can be obtained by dimerization of a ketoester of the Formula R 9C (= 0) CH 2 C 2 Et according to the method of Arndt (Syn. Org., Coll. Vol. III, p 231), followed by deacylation according to the method of Collie et al. , (J. Chem. Soc. 1907, 91, page 787 and its references). The oxygen atom of the ring can be replaced by nitrogen by a treatment with concentrated aqueous ammonium hydroxide, according to the method of Wang (J *, Heterocyclic Chem. 1979, 1, 389-392). The compound of Formula (XXI) can be nitrated in a manner similar to the transformation of the compound of Formula (III), to obtain a compound of Formula (XXII). The groups hydroxy of the compound of the formula (XXII) can be transformed into leaving groups Y using the techniques described above for the transformation of the compound of the formula (IV) into a compound of the formula (V). The CY group can be selectively replaced by a nucleophilic group X and the other group Y of the compound of the formula (XXIV) can be replaced by NHR by a treatment with a compound of the formula R NH2, either without solvent, or well, in an appropriate solvent (such as a high-boiling alcohol) at temperatures sufficiently high to effect coupling. The compound of the Formula (XXV), subsequently, can be used in the same general manner as the compound of the Formula (XI), to generate compounds of the Formula (I).

Scheme IV IXXXI) (xxxm) Further functionalization of this class of compounds can be carried out, using a compound of Formula (XXVI) (Scheme IV), which represents some pyridine or some pyridine compound (either uncyclized, such as the compounds of the Formulas (XI) or (XXV), or else, a cyclized compound, bearing a leaving group Y. The group Y can be replaced by phenyl or pyridyl using coupling reactions using a phenyl (or pyridyl) compound of the Formula (XXVII) or Formula (XXIX)) and an appropriate palladium catalyst For example, the acids Arylboronic (Z = B (0H) 2) can be coupled to a heterocyclic halide using catalytic amounts of tetrakis (triphenylphosphine) palladium, which is the method of Suzuki et al. , (Synthetic Communications 1981, 11, p.513-519). Other suitable reagents for this coupling reaction include organomagnesium reagents (Z = MgBr or MgCl) (with nickel (II) chloride as catalyst, according to the method of Sugimori et al., Synthetic Communications 1991, 21, p.481 -487) or organozinc reagents (Z = ZnCl) (in accordance with the method of Negishi et al., J. Org. Chem. 1977, 42, pp. 1821-1823). Other carbon substituents may be introduced into the compound of Formula (XXVI) by treatment with a sodium salt (generated by the use of a base such as sodium ethoxide or sodium hydride) of an active methylene or methine reagent (by example, wherein B and D are groups that stabilize adjacent anions, such as keto, carboalkoxy, cyano, alkyl or alkylsulfonyl, etc.). The resulting compounds of Formula (XXXI) can be further modified by transformation of groups B and D into groups R2 and R3. Technicians in the field of organic synthesis will readily understand the possible variations of these transformations to prepare a number of different substituents of groups R1, R2 and R3.

The preparation of the compounds of the Formula (I) wherein the groups R 1 and R 4 are taken together to form a ring, can be carried out starting from a compound of the Formula (XXXIII) (Scheme V), where X 'designates a group NHR 2 , OH, SH or CHR2R3. This compound can be treated with a base (such as sodium hydride) in an appropriate solvent, followed by a reagent carrying reactive terminals at both ends (for example, a dihalo alkan, a haloester, etc.). The X 'and amide NH groups will be coupled with such reagents under these conditions, to form the third ring of the compound of the Formula (XXXIV). The amide group can subsequently be modified in the manner described above to obtain the final product of Formula (XXXV). The compounds of Formula (I) wherein R 4, R 5 and R are considered together to form a heteroaromatic ring, can be prepared using the strategy shown in Scheme VI.

Scheme V (XXXffl) (XXXIV) (XXXV) The compound of the Formula (XIV) can be transformed into an amidine of the Formula (XXXVI) using the conditions described above for the preparation of the compound of the Formula (XIX). Amidine is treated with an α-halo- or α-hydroxyketone, under conditions such as refluxing alcohol, to obtain the imidazole compound of Formula (XXXVII). The compound of Formula (XIV) can be transformed into a fused tetrazole compound of Formula (XXXVIII) using the conditions of Duncia et al. , (J. Org. Chem. 1991, 56, P. 2395).

Scheme VI (xxxvm) The experimental methods listed below for Examples 1, 17, 24, 42, 131, 143, 155 and 248 can be used in the preparation of all the compounds shown in Tables I (pyrimidines) and II (pyridines). Example 1 Preparation of 8- (2-bromo-4-isopropylphenyl) -4- (ethylbutylamino) -2-methyl-5,6,7,8-tetrahydropteridin-6-one Part A. A solution of 4, 6 dichloro-2-methyl-5-nitropyrimidine (prepared using the methods of Albert et al., J. Chem. Soc. 1954, p.3832) (2.77 g, 13.3 mmol) in absolute ethanol (25 ml) was cooled to 0 ° C and treated with triethylamine (2.00 ml, 14.3 mmol). Then, a solution of ethylbutylamine (1.80 ml, 13.2 mmol) in ethanol (3 ml) was added dropwise and with stirring. The mixture left under stirring and warmed to room temperature overnight, then extracted by partition in water and ethyl acetate (100 ml each). The organic phase was separated, washed with an aqueous solution of saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, dichloromethane), to obtain 4-chloro-6- (ethylbutylamino) -2-methyl-5-nitropyrimidine as an oil (3.34 g, 12.2 mmol, 92%). . Spectral data CCF RF 0.59 (dichloromethane). ""? NMR (300 MHz, CDC13): d 3.45 (2H, q, J = 7.0 Hz), 3.38 (2H, t, J = 7.7 Hz), 2.50 (3H, s), 1.62-1.52 (2H, m), 1.38-1.26 (2H,), 1.20 (3H, t, J = 7.0 Hz), 0.94 (3H , t, J = 7.3 Hz). MS (NH 3 -Cl): m / e 276 (4), 275 (40), 274 (16), 273 (100). Part B. The product from Part A above (2.97 g, 10.9 mmol) was dissolved in ethoxyethoxyethanol solution (11 ml) and treated with 2-bromo-4-isopropylaniline (2.34 g, 10.9 mmol). The mixture was heated at 120 ° C for 4 hours and then cooled and partitioned in water and ethyl acetate (100 ml each). The organic phase was separated and washed with two additional portions of water (100 ml each) and brine. (100 ml). The aqueous phases were re-extracted in sequence with more ethyl acetate (100 ml). The The extracts were combined and the combined was dried over sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, 5:95 ethyl acetate-hexane) to obtain 6- (2-bromo-4-isopropylphenylamino) -4- (ethylbutylamino) -2-methyl-5-nitropyrimidine in form of an oil (3.05 g, 6.77 mmol, 62%). Spectral data CCF RF 0.56 (ethyl acetate-hexane 20:80). 1 H NMR (300 MHz, CDC13): d 10.30 (1H, br s), 8.32 (1H, d, J = 8.4 Hz), 7.45 (1H, d J = 1.8 Hz), 7.19 (1H, dd, J = 8.4 , 1.8 Hz), 3.52-3.42 (4H, m), 2.88 (1H, heptet, J = 7.0 Hz), 2.40 (3H, s), 1.70-1.58 (2H, m), 1.39-1.29 (2H, m, 1.26 (3H, t, obscured), 1.25 (6H, d, J = 7.0 Hz), 0.94 (3H, t, J = 7.1 Hz) MS (NH3 -Cl): m / e 453 (24), 452 (100), 45 (26), 450 (99). The product from Part B above (26 mg, 568 μmol) was dissolved in 1: 1 dioxane-water (3 ml) and treated with concentrated aqueous ammonium hydroxide (0.5 ml). stirring, solid sodium dithionite (440 mg, 2.53 μmol) in 3 portions over a period of 1 hour The resulting solution was allowed to stir for an additional 8 hours, then extracted by partition in water and ethyl acetate (100 ml) The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. purified by elution through a short plug of silica gel (ethyl acetate-hexane 20:80), and after evaporation was obtained 5-amino-6- (2-bromo-4-isopropylphenylamino) -4- (ethylbutylamino ) -2-pure methylpyrimidine in the form of an oil (198 mg, 472 μmol, 83%). Spectral data: CCF R? 0.26 (ethyl acetate-hexane :90). ^? NMR (300 MHz, CDC13): d 8.15 (1H, d, J = 8.4 Hz), 7.38 (2H, d, J = 2.2 Hz), 7.15 (1H, dd, J = 8.4, 2.2 Hz), 7.04 (1H, br s), 3.30-3.19 (4H, m), 3.08 (2H, br s), 2.85 (1H, heptet, J ** = 7.0 Hz), 2.47 (3H, s), 1.57-1.44 (2H, m), 1.39-1.26 (2H,), 1.23 (6H, d, J ** = 7.0 Hz ), 1.11 (3H, t, J = 7.0 Hz), 0.91 (3H, t, J = 7.1 Hz). MS (NH3-CI): m / e 424 (3), 422 (100, 421 (26), 420 (100), Part D. A dispersion of sodium hydride in mineral oil (0.26 gp / p, 5.42 mmol) it was washed with hexane and the hexane was removed by decanting The remaining solid was dried under vacuum and suspended in anhydrous dimethylformamide (5 ml) The resulting suspension was cooled in an ice bath while the product from Part C above ( 1.78 g, 4.23 mmol) in dimethylformamide solution (5 ml) was added slowly with a syringe After the evolution of hydrogen was complete, the mixture was slowly treated with ethyl bromoacetate (0.47 ml, 4.24 mmol) with a syringe and mix it was left stirring for 10 hours. It was extracted by partition in water and ethyl acetate (100 ml each) and the organic phase was washed with two additional portions of water (100 ml each) and with brine (100 ml). The aqueous phases were extracted again in sequence with ethyl acetate (100 ml) and the extracts were combined and the combined was dried over sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, 10:90 ethyl acetate-hexane) to obtain the title product as a solid (1.35 g, 2.93 mmol, 69%). Spectral data: p.f. 146-147 ° C. CCF RF 0.49 (ethyl acetate-hexane 50:50) LH NMR (300 MHz, CDCl3): d 7.53 (1H, s), 7.36 (1H, br s), 7.25 (2H, s), 4.44 (1H, d, J = 15 Hz), 4.25 (1H, d, J = 15 Hz), 3.29-3.15 (4H,), 2.94 (1H, heptet, J = 7.0 Hz), 2.29 (3H, s), 1.54-1.45 (2H, m), 1.39-1.29 (2H, m), 1.28 (6H, d, J = 7.0 Hz), 1.11 (3H, t, J = 7.1 Hz), 0.92 (3H, t, J = 7.1 Hz). MS (NH3-CI): m / e 464 (3), 463 (24), 462 (100), 461 (26), 460 (99). Analysis calculated for C22H30BrN5O: C, 57.39; H, 6.58; N, 15.21; Found: C, 56.74; H, 6.02; N, 14.41. Examples 143 and 155 Preparation of 8- (2-bromo-4-isopropylphenyl) -2,5-dimethyl-4- (ethylbutylamino) -5,6,7,8-tetrahydropheridin-6-one and 8- (2- bro? no-4-isopropylphenyl) -4- (ethylbutylamino) -2,5,7-trimethyl- , 6, 7, 8-tetrahydropteridin-6-one Part A. A suspension of sodium hydride in mineral oil (200 mg of 50% w / w, 4.17 mol) was washed with hexane, dried under vacuum and suspended in anhydrous dimethylformamide (5 ml). This suspension was cooled to 0 ° C while a solution of the compound of Example 1 (1.58 g, 3.43 mmol) in dimethylformamide (5 ml) is added slowly with a syringe. The resulting mixture was allowed to stir for 1 hour and then treated with methyl iodide (0.30 ml, 4.82 mmol) with a syringe. The mixture was allowed to stir overnight and then extracted by partition in water and ethyl acetate (100 ml each). The organic phase was washed with two additional portions of water and one of brine. The aqueous fractions were re-extracted in sequence with more ethyl acetate and the organic phases were combinedThe combined was dried over sodium sulfate, filtered and evaporated. The residual oil was separated by column chromatography (silica gel, 10:90 ethyl acetate-hexane) to obtain two fractions. The first compound leaving the column was the title compound of Example 155 (150 mg, 0.31 mmol, 9%): CCF RF 0. 29 (ethyl acetate-hexane 20:80). "" "H NMR (300 MHz, CDC13): d 7.50 (1H, d, J = 1.8 Hz), 7.33 (1H, d, J = 8.0 Hz), 7.21 (1H, dd, J = 8.0, 1.8 Hz), 4.23 (1H, q, J = 7.3 Hz), 3.22 (3H, s), 3.19 (4H, br), 2.92 (1 H, heptet, J = 7.0 Hz), 2.30 (3H, s), 1.55 (2H, br), 1.43-1.00 (8H, br), 1.27 (6H # d, J = 7.0 Hz), 0.91 (3H, br, t, J = 7 Hz). MS (NH3-CI): m / e 492 (3), 491 (28), 490 (96), 489 (30), 488 (100). The second compound leaving the column was the title compound of Example 143 (1.30 g, 2.74 mmol, 80%): TLC RF 0.22 (ethyl acetate-hexane 20:80).

X H NMR (300 MHz, CDCl 3): d 7.48 (1H, s), 7.21 (2H, s), 4. 19 (2H, br), 3.21 (3H, s), 3.18 (4H, v br), 2.91 (1H, heptet, J = 6.6 Hz), 2.30 (3H, s), 1.55-1.46 (2H, m ), 1. 35-1.25 (2H, m), 1.27 (6H, d, J = 6.6 Hz), 1.11 (3H, br, J = 7.0 Hz), 0.90 (3H, t, J = 7.0 Hz). MS (H3-CI): m / e 478 83), 477 (28), 476 (98), 475 (30), 474 (100). Example 24 Preparation of - (2-bromo-4-isopropylphenyl) -4- (ethylbutylamino) -2-methyl-5, 6, 7, 8-tetrahydropteridine A solution of the compound of Example 1 (650 mg, 1.41 mmol) in tetrahydrofuran Anhydrous (5 ml) was treated with a solution of borane in tetrahydrofuran (3 ml, 1 M, 3 mmol). The resulting solution was allowed to stir for 20 hours and then slowly emptied into an aqueous solution of 1 N sodium bicarbonate (10 ml) under stirring. The mixture was stirred until gas evolution was complete and then extracted with dichloromethane (twice, 30 ml). The organic extracts they were combined and the combined was dried over sodium sulfate, filtered and evaporated. The residual material was purified by elution through a short plug of silica gel (30:70 ethyl acetate-hexane) and after evaporation the pure title compound was obtained as an oil (429 mg, 1.04 mmol, 74%). Spectral data: CCF RF 0.50 (ethyl acetate-hexane 30:70). E NMR (300 MHz, CDC13): d 7.50 (1H, d, J = 1.8 Hz), 7.24 (1H, d, J = 8. 4 Hz), 7.18 (1H, dd, J = 8.4, 1.8 Hz), 3.88-3.39 (5H, br m), 3.22-3.09 (4H, m), 2.91 (1H, heptet, J = 7.0 Hz), 2.25 (3H, s), 1.52-1.41 (2H, m), 1.38-1.24 (2H, m), 1.27 (6H, d, J == 7.0 Hz), 1.08 (3H, t, J = 7.1 Hz), 0.91 (3H, t, J = 7.0 Hz). MS (ESI): m / e 450 (3), 449 (23), 448 (98), 447 (25), 446 (100). A solid derivative obtained by precipitation of the hydrochloride salt of the ether, melting point 79-81 ° C, was obtained. Example 17 Preparation of 8- (2-bromo-4-isopropylphenyl) -2-methyl-4- (2-trifluoromethylphenyl) -5,6,7,8-tetrahydropteridin-6-one Part A. A solution of 2- trifluoromethylphenylboronic acid (prepared according to the methods described in the review of N. My aura and A. Suzuki, Chem. Rev. 1995, 95, p 2457) (1.00 g, 5.27 mmol), 4,6-dichloro-2- methyl-5-nitropyrimidine (0.91 g, 4.39 mmol) and tetrakis (triphenylphosphine) palladium (147 mg) in benzene (15 ml) was treated with an aqueous sodium carbonate solution (6 ml, 1 M). This mixture was refluxed for 6 hours and then cooled and partitioned off in water and ethyl acetate (60 ml each). The organic phase was washed with brine and the aqueous phases were re-extracted in sequence with more ethyl acetate. The organic extracts were combined and the combined was dried over sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, ethyl acetate-hexane 15:85), to obtain 4-chloro-2-methyl-5-nitro-6- (2-trifluoromethylphenyl) pyrimidine (0.64 g, 2.01 mmol, 38%) in the form of a waxy solid. Spectral data: RF 0.40 (ethyl acetate-hexane 20:80). 1 H NMR (300 MHz, CDC13): d 7.84-781 (lH n) m 7.69.7.63 (2H, m), 7.38-7.35 (1H,), 2.84-7.81 (1H, m), 7.69.7.63 (2H, m), 7.38-7.35 (1H, m), 2.84 (3H, s). MS (NH3-CI): m / e 320 (24), 319 (26), 318 (100). Part B. A solution of the compound prepared in Part A above (1.07 g, 3.37 mmol), and 2-bromo-4-isopropylaniline (0.87 g, 4.04 mmol) in tetrahydrofuran. (20 ml), refluxed for 5 hours and then cooled and evacuated in 100 ml of ethyl acetate. This mixture was washed with an aqueous solution of sodium bicarbonate (100 ml, 1 N) and with brine, and then dried on sodium sulfate, filtered and evaporated. The resulting solid was triturated with petroleum ether-diethyl ether 1: 1, filtered and dried under vacuum to obtain 4- (2-bromo-4-isopropylphenylamino) -2-methyl-5-nitro-6- (2 -trifluoromethylphenyl) -pyrimidine pure (1.51 g, 3.05 mmol, 90%). Spectral data: p.f. 152-154 ° C. RF 0.37 (20:80 ethyl acetate-hexane). XH NMR (300 MHz, CDC13): d 10.20 (1H, br s), 8.2 (1H, d, J = 8.4 Hz), 7.78 (1H, d, J = 7.7 Hz), 7.65-7.57 (2H,), 7.52 (1H, d J = 1.8 Hz), 7.35 (1H, d, J = 7.0 Hz), 7.28 (1H, br s), 2.93 (1H, m), 2.66 (3H, s), 1.29 (6H, d , J = 7.0 Hz). MS (NH3-CI): m / e 498 (24, 497 (100), 496 (28), 495 (100), Part C. In this part, the same procedure used for the reduction of a nitro group in the Example 1, Part C. Thus, the compound from Part B above was transformed into 5-amino-4- (2-bromo-4-isopropylphenylamino) -2-methyl-6- (2-trifluoromethylphenyl) -pyrimidine, with 32% efficiency RF spectral data 0.11 (20:80 ethyl acetate-hexane) 1 H NMR (300 MHz, CDCl 3): d 8.58 (1H, d, J = 8.4 Hz), 7.83 (1H, d, J = 7.7 Hz), 7.67-7.58 (3H, m), 7.43 (1H, d, J = 1.8 Hz), 7.41 (1H, s), 7.25 (1H, dd, J = 8.4, 1.8 Hz), 2.89 (1H, m), 2. 83 (2H, br s), 2.59 (3H, s), 1.26 (6H, d, J = 7.0 Hz). S (NH3-CI): m / e 468 (24), 467 (100), 466 (30), 465 (99).

Part D. In this part the same procedure used for the cyclisation reaction of Example 1, Part D was used. Thus, the compound of Part C above was transformed into the title compound, in a yield of 60%. Spectral data: p.f. 238-239 ° C. RF 0.20 (ethyl acetate-hexane 50:50). 1 H NMR (300 MHz, CDC13): d 7.85 (1H, d, J = 8.4 Hz), 7.73-7.59 (3H, m), 7. 48-741 (1H, m), 7.33 (1H, s), 7.30 (1H, s), 7.00 (1H, br s), 4.46 (1H, d, J = 16.8 Hz), 4.42 (1H, d, J = 16.8 Hz), 2.97 (1H,), 2.40 (3H, s), 1.31 (6H, d, J = 6.6 Hz). MS (NH3-CI): m / e 508 (26), 507 (100), 506 (30), 505 (99). Example 42 Preparation of 2- [8- (2-bromo-4-isopropylphenyl) -2-methyl-6-oxo-5,6,7,8-tetrahydropteridin-4-yl] -diethylmalonate A suspension of hydride Sodium in mineral oil was washed with hexane and dried in vacuo, then taken up in tetrahydrofuran. This mixture was cooled to 0 ° C and treated with diethyl malonate (1.1 eq.). After hydrogen evolution of gaseous hydrogen was completed, the resulting solution was treated with 8- (2-bromo-4-isopropylphenyl) -4-chloro-2-methyl-5, 6, 7, 8-tetrahydropteridin-6- ona (see Example SF445, Part A, below, 1.0 eq.). The solution was heated to reflux until thin-layer chromatography showed that the consumption of the raw materials was almost complete. The The mixture was allowed to cool and was poured into an aqueous ammonium chloride solution. This mixture was extracted twice with ethyl acetate and the extracts were washed with brine, combined and the combined was dried over sodium sulfate, filtered and evaporated. The residue was separated by column chromatography to obtain the title compound. Example 131 Preparation of 8- (2-bromo-4-isopropylphenyl) -4- (ethylbutylamino) -2-methyl-5, 6, 7, 8-tetrahydropteridin-6-thione A solution of the compound of Example 1 (323 mg, 0. 70 mmol) in toluene (10 ml) was treated with the Reagent from Lawesson (170 mg, 0.42 mmol). The resulting mixture was refluxed for 6 hours and then cooled and evaporated. The residue was separated by column chromatography (silica gel, 10:90 ethyl acetate-hexane), to obtain the title product, which was purified by recrystallization from ethyl acetate-hexane (280 mg, 0.59 mmol, 84%). %). Spectral data: p.f. 148-149 ° C (ether-hexane). CCF RF 0.31 (ethyl acetate-hexane :80). **? NMR (300 MHz, CDC13): d 9.01 (1H, br s), 7.51 (1H, s), 7.22 (2H, s), 4.77 (1H, br d, J = 15.7 Hz), 4.56 (1H, br d, J = 15.7 Hz), 3.40-3.22 (4H, m), 2.92 (1H, heptet, J = 7.0 Hz), 2.29 (3H, s), 1.62-1.52 (2H,), 1. 40-1.30 (2H, m), 1.28 (6H, d, J = 7.0 Hz), 1.18 (3H, t, J = 7.0 Hz), 0.95 (3H, t, J = 7.3 Hz). MS (NH3-CI): m / e 479 (26), 478 (100), 477 (30), 476 (95). Analysis calculated for C22H3oBrN5S: C, 55.46; H, 6.36; N, 14.70; found: C, 55.54; H, 6.38; N, 14.37. Example 248 Preparation of 8- (2-bromo-4-isopropylphenyl) -4- (ethylbutylamino) -2-methyl-5,6,7,8-tetrahydropteridin-6-imine Here the method of Robba et al. , Tetrahedron Letters 1992, 33, p. 2803-2804. Thus, a solution of the compound of Example 131 in tetrahydrofuran (0.5 M) was heated to 55 ° C and treated with 1.5 equivalents of mercuric chloride. Gaseous ammonia was then bubbled and addition was continued until 5 minutes after the appearance of a mercuric sulfide precipitate.

The reaction mixture was allowed to stir for an additional hour, then cooled, filtered through celite and evaporated. The residue was triturated with a small amount of water, filtered and dried to obtain the title compound. Modifications of the procedures of Examples 501, 698 and 704 presented below can be used to prepare many of the compounds listed in Table III.

Example 501 Preparation of 10- [2-bromo-4- (1-methylethyl) -phenyl] -4-butyl-9,10-dihydro-2-methyl-4i ?, 8H-pyrazino [3,2, 1-des ] -pteridin-5,8 (6H) -dione Part A. Sodium hydride (dispersion in mineral oil, 48 mg, 1.00 mmol) was washed with hexane, dried in vacuo and taken up in dimethylformamide (5 ml). To this mixture was added, with stirring, a solution of 5-amino-4- (2-bromo-4-isopropylphenylamino) -6-chloro-2-methylpyrimidine (311 mg, 0.87 mmol) in dimethylformamide (5 ml). After stirring for 30 minutes, the mixture was treated with ethyl bromoacetate (0.10 ml, 0.90 mmol) in one portion. The mixture was allowed to stir for 18 hours, then it was poured into water (100 ml). This mixture was extracted twice with ethyl acetate (100 ml each) and the organic extracts were washed in sequence with two portions of water (100 ml each) and brine (100 ml) and then combined, the combined was dried on sodium sulfate, filtered and evaporated. The residual material was separated by column chromatography (silica gel, 20:80 ethyl acetate-hexane) to obtain two fractions, the first being (8- (2-bromo-4-isopropylphenyl) -4-chloro-2- methyl-6-oxo-5,6,7,8-tetrahydropteridin-5-yl) ethyl acetate (89 mg, 0.18 mmol, 21%) and the second being 8- (2-bromo-4-) isopropylphenyl) -4-chloro-2-methyl-5,6,7,8-tetrahydropteridin-6-one (89 mg, 0.22 mmol, 26%). Spectral data for the first fraction: CCF RF 0.25 (ethyl acetate-hexane 30:70). X NMR (300 MHz, CDC13): d 7.53 (1H, d, J = 1.8 Hz), 7.26 (1H, dd, J = 8.4, 1.8 Hz), 7. 22 (1H, d, J = 8.4 Hz), 4.88 (1H, d, J = 15 Hz), 4.84 (1H, d, J = 15 Hz), 4.47 (1H, d, J = 15.4 Hz), 4.27 (1H, d, J = 15.4 Hz), 4.25 (2H, q, J = 7.3 Hz), 2.95 (1H , heptet, J = 7.0 Hz), 2.38 (3H, s), 1.29 (3H, t, J = 7.3 Hz), 1.28 (6H, d, J = 7.0 Hz). MS (NH3-CI): m / e 486 (6), 485 (26), 484 (23), 483 (100), 482 (18), 481 (76). Part B. A solution of the first fraction from Part A above (89 mg, 0.18 mmol) in butylamine (1.0 mL, 10.1 mmol) was treated with glacial acetic acid (0.11 mL, 0.19 mmol) and the resulting solution was heated to reflux for 20 hours. The mixture was cooled and evaporated and the residue was separated by column chromatography (silica gel, ethyl acetate-hexane 15:85), to obtain the title compound as a solid (50 mg, 0.10 mmol, 57 %). Spectral data: p.f. 207- 208 ° C. CCF RF 0.29 (ethyl acetate-hexane 30:70)? NMR (300 MHz, CDCl 3): d 7.54 (1 H, d, J = 1.8 Hz), 7.27 (1 H, dd, J = 8.4, 1.8 Hz), 7.23 (1 H, d, J 8.4 Hz), 4.66 (1 H, d, J = 18.6 Hz), 4.55 (2H, br d, J = 17 Hz), 4.32 (1H, d, J = 16.5 Hz), 4.12 (2H, t, J = 7.5 Hz), 2.95 (1H, heptet, J = 7.0 Hz), 2.33 (3H, s), 1.70-1.59 (2H, m) , 1.45-1.35 (2H, m), 1.29 (6H, d, J = 7.0 Hz), 0.96 (3H, t, J = 7.1 Hz). MS (NH3-CI): / e 476 (4), 475 (25), 474 (100), 473 (27), 472 (99). Analysis calculated for 22H26BEN5O2: c '55.94; H, 5.56; N, 14.83; found: C, 54.13; H, 5.34; N, 13.98. Example 698 Preparation of 4- [2-bromo-4- (1-methylethyl) -phenyl-5, 6, 9, 10-tetrahydro-2-methyl-6-oxo-4.H, 8i? -pyrido [3, Diethyl 2, 1-de] -pteridin-10,10-dicarboxylate A dispersion of sodium hydride was washed to remove the oil with hexane and dried under vacuum. Dimethylformamide was added and the mixture was cooled to 0 ° C. A solution of the compound of Example 42 (0.45 eq. Based on sodium hydride) in dimethylformamide was added and the mixture was stirred for one hour. Then, a solution of 1,2-dibromoethane (1.0 eq. Based on the substrate) in dimethylformamide was added slowly and dropwise. The mixture was left stirring overnight and then poured into water. The resulting mixture was extracted twice with ethyl acetate and the extracts were washed twice more with water in sequence, then brine, then combined and the combined was washed over sodium sulfate, filtered and evaporated. The residue was separated by column chromatography to obtain the title compound. Example 704 Preparation of 4- [2-bromo-4- (1-methylethyl) -phenyl] -5, 6, 9, 10-tetrahydro-10, 10-bis (methoxymethyl) -2-methyl-4if / 8H-pyrido [3, 2, 1-es] pteridine Part A. A solution of the compound of Example 698 in methylene chloride was cooled to 0 ° C and a solution of diisobutylaluminum hydride (7 eq.) In chloride was added slowly with a syringe. of methylene. The mixture was allowed to stir and was allowed to reach room temperature until the substrate was consumed, then the reaction mixture was slowly distributed in a 1 N HCl solution, under stirring, in an ice bath. Subsequently, the mixture was neutralized to pH 7 with solid sodium bicarbonate and extracted twice with methylene chloride. The extracts were combined and the combined was dried over sodium sulfate, filtered and evaporated. The residue was separated by column chromatography to obtain 4- [2-bromo-4- (1-methylethyl) -phenyl] -5,6,9,1-tetrahydro-10, 10-bis (hydroxymethyl) -2-methyl -4H, 8H-pyrido [3,2, 1-de] pteridine. Part B. A dispersion of sodium hydride was washed to remove the oil with hexane and dried under vacuum. Dimethylformamide was added and the suspension was cooled to 0 ° C and a solution of the above Part A compound in dimethylformamide was slowly added. After stirring for 1 hour, the mixture was treated with eq. of methyl iodide. The mixture was allowed to stir for at least 6 hours and then emptied into water. This mixture was extracted twice with ethyl acetate and the extracts were washed sequentially twice with water and once with brine, then combined and the combined was dried over sodium sulfate, filtered and evaporated. Subsequently, chromatography was used to isolate the title product. Modifications of the procedures of Examples 719 and 759 presented below can be used to prepare many of the compounds listed in Table IV. Example 719 Preparation of 5- [2-bromo-4- (1-methylethyl) -phenyl] -N-butyl-N-ethyl-4,5-dihydro-7-methyltetrazolo [1,5-f] -pteridin-9 - a ina A solution of the compound of Example 1 (358 mg, 0. 78 mmol) in tetrahydrofuran (10 ml) was treated with trimethylsilylazide (0.21 ml, 1.58 mmol), diethyl azodicarboxylate (0.25 ml, 1.59 mmol) and triphenylphosphine (408 mg, 1.56 mmol). The resulting solution was stirred for 20 hours and then evaporated. The residual material is separated by column chromatography (silica gel, 20:80 ethyl acetate-hexane) to obtain the title product as a low melting solid. (147 mg, 0.30 mmol, 39%). Spectral data: CCF RF 0.37 (30:70 ethyl acetate-hexane)? t H NMR (300 MHz, CDC13) d 7.52 (1H, d J = 1.8 Hz), 7.26 (1H, dd, J = 8.0, 1.8 Hz), 7.21 (1H, d, J = 8.0 Hz), 5.23 (1H, d, J = 15.0 Hz), 4.98 (1H, d, J = 15.0 Hz), 3.56-3.48 (4H, m), 2.94 (1H, heptet, J = 7.0 Hz), 2.28 (3H, s), 1.69-1.59 (2H,), 1.35-1.25 (2H, m), 1.29 (6H, d, J = 7.0 Hz), 1.21 (3H, t, J = 7.1 Hz) , 0.90 (3H, t, J = 7.3 Hz). MS (NH3-CI): m / e 488 (17), 487 (64), 486 (18), 485 (63), 459 (100), 457 (97). Example 759 Preparation of 5- [2-bromo-4- (1-methylethyl) -phenyl] -N-butyl-N-ethyl-5,6-dihydro-3-methylimidazo (1,2-f) -pteridin-1 -amine A solution of the compound of Example 248 and a slight excess of diethylacetal of bromoacetaldehyde in ethanol was heated to reflux until the raw material was consumed. The reaction mixture was evaporated and the residual material was purified by chromatography or by recrystallization, to obtain the title product.

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? Ui Kl • - vO - sv ui r ?? m. o to as o o O X X X z z z z z z z z z z z o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o Z 2 2 2 z z z z z z z z z 2 Z s x x a O cp ß > = - m n Xo Xo X or ox X or X O X oX G6 cs 03 00 03? 03 03 os os ao 03 ro 09 cs oo 00 00 03 03 03 00 03 -J -4 ov OV OV OV sv sv sv sv sv st Ul l ui Ul Ul ui l Ul u > Ul * O to 03 -4 sv Ul * »Ul NI o tO ao -j st l o Ul KJ O o o o o o o o o o o o o o o o o o o o o o o X X S X X X X X X X X X X X X or x x x X z z Z 2 Z 2 Z 2 Z 2 2 Z Z Z Z Z Z Z Z Z Z 2 Z 2 Z 2 Z 2 Z 2 Z 2 Z Z 2 2 2 2 2 2 Z 2 2 2 2 2 X X X X X X X > c. O Pl c PJ i- o o o o o o o o o o X X X n 2 2 2 2 2 2 2 2 2 2 2 o o X X ? Q 03 03 03 03 03 OD 03 03 03 03 03 03 00 00 03 03 09 03 09 03 09 09 09 09 03 00 to O to to VO tO O VO OS 03 03 03 03 03 03 09 03 00 -4 -J -J -4 -4 -4 -J -J -4 sv Ul o i Kl r * O to 09 -4 sv Ul «» w NI O to 00 -J sv Ul tm w NI o o o o o o o o o o o o o o o o o o o o X X X X s X X X X X s or X X X or o or X X X or x o or x x o o o o 2 o o X X or o o o 2 - 2 Z 2 2 2 Z 2 2 Z Z Z Z 2 2 2 Z X X X X X X X X o o o o o o o o o o o o s X X X s X X o o X o o o o o o s X X X x x x x x o o o X o = X x x x x X X Ü? ? or ? ? ? ? or ? or ?* ? ? or ? ? "?? D u? ? or 2 Z 2 2 2 2 «-. - ._. * - 2 2 2 2 2 2 2 2 2 2 2 2 2 = = = = = = = = = = = = x = s x = x x x x x x x x x? u u * _ U t,? ? u t U u u * _ u? ? u u u u u u u u u u or = = = = = = = = x x x x x x x x x u u u u or u u u? u u? ? ? or ? ? ? or ? ? ? ? ? u u? ? ? or ? s s s x X X x s s? ? U u? u u? x s x? ? ? ? ? ? ? MF u ot x x s x x x x u? ? ? ? ? ? ? O Ü O? ü u ü? Or s? ? ? ? ? ? ? ? or? u or you 5 X S X S X S X X X x s 2 Z ZZZ. -Z z X X X -Z X X zz? ? ? ? O y \ r? ? ? ? ? ? Ü ü u? or ? ^ u? u u? v O U rJ u r,? ? ? ? u u? or ? ? ? ? ? X X 3; X ™ s X X ¡? X ?? ? ? ? ? s S X s u? ? ü ü u? ? ? or ? ? ? u u u u? ? ? ? ? J? or ? ? ? ? or ? or ? ? or ? ? ? ? ? u u? X x x x x x X X X X X X? or ? ? ? u u u u u u? ? or vo r ~ o - t vo rco st O mA GM vo i- ov O r f m m st st st st o st st o st ov sv st ov st ov st 86 UTILITY CRF-1 Receptor Binding Assay for the Evaluation of Biological Activity The following is a description of the isolation of cell membranes containing cloned human CRF-R1 receptors for use in the standard binding assay, as well as a description of the trial itself. Messenger RNA was isolated from human hippocampi. The mRNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by polymerase chain reaction (PCR) from the start codons to the stop codons. The resulting PCR fragment was cloned into an EcoRV site of the pGEMV gene, from which the insert was recovered using Xhol + Hbal enzymes and cloned into the Xhol + Hbal sites of the p? T? 3ar vector (which contains a CMV promoter, splicing SV40? t 'and early poly A signals, or origin of viral replication of the Epstein-Barr virus and a selectable marker of hygromycin). The resulting expression vector, called phchCRFR was transfected into 293EBNA cells and the cells that retained the episome in the presence of 400 μM hygromycin were selected. The cells that survived 4 weeks of hygromycin selection were mixed in a pool, adapted to grow in suspension and used to generate membranes for the binding assay described below. Then, Q aliquots containing about 1 x 10 suspended cells were centrifuged to form a pellet and frozen. For the binding assay, a frozen pellet of the above described containing 293EBNA cells transfected with hCRFR1 receptors, was homogenized in 10 ml of ice-cold tissue regulatory solution (50 mM HEPES regulatory buffer pH 7.0, containing MgCl2 M, 2 mM EGTA, 1 μg / 1 aprotinin, 1 μg / ml leupeptin and 1 μg / ml of pepstatin). The homogenate was centrifuged at 40,000 x g for 12 minutes and the resulting pellet was homogenized in 10 ml of tissue regulating solution. After another 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 are performed in 96-well plates; each having 300 μl of capacity. To each well 50 μl of the dilutions of the test drug are added (the final concentration of the drug varies from 10 -10 1015 M) 100 μl of 125I-CRF ovine (125I-o-CRF) (the final concentration is 150 pM) and 150 μl of the cell homogenate described above. After, the plates are left in incubation at room temperature for 2 hours before filtering the incubation on GF / F filters (pre-wetted with 0.3% polyethyleneimines) using an appropriate cellular harvester. The filters are rinsed twice with ice-cold buffer and then the individual filters are removed and subjected to a radioactivity assay in a gamma counter. The curves of inhibition of the binding of 125 I-o-CRF to the cell membranes, at several dilutions of the test drug, are analyzed by means of a program of adjustment of interactive LIGAND curves (JP.J. Munson and D. Rodbard, Anal. Biochem. 107: 220 (1980), which provides Ki values for inhibition, which are subsequently used to evaluate biological activity.A compound is considered to be active if it has a Ki value of less than about 10,000 nM CRF Inhibition Inhibition of CRF Stimulated Adenylate Cyclase Enzyme Activity The inhibition of CRF-stimulated adenylate cyclase enzyme activity was performed in the manner described by G. Battaglia et al., Synapse 1: 572 (1987) In brief, the tests were carried out at 37 ° C for 10 minutes in 200 ml of buffer solution containing 100 piM Tris-HCl (pH 7.4 at 37 ° C), 10 mM MgCl 2, 0.4 mM EGTA, 0.1% bovine serum albumin, 1 mM isobutylmethylxanthine (IBMX), 250 units / ml of phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine triphosphate, 100 nM oCRF, antagonist peptides (varying the concentration from 10 to 10 M) and 0. 8 mg of original tissue in wet weight (approximately 40-60 mg of protein). The reactions were initiated by the addition of ATP [P] ATP (approximately 2-4 mCi / tube) and terminated by the addition of 100 ml of 50 mM Tris-HCl, 45 mM ATP and 2% sodium dodecylsulfate. 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 [32P] AMPc of [32P] ATP was made by sequential elution in Dowex and alumina columns. The recovery was consistently greater than 80%. Some compounds of the present invention were tested in this assay and found to be active. Biological Analysis in vivo The in vivo activity of the compounds of the present invention can be tested using any of the biological assays available and accepted in the art. Some of these tests include the Acoustic Starter Test, the Ascending Ladder Test and the Chronic Administration Test. These and other useful models for testing the components of the present invention have been described in C.W. Berridge and A. J. Dunn Brain Research Reviews 15:71 (1990). The compounds can be tested on any species of rodent or small mammal. The description of the assays herein is not intended to limit the possibilities of the invention. The compounds of the present invention have utility in the treatment of disorders associated with abnormal levels of corticotropin releasing factor in patients suffering from depression, affective disorders and / or anorexia. The compounds of the present invention can be administered for the treatment of these abnormalities by means that produce a 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 other pharmaceutical products, either as an individual therapeutic agent, or in combination with therapeutic agents. The compounds of the present invention are they can be administered alone, but in general they will be administered with a pharmaceutical vehicle selected based on the route of administration and normal pharmaceutical practice. The dose administered will vary depending on the use of known factors such as the pharmacodynamic character of the particular agent and its mode and route of administration; the age, weight and state of health of the patient; the nature and degree of the symptoms; the type of concurrent treatment; the frequency of the treatment and the desired effect. For use in the treatment of said diseases or disorders, the compounds of the present invention can be administered daily orally at a dose of the active ingredient of 0.002 to 200 mg / kg of body weight. Ordinarily, a dose of 0.01 to 10 mg / kg in divided doses of one to four 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 to about 100 mg of the active ingredient per unit. In these pharmaceutical compositions, the active ingredient will normally be present in an amount of about 0.5 to 95% by weight, based on the total weight of the composition. The active ingredient can be administered by 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 the present invention can also be administered parenterally in sterile liquid pharmaceutical formulations. Gelatin capsules can be used to contain the active ingredient and a suitable vehicle such as, but not limited to, lactose, starch, magnesium stearate, stearic acid or cellulose derivatives. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be manufactured in the form of sustained release products to provide a continuous release of the drug over a period of time. The compressed tablets can be coated with sugar or with a film to mask any unpleasant taste or they can be used to protect the active ingredient 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 oils acceptable, saline, aqueous dextrose (glucose) and sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable vehicles for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, pH-regulating substances. Antioxidant agents such as sodium bisulfite, sodium sulfite or ascorbic acid, either alone or in combination, are suitable stabilizing agents. You can also use citric acid and its salts, and EDTA. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl paraben or propyl paraben and chlorobutanol. Suitable pharmaceutical carriers are described in "Remington 's Pharmaceutical Sciences", A. Osol, which is a reference standard in this field. The pharmaceutical forms useful for the administration of the compounds of the present invention can be illustrated as follows: Capsules A large number of capsule units are prepared by filling two pieces of normal hard gelatin capsules, each with 100 mg of the ingredient. active powder, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate. Soft Gelatin Capsules A mixture of the active ingredient is prepared in a digestible oil such as soybean oil, cottonseed oil or olive oil and is injected by means of a positive displacement, to the gelatine of 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 such that the dosage unit has 100 mg of the active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings can be applied to increase taste characteristics or to delay absorption. The compounds of the present invention can also be used as reagents or standards in the biochemical study of functions, alterations and neurological diseases. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as an antecedent, what is contained in the following is claimed as property.

Claims (12)

1. CLAIMS 1. A method for the treatment of an affective disorder, anxiety, depression, intestinal irritation syndrome, post-traumatic stress disorder, anorexia nervosa or other eating disorder, symptoms caused by withdrawal of drugs or alcohol, drug dependence or inflammatory disorders in a mammal, characterized in that it comprises administering to the mammal a therapeutically effective amount of a CRF antagonist compound of Formula I: or a pharmaceutically acceptable salt or prodrug thereof, wherein: A is an N atom or a C-R radical; X is an atom of H, a radical OR 1, S (0) nR1, NR1R2, CR 1R2R3, phenyl (optionally substituted with 1 to 4 groups which are independently selected from halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano , OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl) or heteroaryl, (optionally substituted in one or all the positions permitted by their valence with groups that are independently selected from halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH , alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl); n is O, 1 OR 2; R is an alkyl radical of 1 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, aryl- (alkyl of 1 to 12 carbon atoms), dialkylaminoalkyl of 3 to 12 carbon atoms, cyanoalkyl of 2 to 13 carbon atoms, carboalkoxy of 2 to 5 carbon atoms- ( alkyl of 1 to 12 carbon atoms), phenyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano , OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl), or heteroaryl (optionally substituted in one at all the positions allowed by its valence, with groups that are independently selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or -phenyl); 3 and R are independently selected from the group consisting of H atoms, alkyl radicals of 1 to 12 carbon atoms, alkoxyalkyl of 2 to 22 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms. carbon, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, aryl- (alkyl of 1 to 12 carbon atoms), dialkylaminoalkyl of 3 to 12 carbon atoms, cyanoalkyl of 2 to 13 carbon atoms , carboalkoxy of 1 to 4 carbon atoms, carboalkoxyalkyl of 2 to 12 carbon atoms, C (= 0) CH 3, phenyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl), or heteroaryl (optionally substituted in one at all the positions allowed by its valence, with groups that are independently selected from the group consisting of halogen, haloalkyl radicals of 1 to 4 carbon atoms. carbon, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 a 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl); R is an H atom, an alkyl radical of 1 to 12 carbon atoms, allyl, propargyl or benzyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms) carbon, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl); R and R can also optionally be considered in conjunction with the other four interconnected atoms, to form a ring of 5 to 9 total atoms, wherein the structural sequence between the group X and the ring nitrogen atom consists of the group (CH2) pW (CH2) q; p and q are independently 0, 1 or 2; is a radical CH2, C (CH3) 2, C (= 0), O, S or NCH3; c "r" 7 p R, R, R and R are independently selected from the group consisting of H atoms, alkyl radicals of 1 to 4 carbon atoms, allyl, propargyl, phenyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 1 to 5 carbon atoms carbon, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl) or benzyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 1 to 5 carbon atoms, cyano , OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH 2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or 'phenyl; R 4, R 5 and R6 can also be considered together with the two atoms interc of the invention, to construct either an imidazole ring, or a tetrazole ring, wherein the imidazole ring is optionally substituted with 1 to 2 groups which are independently selected from the group consists of alkyl radicals of 1 to 4 carbon atoms or phenyl; R and R can also be considered together as an O, S atom or a NR 12 radical; R is a phenyl radical (optionally substituted with 1 to 4 groups selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms , thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano), pyridyl (optionally substituted with 1 to 4 groups which are selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano), or pyrimidyl (optionally substituted with 1 to 4 groups that are selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano); R "or is an atom of H, an alkyl radical of 1 to 4 carbon atoms or cyano; Rsi * 1" I1"is an atom of H, an alkyl radical of 1 to 4 carbon atoms or halogen; is an H atom, an alkyl radical of 1 to 4 carbon atoms or phenyl; aryl is phenyl, biphenyl or naphthyl; and heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl or pyrazolyl.
2. 2. The method according to claim 1, characterized in that in the compound of Formula I, X is a radical OR1, NRXR2, CRVR
3. 3 O phenyl (optionally substituted in the 2-position with CF3, nitro, halogen or cyano; R is an alkyl radical of 1 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl- (alkyl of 1 to 12 carbon atoms) carbon), dialkylaminoalkyl of 3 to 12 carbon atoms or phenyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of halogen, haloalkyl, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl ). R is an H atom or an alkyl radical of 1 to 4 carbon atoms; R and R are either an H atom or an alkyl radical of 1 to 4 carbon atoms; R
4. 4, R 5 and R 6 can also be considered together with the two interconnected atoms, to constitute a tetrazole ring; 9 R is a phenyl radical (optionally substituted with 1 to 4 groups selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms , thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano), 3-pyridyl (optionally substituted with 1 to 4 groups which are selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms , thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano), or 5-pyrimidyl (optionally substituted with 1 to 4 groups that are selected from the group consisting of halo radicals geno, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 atoms of carbon, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano); R,? ± uo is a CH3 radical; and R is an H atom. The method according to claim 2, characterized in that in the compound of Formula I: A is N; X is NR1R2 or CR ^ R3; R is alkyl of 1 to 6 carbon atoms or alkoxyalkyl of 2 to 8 carbon atoms; R 2 and R 3 are independently an H atom, an alkyl radical of 1 to 6 carbon atoms or alkoxyalkyl of 2 to 8 carbon atoms; R is an H atom; R and R are H atoms; R 7 and R 8 are independently H atoms or radicals CH3; 9 and R is a phenyl radical (optionally substituted with 1 to 4 groups which are selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 atoms carbon alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano). The method according to claim 1, characterized in that the compound of Formula I is selected from the group consisting of: 8- (2-bromo-4-isopropylphenyl) -4- (ethylbutylamino) -2-methyl-5 , 6, 7, 8-tetrahydropteridine; 8- (2-Chloro-4,6-dimethoxyphenyl) -4- (ethylbutylamino) -2-methyl-5,6,7,8-tetrahydropteridine; 4- (ethylbutylamino) -2-methyl-8- (2,4,6-trimethylphenyl) -5,6,7,8-tetrahydropteridine); and 4- (l-methoxy-2-butyl) amino-2-methyl-8- (2,4,6-trimethylphenyl) -5,6,7,8-tetrahydropteridine.
5. 5. An antagonist compound of the CRF having the Formula I: * .-. or a pharmaceutically acceptable salt or prodrug thereof, characterized in that: A is an N atom or a C-R11 radical; 1 1 1 2 X is an atom of H, a radical OR, S (0) nR / NR R, CR 1R2R3, phenyl (optionally substituted with 1 to 4 groups which are independently selected from halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano , OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl) or heteroaryl, (optionally substituted in one or all positions allowed by its valence with groups that are independently selected from halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl); n is 0, 1 or 2; R is an alkyl radical of 1 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, aryl- (alkyl of 1 to 12 carbon atoms), dialkylaminoalkyl from 3 to 12 carbon atoms, cyanoalkyl of 2 to 13 carbon atoms, carboalkoxy of 2 to 5 carbon atoms- (alkyl of 1 to 12 carbon atoms), phenyl (optionally substituted with 1 to 4 groups which are independently selected of the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl), or heteroaryl (optionally substituted in one at all positions permitted by its valence, with groups that are selected independently of group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH , thioalkyl of 1 to 4 atoms carbon, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl); R3 are independently selected from the group consisting of H atoms, alkyl radicals of 1 to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, aryl- (alkyl of 1 to 12 carbon atoms), dialkylaminoalkyl of 3 to 12 carbon atoms, cyanoalkyl of 2 to 13 carbon atoms, carboalkoxy from 1 to 4 carbon atoms, carboalkoxyalkyl of 2 to 12 carbon atoms, C (= 0) CH 3, phenyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl), or heteroaryl (optionally substituted in one to all the positions allowed by its valence, with groups that are independently selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5. carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl); R is an H atom, an alkyl radical of 1 to 12 carbon atoms, allyl, propargyl or benzyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms) carbon, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl); R 1 and R 4 can also optionally be considered together with the other four interconnected atoms, to form a ring of 5 to 9 total atoms, where the structural sequence between the group X and the nitrogen atom of the ring consists of the group (CH2) pW (CH2) q; p and q are independently 0, 1 or 2; W is a radical CH2, C (CH3) 2, C (= 0), 0, S or NCH3; R5, R, R and R8 are independently selected from the group consisting of H atoms, alkyl radicals of 1 to 4 carbon atoms, allyl, propargyl, phenyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of of halogen radicals, haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 1 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH 2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl) or benzyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of halogen radicals , haloalkyl of 1 to 4 carbon atoms, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy of 1 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms arbono, dialkylamino of 2 to 8 carbon atoms or phenyl; R4, R and R6 can also be considered in conjunction with the two interconnected atoms, to construct either an imidazole ring, or a tetrazole ring, wherein the imidazole ring is optionally substituted with 1 to 2 groups which are independently selected from the group which consists of alkyl radicals of 1 to 4 carbon atoms or phenyl; 9 R is a phenyl radical (optionally substituted with 1 to 4 groups selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms , thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano), pyridyl (optionally substituted with 1 to 4) groups which are selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano), or pyrimidyl (optionally substituted with 1 to 4 groups which are selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano); R, 4? "" Or is an atom of H, an alkyl radical of 1 to 4 carbon atoms or cyano; R, * 11"11 * is an atom of H, an alkyl radical of 1 to 4 carbon atoms or halogen, R," 12 * is an atom of H, an alkyl radical of 1 to 4 carbon atoms or phenyl; aryl is phenyl, biphenyl or naphthyl; and heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl or pyrazolyl.
6. 6. A compound according to claim 5, characterized in that: X is a radical OR1, NR ^ 2, CR ^ R3 or phenyl (optionally substituted in the 2-position with CF3, nitro, halogen or cyano; R1 is an alkyl radical of 1; to 12 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl- (alkyl of 1 to 12 carbon atoms), dialkylaminoalkyl of 3 to 12 carbon atoms or phenyl (optionally substituted with 1 to 4 groups which are independently selected from the group consisting of halogen, haloalkyl, nitro, alkyl of 1 to 4 carbon atoms, carboalkoxy 2 to 5 carbon atoms, cyano, OH, alkoxy of 1 to 4 carbon atoms, SH, thioalkyl of 1 to 4 carbon atoms, NH2, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbon atoms or phenyl). R is an H atom or an alkyl radical of 1 to 4 carbon atoms; R and R are either an H atom or an alkyl radical of 1 to 4 carbon atoms; R, R and R can also be considered in conjunction with the two interconnected atoms, to constitute a tetrazole ring; R is a phenyl radical (optionally substituted with 1 to 4 groups which are selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano) , 3-pyridyl (optionally substituted with 1 to 4 to groups which are selected from the group consisting of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano) or 5-pyrimidyl (optionally substituted with 1 to 4 groups that are select from the group consisting of halogen radicals, haloalkyl of 1 to 4 atoms carbon, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano); R 10 is a CH 3 radical; and R is an H atom. A compound according to claim 6, characterized in that: A is N; X is NRXR2 or CR ^ R3; R is alkyl of 1 to 6 carbon atoms or alkoxyalkyl of 2 to 8 carbon atoms; R 2 and R 3 are independently an H atom, an alkyl radical of 1 to 6 carbon atoms or alkoxyalkyl of 2 to 8 carbon atoms; R is an H atom; R and R are H atoms; "
7. 7 R R and R are independently H atoms or radicals CH3; 9 and R is a phenyl radical (optionally substituted with 1 to 4 groups which are selected from the group consists of halogen radicals, haloalkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, dialkylamino of 2 to 6 carbon atoms, nitro, carboalkoxy of 2 to 5 carbon atoms or cyano).
8. 8. A compound according to claim 7, characterized in that it is selected from the group consisting of: 8- (2-bromo-4-isopropylphenyl) -4- (ethylbutylamino) -2-methyl-5, 6, 7, 8 -tetrahydropteridine; 8- (2-Chloro-4,6-dimethoxyphenyl) -4- (ethylbutylamino) -2-methyl-5,6,7,8-tetrahydropteridine; 4- (ethylbutylamino) -2-methyl-8- (2,4,6-trimethylphenyl) -5,6,7,8-tetrahydropteridine); and 4- (1-methoxy-2-butyl) amino-2-methyl-8- (2, 4, 6-trimethylphenyl) -5,6,7,8-tetrahydropteridine.
9. 9. A composition characterized in that it comprises a therapeutically effective amount of the compound according to claim 5 and a pharmaceutically suitable carrier.
10. 10. A composition characterized in that it comprises a therapeutically effective amount of a compound according to claim 6 and a pharmaceutically suitable carrier.
11. 11. A composition characterized in that it comprises a therapeutically effective amount of a compound according to claim 7 and a pharmaceutically suitable carrier.
12. 12. A composition characterized in that it comprises a therapeutically effective amount of a compound according to claim 8 and a pharmaceutically suitable carrier.