MXPA98007868A - Pyrimidines and triazines replaced with ariloxy yariltio and derivatives from mis - Google Patents

Abstract

The present invention provides novel compounds and pharmaceutical compositions thereof, and methods for using same in the treatment of affective, anxiety, pressure disorders, post-traumatic stress disorders, eating disorders, supranuclear palsy, irritable bowel syndrome. , immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, symptoms of drug and alcohol suppression, drug addiction, inflammatory disorders or fertility problems. The novel compounds provided by this invention are those of formula (I) wherein R 1, R 3, R 5, q, z, y, v, x, and X 'are as defined in the present

Description

PYRIMIDINES AND TRIAZINES REPLACED WITH ARILOXI AND ARILTIO, AND DERIVED FROM THE SAME FIELD OF THE INVENTION The present invention relates to novel compounds, pharmaceutical compositions containing such compounds and methods for using same in the treatment of affective disorders, anxiety, depression, post-traumatic stress disorders, eating disorders, supra-nuclear paralysis, Irritable bowel, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, symptoms of drug and alcohol suppression, drug addiction, inflammatory disorders or fertility problems.

BACKGROUND OF THE INVENTION The corticotropin releasing factor (hereinafter referred to as CRF), a peptide of 41 amino acids, is the primary physiological regulator of the secretion of the peptide derived from proopiomelanocortin (POMC) from the anterior pituitary or pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80: 4851 (1983); REF. 23318 W. Vale et al., Science 213: 1394 (1981)]. In addition to its endocrine role in the pituitary gland, the immunohistochemical localization of CRF has shown that the hormone has a wide extrahypothalamic distribution in the central nervous system and produces a. broad spectrum of autonomous, electrophysiological and behavioral effects, consistent with a role of neurotransmitter or neuromodulator in the brain [. Vale et al., Rec. Prog. Horm. Res. 39: 245 (1983); G.F. Koob, Persp. Behav. Med. 2:39 (1985); E.B. De Souza et al., J. Neurosci. 5: 3189 (1985)]. There is also evidence that CRF can also play a significant role in the integration of the immune system response to physiological, psychological and immunological stressors [J.E. Blaloc, Physiological Reviews 69: 1 (1989); J.E. Morley, Life Sci. 41: 527 (1987)]. Clinical data have shown that CRF may have implications in psychiatric disorders and neurological diseases that include depression, anxiety-related disorders, and eating disorders. The role of CRF has also been postulated in the etiology and pathology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis to the extent that it is related to the dysfunction of CRF neurons in the nervous system. central [for a review, see EB De Souza, Hosp. Practice 23:59 (1988)]. In affective disorders, or major depression, the concentration of CRF is significantly increased in the cerebrospinal fluid (CSF) of 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 decreases significantly in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C.B. Nemeroff et al., Arch. Gen Psychiatry 45: 577 (1988)]. In addition, there is a suspended response of adrenocorticortropin (ACTH) to CRF (administered via i.v.) observed in depressed patients [P.W. Gold et al., Am. J. Psychiatry 141: 619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9: 147 (1984); P.W. Gold et al., New Engl. J. Med. 314: 1129 (1986). Preclinical studies in rats and non-human primates provide additional support for the hypothesis that CRF hypersecretion may be involved in 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 amount of CRF receptors in the brain [Grigoriadis et al. , Ne uropsychopharma col ogy 2:53 (1989)]. There has also been a postulated role for CRF in the etiology of related disorders. with anxiety. CRF produces anxiogenic effects in animals and interactions between benzodiazepine / non-benzodiazepine anxiolytics and CRF has 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 16:83 (1986)]. Preliminary studies using the putative receptor antagonist of CRF, ovine-helical CRF (9-41) in a variety of behavioral paradigms demonstrate 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 (1990)]. The neuroguimic, endocrine and receptor binding studies have shown, all interactions between CRF and benzodiazepine anxiolytics providing additional evidence of the relationship of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both conflict tests [K.T. Britton et al., Psychopharmacology 86: 170 (1985); K.T. Britton et al., Psychopharmacology 94: 306 (1988)] as in the acoustic stress test [N. R. Swerdlow et al., Psychopharmacology 88: 147 (1986)] in rats. The benzodiazepine receptor antagonist (Rol5-1788), which did not exhibit behavioral activity in the operant conflict test, reverses the effects of CRF in a dose-related manner while the inverse benzodiazepine agonist (FG7142) improves the CRF shares [KT Britton et al., Psychopharmacology 94: 306 (1988)]. The mechanisms of action sites through which anxiolytics and standard antidepressants produce their therapeutic effects are still to be elucidated. However, hypotheses have been established that are involved in the suppression of hypersecretion of CRF that is observed in these disorders. It is of particular interest that preliminary studies examining the effects of a CRF receptor antagonist (CRF9-41 a.-helical) on a variety of behavioral paradigms have shown that the CRF antagonist produces "anxiolytic-like" effects qualitatively. similar to those of benzodiazepines [for a review, see GF Koob and K.T. Britton, In: Corti cotropin -Releas ing Factor: Basic and Clinical Studies of a Neuropeptide, E.B. De Souza and C.B. ? emeroff eds., CRC Press p221 (1990)].

In order to study these specific receptor proteins for cell surface, compounds should be identified which can interact with the CRF receptor in a specific manner established by the pharmacological profile of the characterized receptor. For this purpose, there is evidence that the direct CRF antagonist compounds and compositions of this invention can attenuate physiological responses to stress-related disorders, and will have potential therapeutic utility for the treatment of depression and anxiety-related disorders. All of the references mentioned above are incorporated herein by reference. The application PCT94 / 1105 describes lN-alkyl-N-arylpyrimidines and derivatives thereof in the treatment of affective disorders, anxiety, depression, post-traumatic stress disorders, eating disorders, supranuclear palsy, irritable bowel syndrome, suppression immune, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, symptoms of drug and alcohol suppression, drug addiction, inflammatory disorders or fertility problems. U.S. Patent No. 5,062,882 describes the synthesis of aryloxytriazines and arylthriarians useful as herbicides.

U.S. Patent Nos. 4,427,437 and 4,460,588 describe the synthesis of aryloxypyrimidines and arylthiopyrimidines useful for the destruction of intestinal parasites, special trematodes and nematodes in homeothermic animals, and / or as herbicides to inhibit the growth of severely damaged plants or to destroy plants. U.S. Patent No. 5,281,707 describes the synthesis and utility of water-soluble aryloxytriazines useful for the thermal and photochemical stabilization of polyamide fiber materials. The compounds and methods of the present invention provide the methodology for the production of specific high affinity compounds capable of inhibiting the action of CRF on their receptor protein in the brain. These compounds would be useful in the treatment of various neurodegenerative disorders, neuropsychiatric and stress-related. It is further stated that the invention can provide compounds and pharmaceutical compositions suitable for use in such a method. The additional advantages of this invention will be apparent to a person familiar with the art from reading the description which follows.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to pyrimidines and triazines substituted with 2-aryloxy and 2-arylthio, and derivatives thereof, pharmaceutical compositions containing such compounds and methods for use in the treatment of affective disorders, anxiety, depression, post-stress disorders. -traumatic, eating disorders, supranuclear paralysis, irritable bowel syndrome, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, symptoms of drug and alcohol depression, drug addiction, inflammatory disorders, fertility problems. Such compounds interact and have antagonist activity in the CRF receptor and therefore have therapeutic effect. [1] This invention provides compounds of formula (I): (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein: Q = 0, S (0) n; R1 is alkenyl, alkenyl or alkynyl of Cx-C4, haloalguil of Cx-C2, halogen, NR6R7, OR8, SR8, CN; R3 is haloalkyl lobe of Ci-Ca, halogen, NR6R7, OR8, SR8, (CH2) kNR6R7, (CH2) k0R8, CH (CHR16CHR160R8) 2, CH (CN) AR, CH (CN) 2, CHR16 (CHR16) p0R8, (CHRls) pAr wherein the aryl group is substituted with 1-3 of R18, (CHR16) pheteroaryl, wherein the heteroaryl group is substituted with 1-3 of R18, 1-tetrahydroquinolinyl, 2-tetrahydroisoguinolinyl, phenyl or heteroaryl substituted with 0-3 selected groups of hydrogen, halogen, Cx-C4 alkoxy, Cx-C4 alkoxy, nitro, cyano, S (O) z-alkoyl of Cj.-C6; V is N; And it is CR2 OR N; Z is N; R2 and is independently selected each time it is presented from the group consisting of hydrogen, halo, halomethyl, cyano, nitro, NRSR7, NH (C0R9), N (C0R9), X and X 'are independently selected, each time they are presented , of the group consisting of alkenyl, halogen, S (0) nR8, OR8, halomethyl, NRX9R1S, CN; Rs is H, halo, C1-C3 alkenyl, C2-C6 alkenyl, haloalkyl of alkoxy of (CHRls) p0R8, (CHR16) pS (0) nR8, (CHR1S) PNR1R1S, cycloalkyl of C3-C6, cycloalgenyl of C4 -C6, CN; Rs and R7 are independently selected each time from the group consisting of: hydrogen, Cg alkoyl, C3-C10 cycloalkyl, C3-C10 cycloalguilalguile, CH (R16) (CHR16) p0R8, (CHR1S) P0R8 , (alkenyl of -heteroaryl or aryl optionally substituted with 1-3 groups which are selected from the following: hydrogen, halogen, alkoxy of Cx-C3 alkoxy, amino, NHC (= 0) (C 1 -C 6 alkoyl), NH ( N alkyl (nitro alkyl, C02 (Cx-C3 alkyl), cyano, S (O) z- (alkyl, or R6 and R7 can be taken together to form - optionally substituted with 0-3 of R17, or , when considered with the commonly attached nitrogen, R6 and R7 can be taken together to form a heterocycle, the heterocycle is substituted on the carbon with 1-3 groups consisting of: hydrogen, -Cg algae, (Cx- alkoxy) C6) -alkoxy of C ^ d, hydroxy or alkoxy of A is CH2, 0, S (0) n, N (C (= 0) R24), N (R19), C (H) (NR14R15), C ( H) (OR20), C (H) (C (= 0) R21), N (S (0) nR21); R8 is hydrogen, C3-C6 cycloalkyl algyl, (CH2) tR22, C3-C10 cycloalkyl , cycloalguilalguilo, - (Cx-Cg aligyl) -aryl, heteroaryl, - (alkylated -heteroaryl or aryl optionally substituted with 1 -3 groups which are selected from the following: hydrogen, halogen, Ci-Cg alkoyl, amino alkoxy, NHC (= 0) (C -.- Cg algayl), NH (N-allyl), CgJa, nitro, C02 (C6-C6 algayl), cyano; S (0) z (Cx-C3 alguyl); R9 is independently selected, each time hydrogen is present, C3-C6 cycloalguyl alkenyl, C2-C4 alkenyl, aryl substituted with 0-3 of Rlβ and - (Cx-C6 alyl) -aryl substituted with 0 -3 of R18, -R14 and R1S are independently hydrogen, C1-C3 alkenyl, C3-C3 cycloalkyl, (CH2) tR22, aryl substituted with 0-3 of R18; R16 is hydrogen or Cx-C4 alkenyl; R17 is hydrogen, CL-CJ alkoyl, (- ^ - C ^ alkoxy, halo, OR23, SR23, NR23R24, Cx-C4 alkoxy, R18 is hydrogen, Cx-C4 algayl, C-haloalkyl, Cj, C (= 0) alkoxy R24, N02, halogen or cyano, R19 is C3-C6 cycloalkyl algayl,. {H2)} 22, aryl substituted with 0-3 of R18; R20 is hydrogen, C (= 0) R22, alkenyl of -C ^ alkenyl of C2-C4; R21 is hydrogen, C1-C4 alkoxy, NR23R24, hydroxyl or C1-C4 alkyl; R22 is cyano, OR24, SR24, NR23R24, C3-C6 cycloalkyl; R23 and R24 are independently selected, each time they occur, from hydrogen or alguil of d-d; k is 1-4; n is independently selected, each time it is presented, from 0-2; p is 0-3; g is 0-3; r is 1-4; t is independently selected, each time it is presented, from 1-6; z = 0-3; w = 1-6; with the proviso, however, that when Y is CR2, then R3 is (CHR16) pAr where the alkyl group is substituted with 1-3 of R1S or (CHR16) pheteroaryl, wherein the heteroaryl group is substituted with 1- 3 of R18. [2] Preferred are compounds of claim 1 wherein: R3 is -d algayl, d-C2 haloalguyl, NR6R7, OR8, CH (CHR16CHR16OR8) 2, CH (CN) AR, CH (CN) 2, CH (R16CHR16) p0R8, (CHR16) pAr, wherein the aryl group is substituted with 1-3 of R18, (CHR16) pheteroaryl, wherein the heteroaryl group is substituted with 1-3 of R18, 1-tetrahydroquinolinyl, 2-tetrahydroisoquinolinyl, phenyl or heteroaryl substituted with 0-3 groups which are chosen from hydrogen, halogen, CX-C4 alkyl, d-C4 alkoxy , nitro, cyano, S (0) z-dd alkyl; R2 is independently selected, each time from the group consisting of hydrogen, halo, methyl, nitro, cyano, NR6R7, NH (COR9). , N (COR9) 2; R6 and R7 are independently selected, each time from the group consisting of: hydrogen, d-d alkeyl, C3-C10 cycloalkyl, cycloalguilalguilo, Cx-C6 alkoxy, (CHRls) p0R8, (CHR16) p0R8, - (alguil of d-Cg) aryl, heteroaryl, - ((d-C6 algayl) -heteroaryl or aryl optionally substituted with 1-3 groups which are selected from the following: hydrogen, halogen, aldyl of dd, Cx-Cg alkoxy, NHC (= 0) (Cx-C6 algayl), NH (d-C6 algayl) N (algayl of d-Cg) 2, C02 (algayl of d-C6), cyano, or R6 and R7 can be taken together to form - (CH2) qA (CH2) r-, optionally substituted with 0-3 of R17 or, when Considered with nitrogen to which they are commonly attached, Rs and R7 can be taken together to form a heterocycle, the heterocycle is substituted on carbon with 1-3 groups consisting of: hydrogen, d-C6 alkyl, alkyl (d-C6) ) -alkoxy of Cx-C4, hydroxy, or d-C6 alkoxy; R8 is hydrogen, CX-C6 alkyl, cycloalkyl C3-C6, (CH2) tR22, C3-C10 cycloalkyl, cycloalkylalkyl, - (d-C6 alkyl) -aryl or heteroaryl optionally substituted with 1-3 groups which are selected from the following: hydrogen, halogen, dd alkyl , Cx-C3 alkoxy, NHC (= 0) (d-Cg alkyl), NH (d-Cg alkyl) N (C1-C6 alkyl) 2, C02 (d-C6 alkyl R14 and R15 are independently hydrogen, d-, C3-C6 cycloalkyl; R17 is hydrogen, d-C4 alkyl / Cx-C4 alkoxy, alkoxy (d-C3) Cx-C4 alkoxy; R18 is hydrogen, alkoyl of d-C4, haloalguilo of Ci-Ca, alkoxy of C2-C4, or cyano; R19 is aldyl of dd, C3-C6 cycloalkyl, aryl substituted with 0-3 of R18, - R22 is cyano, OR24, SR24, NR23R24, C3-C6 alkenyl or cycloalguilo, R23 and R24 are independently selected each time present hydrogen or alger of d-C4; t is independently selected each time it is presented from 1-3; w is 1-3; with the proviso, however, that when Y is CR2, then R3 is (CHR16) pAr where the aryl group is substituted with 1-3 of R18 or (CHR16) pheteroaryl, wherein the heteroaryl group is substituted with 1- 3 of R18. [3] Further preferred are those compounds of claim 2 wherein: R1 is d-C2 alkyl, halide, NR6R7, OR8; R3 is d-C4 alkyl haloalkyl of C? -C2, NR6R7, OR8, (CH2) kNR6R7, (CH2) kNR6R \ (CH2) kOR8; And it's N; X and X 'are independently selected, each time they occur, from the group consisting of methyl, hydrogen, Cl, Br, I, OR8, NR14R15, CN, S (0) nR8; Rs is H, halo, d-C6 algayl, 5 d-C3 haloalguyl, d-C3 alkoxy, (CHRls) pOR8, (CHR16) pNR14Rls, C4-C3 cycloalkyl; R6 and R7 are independently selected each time they are presented from the group consisting of: alguilo of d-d, (CHR16) pR8; 10 or can be taken together to form - (CH2) .- A (CH2) r-, optionally substituted with CH20CH3; A is CH2, 0, S (0) n, N (C (= 0) R18), N (R19), C (H) (0R20); R8 is hydrogen, d-C3 alkyl, C3-C6 cycloalkyl, (CH2) tR; R9 is hydroxy, alkoyl of d-C4 or methoxy; R13 is OR19, SR19, NR23R24, C3-C6 cycloalkyl; R14 and R15 are independently hydrogen, d-C2 alkenyl, C3-C6 cycloalkyl; R16 is hydrogen; R18 is hydrogen, alkoyl of d-C4, haloalguil of d-C2, alkoxy of Cx-C4, C (= 0) R24, or cyano; R19 is alxyl of Cx-C3; R20 is hydrogen, Cx-C2 alkenyl or alkenyl ? D < -2 ~ 'R22 is OR24; R23 and R24 are independently selected, each time from hydrogen, or Cx-C2 alkenyl; k is 1-3; m is 1-4; n is independently selected, each time it is presented 0-2 p is 0-2 g is 0-2 r is 1-2 t is independently selected each time it is presented 1-3; w is 1-3. [4] Most preferred are compounds of claim 1 which are selected from the group: a) 2- [2-Bromo-6-methoxy-4- (1-methyletenyl) phenoxy] -4-methyl-6- (4-morpholinyl) -1,3,5-triazine; b) 2- [2-Bromo-6-methoxy-4- (1-methyletenyl) phenoxy] -4-methyl-6- (bis (2-methoxyethyl) amino) -1,3,5-triazine; c) 2- [2-Bromo-6-methoxy-4- (1-methylethhenyl) phenoxy] -4-methyl-6- (N-propyl-N-cyclopropylmethylamino) -1,3,5-triazine; d) 2- [2-Bromo-6-methoxy -4 (1-methyletenyl) phenoxy] 4-methyl-β- (1-homopiperidinyl) -1,3,5-triazine; e) 2- [2-Bromo-6-methoxy-4- (1-methyletenyl) phenoxy] 4-methyl-6- (diethylamino) -1,3,5-triazine; f) 2- [2-Bromo-6-methoxy -4 (1-methyletenyl) phenoxy] 4-methyl-6- (N-butyl-N-ethylamino) -1,3,5-triazine; g) 2- [2-Bromo-6-methoxy -4 (1-methylethyl) phenoxy] 4-methyl-6- (4-thiomorpholinyl) -1,3,5-triazine; h) 2- [2-Bromo-6-methoxy -4 (1-methylethyl) phenoxy] 4-methyl-6- (2- (1-methoxybutyl) amino) -1,3,5-triazine; i) 2- [2-Bromo-6-methoxy-4- (1-methyletenyl) phenoxy] 4-methyl-6- (1-piperidinyl) -1,3,5-triazine; j) 2- [2-Bromo-6-methoxy-4- (1-methyletenyl) phenoxy] -4-methyl-6- (1- (1.2.3.4-tetrahydroquinolinyl)) -1,3,5 triazine; k) 2- [2-Bromo-6-methoxy-4- (1-methylethyl) phenoxy] 4-methyl-6- (1-pyrrolidinyl) -1,3,5-triazine; 1) 2- [2-Bromo-6-methoxy-4- (1-methyletenyl) phenoxy] -4-methyl-6- (1- (2-ethylpieridinyl)) -1,3,5-triazine; m) 2- [2-Bromo-6-methoxy-4- (1-methyletenyl) phenoxy] -4-methyl-6- (2- (1.2.3.4-tetrahydroisoquinolinyl)) -1,3,5-triazine; n) 2- [2-Bromo-6-methoxy-4- (1-methylethhenyl) phenoxy] -4-methyl-6- (1- (1,3,5,6-tetrahiropiperidinyl) -1,3,5-triazine; o) 2- [2-Bromo-6-methoxy-4- (1-methyletenyl) phenoxy] -4-methyl-6- (1- (2-trifluoromethylphenyl)) -1,3,5-triazine; p) 2- [2-Bromo-6-methoxy-4- (1-methylethyl) phenoxy] -4-methyl-6- (4-morpholinyl) -1,3,5-triazine; q) 2- [2-Bromo-6-methoxy-4- (1-methylethyl) phenoxy] -4-methyl-6- (bis (2-methoxyethyl) amino) -1,3,5-triazine; r) 2- [2-Bromo-6-methoxy-4- (1-methylethyl) phenoxy,] -4-methyl-6- (N-propyl-N-cyclopropylmethylamino) -1,3,5-triazine; s) 2- [2-Bromo-6-methoxy-4- (1-methylethyl) phenoxy] -4-methyl-6- (1-homopiperidinyl) -1,3,5-triazine; t) 2- [2-Bromo-β-methoxy-4- (1-methylethyl) phenoxy] -4-methyl-6- (N-butyl-N-ethylamino) -1,3,5-triazine; u) 2- [2-Bromo-6-methoxy-4- (1-methylethyl) phenoxy] -4-methyl-6- (4-thiomorpholinyl) -1,3,5-triazine; v) 1- [3-Bromo-5-methoxy-4 - [[4-methyl-6- (4-morpholinyl) -1,3,5-triazinyl-2-yl] oxy] phenyl] ethanone; w) 1- [3-Bromo-5-methoxy-4- [[4-methyl-6- (bis (2-methoxyethyl) amino) -1,3,5-triazinyl-2-yl] oxy] phenyl] ethanone; x) 1- [3-Bromo-5-methoxy-4 - [[4-methyl-6 - (4-thiomorpholinyl) -1,3,5-triazinyl-2-yl] oxy] phenyl] ethanone; y) 1- [3-Bromo-5-methoxy-4- [[4-methyl-6- (diethylamino) -1,3,5-triazinyl-2-yl] oxy] phenyl] ethanone; z) 1- [3-Bromo-5-methoxy -4 - [[4-methyl-6- (1-piperidinyl) -1,3,5-triazinyl-2-yl] oxy] phenyl] ethanone; aa) 3-Bromo-4- [[6-methyl-4 (bis (2-methoxyethyl) amino) -1,3,5-triazin-2-yl] oxy] -5-methoxy-alpha, alpha-dimethylbenzenemethanol; bb) 3-Bromo-4- [[6-methyl-4 (N-propyl-N-cyclopropylmethylamino) -1,3,5-triazin-2-yl] oxy] -5-methoxy-a, a- dimethylbenzenemethanol; cc) 3 -Bromo-4 - [[6-met il-4 (2 - (1-methoxybutyl) amino) -1,3,5-triazin-2-yl] oxy] -5-methoxy-alpha, alpha -dimethylbenzenemethanol; dd) 3-Bromo-4- [6-methyl-4- (4-thiomormofolinyl) -1,3,5-triazin-2-yl] oxy] -5-methoxy-alpha, to the f -dimethylbenzenemethanol; ee) 3-bromo-4- [[6-methyl-4- (1-piperidinyl) -1, 3, 5-triazin-2-yl] oxy] -5-methoxy-alpha, alpha-dimethylbenzenemethanol; ff) 3-Bromo-4- [[6-methyl-4- (1-homopiperidinyl) -1, 3, 5-triazin-2-yl] oxy] -5-methoxy-alpha, to the f -dimethylbenzenemethanol; gg) 3-Bromo-4 - [[6-met-il-4 (1- (2-trifluoromethylphenyl)) -1,3, 5-triazin-2-yl] oxy] -5-methoxy-alpha a, alf a-dimethylbenzenemethanol; hh) 2- (2,4,6-Trio-phenoxy) -4-methyl-6- (4-morpholinyl) -1,3,5-triazine; ii) 2 - (2, 4, 6-Trichlorophenoxy) -4-methyl-6- (4-morpholinyl) -1,3,5-triazine; j j) 2- (2-chloro-4,6-dimethoxyphenoxy) -4-methyl-6- (4-morpholinyl) -1,3,5-triazine; Y kk) 2- [(2,6-Dibromo-4- (1-methylethyl)) phenoxy] -4-methyl-6- (N-ethyl-N-butylamino) -1,3,5-triazine uu) 2- [(2,6-Dibromo-4- (1-methylethyl)) phenoxy] -4-methyl-6- (bis (2-methoxyethyl) amino) -1,3,5-triazine. [5] A method for treating affective disorders, anxiety or depression in mammals is also provided by this invention, which comprises administering to the mammal a therapeutically effective amount of a compound provided herein. [6] Pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound provided herein are also provided by this invention. [7] The compounds provided by this invention (and especially labeled compounds of this invention) are also useful as standards and reagents for determining the ability of a pharmaceutical drug or other chemical compound to bind to the CRF receptor. These may be provided in commercial equipment comprising a compound provided by this invention.

DETAILED DESCRIPTION OF THE INVENTION In the present invention it has been found that the compounds provided are useful as corticotropin releasing factor antagonists and for the treatment of affective disorders, anxiety or depression. The present invention also provides methods for the treatment of affective disorders, anxiety or depression by administering to a compromised host a pharmaceutically or therapeutically effective or acceptable amount of a compound of formula (I) as described above. By "therapeutically effective amount" is meant an amount of a compound of the present invention effective to antagonize the abnormal level of CRF or to treat the symptoms of affective disorders, anxiety or depression in a host. The compounds described herein may have asymmetric centers. All chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C = N double bonds and the like may also be present in the compounds described herein, and all stable isomers are contemplated in the present invention. It will be appreciated that certain compounds of the present invention contain an asymmetrically substituted carbon atom and can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as separation of racemic forms by synthesis, or by optically active starting materials. Furthermore, it will be noted that the cis and trans geometric isomers of the compounds of the present invention are described, and that they can be isolated as a mixture of isomers or as separate isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of the structures are included, unless the specific stereochemistry of the isomeric form is specifically indicated. When any variable (for example R1 to R10, m, n, A, W, Z, etc.) occurs more than once in any constituent or in the form (I), or in any other formula in the present, its Definition of each time it is presented is independent of its definition in each time it is presented. Thus, for example, in -NR8R9, each of the substituents can be independently selected from the list of defined possible groups R8 and R9. In addition, combinations of substituents and / or variables are also permissible only if such combinations result in stable compounds. As used in thisit is intended that "alguilo" include saturated aliphatic hydrocarbon groups, both branched and straight chain, having a specified number of carbon atoms. It is intended that the term "algenyl" include hydrocarbon chains of straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur at any stable point along the chain, such as ethynyl, propynyl, and the like. It is intended that the term "alguinyl" include hydrocarbon chains of straight or branched configuration and one or more triple carbon-carbon bonds which may occur at any stable point along the chain, such as ethynyl, propynyl and the like. The term "haloalguyl" is intended to include saturated aliphatic hydrocarbon groups of both branched and linear chains having the specified number of carbon atoms, substituted with 1 or more halogen; "alkoxy" represents an alkyl group of numbers of indicated carbon atoms attached through an oxygen bridge, - "cycloalkyl" is intended to include saturated ring groups, which include monocyclic, bicyclic or polycyclic ring systems such as cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl and so on. The terms "halo" or "halogen", as used herein, refer to fluorine, chlorine, bromine and iodine. As used herein, the terms "aryl" or "aromatic residue" are intended to mean phenyl, biphenyl or naphthyl. The term "heteroaryl" is meant to include unsubstituted, monosubstituted or disubstituted monocyclic or bicyclic 5-, 6- or 10-membered aromatic rings, which optionally may contain from 1 to 3 heteroatoms which are selected from the group consisting of O, N, and S, and they are expected to be active. They are included in the definition of the heteroaryl group, but are not limited to the following: 2-, or 3-, or 4-pyridyl; 2- or 3 -furyl; 2-, or 3-benzofuranyl; 2- or 3-thiophenyl; 2- or 3-benzo [b] thiophenyl; 2- or 3- or 4-guinolinyl; 1- or 3- or 4-isoguinolinyl; 2- or 3-pyrrolyl; 1- or 2- or 3-indolyl; 2- or 4- or 5-oxazolyl; 2-benzoxazolyl; 2- or 4- or 5-imidazolyl; 1- or 2-benzimidazolyl; 2- or 4- or 5-thiazolyl; 2-benzothiazolyl; 3- or 4- or 5-isoxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4- or 5-isothiazolyl; 3- or 4-pyridazinyl; 2- or 4- or 5-pyrimidinyl; 2-pyrazinyl; 2-triazinyl; 3- or 4-cinolinyl; 1-phthalacinyl; 2- or 4-quinazolinyl; or a 2-quinoxalinyl ring. Particularly preferred are 2-, 3-, or 4-pyridyl; 2- or 3-furyl; 2-, or 3-thiophenyl; 2-, 3-or 4-quinolinyl; or 1-, 3-, or 4-isoquinqlinyl. As used herein, it is intended that "ca-rbociclo" or "carbocyclic residue" means cualguier monocyclic or bicyclic 3- to 7-membered monocyclic or bicyclic or 7 to 14 membered ring or a polycyclic carbon up to 26 members, any of which may be saturated, partially unsaturated or aromatic. Examples of such carbocycles include, but are not limited to cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl or tetrahydronaphthyl (tetralin). As used herein, the term "heterocycle" is intended gue signifigue an optionally substituted stable 5 to 7 members or a bicyclic heterocyclic ring of 7 to 10 members which is saturated or unsaturated, and which consists of carbon atoms and 1 to 4 heteroatoms gue are independently selected from the group gue consisting of N, O and S, and wherein the nitrogen and sulfur are optionally oxidized and nitrogen is optionally quaternized, and including any bicyclic group in which any of the heterocyclic rings defined above is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group on any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted at a carbon or nitrogen atom, if the resulting compound is stable. Examples of such heterocycles include, but are not limited to pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, guinolinilo, isoguinolinilo or benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl , 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisogininnyl, decahydroquinolinyl or octahydroisoguinolinyl, azocinyl, triazinyl, 6H-1, 2, 5-thiadiazinyl, 2H-6H-1, 5, 2-dithiazinyl, thiophenyl, thiantrenyl, furanyl, pyranyl , isobenzofuranyl, chromenyl, xanthenyl, phenoxythiinyl, 2H-pyrrolyl, pyrrolo, imidazolyl, pyrazolyl, isothiazolyl, isoxazole, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindol, 3H-indolyl, indolyl, lH-indazolyl, purinyl, 4H-guinolizinyl , isoguinolinilo, guinolinilo, phthalazinyl, naphthyridinyl, guinoxalinilo, guinazolinilo, cinnolinyl, pteridinyl, 4aíf-carbazole, carbazole, ß-carbolinyl, faith nantridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, fenarsazinyl, phenothiazinyl, furazanyl, phenazinyl, isocromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, guinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused and spiro ring compounds containing, for example, the above heterocycles. The term "substituted" as used herein, means that one or more hydrogens on the designated atoms is substituted with a selection of the indicated group, with the proviso that the normal valence of the designated atom is not exceeded, and that the substitution result in a stable compound. When a substituent is keto (ie, = 0), then 2 hydrogens on the atom are substituted. By "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive isolation with a useful degree of purity from a reaction mixture., and its formulation in an effective therapeutic agent. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound of formula (I) is modified by making acids or bases of the compound of formula (I). Examples of pharmaceutically acceptable salts include, but are not limited to, residues of mineral or organic acid salts or basic residues such as amines; alkaline or organic salts of acidic residues such as carboxylic acids; and similar. The term "prodrugs" is considered to be covalently linked carriers which release the original drug according to formula (I) in vivo when such a prodrug is administered to a mammalian subject. The prodrugs of the compounds of formula (I) are prepared by modifying functional groups present in the compounds such that the modifications are separated, either by usual manipulation or in vivo, to the original compounds. The prodrugs include compounds of formula (I) wherein hydroxy, amine or sulfhydryl groups are attached to any group such that, when administered to a mammalian subject, they are separated to form a free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to acetate, formate and benzoate, alcohol derivatives and amine functional groups in the compounds of formula (I); and similar.

The pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture thereof. two; generally a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred. Lists of suitable salts are found in Remincrton's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the description of which is incorporated herein by reference. Synthesis The novel 2-pyrimidinamines and substituted triazines in the present invention can be prepared by one of the general schemes indicated below wherein R1, R3, R5 / Q, X 'etc. they are as defined before. The compounds of formula (I) can be prepared, wherein V, Y and Z are N, as shown in Esquemas 1 and 2. For example, the treatment of acetovanillone (II, X = OMe) with bromine in a solvent halogenated, such as, but not limited to, 1,2-dichloroethane or chloroform, provides 3-bromo-4-hydroxy-5-methoxyacetophenone (III) which, by condensation with Grignard reagent such as methylmagnesium bromide in an aprotic solvent such as, but not limited to, diethyl ether or THF, provides tertiary carbinol (IV, R16 = H). Deprotonation of IV with sodium hydroxide in a solvent such as water or alcohol followed by treatment of the resulting phenoxide with 4,6-dichloro-2-methyltriazine (V) in solvents such as acetonitrile or DMF yields chlorophenoxytriazine (VI). Helv. Chim. Minutes , 33, 1365 (1950). The treatment of triazine (VI) with several primary and secondary amines such as morpholine in solvents such as, but not limited to dioxane, ethylene glycol, methoxyethoxyethanol, etc., produces the amino phenoxytriazine (VII). Dehydration of acid-catalyzed carbinol (VII) in solvents such as benzene, toluene, THF, etc., provides the olefin (VIII) which, by hydrogenation in the presence of a catalyst such as platinum black, provides the substituted phenoxy derivatives 4-alguilo (IX). The use of other Grignard reagents provides the opportunity to produce compounds with different alger groups at the 4-position of the phenyl ring in formulas IV, VI, VII, VIII and IX of Esguema 1. Variations in the 4-position of the triazine ring also they are considerable and do not include only secondary amino groups (of primary amines) and tertiary (secondary amines) in Rog 1 and R7, but also aryl and heteroaryl substituents derived from the appropriate organometallic reagents, as shown in Schemes 3 and 4. Scheme 1 (Ka) Scheme 2 Compounds of formula (I), wherein X and X 'halogen or methyl, may also be prepared as shown in Scheme 2 by the use of 2,6-dihalo or 2,6-dimethylphenols appropriately substituted in 4 (IVa ). These compounds are prepared from a variety of substituted phenols which are commercially available such as, but not limited to, 2,4,6-trichloro-, 2,4,6-tribromo- and 2,4,6-trimethylphenols, or obtained by methods established in the literature by a person familiar with the art. Subsequent to condensation with V to provide aryloxychloropyrimidine (Via), the amination may provide the objective compounds IXa which represent the formula I wherein X and X 'are as defined in the above, wherein R1, R3 and Rs are as previously described, and Q is O. Alternatively, they can substitute the phenols of schemes 1 and 2 with the thiophenols appropriately substituted to prepare the corresponding sulfur analogs of those compounds described in these Schemes (Q = S). These, in turn, can be oxidized to the corresponding sulfoxides or sulfones by oxidizing agents such as, but not limited to, oxone, sodium metaperiodate, potassium permanganate, m-chloroperbenzoic acid, dimethyldioxirane, peracetic acid, hydrogen peroxide, etc. .

The compounds of formula I wherein Y is CR2 and R3 is selected from (CHR16) pAr wherein the aryl group is substituted with 1-3 of R18, (CHR16) -heteroaryl, wherein the heteroaryl group is substituted by 1- 3 of R18, can be prepared as shown in Scheme 3. The treatment of IVa with a base such as sodium hydroxide in a protic solvent such as water or alcohol, followed by condensation of the resulting phenoxide, with the 4-6 known dichloro-2-methyl-5-nitropyrimidine [J. Chem. Soc. 3832 (1954); ibid, 677 (1944)] provides the aryloxychloronitropyrimidine, Xa. The reaction of Xa with an organometallic reagent R3M, wherein M is magnesium or magnesium halide or lithium or other suitable metal with and without a catalyst such as copper, nickel, palladium or zinc, provides aryloxy-, aryl- or heteroarylnitropyrimidine, Xla . Comprehensi e Orqanic Chemistry, vol. 13. Chapter 15, (Barton and Ollis, eds., Pergamon, N.Y.). Xla can then be reduced with iron powder in acetic acid to provide the aminopyrimidine derivative (XlIIa). This amino group can be further transformed into several substituted aryloxypyrimidines (XVa) using standard amino group transformation technology. This methodology includes, but is not limited to, diazmonium salt guímica (Sandmeyer, etc.), acylation guímica, reductive amination guímica, etc. The sequence described in Scheme 4 provides a further example of this process. The treatment of carbinol (IV) with sodium hydroxide in a protic solvent such as water or alcohol, followed by condensation of the phenoxide. resulting with the known 4,6-dichloro-2-methyl-5-nitropyrimidine [J. Chem. Soc. 3832 (1954); ibid, 677 (1944)]. provides the aryloxychloro-nitropyrimidine (X). The reaction of X with an organometallic reagent, R3M, wherein M is magnesium or magnesium halide or lithium or other suitable metal, with or without catalyst such as copper, nickel, palladium or zinc, provides aryloxy-, aryl- or heteroaryl-nitropyrimidine, XI. Comprehensive Organic Chemistry, vol. 13, chapter 15, (Barton and Ollis, eds., Pergamon, N.Y.). XI can be dehydrated to olefin XII with acid catalysts. The reduction of the nitro group can be carried out using Fe powder in acetic acid to provide diaminopyrimidine (XIII) which can be acetylated with acetyl chloride in the presence of a tertiary amine, such as triethylamine, in a solvent such as dichloromethane, a acetamide (XIV). Alternatively, XII can be successfully hydrogenated on platinum black in activated carbon to provide nitropyrmidine (XV) and aminopyrimidine (XVI), respectively.

Alternatively, the phenols of Schemes 3 and 4 may be substituted with the appropriately substituted thiophenols, to prepare the corresponding sulfur analogs of those compounds described in these Schemes. These, in turn, that is, XIV, XV, XVa, can be oxidized to the corresponding sulfoxides or sulfones by oxidizing agents such as, but not limited to, oxone, sodium metaperiodate, potassium permanganate, m-chloroperbenzoic acid, dimethyldioxirane, peracetic acid, hydrogen peroxide, etc.

(IV «) (X«) Q »0, S R3M (XV-i) (Xma) < XI ») SCHEME 3 SCHEME 4 The compounds of the invention and their synthesis are further illustrated by the following examples and preparations.

Example 1 3 - . 3-bromo-4-hydroxy-5-methoxyacetophenone Bromine (9.62 g) in 30 ml of chloroform is added dropwise to a solution of acetovanillone (10.0 g) in 150 ml of chloroform which is maintained at 0 ° -5 ° C so that the temperature does not increase above 5 ° C. ° C. After the addition is complete, the mixture is stirred at 0 ° -5 ° C for 4 hours. The residue is treated with water. The organic layer is dried over MgSO4 and distilled off from the solvent under reduced pressure to provide a pinkish powder which is triturated with ether and filtered to provide 3-bromo-4-hydroxy-5-methoxyacetophenone, m.p. 148-152 ° C.

Example 2 3-bromo-4-hydroxy-5-methoxy-a, a-dimethylbenzene-methanol Ethylmagnesium bromide (3M in diethyl ether, 11.42 ml) is added dropwise to a solution of 5-bromo-4-hydroxy-3-methoxyacetophenone (3.0 g) in anhydrous tetrahydrofuran (60 ml) maintained at 0 ° -5 ° C under N2 gaseous, so that the temperature does not increase above 5 ° C. After the addition is complete, the solution is stirred at room temperature for 2 hours, saturated ammonium chloride is added dropwise until the effervescence ceases The mixture is treated with an excess of saturated ammonium chloride, the organic layer is dried over MgSO 4 and the solvent is distilled off under reduced pressure to provide 3-bromo-4-hydroxy-5-methoxy-a, a-dimethylbenzene-methanol. as a viscous oil which solidifies over a period of time, mp 107-112 ° C.

Example 3 3-bromo-4-y- "4-chloro-6-methyl-1,3,5-triazin-2-yl] oxyl-5-methoxy-a, a-dimethylbenzene-methanol 3-Bromo-4-hydroxy-5-methoxy-a, a-dimethylbenzenemethanol (1.16 g) is dissolved in 10% NaOH (1.78 g) and 5 ml of water. The solvent is distilled off under reduced pressure. The salt is taken up in 50 ml of acetonitrile and cooled to 0 ° -5 ° C. 2, 4-Dichloro-6-methyl-1,3,5-triazine (0.61 g) is added and the mixture is stirred at 0 ° -5 ° C for 1 hour. The solvent is removed under reduced pressure and the residue is extracted with methylene chloride. The extracts are combined and distilled off under reduced pressure to provide 3-bromo-4- [[4-chloro-6-methyl-1,3,5-triazin-2-yl] oxy] -5-methoxy-a. , α-dimethylbenzenemethanol.

Example 4 3-bromo-4- T6-methyl-4- (4-morpholinyl) -1,3,5-triazin-2-yl-oxy] -5-methoxy-a, a-dimethylbenzene-methanol To a solution of 3-bromo-4- [[4-chloro-6-methyl-1,3,5-triazin-2-yl] oxy] -5-methoxy-a, a-dimethylbenzenemethanol (3.0 g) in 1 , Anhydrous 4-dioxane (80 ml), morpholine (1.39 ml) is added and the solution is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue is taken up in water and extracted with methylene chloride. The extracts are combined and dried over MgSO4. The solvent is distilled off under reduced pressure and the residue is purified on silica gel using a 2: 1 mixture of ethyl acetate and hexane to provide 3-bromo-4- [[6-methyl-4- (4-morpholinyl ) -1,3,5-triazin-2-yl] oxy] -5-methoxy-a, a-dimethylbenzenemethanol as a colorless powder, mp 199-201 ° C.

TABLE 1 CH2CH2 CH2CH20CH3 92-94 CH2CH2CH3 CH2 (CHCH2CH2) 144-147 H CH (CH2CH3) CH20CH3 (CH2) S 86-98 (CH2) 4 152-153 CH2CH2SCH2CH2 161-167 Example 5 2- r 2 -bromo-6-methoxy-4- (1-methylethyl) phenoxy-4-methyl-6- (4-morpholinyl) -1,3,5-triazine To a solution of 3-bromo-4- [[6-methyl-4- (4-morpholyl) -1,5,5-triazin-2-yl] oxy] -5-methoxy-a, -dimethylbenzene ethanol (1.92 g) in 80 ml of benzene, a small amount of p-toluenesulfonic acid is added. The solution is refluxed under azeotropic conditions for 16 hours. Once cooled to room temperature, the solution is washed with saturated NaHCO 3 followed by water. The organic phase is dried over MgSO 4 and the solvent is removed under reduced pressure. The residue is purified on silica gel using a mixture of ethyl acetate 1: 1 and hexane to give 2- [2-bromo-6-methoxy-4- (1-methylethyl) phenoxy] -4-methyl-6- ( 4-morpholinyl) -1,3,5-triazine as a colorless compound, mp 63-67 ° C. TABLE 2 CH2CH2OCH2CH2 63-67 CH2CH2OCH3 CH2CH20CH3 CH2 CH2 CH3 CH2 (CHCH2CH2) oil CH2CH3 CH2 CH2 CH2 CH3 oil H CH (CH2CH3) CH2OCH3 119-121 CÍI2 ^ "2 ^ ^ *** 2 ^ - * - ^ 2 147-151 (CH2 ) S (CH2) 4 154-161 (CH2) 6 103-105 (CH2) 4CH (CH2CH3) 58-64 CH2CH2CHCHCH2 51-54 Example 6 2- Í2-Bromo-6-methoxy-4- (1-methyletenyl) phenoxy] -4-methyl-6- (4-morpholinyl) -1,3,5-triazine % platinum black (0.20 g) is added to a solution of2- [2-bromo-6-methoxy-4- (1-methylethyl) phenoxy] -4-methyl-6- (4-morpholinyl) -1, 3 , 5-triazine (0.18 g) in 50 ml of ethanol. The mixture is hydrogenated at a pressure of 1.9 kg / cm2 (27 psi) for 16 hours. The mixture is filtered through celite and the filtrate is distilled off under reduced pressure to provide 2- [2-bromo-6-methoxy-4- (1-methylethyl) phenoxy] -4-methyl-6- (4- morpholinyl) -1, 3,5-triazine as a colorless powder, mp 131-133 ° C. TABLE 3 CH2CH20CH3 CH2CH2OCH3 CH2 CH2 CH3 CH2 (CHCH2CH2) H CH (CH2CH3) CH2OCH3 121-127 CH2CH20CH2CH2 131-133 C --- H2 CH2 S C-H2 v-.H2 112-118 Example 7 1- f3-bromo-5-methoxy -4- \ f4-Methyl-6- (4-morpholinyl) -1,3,5-triazin-2-ill oxyl phenyl] ethanone Dissolve 3-bromo-4-hydroxy-5-methoxyacetophenone (3.60 g) in 10% NaOH (5.86 g) and 10 ml of water. The solvent is distilled off under reduced pressure. The salt is treated in 50 ml of acetonitrile and cooled to 0-5 ° C. 2,4-Dichloro-6-methyl-1,3,5-triazine (2.40 g) is added and the mixture is stirred at 0 ° -5 ° C for 1 hour. Subsequently the solvent is removed from the mixture under reduced pressure. The residue is extracted with methylene chloride. The extracts are combined and distilled off under reduced pressure to provide a solid which is dissolved in 120 ml of anhydrous 1,4-dioxane, and the resulting solution is treated with 2.64 ml of morpholine. The mixture is stirred at room temperature for 2 hours and the solvent is subsequently removed under reduced pressure. The residue is taken up in water and extracted with methylene chloride. The combined methylene chloride extracts are dried over MgSO4 and evaporated under reduced pressure to provide 1- [3-bromo-5-methoxy-4- [[-methyl-6- (4-morpholinyl) -1, 3, 5 -triazin-2-yl] oxy] phenyl] ethanone, mp 159-162 ° C.

TABLE 4 R Ex P.F. (° C) CH2CH20CH3 (..-, i2 (_-- xl 2 J (_. 3 82-86 CH2CH2OCH2CH2 159-162 CH CH2 S CH2 CH2 158-170 (CH2) 111-115 Utility Receptor binding assay in vi tro: Weaving preparation: Rats are slaughtered by decapitation Sprague Dawley MALE (180-200 g) and the bark is dissected on ice, the whole is frozen in liquid nitrogen and stored at -70 ° C until use. On the day of the assay, the frozen tissue is weighed and homogenized in 20 volumes of ice-cooled buffer containing 50 mM Tris, MgCl210 mM, 2 mM EGTA, pH 7.0 at 22 ° C using a Polytron (Brinkmann Instruments, Westbury, NY; adjust 6) for 20 s. The homogenate is centrifuged at 48,000 x g for 10 min at 4 ° C. The supernatant is discarded and the pellet is rehomogenized in the same volume of buffer and centrifuged at 48,000 x g for 10 min at 4 ° C. The resulting pellet is resuspended in the above buffer to a final concentration of 20-40 mg of the original wet weight / ml and is used in the assays described below. Protein determinations are performed according to Lowry's method [Lowry et al., J ". Biol. Chem. 193-265 (1951)] using bovine serum albumin as a standard.

CRF receptor binding: The receptor binding assays were carried out essentially as described by E.B. De Souza, J. Neurosci. 7:88 (1987).

Saturation curve analysis In saturation studies, 100 μl of 125 I-ovine CRF (50 pM - 10 nM final concentration), 100 μl of assay buffer (with or without 1 mM r / hCRF final concentration, to define nonspecific binding) and 100 μl of membrane suspension (as described above) were added in sequence to 1.5 ml of polypropylene microcentrifuge tubes for a final volume of 300 μl. All tests were carried out until equilibrium for 2 h at 22 ° C as described by E.B. De Souza, J. "Neurosci., 7:88 (1987) .The reaction was terminated by centrifugation of the tubes in a Beckman microcentrifuge for 5 min at 12,000 x g. Aliquots of the supernatant were collected to determine the concentration of" free "radioligand. The remaining supernatant was aspirated and the pellets were gently washed in ice-cold PBS plus 0.01% Triton X-100, centrifuged again and monitored for bound radioactivity., as described before. The data were analyzed from the saturation curves using the LIGAND nonlinear least squares curve fitting program [P.J. Munson and D. Rodbard, Anal. Biochem. 107: 220 (1980)]. This program has the distinct advantage of adjusting raw experimental data in an untransformed coordinate system where errors are more likely to be distributed normally, and not correlating them with the independent variable. The LIGAND program does not expect the non-specific union to be defined arbitrarily by the researcher, instead it estimates the value as an independent variable of the whole data set. The parameters for affinity constants (KD) and receiver densities (Bmax) are also provided together with the statistics of the general "fit" of the estimated parameters of the untreated data. This program also offers the versatility of simultaneously analyzing multiple curves, which improves the reliability of the data analysis and therefore the validity of the final estimated parameters for any saturation experiment.

Competition curve analysis In competition studies, 100 μl was incubated [12SI] ovine CRF ([125I] or CRF, final concentration, 200-300 pM) together with 100 μl of buffer (in the presence of varying concentrations of competing ligands, typically 1 pM to 10 mM) and 100 μl of membrane suspension was prepared before to provide a total reaction volume in 300 μl. The reaction was initiated by the addition of membrane homogenates, allowed to proceed to equilibrium for 2 h at 22 ° C and was finalized by centrifugation (12,000 x g) in a Beckman microcentrifuge to separate the bound radioligand from the free radioligand. The resulting pellets were washed on the surface twice by centrifugation with 1 ml of ice-cold phosphate-buffered saline and 0.01% triton X-100, the supernatants were discarded and the pellets were onitored to determine radioactivity at approximately 80 % efficiency The level of non-specific binding was defined in the presence of 1 μM of unlabeled rat / human CRF (r / hCRF). The data of the competition curves are analyzed by the LIGAND program. For each competition curve, the affinity estimates of the radiolabeled ligand for the CRF receptor ([12SI] CRF) were obtained in independent saturation experiments (as described above) and these estimates were restricted during the analysis of the constants Apparent inhibition (Ki) for the peptides tested. Typically, the data were analyzed using the one-site or two-site model by comparing the "goodness of fit" between the models in order to accurately determine Ki. The statistical analysis provided by LIGA? D allows the determination of whether a single site or multiple site model should be used. For both peptides (a-helical CRF9.41 and d-PheCRF12.41), as well as for all compounds of this invention, the data fit significantly with the one-site model the two-site model was not possible or did not improve significantly adjust the estimated parameters to the data. The results of the in vi tro test of the compounds of the invention of formula I demonstrate binding affinities for the CRF receptor, expressed as the K ± value in the range of 2-5000 nM. It was found, for a representative number of compounds of the invention, that any form of the compound, either as a free base or as a hydrochloride, produces essentially the same inhibition value in the binding assay.

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

CRF-R1 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 assay itself. Human hippocampal messenger RNA was isolated. He MRNA was subjected to reverse transcription using oligo (dt) 12-18 and the coding region was amplified by PCR from the start codons to the stop codons. The resulting fragment by PCR was cloned in the EcoRV or pGEMV site, where the insert was re-obtained using Xhol + Xbal and cloned in the Xhol + Xbal sites of the pm3ar vector (which contains a CMV promoter, the "t" junction). "SV40 and early poly A signals, a viral replication origin of Epstein-Barr and a selectable marker for hygromycin). The resulting expression vector, called phchCRFR, is transfected into 293EBNA cells and cells that retain the episome in the presence of 400 μM hygromycin are selected. Cells that survive 4 weeks of hygromycin selection were harvested, adapted for growth in suspension and used to generate membranes for the binding assay described below. Subsequently, individual aliquots containing approximately 1 x 108 of the suspended cells were centrifuged to form a pellet and frozen. For the binding assay, a frozen pellet described above containing 293EBNA cells transfected with hCRFR1 receptors is homogenized in 10 ml of ice-cooled tissue buffer (50 mM HEPES buffer, pH 7.0, containing 10 mM MgCl2, 2 mM EGTA, 1 μg / 1 of aprotinin, 1 μg / ml of leupeptin and 1 μg / ml of pepstatin). The homogenate was centrifuged at 40,000 x g for 12 min and the resulting pellet was homogenized again in 10 ml of tissue buffer. After further centrifugation at 40,000 x g for 12 min, the pellet is resuspended at a protein concentration of 360 μg / ml to be used in the assay. The binding assays are performed in 96-well plates; each well has a capacity of 300 μl. To each well, 50 μl of the dilutions of the test drug are added (the final concentration of the drugs varies from 10"10 to 10" 5 M), 100 μl of 12SI-o-CRF (final concentration, 150 pM) and 150 μl of the cell homogenate described above. Subsequently, the plates are allowed to incubate at room temperature for 2 hours before filtering the incubation on GF / F filters (pre-rinsed with 0.3% polyethylenimine) using an appropriate cell harvester. The filters are rinsed twice with ice-cooled assay buffer before removing individual filters and determining radioactivity in a gamma counter. The curves of cell membrane binding 125 I-o-CRF inhibition at various dilutions of the test drugs were analyzed by an interactive curve fitting program LIGAND, which provides Kt values for inhibition which are then used to determine the biological activity.

Biological test in vivo The in vivo activity of the compounds of the present invention can be determined using any of the biological assays available and accepted within the art. Illustrative of these tests is the acoustic startle test, the chair climbing test, and the chronic administration test. These and other useful models for testing compounds of the present invention have been delineated in C.W. Berridge and A.J. Dunn Brain Research 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 scope of the invention. The results of the following tests demonstrate that the compounds of this invention have utility in the treatment of imbalances associated with abnormality in the levels of corticotropin releasing factor in patients suffering from depression, affective disorders and / or anxiety. In addition, such compounds may be useful in the treatment of affective disorders, anxiety, depression, post-traumatic stress disorders, eating disorders, supranuclear palsy, irritable bowel syndrome, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, symptoms of drug and alcohol suspension, drug addiction, inflammatory disorders or fertility problems. The compounds of this invention can be administered to treat such abnormalities by means of contact production of the active agent with the site of action of the agent in the body of a mammal. The compounds may be administered by any conventional means available for use in conjunction with pharmaceutical substances either as an individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier that is selected based on the chosen route of administration and standard pharmaceutical practice. The dosage administered will vary based on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration.; the recipient's age, weight and health; the nature and extent of the symptoms; the class of concurrent treatment; the frequency of treatment and the desired effect. For use in the treatment of such diseases or conditions, the compounds of this invention can be administered orally every day at a dosage of the active ingredient from 0.002 to 200 mg / kg of body weight. Usually, a dose of 0.01 to 10 mg / kg in divided doses, one to four times a day, or in a sustained release formulation, is effective to obtain the desired pharmacological effect. Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of the active ingredient per unit. In these pharmaceutical compositions, the active ingredient will usually 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 orally in solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups and / or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dosage formulations. Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as, but not limited to lactose, starch, magnesium stearate, stearic acid or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both the tablets and the capsules can be manufactured as sustained release products to provide continuous release of the medication over a period of time. The compressed tablets can be sugar coated or film coated, to mask any unpleasant taste or are used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract. Liquid dosage forms for oral administration may contain coloring or flavoring agents to increase patient acceptance. In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose) and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, butter substances. Antioxidant agents such as sodium bisulfite, sodium sulfite or ascorbic acid, either alone or in combination, are suitable stabilizing agents. It also uses citric acid and its salts, and EDTA. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methylparaben or propylparaben and chlorobutanol.

Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences," A. Osol, a standard reference in the art. The pharmaceutical dosage forms useful for administration of the compounds of this invention can be illustrated as follows: Capsules A large number of capsule units are prepared by filling two standard two-piece hard gelatin capsules, each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

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

Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg of 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 palatability or delay absorption. The compounds of this invention can also be used as reagents or standards in the biochemical study of neurological function, dysfunctions and diseases. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates. Having described the invention as above, property is claimed as contained in the following:

Claims (13)

1. A compound of formula (I) (I) or a pharmaceutically acceptable salt or prodrug thereof, characterized in that: Q = O, S (0) n; R1 is alkyl, alkenyl or alginyl of Cx-C4, haloalguilo of C-C2, halogen, NR6R7, OR8, SR8, CN; R3 is C 1 -C 8 alkenyl, haloalkyl of C-Q 2, halogen, NR 6 R 7, OR 3, SR 8, (CH 2) kNR 6 R 7, (CH 2) k 0 R 8, CH (CHR 16 CHR 16 OR 8) 2, CH (CN) AR, CH (CN) 2, CHR16 (CHR16) p0R8, (CHRls) pAr wherein the aryl group is substituted with 1-3 of R18, (CHR16) pheteroaryl, wherein the heteroaryl group is substituted with 1-3 of R18, 1-etrahydroquinolinyl, 2-tetrahydroisoquinolinyl , phenyl or heteroaryl substituted with 0-3 selected groups of hydrogen, halogen, Ci-Cj alkyl, C ^ d alkoxy, nitro, cyano, S (O) zz-alkyl of V is N; And it's CR2 or N; Z is N; R2 and is independently selected each time it is presented from the group consisting of hydrogen, halo, halomethyl, methyl, cyano, nitro, NR6R7, NH (COR9), N (COR9); X and X 'are independently selected, each time they occur, from the group consisting of alkenyl, halogen, S (0) nR8, OR8, halomethyl, NR19R1S, CN; R5 'is H, halo, Ci-Cg alkenyl, alkenyl C2-C6, haloalguyl of (CHR16) p0R8, (CHR16) pS (0) nR8, (CHR16) pNR14Rls, C3-C6 cycloalkyl, C4-C6 cycloalgenyl, CN; R6 and R7 are independently selected each time from the group consisting of: hydrogen, C3-C10 cycloalkyl algilo, C3-C10 cycloalguilalguilo, CH (R16) (CHR1S) P0R8, (CHR16) p0R8, (alguilo of d-Cg) -aryl, heteroaryl, - (Ci-Cg alkoyl) -heteroaryl or aryl optionally substituted with 1-3 groups which are selected from the following: hydrogen, halogen, C ^ Cg alkoxy, amino, NHC (= 0) (Ci-Cg alkyl), NH (N-C 1 -C 6 alkyl) 2, nitro, C02 (Cx-Cg alkyl), cyano, S (0) z- (Ci alkyl) -Cg), or Rβ and R7 can be taken together to form - (CH2) qA (CH2) r-, optionally substituted with 0-3 of R17, or, when considered with commonly attached nitrogen, Rs and R7 can be taken taken together to form a heterocycle, the heterocycle is substituted on the carbon with 1-3 groups consisting of: hydrogen, alkyl (Ci-Cg alkyl) -alkoxy of C ^ -C *, hydroxy or Ci-Cg alkoxy , - A is CH2, O, S (0) n, N (C (= 0) R2 4), N (R19), C (H) (NR14R15), C (H) (OR20), C (H) (C (= 0) R21), N (S (0) nR21); R8 is hydrogen, cycloalkyl alkyl of C3-Ce, (CH2) tR22, C3-C10 cycloalkyl, cycloalkylalkyl, - (alkyl-aryl, heteroaryl, - (Cj-Cg alkyl) -heteroaryl or aryl optionally substituted with 1-3 groups which are selected from the following: hydrogen, halogen, Ci-Cg alkoxy alkyl, amino, NHC (= 0) (alkyl, NH (Cj-Cg alkyl), N (nitro alkyl, C02 (alkyl, cyano; S (O ) z (alkyl) R9 is independently selected, each time it occurs, from hydrogen, dd alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C4 alkenyl, aryl substituted with 0-3 of R18 and - (alkyl-aryl substituted with 0-3 of R18; R14 and R1S are independently hydrogen, Ci-Cg alkyl, C3-C6 cycloalkyl, (CH2) tR22, aryl substituted with 0-3 of R18; R16 is hydrogen or C, C4, R17 alkyl is hydrogen, CX-C4 alkyl, C ^ j alkoxy, halo, OR23, SR23, NR3R24, Cx-C3 alkyl, C-C alkoxy; R18 is hydrogen, C-L-C-haloalkyl alkyl of C-L-C, C2-C2 alkoxy, C (= 0) R24, N02, halogen or cyano; R19 is C3-C3 cycloalkyl alkyl, (CH2) WR22, aryl substituted with 0-3 of R18; R20 is hydrogen, C (= 0) R22, d-d alkyl, C2-C4 alkenyl; R21 is hydrogen, Cx-C4 alkoxy, NR23R24, hydroxyl or d-d alkyl; R22 is cyano, OR24, SR24, NR23R24, C3-C6 cycloalkyl; 23 and R24. they are independently selected, each time they occur, from hydrogen or d-d alkyl; k is 1-4; n is independently selected, each time it is presented, from 0-2; p is 0-3 q is 0-3 r is l-4 t is independently selected, each time it is presented, from 1-6; z = 0-3; w = 1-6; with the proviso, however, that when Y is CR2, then R3 is (CHR16) Ar wherein the alkyl group is substituted with 1-3 of R18 or (CHR16) pheteroaryl, wherein the heteroaryl group is substituted with 1- 3 of R18.
2. 2. The compound according to claim 1, characterized in that: R3 is CX-C4 alkyl, d-C2 haloalkyl, NR6R7, OR8, CH (CHR16CHR16OR8) 2, CH (CN) AR, CH (CN) 2, CH (R16CHR16) p0R8, (CHRls) pAr, wherein the aryl group is substituted with 1-3 of R18, (CHR16) pheteroaryl, wherein the heteroaryl group is substituted with 1-3 of R18, 1-tetrahydroquinolinyl, 2-tetrahydrois? quinolinyl, phenyl or heteroaryl substituted with 0-3 groups which are chosen from hydrogen, halogen, d-C4 alkyl, Cx alkoxy -C4, nitro, cyano, S (0) z-alkyl of -; R2 is independently selected, each time it occurs, from the group consisting of hydrogen, halo, methyl, nitro, cyano, NR6R7, NH (C0R9),? (COR9) 2; R6 and R7 are independently selected, each time from the group consisting of: hydrogen, d-C3 alkeyl, C3-C10 cycloalkyl, cycloalguilalguil, d-C3 alkoxy, (CHR16) p0R8, (CHR16) pOR8 , - (C1-C6 alkyl) aryl, heteroaryl, - (d-C6 alkyl) -heteroaryl or aryl optionally substituted with 1-3 groups which are selected from the following: hydrogen, halogen, alkyl, d-alkoxy -C6 / NHC (= 0) (d-C6 alkyl), NH (d-C6 alkyl) N (C1-C6 alkyl) 2, C02 (d-C6 alkyl), cyano, or R6 and R7 are can take together to form - (CHjJqAÍCHj) ..-, optionally substituted with 0-3 of R17 or, when considered with the nitrogen to which they are commonly attached, R6 and R7 can be taken together to form a heterocycle, the heterocycle is substituted on carbon with 1 -3 groups consisting of: hydrogen, d-C3-alkoyl, alkoxy (Ci-Cg) -d-C4-alkoxy, hydroxy, or dd-alkoxy; R8 is hydrogen, d-d alkeyl, C3-C6 cycloalkyl, (CH2) tR22, C3-C10 cycloalkyl, cycloalguilalguil, - (C6-alkoyl) -aryl or heteroaryl optionally substituted with 1-3 groups which are selected from the following: hydrogen, halogen, d-C6 alkyl, dd alkoxy, NHC (= 0) (d-alkyl) C6), NH (Cx-C6 alkyl) N (CX_CS alkyl) 2 C02 (alkyl of -), R14 and R15 are independently hydrogen, d-Cg alkyl, C3-C3 cycloalkyl; R17 is hydrogen, CX-C4 alkyl, d-C4 alkoxy, alkyl (Ci-Cg) Cx-C4 alkoxy; R18 is hydrogen, CX-C4 alkyl, C2-C2 haloalkyl, C2-C4 alkoxy, or cyano; R19 is Cx-C6 alkyl, C3-C3 cycloalkyl, aryl substituted with 0-3 of R18; R22 is cyano, OR24, SR24, NR23R24, C3-C6 alkyl or cycloalkyl; R23 and R24 are independently selected each time they occur of hydrogen or Cx-C4 alkyl; t is independently selected each time it is presented 1-3; w is 1-3; with the proviso, however, that when Y is CR2, then R3 is (CHR16) pAr where the aryl group is substituted with 1-3 of R18 or (CHR16) pheteroaryl, wherein the heteroaryl group is substituted with 1- 3 of R18.
3. 3. The compound according to claim 2, characterized in that: R1 is Cx-C2 alkyl, halide, NR6R7, OR8; R3 is CX-C4 alkyl, C2-C2 haloalkyl, NR6R7, OR8, (CH2) kNR6R7, (CH2) kNR6R7, (CH2) kOR8; And it's N; X and X 'are independently selected, each time they occur, from the group consisting of methyl, hydrogen, Cl, Br, I, OR8, NR14R1S, CN, S (0) nR8; R5 is H, halo, d-C6 alkyl, d-C3 haloalkyl, CX-C6 alkoxy, (CHR16) pOR8, (CHR16) pNR14Rls, C4-C3 cycloalkyl; R6 and R7 are independently selected each time they occur from the group consisting of: CX-C3 alkyl, (CHR16) pR8; or they can be taken together to form - (CH2) gICH;,) r-, optionally substituted with CH20CH3; A is CHj, O, S (0) n, N (C (= 0) R18), N (R19), C (H) (OR20); R8 is hydrogen, d-C6 alkyl, cycloalkyl
4. C3-C6, (CH2) tR22; R9 is hydroxy, CX-C4 alkyl or methoxy; R13 is OR19, SR19, NR23R24, C3-C3 cycloalkyl. R14 and R1S are independently hydrogen, Cx-C2 alkyl, C3-C3 cycloalkyl;
5. R16 is hydrogen; R 13 is hydrogen, C 1 -C 4 alkyl, C 1 -C 2 haloalkyl, C x C 4 alkoxy, C (= 0) R 24, or cyano; R19 is Cx-C3 alkyl; R20 is hydrogen, C2-C2 alkyl or alkenyl of
6. R22 is OR24; R23 and R24 are independently selected, each time it occurs, from hydrogen or Cx-d alkyl. k is 1-3; m is 1-4; n is independently selected, each time it is presented 0-2, p is 0-2 q is 0-2 r is 1-2, t is independently selected each time it is presented 1-3; w is 1-3. 4. The compound according to claim 1, characterized in that it is selected from the group: a) 2- [2-Bromo-6-methoxy-4- (1-methyletenyl) phenoxy] -4-methyl-6- (4-morpholinyl) ) -1,3, 5-triazine; b) 2- [2-Bromo -6-methoxy -4 (1-methyletenyl) phenoxy] 4-methyl-6- (bis (2-methoxyethyl) amino) -1,3,5-triazine; c) 2- [2-Bromo-6-methoxy-4- (1-methylethyl) phenoxy] 4-methyl-6 - (N-propyl-N-cyclopropylmethylamino) -1,3,5-triazine; d) 2- [2-Bromo-6-methoxy-4- (1-methylethyl) phenoxy] 4-methyl-6- (1-homopiperidinyl) -1,3,5-triazine; e) 2- [2-Bromo-6-methoxy-4 (l-methyletenyl) phenoxy] 4-methyl-6- (diethylamino) -1,3,5-triazine; f) 2- [2-Bromo-6-methoxy-4 (l-methyletenyl) phenoxy] 4-methyl-β- (N-butyl-N-ethylamino) -1,3,5-triazine; g) 2- [2-Bromo-6-methoxy-4 (l-methyletenyl) phenoxy] 4-methyl-6- (4-thiomorpholinyl) -1,3,5-triazine; h) 2- [2-Bromo-6-methoxy-4- (l-methyletenyl) phenoxy] 4-methyl-6- (2- (1-methoxybutyl) amino) -1,3,5-triazine; i) 2- [2-Bromo-6-methoxy-4 (l-methyletenyl) phenoxy] 4-methyl-6- (1-piperidinyl) -1,3,5-triazine; j) 2- [2-Bromo-6-methoxy-4- (l-methyletenyl) phenoxy] 4-me il-6- (1- (1.2.3.4-tetrahydroquinolinyl)) -1,3,5 triazine; k) 2- [2-Bromo-6-methoxy-4- (1-methylethyl) phenoxy] 4-methyl-6- (1-pyrrolidinyl) -1,3,5-triazine; 1) 2- [2-Bromo-6-methoxy-4- (l-methyletenyl) phenoxy] 4-methyl-6- (1- (2-ethylpieridinyl)) -1,3,5-triazine; m) 2- [2-Bromo-6-methoxy-4- (l-methyletenyl) phenoxy] -4-methyl -6- (2 - (1.2.3.4-tetrahydroisoquinolinyl)) -1,3,5-triazine; n) 2- [2-Bromo-6-methoxy-4- (l-methyletenyl) phenoxy] -4-methyl-6- (1- (1,3,5,6-tetrahiropiperidinyl) -1,3,5-triazine; o) 2- [2-Bromo-6-methoxy-4- (l-methyletenyl) phenoxy] -4-methyl-6- (1- (2-trifluoromethylphenyl)) -1,3,5-triazine; p) 2- [2-Bromo-6-methoxy-4- (1-methylethyl) phenoxy] -4-methyl-6- (4-morpholinyl) -1,3,5-triazine; q) 2- [2-Bromo-6-methoxy-4- (1-methylethyl) phenoxy] -4-methyl-6- (bis (2-methoxyethyl) amino) -1,3,5-triazine; r) 2- [2-Bromo-6-methoxy-4- (1-methylethyl) phenoxy] -4-methyl-6- (N-propyl-N-cyclopropylmethylamino) -1,3,5-triazine; s) 2- [2-Bromo-6-methoxy-4- (1-methylethyl) phenoxy] -4-methyl-6- (1-homopiperidinyl) -1,3,5-triazine; t) 2- [2-Bromo-6-methoxy-4- (1-methylethyl) phenoxy] -4-methyl-6- (N-butyl-N-ethylamino) -1,3,5-triazine; u) 2- [2-Bromo-6-methoxy-4- (1-methylethyl) phenoxy] -4-methyl-6- (4-thiomorpholinyl) -1,3,5-triazine; v) 1- [3-Bromo-5-methoxy-4- [[4-methyl-6- (4-morpholinyl) -1,3,5-triazinyl-2-yl] oxy] phenyl] ethanone; w) 1- [3-Bromo-5-methoxy-4- [[4-methyl-6- (bis (2-methoxyethyl) amino) -1,3,5-triazinyl-2-yl] oxy] phenyl] ethanone; x) 1- [3-Bromo-5-methoxy-4 - [[4-methyl -6- (4-thiomorpholinyl) -1,3,5-triazinyl-2-yl] oxy] phenyl] ethanone; y) 1- [3-Bromo-5-methoxy-4- [[4-methyl-6- (diethylamino) -1,3,5-triazinyl-2-yl] oxy] phenyl] ethanone; z) 1- [3-Bromo-5-methoxy-4 - [[4-methyl-6- (1-piperidinyl) -1,3,5-triazinyl-2-yl] oxy] phenyl] ethanone; aa) 3-Bromo-4- [[6-methyl-4 (bis (2-methoxyethyl) amino) -1,3,5-triazin-2-yl] oxy] -5-methoxy-alpha, alpha-dimethylbenzene tanol; bb) 3-Bromo-4- [[6-methyl-4 (N-propyl-N-cyclopropylmethylamino) -1, 3, 5-triazin-2-yl] oxy] -5-methoxy-alpha, alpha a- dimethylbenzenemethanol; cc) 3 -Bromo-4 - [[6-methyl-4 (2 - (1-methoxybutyl) amino) -1,3,5-triazin-2-yl] oxy] -5-methoxy-alpha, alpha a- dimethylbenzenemethanol; dd) 3-Bromo-4- [6-methyl-4- (4-thiomormofolinyl) -1,3,5-triazin-2-yl] oxy] -5-methoxy-alpha, alpha-dimethylbenzene-tanol; ee) 3-bromo-4- [[6-methyl-4 (l -piperidinyl) -1,3,5-triazin-2-yl] oxy] -5-methoxy-alpha, alpha-dimethylbenzenemethanol; ff) 3-Bromo-4- [[6-methyl-4- (1-homopiperidinyl) -1, 3, 5-triazin-2-yl] oxy] -5-methoxy-alpha, to fa -dimethylbenzene ethanol, gg) 3-Bromo-4 - [[6-methyl-4 (1 - (2-trifluoromethylphenyl)) -1,3,5-triazin-2-yl] oxy] -5-methoxy-alpha, alpha-dimethylbenzenemethanol; hh) 2- (2,4,6-Trio-phenoxy) -4-methyl-6- (4-morpholinyl) -1,3,5-triazine; ii) 2- (2,4,6-Trichlorophenoxy) -4-methyl-6- (4-morpholinyl) -1,3,5-triazine, - jj) 2- (2-chloro-4,6-dimethoxyphenoxy) -4-methyl-6- (4-morpholinyl) -1,3,5-triazine; and kk) 2- [(2,6-Dibromo-4- (1-methylethyl)) phenoxy] -4-methyl-6- (N-ethyl-N-butylamino) -1,3,5-triazine uu) 2 - [(2,6-Dibromo-4- (1-methylethyl)) phenoxy] -4-methyl-6- (bis (2-methoxyethyl) amino) -1, 3, 5-triazine. A method for treating affective disorders, anxiety or depression in mammals, characterized in that it comprises administering to the mammal a therapeutically effective amount of a compound according to claim 1. 6. A method for treating affective disorders, anxiety or depression in mammals, characterized in that it comprises administering to the mammal a therapeutically effective amount of a compound according to claim 2.
7. 7. A method for treating affective disorders, anxiety or depression in mammals, characterized in that it comprises administering to the mammal a therapeutically effective amount of a compound in accordance with with claim 3.
8. 8. A method for treating affective disorders, anxiety or depression in mammals, characterized in that it comprises administering to the mammal a therapeutically effective amount of a compound according to claim 4.
9. 9. A pharmaceutical composition characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount. of a compound according to claim 1.
10. 10. A pharmaceutical composition characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 2.
11. 11. A pharmaceutical composition characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 3.
12. 12. A pharmaceutical composition characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount. A pharmaceutical composition characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 5.