MXPA00009575A - Aminoalkyl substituted pyrrolo[2,3-b]pyridine and pyrrolo[2,3-d]pyrimidine derivatives:modulators of crf1 receptors - Google Patents

Abstract

Disclosed are compounds of formula (I), wherein Ar, Q1, Q2, R1, W and X are substituents as defined herein, which compounds are water-soluble CRF1 receptor antagonists, and are therefore useful for the treatment of psychiatric disorders and neurological diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders, as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.

Description

DERIVATIVES OF PIRRÓLO [2,3-B] IRIDINA AND PIRRÓLO [2,3- DjPIRIMIDINA SUBSTITUTED WITH AMINOALQÜILO: MODULATORS OF CRFi RECEIVERS BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to pyrrolo [3, 2-e] pyridine and pyrrolo [2, 3-b] pyrimidine substituted with aminoalkyl derivatives, to pharmaceutical compositions containing such compounds and to their use for the treatment of psychiatric disorders and neurological diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, eating disorders and supranuclear palsy, as well as the treatment of immunological, cardiovascular or heart-related diseases and associated with colonic hypersensitivity with psychopathological alteration and tension.

Description of Related Art The corticotropin release factor Ref.123626 (referred to herein as CFR), a peptide of 4.1 amino acids, is the primary physiological regulator of the secretion of peptides derived from proopiomelanocortin (POMO from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. USA) 80: 4851 (1983); Vale et al., Science 213: 1394 (1981).] In addition to its endocrine role in the pituitary gland, the immunohistochemical localization of CRF has shown that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulatory role in the brain [W. Vale et al., Rec. Prog. Horm. Res. 39: 245 (1983); GF Koob , Persp Behav, Med. 2:39 (1985), EB De Souza et al, J. Neurosci., 5: 3189 (1985).] There is also evidence that CRF plays a significant role in the integration of the response of the system i immune to physiological, psychological and immunological stress agents [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 cardiovascular disorders. feeding, a role for 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 because they are related to the dysfunction of CRF neurons in the central nervous system [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 cerebral spinal fluid 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 is significantly reduced in the frontal cortex of suicidal victims, consistent with a hypersecretion of CRF [C.B. Nemeroff et al., Arch. Gen. Psychiatry 45: 577 (1988)]. There is also an adrenocorticotropin (ACTH) response mitigated to CRF (administered i.v.) observed in depressed patients [P. . Gold et al., Am J. Psychiatry 141: 619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9: 147 (1984); P.

. Gold et al., New Eng. J. Med. 314: 1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms observed in human depression [R.M. Sapolsky, Are. Gen. Psychiatry 46: 1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and therefore modulate the numbers of CRF receptors in the brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)} . There has also been a postulated role for CRF in the etiology of disorders related to anxiety. CRF produces anxiogenic effects in animals and interactions between benzodiazepine / benzodiazepine anxiolytics other than benzodiazepine and CRF have been demonstrated in a variety of behavioral anxiety models [D.R. Britton et al., Life Sci. 31: 363 (1982); C.W. Berrigde and A.J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies that use the CRF of the sheep of the propeller a. of the putative CRF receptor antagonist (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to benzodiazepines [C.W. Berridge and A.J. Dunn Horm. Behav. 21: 393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics, which provides additional evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both the conflict test [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 (Ro 15-1788), which had no behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the inverse agonist of benzodiazepine ( FG 7142) improved the actions of the CRF [KT Britton et al., Psychopharmacology 94: 306 (1988)]. It has been further postulated that CRF has a role in immunological, cardiovascular or heart-related diseases such as hypertension, tachycardia and congestive heart failure, seizures or osteoporosis. CRF has also been implicated in premature births, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, postoperative ileus and colonic hypersensitivity associated with psychopathological alteration and tension. The mechanisms and action sites through which standard anxiolytics and antidepressants produce their therapeutic effects are yet to be discovered. However, it 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 (CRF 9-41 a-helical) in a variety of behavioral paradigms have shown that the CRF antagonist produces "anxiolytic-like" effects "qualitatively similar to benzodiazepines [for a GF review] Koob and K.T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De? Ouza and C. B. Nemeroff eds., CRC Press p221 (1990)].

Brief Description of the Invention In one aspect, the present invention provides novel compounds which bind to corticotropin releasing factor receptors, thereby altering the anxiogenic effects of CRF secretion.

The compounds of the present invention are useful for the treatment of psychiatric disorders and neurological diseases, disorders related to anxiety, post-traumatic stress disorder, supranuclear palsy and eating disorders as well as the treatment of immunological, cardiovascular or heart-related diseases. and colonic hypersensitivity associated with psychopathological alterations and stress in mammals. According to another aspect, the present invention provides the novel compounds of Formula I (described below) which are useful as antagonists of the corticotropin releasing factor. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress hypersecretion of CRF. The present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the suppression of CRF hypersecretion, and / or for the treatment of anxiogenic disorders. In another aspect, the present invention provides novel compounds, compositions and pharmaceutical methods which can be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other eating disorders, withdrawal symptoms of drugs or alcohol, drug addiction, inflammatory disorder, Fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a selected disorder of inflammatory disorders such as arthritis Rheumatoid and osteoarthritis, pain, asthma, psoriasis and allergies; the generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; the disorder of post-traumatic stress; sleep-induced stress disorders; The perception of pain such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, depression induced by child abuse, and postpartum depression; dyia; bipolar disorders; cyclothymia; the fatigue syndrome; stress-induced headache; cancer, infections caused by the immunodeficiency virus human (HIV); neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic color, diarrhea, and postoperative ileus and colonic hypersensitivity associated with psychopathological alterations or stress; eating disorders such as anorexia and bulimia nervosa; the hemorrhagic tension; psychotic episodes induced by tension; the syndrome of autiroid disease; the syndrome of inappropriate antidiarrheal hormone (ADR); the obesity; infertility; traumas of the head; spinal cord trauma, ischemic neuronal damage (for example, cerebral ischemia such as cerebral hippocampal ischemia); the excitotoxic neuronal damage; epilepsy; Cardiovascular and heart-related disorders that include hypertension, tachycardia, and congestive heart failure; The attacks; immune dysfunctions including stress-induced immune dysfunctions (eg, stress-induced fevers in humans and the following animal diseases: porcine strain syndrome, cattle bovine fever, paroxysmal fibrillation of equines, and dysfunctions induced by confinement in chickens, the tension of changing direction in the sheep or the tension related to the interaction of the human-animal in dogs); muscle spasms; urinary incontinence; senile dementia of the Alzheimer's type; dementia due to multiple infarctions; amyotrophic lateral sclerosis; dependencies of chemical substances and addictions (for example, dependence on alcohol, cocaine, heroin, benzodiazepines, or other drugs); the symptoms of abstaining from drugs or alcohol; osteoporosis; and psychosocial dwarfism and hypoglycemia in mammals. In a further aspect of the invention, the compounds provided by this invention (and especially the radiolabelled compounds of this invention) are also useful as standards and reagents in determining the ability of a pharmaceutical potential to bind to the CRFi receptor. The novel compounds encompassed by the present invention can be described by General Formula I: wherein Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, carboxamido, lower alkylcarboxamido, N, N-dialkylcarboxamido lower, lower alkyl, lower alkoxy, with the proviso that at least one of the positions ortho or para with respect to the fixation point of Ar the tricyclic ring system is replaced; R1 is hydrogen, halogen, trifluoromethyl, lower alkyl, or (C? -C6 alkyl) -G1-R2 wherein G1 is oxygen or sulfur and R2 is hydrogen or alkyl with Ci- C6; W is N or C-R3 wherein R3 is hydrogen or lower alkyl; Q1 is hydrogen, lower alkyl, halogen, lower alkoxy, amino, methylamino, dimethylamino, hydroxymethyl, or S0n (alkyl with C1-C4) wherein n is 0, which is 2, cyano, hydroxy, -C (O) (alkyl with Ci- C4), -CHO, -C02 (alkyl with C1-C4), -C02 (alkenyl with C1-C4, or -C02 (alkynyl with C1-C4); Q2 is hydrogen, lower alkyl, halogen, hydroxymethyl, methoxymethyl , or lower alkoxy, X is k », and --A 'N' ^ and I where VI and V2 are CH2, CO, CS, S02 or CH (lower alkyl), with the proviso that both V1 and V2 can not be both CO, C? or S02; Y1 and Y2 independently represent a bond or lower alkylene; A1 is NRR5 wherein R4 and R5 are independently hydrogen or a lower alkyl group which optionally forms a heterocycloalkyl group with Y1; lower alkanoyl, lower alkylsulfonyl, with the proviso that R 4 and R 5 can not be both alkanoyl or alkylsulfonyl; or NR4R5 taken together form a heterocycloalkyl with C3-C6 or a group of the formula: where e and f are independently 1, 2 or 3 and the sum of e and f is at least 3; and G2 is ^ ¡^^^ NR wherein R is hydrogen or lower alkyl, or CH (C0-C6 alkylene) -G3-R7 wherein G3 is CONH, CONH (lower alkyl), NH, NH (lower alkyl) and R7 is hydrogen or lower alkyl; or CONH2, CO [N (lower alkyl JR8] wherein R8 is hydrogen or lower alkyl, is hydrogen, lower alkyl, (alkylene with C? -C6I-G4-R9 where G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or lower alkyl; wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4- , or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2- pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is mono- or optionally disubstituted with halogen, trifluoromethyl, amino, lower alkyl, lower alkoxy, with the condition that tetrazolyl can have at most one substituent; Z1 is lower alkyl; and V2, Y2 and A2 are as defined above; wherein Z2 is carbon or nitrogen; wherein when Z2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R10 is carboxamido, or (lower alkylene) -G5-R where G5 is NH, NH (lower alkyl) and R11 is hydrogen or lower alkyl; when Z2 is carbon, n is 1 or 2 and p is 1 or 2, R10 is amino; or when Z2 is nitrogen, n is 1 or 2 and p is 1 or 2, R10 is hydrogen; or (iv) a nitrogen heterocycle of the formula: wherein the ring of N represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (lower alkylene) -G6-R12 wherein G6 is NH, NH (lower alkyl ) and R12 is hydrogen or lower alkyl.

The compounds of Formula I are antagonists at the CRFi receptor and are useful in the diagnosis and treatment of stress-related disorders such as post-traumatic stress disorder (PT? D) as well as depression, pain of head and anxiety.

Detailed description of the invention The novel compounds encompassed by the present invention can be described by the general Formula I: wherein Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionally mono-, di-, or trisubstituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, carboxamido, lower alkylcarboxamido, N, N-dialkylcarboxamido lower, lower alkyl, lower alkoxy, with the proviso that at least one of the positions ortho or para with respect to the fixation point of Ar to the system of tricyclic ring is substituted; R1 is hydrogen, halogen, trifluoromethyl, lower alkyl, or (Ci-Cd alkyl) -G1-R2 wherein G1 is oxygen or sulfur and R2 is hydrogen or alkyl with Ccy6; W is N or C-R3 wherein R3 is hydrogen or lower alkyl; Q1 is hydrogen, lower alkyl, halogen, lower alkoxy, amino, methylamino, dimethylamino, hydroxymethyl, or SOn (alkyl with C1-C4) wherein n is O, 2, cyano, hydroxy, -C (0) (alkyl with Ci- C4), -CHO, -C02 (alkyl with C1-C4), -C02 (alkenyl with C1-C4), or -CO2 ( alkynyl with C1-C4); Q2 is hydrogen, lower alkyl, halogen, hydroxymethyl, methoxymethyl, or lower alkoxy; X is AVvyvVA2 (i) vw where VI and V2 are CH2, CO, CS, S02 or CH (lower alkyl), with the proviso that both V1 and V2 can not be both CO, CS or S02; Y1 and Y2 independently represent a bond or lower alkylene; A1 is NRR5 wherein R4 and R5 are independently hydrogen or a lower alkyl group which optionally forms a heterocycloalkyl group with Y1; lower alkanoyl, lower alkylsulfonyl, with the proviso that R 4 and R 5 can not be both alkanoyl or alkylsulfonyl; or NR4R5 taken together form a heterocycloalkyl with C3-C6 or a group of the formula: (CH2). (CH2) (\ / N where e and f are independently 1, 2 or 3 and the sum of e and f is at least 3; and G2 is NR6 wherein R6 is hydrogen or lower alkyl, or CH (alkylene with C0-C6) -G3-R7 wherein G3 is CONH, CONH (lower alkyl), NH, NH (lower alkyl) and R7 is hydrogen or lower alkyl; or CONH2, CO [N (lower alkyl) R8] wherein R8 is hydrogen or lower alkyl; is hydrogen, lower alkyl, (alkylene with C? -C6) -G-R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or lower alkyl; wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4- , or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2- pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is mono- or optionally disubstituted with halogen, trifluoromethyl, amino, lower alkyl, lower alkoxy, with the proviso that tetrazolyl can have at most one substituent; Z1 is lower alkyl; and V2, Y2 and A2 are as defined above; wherein Z2 is carbon or nitrogen; wherein when Z2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R10 is carboxamido, or (lower alkylene) -G5-R wherein G5 is NH, NH (alkyl) lower) and Ru is hydrogen or lower alkyl; when Z2 is carbon, n is 1 or 2 and p is 1 or 2, R10 is amino; or when Z2 is nitrogen, n is l or 2 and p is l or 2, R10 is hydrogen; or (iv) a nitrogen heterocycle of the formula: T-N ' wherein the ring of N represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (lower alkylene) -G6-R12 wherein G6 is NH, NH (lower alkyl ) and R12 is hydrogen or lower alkyl.

Preferred compounds of the invention have the formula II: II wherein: each R 4 independently represents lower alkyl; Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, carboxamido, lower alkylcarboxamido, N, N-dialkylcarboxamido lower, lower alkyl, lower alkoxy, with the proviso that at least one of the positions ortho or para with respect to the fixation point of Ar to the system of tricyclic ring is substituted; R1 is hydrogen, halogen, trifluoromethyl, lower alkyl, or (Ci-Cd alkyl) -G1-R2 wherein G1 is oxygen or sulfur and R2 is hydrogen or alkyl with Cj-c6; W is N or C-R3 wherein R3 is hydrogen or lower alkyl; Q1 is hydrogen, lower alkyl, halogen, lower alkoxy, amino, methylamino, dimethylamino, hydroxymethyl, or SOn (alkyl with C1-C4) wherein n is 0, lo 2, cyano, hydroxy, -C (O) (alkyl with Ci- C4), -CHO, -C02 (alkyl with C1-C4), -C02 (alkenyl with C1-C4), or -C02 (alkynyl with C1-C4); Q2 is hydrogen, lower alkyl, halogen, hydroxymethyl, methoxymethyl, or lower alkoxy; X is A .X. N YJ (i) where VI and V2 are CH2, CO, CS, S02 or CH (lower alkyl), with the proviso that both V1 and V2 can not be both CO, CS or S02; Y1 and Y2 independently represent a bond or lower alkylene; A1 is NR4R5 wherein R4 and R5 are independently hydrogen or a lower alkyl group which optionally forms a heterocycloalkyl group with Y1; lower alkanoyl, lower alkylsulfonyl, with the proviso that R 4 and R 5 can not be both alkanoyl or alkylsulfonyl; or NRR5 taken together form a heterocycloalkyl with C3-C6 or a group of the formula: where e and f are independently 1, 2 or 3 and the sum of e and f is at least 3; Y ^ Yes ^ j ^ J! ^ G ^ is NR6 wherein R6 is hydrogen or lower alkyl, or CH (alkylene with C0-C6) -G3-R7 where G3 is CONH, CONH (lower alkyl), NH, NH (lower alkyl) and R7 is hydrogen or lower alkyl; or CONH2, CO [N (lower alkyl) R8] wherein R8 is hydrogen or lower alkyl; is hydrogen, lower alkyl, (alkylene with C? -C6) -G4-R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or lower alkyl; wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4- , or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2- pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is mono- or optionally disubstituted with halogen, trifluoromethyl, amino, lower alkyl, lower alkoxy, with the condition that tetrazolyl can have at most one substituent; Z1 is lower alkyl; and V2, Y2 and A2 are as defined above; wherein Z2 is carbon or nitrogen; wherein when Z2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R10 is carboxamido, or (lower alkylene) -G5-Rn wherein G5 is NH, NH (lower alkyl) and R11 is hydrogen or lower alkyl; when Z2 is carbon, n is l or 2 and p is l or 2, R10 is amino; or when Z2 is nitrogen, n is l or 2 and p is l or 2, R10 is hydrogen; or (iv) a nitrogen heterocycle of the formula: wherein the ring of N represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (lower alkylene) -G6-R12 wherein G6 is NH, NH (lower alkyl ) and R12 is hydrogen or lower alkyl.

In Formula II, Q1 and Q2 preferably independently represent hydrogen, methyl, or ethyl. The most preferred compounds of Formula II are those wherein N-V2-Y2-A2 represent N-cyclopropylmethyl. Other more preferred compounds of Formula II include those wherein one of Q1 and Q2 is methyl or ethyl and the other is hydrogen. Still other more preferred compounds of Formula II are those wherein N-V-Y2-A2 represent N-cyclopropylmethyl, Q1 is methyl or ethyl, and -V1-Y1-A1 represents Ky r \ & ^ "Vfk hereinafter Formula II-a, wherein Rb is hydrogen or methyl; t is 1, 2 or 3, more preferably 1; Rx is hydrogen, alkyl with Cj.-C6, phenyl (C? -C6) alkyl wherein phenyl is mono- or disubstituted independently with C? -C6 alkyl, C? -C6 alkoxy, halogen, or hydroxy; and Ry is hydrogen, alkyl with C? -C6, (C3-C6) cycloalkyl; or NRxRy represents pyrrolidinyl, N- (dC6) alkylpyrrolidin-2-yl, piperidinyl, morpholinyl, or N- (C6C6) alkylpiperazinyl.

The preferred compounds particularly of the Formula II includes those wherein N-V2-Y2-A2 represents N-cyclopropylmethyl, Q1 is methyl, and -V1-Y1-A1 represents Il-a wherein R is hydrogen, and t is 1. Preferred R "and Ry groups in particular they are independently hydrogen or alkyl with C? -C2, or where NRxRy represents pyrrolidinyl, piperidinyl or piperazinyl. Other preferred compounds of the invention have the formula III: III wherein each of Ra independently represents lower alkyl; Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, carboxamido, lower alkylcarboxamido, N, N-dialkylcarboxamido lower, lower alkyl, lower alkoxy, with the proviso that at least one of the positions ortho or para with respect to the fixation point of Ar to the system of tricyclic ring is substituted; R1 is hydrogen, halogen, trifluoromethyl, lower alkyl, or (Ci-Cβ alkyl) -G1-R2 wherein G1 is oxygen or sulfur and R2 is hydrogen or alkyl with Ci- C6; W is N or C-R3 wherein R3 is hydrogen or lower alkyl; Q1 is hydrogen, lower alkyl, halogen, lower alkoxy, amino, methylamino, dimethylamino, hydroxymethyl, or SOn (alkyl with CX-C) wherein n is 0, 1 or 2, cyano, hydroxy, -C (0) (alkyl) with Ci- C4), -CHO, -C02 (alkyl with C1-C4), -C02 (alkenyl with C1-C4), or -C02 (alkynyl with C1-C4); Q2 is hydrogen, lower alkyl, halogen, hydroxymethyl, methoxymethyl, or lower alkoxy; X is (1) AVVW v «A * where VI and V2 are CH2, CO, CS, S02 or CH (lower alkyl), with the proviso that both V1 and V2 can not be both CO, CS or S02; Y1 and Y2 independently represent a bond or lower alkylene; A1 is NRR5 wherein R4 and R5 are independently hydrogen or a lower alkyl group which optionally forms a heterocycloalkyl group with Y1; lower alkanoyl, lower alkylsulfonyl, with the proviso that R 4 and R 5 can not be both alkanoyl or alkylsulfonyl; or NR4R5 taken together form a heterocycloalkyl with C3-C6 or a group of the formula: (CH2), (CH2), \ / N where e and f are independently 1, 2 or 3 and the sum of e and f is at least 3; and G2 is NR6 where Rd is hydrogen or lower alkyl, or CH (C0-C6 alkylene) -G3-R7 wherein G3 is CONH, CONH (lower alkyl), NH, NH (lower alkyl) and R7 is hydrogen or lower alkyl; or CONH2, C0 [N (lower alkyl) R8] wherein R8 is hydrogen or lower alkyl; is hydrogen, lower alkyl, (alkylene with C? -C6) -G4-R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or lower alkyl; Heteroapl and "yl wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4- , or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is mono- or optionally disubstituted with halogen, trifluoromethyl, amino, lower alkyl, lower alkoxy, with the proviso that tetrazolyl can have at most one substituent; Z1 is lower alkyl; and V2, Y2 and A2 are as defined above; (iii) wherein Z2 is carbon or nitrogen; wherein when Z2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R10 is carboxamido, or (lower alkylene) -G5-Ru wherein G5 is NH, NH (lower alkyl) and R11 is hydrogen or lower alkyl; when Z2 is carbon, n is l or 2 and p is l or 2, R10 is amino; or when Z2 is nitrogen, n is 1 or 2 and p is 1 or 2, R10 is hydrogen; or (iv) a nitrogen heterocycle of the formula: (X wherein the N ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (lower alkylene) -G6-R12 wherein G6 is NH, NH (lower alkyl) and R12 is hydrogen or lower alkyl.

In Formula III, Q1 and Q2 preferably independently represent hydrogen, methyl, or ethyl. Particularly preferred compounds of Formula III are those wherein N-V2-Y2-A2 represent N- cyclopropylmethyl. Other more preferred compounds of the Formula III includes those in which one of Q1 and Q2 is methyl or ethyl and the other is hydrogen. Still other more preferred compounds of the Formula III are those in which N-V2-Y2-A2 represent N-cyclopropylmethyl, Q1 is methyl or ethyl, and -V1-Y1-A1 represents hereinafter Formula Ill-a, wherein Rb is hydrogen or methyl; t is 1, 2 or 3, more preferably 1; Rx is hydrogen, alkyl with C? -C6, phenyl (Ci-C?) Alkyl wherein phenyl is mono- or disubstituted independently with alkyl with Ci-C?, Alkoxy with C? -C6, halogen, or hydroxy; and Ry is hydrogen, alkyl with C? -C6, (C3-C6) cycloalkyl; or NRxRy represents pyrrolidinyl, N- (C? -Cß) alkylpyrrolidin-2-yl, piperidinyl, morpholinyl, or N- (Cj.-C6) alkylpiperazinyl.

Particularly preferred compounds of Formula III include those wherein N-V2-Y-A2 represent N-cyclopropylmethyl, Q1 is methyl, and -V1-Y1-A1 represent Ill-a wherein Rb is hydrogen, and t is 1. The Particularly preferred Rx and Ry groups are independently hydrogen or alkyl with C? -C2, or where NRxRy represents pyrrolidinyl, piperidinyl or piperazinyl. Preferred compounds of the invention include the following: 4- (N- (2-Pyrrolidinyl) ethyl-N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2,3-b] pyridine 4- (N- (2-Pyrrolidinyl) ethyl-N-cyclopropylmethyl) amino-2,5-dimethyl-7- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyridine 4- (N- (2-Piperidinyl) ethyl-N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2,3-b] pyridine 4- (N- (2-Morpholinyl) ethyl-N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2,3-b] pyridine 4- (N- (2-Piperazinyl) ethyl-N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2,3-b] pyridine 4- (N- (2-Morpholinyl) ethyl-N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2, 3-b] pyridine 4- (N- (2-Piperazinyl) ethyl-N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2, 3-b] pyridine 4- (N- (2-Methylamino) ethyl-N-cyclopropylmethyl) amino-2,5-dimethyl-7- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyridine 4- (N- (2-Dimethylamino) ethyl-N-cyclopropylmethyl) amino-2,5-dimethyl-7- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyridine 4- (N- (2-Ethylmethylamino) ethyl-N-cyclopropylmethyl) amino-2,5-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyridine 4- (N- (2-Etylamino) ethyl-N-cyclopropylmethyl) amino-2,5-dimethyl-7- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyridine 4- (N- (2-Diethylamino) ethyl-N-cyclopropylmethyl) amino-2,5-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyridine 4- (N- (2-Piperazinyl) ethyl-N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2, 3-b] pyridine 4- (N- (2- (4-Methylpiperazinyl) ethyl-N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2, 3-b] pyridine.

In certain situations, the compounds of the Formula I may contain one or more asymmetric carbon atoms, so that the compounds may exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In these situations, the single enantiomers, that is, the optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. The resolution of the racemates can be effected, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral HPLC column. Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to, the compounds in Table I and their pharmaceutically acceptable acid addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. On the contrary, if the product is a free base, An addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to the conventional procedures for preparing the acid addition salts from the base compounds. Non-toxic pharmaceutical salts include the salts of the acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkaloic acids such as acetic, HOOC - (CH2) n-ACOOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of pharmaceutically acceptable non-toxic addition salts. The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which can be employed to prepare the pharmaceutically acceptable, non-toxic addition salts, and the acylated prodrugs of the encompassed compounds. by Formula I. By "alkyl", "lower alkyl", or C 1 -C 6 alkyl in the present invention are meant straight or branched chain alkyl groups having 1-6 atoms of carbon optionally forming a carbocycle of 3 to 6 atoms, such as, for example, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, 2-pentyl , isopentyl, neopentyl, cyclopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, cyclohexyl. By alkylene with Co-Ce is meant a direct bond or an alkylene group with Ci-Ce, which optionally forms a carbocycle of 3 to 6 atoms, such as methylene, ethylidene, propylidene, butylidene, pentylidene, cyclopentylidene, hexylidene, cyclohexylidene. By "alkoxy""lower alkoxy" or Ci-C6 alkoxy in the present invention means straight or branched chain alkoxy groups having 1-6 carbon atoms which optionally form a carbocycle of 3 to 6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, cyclopropylmethoxy, n-butoxy, sec-butoxy, terbutoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, cyclopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, cyclohexoxi . By "alkanoyl", "lower alkanoyl", or alkanoyl with Ci-Cβ in the present invention is meant straight or branched chain alkanoyl groups having 1-6 carbon atoms which optionally form a carbocycle of 3 to 6 atoms, such for example, acetyl, propionyl, isspropionyl, cyclopropionyl, butanoyl, pentanoyl, cyclopentanoyl, hexanoyl, cyclohexanoyl. CONH represents an amide functional group, that is, The term "heterocycle" or "heterocycloalkyl" means a group of monocyclic or bicyclic hydrocarbons in which one or more of the carbon atoms have been replaced with a heteroatom, for example, oxygen, sulfur or nitrogen. Such groups preferably have 4 to 10 carbon atoms and 1 to 4 heteroatoms. By the term "halogen" in the present invention is meant fluorine, bromine, chlorine, and iodine. The interaction of pyrrolo [3,2-e] pyridine and pyrrolo [2, 3-b] pyrimidine derivatives substituted with aminoalkyl of the invention with the VRFi receptors is shown in the following examples. This interaction leads to the pharmacological activities of these compounds as illustrated in the relevant animal models. Because the compounds of Formula I are effective CRFi receptor antagonists, they are useful for the treatment of psychiatric disorders, neurological diseases, immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological alterations and tension. The compounds of the general formula I can be administered orally, topically, parenterally, by inhalation or spray or rectally in unit dosage formulations containing conventional, non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral when used herein includes techniques of subcutaneous, intravenous, intramuscular injections, intrasternal injection or infusion techniques. In addition, a pharmaceutical formulation comprising a compound of the general Formula I and a pharmaceutically acceptable carrier is provided. One or more compounds of the general Formula I may be present in association with one or more pharmaceutically acceptable, non-toxic carriers and / or diluents and / or auxiliaries, and if desired other active ingredients. The pharmaceutical compositions containing the compounds of the general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous suspensions or oily, dispersible powders or granules, emulsion, soft or hard capsules, or syrups or elixirs. Compositions proposed for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and agents preservatives to provide pharmaceutically elegant preparations suitable for oral ingestion. The tablets contain the active ingredient mixed with pharmaceutically acceptable, non-toxic excipients, which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a material for Time delay such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oily medium, for example arachis oil, liquid paraffin or olive oil. The aqueous suspensions contain the active materials mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum.; the dispersing or wetting agents may be a phosphatide which is naturally present, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with alcohols long chain aliphatics, for example heptadecaethylene oxyketanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monoleate, or the condensation products of ethylene oxide with the partial esters derived from the fatty acids and hexitol anhydrides, for example polyethylene monooletate sorbitan. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. . Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those described above, and flavoring agents may be added to provide oral preparations suitable for oral ingestion. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. The dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water, providing the active ingredient mixed with a dispersing or wetting agent, a suspending agent and one or more condoms Suitable dispersing agents or humectants and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be gums which are naturally present, for example acacia gum or tragacanth gum, phosphatides which are naturally present, for example soy beans, lecithin, and partial esters or esters derived from fatty acids and hexitol, the anhydrides, for example the sorbitan monooleate, and the condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. The syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations can also contain an emollient, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of an injectable, sterile aqueous or oleaginous suspension. This suspension can be formulated according to the known art using these dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed, sterile oils are conventionally employed as a suspension medium or solvent. For this purpose any sweet fixed oil can be employed including mono or synthetic diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable substances. The compounds of the general formula I can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid to Ordinary temperatures but liquid at the rectal temperature and therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. The compounds of the general Formula I can be administered parenterally in a sterile medium. The drug, depending on the vehicle and the concentration used, can be either suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. Dosage levels of order from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the conditions indicated above (about 0.5 mg to about 7 g per patient per day). The amount of the active ingredient that can be combined with the carrier materials to produce a unit dosage form will vary depending on the host treated and the particular mode of administration. Dosage unit forms will generally contain from about 1 mg to about 500 mg of an active ingredient. It will be understood, however, that the level of specific doses for any particular patient it will depend on a variety of factors including the inactivity of the specific employee, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, the combination of drugs and the severity of the particular disease suffered by the therapy.

Preparation of Pyrrolo [3, 2-e] pyridine and Pyrrolo [2, 3-b] pyrimidine analogs Substituted with aminoalkyl An illustration of the preparation of the compounds of the present invention is given in Scheme I, Scheme II and Scheme III. Those skilled in the art will recognize that the starting materials can be varied and additional steps can be employed to produce the compounds encompassed by the present invention.

Scheme I known in the art wherein Ar, Q1, Q2, R1 and R3 are as defined above for Formula I; and R14, R15 and Rld are encompassed by the definition of X for Formula I.

Scheme II known in the prior art wherein Ar, Q1, Q2, R1 ** above for Formula I; and R15 and R16 are encompassed by the definition of X for Formula I.

Scheme III known in the prior art wherein Ar, Q1, Q2, and R1 are as defined above for Formula I, and R15, Rld, and R17 are encompassed by the definition of X for Formula I. Descriptions of all articles and references mentioned in this application , including patents, are incorporated herein for reference. The preparation of the compounds of the present invention is further illustrated by the following Examples, which are not proposed to be limiting of the invention in its spirit or scope with respect to the specific procedures and compounds described therein. Commercial reagents are used without further purification. THF refers to tetrahydrofuran. Ambient or normal temperature refers to the range of 20 to 25 ° C. The concentration involves the use of a rotary evaporator. CCD refers to thin layer chromatography. The spectral data of the mass are obtained by the methods of either Cl or APCl.

Example 1 A. 4- (N-C? Clopropylmethyl) amino-3,6-dimethy1-1- (2,4,6-trimethylphenyl) pyrrolo [2, 3-b] pyridine A solution of dichloroethane (70 ml) containing 4-amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2, 3-b] pyridine (11 g) and cyclopropanecarbonyl chloride (3.4 ml) at reflux is treated with the dropwise addition of N, -diisopropylethylamine (6.6 ml). After heating for 0.5 hours the reaction is cooled to room temperature and poured into an aqueous potassium carbonate solution. The product is extracted with dichloromethane, it is dried over sodium sulfate, filtered and concentrated. The concentrate is redissolved in THF (100 ml) and mixed with the borane-methyl sulfide complex (10M, 10.3 ml). The mixture is refluxed for 8 hours and reduced to room temperature with a large excess of methanol (approximately 100 ml). The mixture is refluxed for 1 hour, then concentrated under reduced pressure. More methanol (another 50 ml) is added to the gummy residue and the solution is reconcentrated to give a white solid.

B. 4- (N- (2-Chloroethyl) -N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2,3-b] pyridine A solution containing the product of Example IA (13 g) and chloroacetyl chloride (3 ml) in dichloroethane (100 ml) is refluxed for 4 hours. The solvent and excess reagent are removed under reduced pressure. Aqueous potassium carbonate is added to the remaining oily residue and extracted with dichloromethane. The extract is dried with sodium sulfate, filtered and concentrated. The latter chloroacetyl compound (15 g) is dissolved in THF (100 ml). Borane-Methyl sulfide complex (10M, 3.4 ml) is added and stirred at room temperature for 15 minutes then for 1 hour at reflux temperature. The solution is cooled again to room temperature, the temperature is reduced with a large excess of methanol (50 ml) and the mixture is refluxed for 1 hour. The solution is concentrated then.

C. 4- (N- (2-dimethylamino) ethyl-N-cyclopropylmethyl) -amino-3,6-dimethyl-1- (2,4 g -trimethylphenyl) pyrrolo [2,3-b] pyridine (Compound 1 ) A steel pump that contains the product of the Example IB (3.8 g), dimethylamine (8 ml) and N-methylpyrrolidone (20 ml) is sealed and heated at 80 ° C for 10 hours. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated.

Example 2 V The following compounds are prepared essentially in accordance with the procedures described in Example 1 and / or Schemes I, II, and III. a) 4- (N- (2-Methylamino) ethyl-N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2,3-b] pyridine (Compound 2) b) 4- (N- (2-pyrrolidinyl) ethyl-N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2,3-b] pyridine (Compound 3) c) 4- (N- (2-Ethylmethylamino) ethyl-N-cyclopropylmethyl) amino-3,6-dimethy1-1- (2,4,6-trimethylphenyl) pyrrolo [2,3-b] pyridine (compound 4) d) 4- (N- (2-Etylamino) ethyl-N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2, 3-b] pyridine (Compound 5) e) 4- (N- (2-Diethylamino) ethyl-N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2,3-b] pyridine (Compound 6) f) 4- (N- (2-Piperidinyl) ethyl-N-cyclopropylmethyl) amino-3, "β-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2,3-b] pyridine (Compound 7 ) g) 4- (N- (2-Morpholinyl> fetil-N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2, 3-b] pyridine (Compound 8) ) h) 4- (N- (2-Piperazinyl) ethyl-N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2,3-b] pyridine (Compound 9) i) 4- (N- (2- (4-Methylpiperazinyl) ethyl-N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2, 3-b] pyridine ( Compound 10) Example 3 4- (N- (2-Aminoethyl) -N-cyclopropylmethyl) amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2, 3-b] pyridine (Compound 11) A solution containing the product of Example IB (500 mg) and sodium azide (22 mg) in N-methylpyrrolidinone (5 ml) is heated at 120 ° C for 2 hours. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated. An ethanol solution (10 ml) of the crude product and 10% palladium on carbon (approximately 200 mg) is hydrogenated for 8 hours at about 1 atmosphere pressure. The suspension is filtered over celite and concentrated.

Example 4 A. 4-Chloro-3, 6-dimethyl-1- (2, 4, 6-trimethylphenyl) -pyrrolo [2,3-b] pyridine The tert-butyl nitrite (0.65 g) is dissolved in acetonitrile (10 ml) and copper (II) chloride (0.68 g) is added. The 4-amino-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2,3-b] pyridine (1.33 g) is then added in portions to the greenish-brown solution and the mixture it is stirred for 12 hours. The acetonitrile is removed by evaporation and the residue is partitioned between water and dichloromethane. The aqueous layer is extracted with more dichloromethane and the combined extract is washed with water, dried over sodium sulfate, filtered and concentrated.

B. 4-Piperazinyl-3,6-dimethyl-1- (2,4,6-trimethylphenyl) pyrrolo [2, 3-b] pyridine (Compound 12) Combine the compound of Example 4A (200 mg) and piperazine (0.58 g) in N-methylpyrrolidinone (2 ml) and heat the solution at 120 ° C for 12 hours. The mixture is poured into water and extracted with ethyl acetate. The extract is washed with aqueous ammonium chloride then with water. The extract is dried over sodium sulfate, filtered and concentrated.

Example 5 A. 4- (N-Cyclopropylmethyl) amino-2,5-dimethyl-7- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyrimidine A mixture containing 4-chloro-2,5-dimethyl-7- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyrimidine (450 mg), cyclopropylmethylamine hydrochloride (800 mg) and triethylamine (1.3 ml) in N-methylpyrrolidinone (3 ml) is heated at 110 ° C in a sealed tube for 4 hours. The mixture is diluted with ethyl acetate and washed with water, aqueous ammonium chloride and brine. Dry over sodium sulfate, filter and concentrate to give a tan solid: MS 335 (M + H).

B. 4- (N- (2-Pyrrolidinyl) ethyl-N-cyclopropylmethyl) -amino-2,5-dimethyl-1- (2-, 4,6-trimethylphenyl) pyrrolo [3,2-e] pyrimidine (Compound 13 ) To a solution of the compound of Example 5A (130 mg) in N, N-dimethylformamide (1 ml) at 0 ° C, under a blanket of nitrogen, sodium hydride (60%, 70 mg) is added. After stirring the solution for 0.5 hour, the hydrochloride of 2-dimethylaminoethyl chloride (135 mg) is added. The mixture is then heated at 40 ° C for 2 hours, then the temperature is reduced with ice and water. It is diluted with ethyl acetate and washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purify by preparative CCD using 10% methanol and 0.5% ammonium hydroxide in dichloromethane as eluent to obtain 100 mg of the product: EM 432 (M + H). ^ fa Example 6 The following compounds are prepared essentially in accordance with the procedures described in Example 5 and / or Schemes I, II, and III. a) 4- (N- (2-Methylamino) ethyl-N-cyclopropylmethyl) amino-2,5-dimethyl-7- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyridine (Compound 14) b) 4- (N- (2-Dimethylamino) ethyl-N-cyclopropylmethyl) amino-2,5-dimethyl-7- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyridine (Compound 15) c) 4- (N- (2-Ethylmethylamino) ethyl-N-cyclopropylmethyl) amino-2,5-dimethyl-7- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyridine (Compound 16) d) 4- (N- (2-Ethylmethylamino) ethyl-N-cyclopropylmethyl) amino-2,5-dimethyl-7- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyridine (Compound 17) e) 4- (N- (2-Diethylamino) ethyl-N-cyclopropylmethyl) amino-2,5-dimethyl-7- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyridine (Compound 18) f) 4- (N- (2-Piperidinyl) ethyl-N-cyclopropylmethyl) amino-2,5-dimethyl-7- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyridine (Compound 19) g) 4- (N- (2-Morpholinyl) ethyl-N-cyclopropylmethyl) amino-2,5-dimethyl-7- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyridine (Compound 20) h) 4- (N- (2-Piperazinyl) ethyl-N-cyclopropylmethyl) amino-2,5-dimethy1-7- (2,4,6-trimethylphenyl) pyrrolo [3,2-e] pyridine (Compound 21) i) 4- (N- (2- (4-Methylpiperazinyl) ethyl-N-cyclopropylmethyl) amino-2,5-dimethy1-7- (2,4,6-trimethylphenyl) irrolo [3, -e] pyridine (Compound 22).

Example 7 The pharmaceutical utility of the compounds of this invention is indicated by the following assays for the activity of the human CRFl receptor.

Test to Verify the Recombinant Human CRFj Receptor Binding Activity The binding of the CRF receptor is effected using a modified version of the assay described by Grigoriadis and De? Ouza (Methods in Neurosciences, Vol. 5, 1991). The membrane pills containing the CRF receptors are resuspended in a 50 mM Tris buffer solution 7.7 containing 10 mM MgCl2 and 2 mM EDTA and centrifuged for 10 minutes at 48,000 gravities. The membranes are again washed and brought to a final concentration of 1500 mg / ml in the binding buffer (Tris buffer above with 0.1% BSA), 15 mM bacitracin and 0.01 mg / ml aprotinin). For the binding assay, 100 ml of the membrane preparation is added to 96-well microtube plates containing 100 ml of 1 5 I-CRF (SA 2200 Ci / mol, final concentration of 100 pM) and 50 ml of the drug . The binding is carried out at room temperature for 2 hours. The plates are then collected on a Brandel 96 cell cavity collector and the filters are counted to verify the gamma emissions on a Wallac 1205 Betaplate liquid scintillation counter. The non-specific binding is defined by the cold 1 mM CRF. IC50 values are calculated with the RS / 1 non-linear curve fitting program (BBN Software Products Corp., Cambridge, MA). The binding affinity for the compounds of Formula I expressed as the IC 50 value, varies in general from about 0.5 nanomolar to about 10 micromolar. Alternatively, the binding activity of the compounds of the formula I with respect to the CRF receptor; Human can be measured as follows: Assay to Verify the Human CRF Receptor Binding Activity in IMR32 cells [125I] Sauvagine binding to CRFj receptors Endogenously expressed in IMR-32 cells: IMR-32 human neuroblastoma cells are grown to an 80% confluence in EMEM containing the Earle and L-glutamine Balanced Salts 2 mM with 10% FBS, 25 mM HEPES, 1 mM Sodium Piruvate, and non-essential amino acids. At this time, the recipients of the cells are treated with 5-bromo-2'-deoxyuridine (Br-dU) 2.5 μM for 10 days. The medium is changed every 3-4 days during the course of the 10-day period. The cells are collected using No-Zyme (JRH Biosciences) and rinsed with PBS. For the preparation of the membrane, the cells are homogenized in the buffer solution of washed (50 mM Tris HCl, 10 mM MgCl 2, 2 mM EGTA, pH 7.4) and centrifuged at 48,000 x g for 10 minutes at 4 ° C. The pills are resuspended, homogenized and centrifuged two additional times > The receptor binding assay is performed using the assay buffer (50 mM Tris HCl, 10 mM MgCl2, 2 mM EGTA, pH 7.4, 0.1% BSA, 0.1 mM bacitracin (22.0 mg / 100 ml)), 150 μg protein / tube, and [125I] Sauvagine (NEN; 100 pM for competition analysis and 10 pM-1 nM for saturation analysis) to give a final volume of 200 uL. Non-specific binding is defined using 2 μM CRF r / h or alpha-helical CRF 9-41. The cells are incubated for 2 hours at room temperature. The test is finished by rapid vacuum filtration (Tomtec: Deepwell 3) through GFC filters pre-refreshed in 1% PEI using 50 M Tris HCl cooled with ice and completely drying by means of air. Specific Union: 70-80%; Kd (nM): 0.30 nM; Bmax (fmol / mg protein): 40-50. The IC50 values are calculated with the RS / 1 non-linear curve fitting program (BBN Software Products Corp., Cambridge, MA). The binding affinity for compounds of Formula I expressed as the IC-50 value, generally ranges from about 0.5 nanomolar to about 10 micromolar.

The invention and the manner and process of manufacture and use, are now described in complete, clear, concise and exact terms to make it possible for any person skilled in the art to which it belongs, makes and uses them. It is to be understood that the foregoing describes the preferred embodiments of the present invention and that modifications may be made thereto without departing from the spirit or scope of the present invention as described in the claims. To distinctly claim and particularly point out the subject matter considered as the invention, the following claims conclude this specification.

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 (9)

1. A compound of the formula or pharmaceutically acceptable salts thereof, characterized in that: Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, carboxamido, lower alkylcarboxamido, N, N-dialkylcarboxamido lower, lower alkyl, lower alkoxy, with the proviso that at least one of the ortho positions or for with respect to the fixation point of Ar to the tricyclic ring system is substituted; R1 is hydrogen, halogen, trifluoromethyl, lower alkyl, or (C? -C6 alkyl) -Gx-R2 wherein G1 is oxygen or sulfur and R2 is hydrogen or alkyl with Ci- C6; W is N or C-R3 wherein R3 is hydrogen or lower alkyl; Q1 is hydrogen, lower alkyl, halogen, lower alkoxy, amino, methylamino, dimethylamino, hydroxymethyl, or SOn (alkyl with C1-C4) wherein n is 0, lo 2, cyano, hydroxy, -C (0) (alkyl with C \ - C4), -CHO, -C02 (alkyl with C1-C4), -C02 (alkenyl with C1-C4), or -C02 (alkynyl with C1-C4); Q2 is hydrogen, lower alkyl, halogen, hydroxymethyl, methoxymethyl, or lower alkoxy; X is (i) where V1 and V2 are CH2, CO, CS, S02 or CH (lower alkyl), with the proviso that both V1 and V2 can not be both CO, CS or S02; Y1 and Y2 independently represent a bond or lower alkylene; A1 is NR4R5 wherein R4 and R5 are independently hydrogen or a lower alkyl group which optionally forms a heterocycloalkyl group with Y1; lower alkanoyl, lower alkylsulfonyl, with the proviso that R 4 and R 5 can not be both alkanoyl or alkylsulfonyl; or NRR5 taken together form a heterocycloalkyl with C3-C6 or a group of the formula: where e and f are independently 1, 2 or 3 and the sum of e and f is at least 3; and G2 is NR6 where Rd is hydrogen or lower alkyl, or CH (C0-C6 alkylene) -G3-R7 wherein G3 is CONH, CONH (lower alkyl), NH, NH (lower alkyl) and R7 is hydrogen or lower alkyl; or CONH2, CO [N (lower alkyl) R8] wherein R8 is hydrogen or lower alkyl; is hydrogen, lower alkyl, (alkylene with C? -Cβ) -G4-R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or lower alkyl; wherein hetero-tile is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4- , or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2- pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is mono- or optionally disubstituted with halogen, trifluoromethyl, amino, lower alkyl, lower alkoxy, with the proviso that tetrazolyl can have at most one substituent; Z1 is lower alkyl; and V2, Y2 and A2 are as defined above; wherein Z2 is carbon or nitrogen; wherein when Z2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R10 is carboxamido, or (lower alkylene) -G5-Ru wherein G5 is NH, NH (lower alkyl) and Ru is hydrogen or lower alkyl; when Z2 is carbon, n is 1 or 2 and p is 1 or 2, R10 is amino; or when Z2 is nitrogen, n is 1 or 2 and p is 1 or 2, R10 is hydrogen; or (iv) a nitrogen heterocycle of the formula: (X) wherein the N ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (lower alkylene) ) -G6-R12 wherein G6 is NH, NH (lower alkyl) and R12 is hydrogen or lower alkyl.

2. A compound according to claim 1, characterized in that W is CH and Q1 and Q2 are independently hydrogen, methyl, or ethyl.

3. A compound according to claim 1, characterized in that W is N and Qa and Q2 are independently methyl or ethyl.

4. A compound according to claim 1, characterized in that W is N, Q1 is methyl, Q2 is hydrogen or methyl, R1 is methyl, Ar is 2,4,6-trimethylphenyl, and X is (N- (2-pyrrolidinyl) ethyl-N-cyclopropylmethyl) amino or (N- (2-dimethylamino) ethyl-N-cyclopropylmethyl) amino.

5. A compound according to claim 1, characterized in that W is CH, Q1 is methyl, Q2 is hydrogen or methyl, R1 is methyl, Ar is 2,4,6-trimethylphenyl, and X is (N- (2-pyrrolidinyl) ethyl-N-cyclopropylmethyl lamino or (N- (2-dimethylamino) ethyl-N-cyclopropylmethyl) amino.

6. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to Claim 1.

7. A method for the treatment or prevention of physiological disorders associated with an excess of CRF, the method is characterized in that it comprises administering to a patient in need thereof a reducing amount of the CRF of a compound according to Claim 1.

8. A method for the treatment of an affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases , anorexia nervosa or other eating disorders, drug addiction, withdrawal symptoms of drugs or alcohol, inflammatory diseases, problems of fertility, infections caused by the human immunodeficiency virus, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, seizures, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which may be effected or facilitated by the antagonism of CRF, including but not limited to disorders induced or facilitated by CRF, in mammals, characterized because it comprises: administering to the mammal an effective amount Therapeutically of a compound according to claim 1.

9. The use of a compound for the manufacture of a medicament for the treatment of an affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression , Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other eating disorders, drug addiction, withdrawal symptoms of drugs or alcohol, inflammatory diseases, cardiovascular or heart-related diseases, the problems of fertility, infections caused by the human immunodeficiency virus, hemorrhagic stress, obesity, infertility, traumas of the head and spinal cord, epilepsy, attacks, ulcers, lateral sclerosis amyotrophic, hypoglycemia or a disorder the treatment of which can be effected or facilitated by the antagonization of the RF, including but not limited to the disorders induced or facilitated by CRF, in mammals, characterized in that it comprises administering to the mammal a Therapeutically effective amount of a compound according to claim 1.