Disclosed are compounds of the formula: ##STR1## PA1 wherein Ar, Q.sup.1, Q.sup.2, R.sup.1, W and X are substituents as defined herein, which compounds are water-soluble CRF.sub.1 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.

BACKGROUND OF THE INVENTION
 1. Field of the Invention
 The present invention relates to aminoalkyl substituted
 pyrrolo[3,2-e]pyridine and pyrrolo[2,3-b]pyrimidine derivatives,
 pharmaceutical compositions containing such compounds, and their use 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.
 2. Description of the Related Art
 Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid
 peptide, is the primary physiological regulator of proopiomelanocortin
 (POMC) derived peptide secretion from the anterior pituitary gland [J.
 Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al.,
 Science 213:1394 (1981)]. In addition to its endocrine role at the
 pituitary gland, immunohistochemical localization of CRF has demonstrated
 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 neuromodulator role in brain [W. 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 plays a significant role in integrating the response of
 the immune system to physiological, psychological, and immunological
 stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley,
 Life Sci. 41:527 (1987)].
 Clinical data provide evidence that CRF has a role in psychiatric disorders
 and neurological diseases including depression, anxiety-related disorders
 and feeding disorders. 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 as they relate to the dysfunction of CRF neurons in the
 central nervous system [for review see E. B. De Souza, Hosp. Practice
 23:59 (1988)].
 In affective disorder, or major depression, the concentration of CRF is
 significantly increased in the cerebral spinal 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).
 Furthermore, the density of CRF receptors is significantly decreased 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 blunted adrenocorticotropin (ACTH) response to CRF
 (i.v. administered) 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 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 seen 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 numbers of CRF
 receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53
 (1989)].
 There has also been a role postulated for CRF in the etiology of
 anxiety-related disorders. CRF produces anxiogenic effects in animals and
 interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF
 have been demonstrated in a variety of behavioral anxiety models [D. R.
 Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn
 Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF
 receptor antagonist .alpha.-helical ovine CRF (9-41) in a variety of
 behavioral paradigms demonstrate that the antagonist produces
 "anxiolytic-like" effects that are qualitatively similar to the
 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 providing further 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)] and in the acoustic startle test [N. R.
 Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The
 benzodiazepine receptor antagonist (Ro 15-1788), which was without
 behavioral activity alone in the operant conflict test, reversed the
 effects of CRF in a dose-dependent manner while the benzodiazepine inverse
 agonist (FG 7142) enhanced the actions of CRF [K. T. 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, stroke and osteoporosis. CRF has also been
 implicated in premature birth, psychosocial dwarfism, stress-induced
 fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity
 associated with psychopathological disturbance and stress.
 The mechanisms and sites of action through which the standard anxiolytics
 and antidepressants produce their therapeutic effects remain to be
 elucidated. It has been hypothesized however, that they are involved in
 the suppression of the CRF hypersecretion that is observed in these
 disorders. Of particular interest is that preliminary studies examining
 the effects of a CRF receptor antagonist (.alpha.-helical CRF.sub.9-41) in
 a variety of behavioral paradigms have demonstrated that the CRF
 antagonist produces "anxiolytic-like" effects qualitatively similar to the
 benzodiazepines [for review see G. F. Koob and K. T. Britton, In:
 Corticotropin-Releasing Factor: Basic and Clinical Studies of a
 Neuropeptide, E. B. De Souza and C.B. Nemeroff eds., CRC Press p221
 (1990)].
 SUMMARY 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, 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
 in mammals. According to another aspect, the present invention provides
 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 CRF hypersecretion. 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,
 pharmaceutical compositions and methods which may 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
 feeding disorder, drug or alcohol withdrawal symptoms, 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 disorder
 selected from inflammatory disorders such as rheumatoid arthritis and
 osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety
 disorder; panic, phobias, obsessive-compulsive disorder; post-traumatic
 stress disorder; sleep disorders induced by stress; pain perception such
 as fibromyalgia; mood disorders such as depression, including major
 depression, single episode depression, recurrent depression, child abuse
 induced depression, and postpartum depression; dysthemia; bipolar
 disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer,
 human immunodeficiency virus (HIV) infections; neurodegenerative diseases
 such as Alzbeimer's disease, Parkinson's disease and Huntington's disease;
 gastrointestinal diseases such as ulcers, irritable bowel syndrome,
 Crohn's disease, spastic colon, diarrhea, and post operative ilius and
 colonic hypersensitivity associated by psychopathological disturbances or
 stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic
 stress; stress-induced psychotic episodes; euthyroid sick syndrome;
 syndrome of inappropriate antidiarrhetic hormone (ADR); obesity;
 infertility; head traumas; spinal cord trauma; ischemic neuronal damage
 (e.g., cerebral ischemia such as cerebral hippocampal ischemia);
 excitotoxic neuronal damage; epilepsy; cardiovascular and heart related
 disorders including hypertension, tachycardia and congestive heart
 failure; stroke; immune dysfunctions including stress induced immune
 dysfunctions (e.g., stress induced fevers in humans and the following
 animal diseases: porcine stress syndrome, bovine shipping fever, equine
 paroxysmal fibrillation, and dysfunctions induced by confinement in
 chickens, sheering stress in sheep or human-animal interaction related
 stress in dogs); muscular spasms; urinary incontinence; senile dementia of
 the Alzheimer's type; multiinfarct dementia; amyotrophic lateral
 sclerosis; chemical dependencies and addictions (e.g., dependencies on
 alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and
 alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and
 hypoglycemia in mammals.
 In a further aspect of the invention, the compounds provided by this
 invention (and especially radiolabeled compounds of this invention) are
 also useful as standards and reagents in determining the ability of a
 potential pharmaceutical to bind to the CRF.sub.1 receptor.
 The novel compounds encompassed by the instant invention can be described
 by general Formula I:
 ##STR2##
 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-lower dialkylcarboxamido, lower
 alkyl, lower alkoxy, with the proviso that at least one of the positions
 ortho or para to the point of attachment of Ar to the tricyclic ring
 system is substituted;
 R.sup.1 is hydrogen, halogen, trifluoromethyl, lower alkyl, or (C.sub.1
 -C.sub.6 alkyl)-G.sup.1 --R.sup.2 where G.sup.1 is oxygen or sulfur and
 R.sup.2 is hydrogen or C.sub.1 -C.sub.6 alkyl;
 W is N or C--R.sup.3 where R.sup.3 is hydrogen or lower alkyl;
 Q.sup.1 is hydrogen, lower alkyl, halogen, lower alkoxy, amino,
 methylamino, dimethylamino, hydroxymethyl, or SO.sub.n (C.sub.1 -C.sub.4
 alkyl) where n is 0, 1 or 2, cyano, hydroxy, --C(O)(C.sub.1 -C.sub.4
 alkyl), --CHO, --CO.sub.2 (C.sub.1 -C.sub.4 alkyl), --CO.sub.2 (C.sub.1
 -C.sub.4 alkenyl), or --CO.sub.2 (C.sub.1 -C.sub.4 alkynyl);
 Q.sup.2 is hydrogen, lower alkyl, halogen, hydroxymethyl, methoxymethyl, or
 lower alkoxy;
 X is
 ##STR3##
 wherein
 V.sup.1 and V.sup.2 are CH.sub.2, CO, CS, SO.sub.2 or CH(lower alkyl), with
 the proviso that both V.sup.1 and V.sup.2 cannot both be CO, CS or
 SO.sub.2 ;
 Y.sup.1 and Y.sup.2 independently represent a bond or lower alkylene;
 A.sup.1 is NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are independently
 hydrogen or a lower alkyl group which optionally forms a heterocycloalkyl
 group with Y.sup.1 ;
 lower alkanoyl, lower alkylsulfonyl, with the proviso that R.sup.4 and
 R.sup.5 cannot both be alkanoyl or alkylsulfonyl; or
 NR.sup.4 R.sup.5 taken together form a C.sub.3 -C.sub.6 heterocycloalkyl or
 a group of the formula:
 ##STR4##
 wherein e and f are independently 1, 2 or 3 and the sum of e and f is at
 least 3; and
 G.sup.2 is
 NR.sup.6 wherein R.sup.6 is hydrogen or lower alkyl, or
 CH(C.sub.0 -C.sub.6 alkylene)-G.sup.3 --R.sup.7 wherein G.sup.3 is CONH,
 CONH(lower alkyl), NH, NH(lower alkyl) and R.sup.7 is hydrogen or lower
 alkyl; or
 CONH.sub.2, CO[N(lower alkyl)R.sup.8 ] wherein R.sup.8 is hydrogen or
 lower alkyl;
 A.sup.2 is hydrogen, lower alkyl, (C.sub.1 -C.sub.6 alkylene)-G.sup.4
 --R.sup.9 wherein G.sup.4 is oxygen or sulfur and R.sup.9 is hydrogen,
 trifluoromethyl or lower alkyl;
 ##STR5##
 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 optionally mono- or disubstituted with
 halogen, trifluoromethyl, amino, lower alkyl, lower alkoxy, with the
 proviso that tetrazolyl can have at most one substituent;
 Z.sup.1 is lower alkyl; and
 V.sup.2, Y.sup.2 and A.sup.2 are as defined above;
 ##STR6##
 where
 Z.sup.2 is carbon or nitrogen;
 where
 when Z.sup.2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R.sup.10 is
 carboxamido, or (lower alkylene)-G.sup.5 --R.sup.1 wherein G.sup.5 is NH,
 NH(lower alkyl) and R.sup.11 is hydrogen or lower alkyl;
 when Z.sup.2 is carbon, n is 1 or 2 and p is 1 or 2, R.sup.10 is amino; or
 when Z.sup.2 is nitrogen, n is 1 or 2 and p is 1 or 2, R.sup.10 is
 hydrogen; or
 (iv) a nitrogen heterocycle of the formula:
 ##STR7##
 wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or
 pyrazolyl, each of which is optionally substituted with amino,
 trifluoromethyl, carboxamido, or (lower alkylene)-G.sup.6 --R.sup.12
 wherein G.sup.6 is NH, NH(lower alkyl) and R.sup.12 is hydrogen or lower
 alkyl.
 The compounds of Formula I are antagonists at the CRF.sub.1 receptor and
 are useful in the diagnosis and treatment of stress related disorders such
 as post traumatic stress disorder (PTSD) as well as depression, headache
 and anxiety.
 DETAILED DESCRIPTION OF THE INVENTION
 The novel compounds encompassed by the instant invention can be described
 by general Formula I:
 ##STR8##
 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-lower dialkylcarboxamido, lower
 alkyl, lower alkoxy, with the proviso that at least one of the positions
 ortho or para to the point of attachment of Ar to the tricyclic ring
 system is substituted;
 R.sup.1 is hydrogen, halogen, trifluoromethyl, lower alkyl, or (C.sub.1
 -C.sub.6 alkyl)-G.sup.1 --R.sup.2 where G.sup.1 is oxygen or sulfur and
 R.sup.2 is hydrogen or C.sub.1 -C.sub.6 alkyl;
 W is N or C--R.sup.3 where R.sup.3 is hydrogen or lower alkyl;
 Q.sup.1 is hydrogen, lower alkyl, halogen, lower alkoxy, amino,
 methylamino, dimethylamino, hydroxymethyl, or SO.sub.n (C.sub.1 -C.sub.4
 alkyl) where n is 0, 1 or 2, cyano, hydroxy, --C(O)(C.sub.1 -C.sub.4
 alkyl), --CHO, --CO.sub.2 (C.sub.1 -C.sub.4 alkyl), --CO.sub.2 (C.sub.1
 -C.sub.4 alkenyl), or --CO.sub.2 (C.sub.1 -C.sub.4 alkynyl);
 Q.sup.2 is hydrogen, lower alkyl, halogen, hydroxymethyl, methoxymethyl, or
 lower alkoxy;
 X is
 ##STR9##
 wherein
 V.sup.1 and V.sup.2 are CH.sub.2, CO, CS, SO.sub.2 or CH(lower alkyl), with
 the proviso that both V.sup.1 and V.sup.2 cannot both be CO, CS or
 SO.sub.2 ;
 Y.sup.1 and Y.sup.2 independently represent a bond or lower alkylene;
 A.sup.1 is NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are independently
 hydrogen or a lower alkyl group which optionally forms a heterocycloalkyl
 group with Y.sup.1 ;
 lower alkanoyl, lower alkylsulfonyl, with the proviso that R.sup.4 and
 R.sup.5 cannot both be alkanoyl or alkylsulfonyl; or
 NR.sup.4 R.sup.5 taken together form a C.sub.3 -C.sub.6 heterocycloalkyl or
 a group of the formula:
 ##STR10##
 wherein e and f are independently 1, 2 or 3 and the sum of e and f is at
 least 3; and
 G.sup.2 is
 NR.sup.6 wherein R.sup.6 is hydrogen or lower alkyl, or
 CH(C.sub.0 -C.sub.6 alkylene)-G.sup.3 --R.sup.7 wherein G.sup.3 is CONH,
 CONH(lower alkyl), NH, NH(lower alkyl) and R.sup.7 is hydrogen or lower
 alkyl; or
 CONH.sub.2, CO[N(lower alkyl)R.sup.8 ] wherein R.sup.8 is hydrogen or
 lower alkyl;
 A.sup.2 is hydrogen, lower alkyl, (C.sub.1 -C.sub.6 alkylene)-G.sup.4
 --R.sup.9 wherein G.sup.4 is oxygen or sulfur and R.sup.9 is hydrogen,
 trifluoromethyl or lower alkyl;
 ##STR11##
 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 optionally mono- or disubstituted with
 halogen, trifluoromethyl, amino, lower alkyl, lower alkoxy, with the
 proviso that tetrazolyl can have at most one substituent;
 Z.sup.1 is lower alkyl; and
 V.sup.2, Y.sup.2 and A.sup.2 are as defined above;
 ##STR12##
 where
 Z.sup.2 is carbon or nitrogen;
 where
 when Z.sup.2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R.sup.10 is
 carboxamido, or (lower alkylene)-G.sup.5 --R.sup.1 wherein G.sup.5 is NH,
 NH(lower alkyl) and R.sup.11 is hydrogen or lower alkyl;
 when Z.sup.2 is carbon , n is 1 or 2 and p is 1 or 2, R.sup.10 is amino;
 or
 when Z.sup.2 is nitrogen, n is 1 or 2 and p is 1 or 2, R.sup.10 is
 hydrogen; or
 (iv) a nitrogen heterocycle of the formula:
 ##STR13##
 wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or
 pyrazolyl, each of which is optionally substituted with amino,
 trifluoromethyl, carboxamido, or (lower alkylene)-G.sup.6 --R.sup.12
 wherein G.sup.6 is NH, NH(lower alkyl) and R.sup.12 is hydrogen or lower
 alkyl.
 Preferred compounds of the invention have formula II:
 ##STR14##
 wherein
 each R.sub.a 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-lower dialkylcarboxamido, lower
 alkyl, lower alkoxy, with the proviso that at least one of the positions
 ortho or para to the point of attachment of Ar to the tricyclic ring
 system is substituted;
 R.sup.1 is hydrogen, halogen, trifluoromethyl, lower alkyl, or (C.sub.1
 -C.sub.6 alkyl)-G.sup.1 --R.sup.2 where G.sup.1 is oxygen or sulfur and
 R.sup.2 is hydrogen or C.sub.1 -C.sub.6 alkyl;
 W is N or C--R.sup.3 where R.sup.3 is hydrogen or lower alkyl;
 Q.sup.1 is hydrogen, lower alkyl, halogen, lower alkoxy, amino,
 methylamino, dimethylamino, hydroxymethyl, or SO.sub.n (C.sub.1 -C.sub.4
 alkyl) where n is 0, 1 or 2, cyano, hydroxy, --C(O)(C.sub.1 -C.sub.4
 alkyl), --CHO, --(C.sub.1 -C.sub.4 alkyl), --CO.sub.2 (C.sub.1 -C.sub.4
 alkenyl), or --CO.sub.2 (C.sub.1 -C.sub.4 alkynyl);
 Q.sup.2 is hydrogen, lower alkyl, halogen, hydroxymethyl, methoxymethyl, or
 lower alkoxy;
 ##STR15##
 wherein
 V.sup.1 and V.sup.2 are CH.sub.2, CO, CS, SO.sub.2 or CH(lower alkyl), with
 the proviso that both V.sup.1 and V.sup.2 cannot both be CO, CS or
 SO.sub.2 ;
 Y.sup.1 and Y.sup.2 independently represent a bond or lower alkylene;
 A.sup.1 is NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are independently
 hydrogen or a lower alkyl group which optionally forms a heterocycloalkyl
 group with Y.sup.1 ;
 lower alkanoyl, lower alkylsulfonyl, with the proviso that R.sup.4 and
 R.sup.5 cannot both be alkanoyl or alkylsulfonyl; or
 NR.sup.4 R.sup.5 taken together form a C.sub.3 -C.sub.6 heterocycloalkyl or
 a group of the formula:
 ##STR16##
 wherein e and f are independently 1, 2 or 3 and the sum of e and f is at
 least 3; and
 G.sup.2 is
 NR.sup.6 wherein R.sup.6 is hydrogen or lower alkyl, or
 CH(.sub.0 -.sub.6 alkylene)-G.sup.3 R.sup.7 wherein G.sup.3 is CONH,
 CONH(lower alkyl), NH, NH(lower alkyl) and R.sup.7 is hydrogen or lower
 alkyl; or
 CONH.sub.2, CO[N(lower alkyl)R.sup.8 ] wherein R.sup.8 is hydrogen or
 lower alkyl;
 A.sup.2 is hydrogen, lower alkyl, (C.sub.1 -C.sub.6 alkylene)-G.sup.4
 --R.sup.9 wherein G.sup.4 is oxygen or sulfur and R.sup.9 is hydrogen,
 trifluoromethyl or lower alkyl;
 ##STR17##
 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 optionally mono- or disubstituted with
 halogen, trifluoromethyl, amino, lower alkyl, lower alkoxy, with the
 proviso that tetrazolyl can have at most one substituent;
 Z.sup.1 is lower alkyl; and
 V.sup.2, Y.sup.2 and A.sup.2 are as defined above;
 ##STR18##
 where
 Z.sup.2 is carbon or nitrogen;
 where
 when Z.sup.2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R.sup.10 is
 carboxamido, or (lower alkylene)-G.sup.5 --R.sup.11 wherein G.sup.5 is NH,
 NH(lower alkyl) and R.sup.11 is hydrogen or lower alkyl;
 when Z.sup.2 is carbon, n is 1 or 2 and p is 1 or 2, R.sup.10 is amino; or
 when Z.sup.2 is nitrogen, n is 1 or 2 and p is 1 or 2, R.sup.10 is
 hydrogen; or
 (iv) a nitrogen heterocycle of the formula:
 ##STR19##
 wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or
 pyrazolyl, each of which is optionally substituted with amino,
 trifluoromethyl, carboxamido, or (lower alkylene)-G.sup.6 --R.sup.12
 wherein G.sup.6 is NH, NH(lower alkyl) and R.sup.12 is hydrogen or lower
 alkyl.
 In Formula II, Q.sup.1 and Q.sup.2 preferably independently represent
 hydrogen, methyl, or ethyl. More preferred compounds of Formula II are
 those where N--V.sup.2 --Y.sup.2 --A.sup.2 represents N-cyclopropylmethyl.
 Other more preferred compounds of Formula II include those where one of
 Q.sup.1 and Q.sup.2 is methyl or ethyl and the other is hydrogen.
 Still other more preferred compounds of Formula II are those where
 N--V.sup.2 --Y.sup.2 --A.sup.2 represents N-cyclopropylmethyl, Q.sup.1 is
 methyl or ethyl, and --V.sup.1 --Y.sup.1 --A.sup.1 represents
 ##STR20##
 hereinafter Formula II-a,
 wherein
 R.sub.b is hydrogen or methyl;
 t is 1, 2 or 3, more preferably 1;
 R.sub.x is hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl(C.sub.1 -C.sub.6)alkyl
 where phenyl is optionally mono- or disubstituted independently with
 C.sub.1 -C.sub.6 alkyl, C.sup.1 -C.sub.6 alkoxy, halogen, or hydroxy; and
 R.sub.y is hydrogen, C.sub.1 -C.sub.6 alkyl, (C.sub.3 -C.sub.6)cycloalkyl;
 or
 NR.sub.x R.sub.y represents pyrrolidinyl, N--(C.sub.1
 -C.sub.6)alkylpyrrolidin-2-yl, piperidinyl, morpholinyl, or N--(C.sup.1
 -C.sub.6)alkylpiperazinyl.
 Particularly preferred compounds of Formula II include those where
 N--V.sup.2 --Y.sup.2 --A.sup.2 represents N-cyclopropylmethyl, Q.sup.1 is
 methyl, and --V.sup.1 --Y.sup.1 --A.sup.1 represents II-a where R.sub.b is
 hydrogen, and t is 1. Particularly preferred R.sub.x and R.sub.y groups
 are independently hydrogen or C.sub.1 -C.sub.2 alkyl, or where NR.sub.x
 R.sub.y represents pyrrolidinyl, piperidinyl or piperazinyl.
 Other preferred compounds of the invention have formula III:
 ##STR21##
 wherein
 each R.sub.a 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-lower dialkylcarboxamido, lower
 alkyl, lower alkoxy, with the proviso that at least one of the positions
 ortho or para to the point of attachment of Ar to the tricyclic ring
 system is substituted;
 R.sup.1 is hydrogen, halogen, trifluoromethyl, lower alkyl, or (C.sub.1
 -C.sub.6 alkyl)-G.sup.1 --R.sup.2 where G.sup.1 is oxygen or sulfur and
 R.sup.2 is hydrogen or C.sub.1 -C.sub.6 alkyl;
 W is N or C--R.sup.3 where R.sup.3 is hydrogen or lower alkyl;
 Q.sup.1 is hydrogen, lower alkyl, halogen, lower alkoxy, amino,
 methylamino, dimethylamino, hydroxymethyl, or SO.sub.n (C.sub.1 -C.sub.4
 alkyl) where n is 0, 1 or 2, cyano, hydroxy, --C(O)(C.sub.1 -C.sub.4
 alkyl), --CHO, --CO.sub.2 (C.sub.1 -C.sub.4 alkyl), --CO.sub.2 (C.sub.1
 -C.sub.4 alkenyl), or --CO.sub.2 (C.sub.1 -C.sub.4 alkynyl);
 Q.sup.2 is hydrogen, lower alkyl, halogen, hydroxymethyl, methoxymethyl, or
 lower alkoxy;
 X is
 ##STR22##
 wherein
 V.sup.1 and V.sup.2 are CH.sub.2, CO, CS, SO.sub.2 or CH(lower alkyl), with
 the proviso that both V.sup.1 and V.sup.2 cannot both be CO, CS or
 SO.sub.2 ;
 Y.sup.1 and Y.sup.2 independently represent a bond or lower alkylene;
 A.sup.1 is NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are independently
 hydrogen or a lower alkyl group which optionally forms a heterocycloalkyl
 group with Y.sup.1 ;
 lower alkanoyl, lower alkylsulfonyl, with the proviso that R.sup.4 and
 R.sup.5 cannot both be alkanoyl or alkylsulfonyl; or
 NR.sup.4 R.sup.5 taken together form a C.sub.3 -C.sub.6 heterocycloalkyl or
 a group of the formula:
 ##STR23##
 wherein e and f are independently 1, 2 or 3 and the sum of e and f is at
 least 3; and
 G.sup.2 is
 NR.sup.6 wherein R.sup.6 is hydrogen or lower alkyl, or
 CH(C.sub.0 -C.sub.6 alkylene)-G.sup.3 --R.sup.7 wherein G.sup.3 is CONH,
 CONH(lower alkyl), NH, NH(lower alkyl) and R.sup.7 is hydrogen or lower
 alkyl; or
 CONH.sub.2, CO[N(lower alkyl)R.sup.8 ] wherein R.sup.8 is hydrogen or
 lower alkyl;
 A.sup.2 is hydrogen, lower alkyl, (C.sub.1 -C.sub.6 alkylene)-G.sup.4
 --R.sup.9 wherein G.sup.4 is oxygen or sulfur and R.sup.9 is hydrogen,
 trifluoromethyl or lower alkyl;
 ##STR24##
 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 optionally mono- or disubstituted with
 halogen, trifluoromethyl, amino, lower alkyl, lower alkoxy, with the
 proviso that tetrazolyl can have at most one substituent;
 Z.sup.1 is lower alkyl; and
 V.sup.2, Y.sup.2 and A.sup.2 are as defined above;
 ##STR25##
 where
 Z.sup.2 is carbon or nitrogen;
 where
 when Z.sup.2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R.sup.10 is
 carboxamido, or (lower alkylene)-G.sup.5 --R.sup.11 wherein G.sup.5 is NH,
 NH(lower alkyl) and R.sup.11 is hydrogen or lower alkyl;
 when Z.sup.2 is carbon, n is 1 or 2 and p is 1 or 2, R.sup.10 is amino; or
 when Z.sup.2 is nitrogen, n is 1 or 2 and p is 1 or 2, R.sup.10 is
 hydrogen; or
 (iv) a nitrogen heterocycle of the formula:
 ##STR26##
 wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or
 pyrazolyl, each of which is optionally substituted with amino,
 trifluoromethyl, carboxamido, or (lower alkylene)-G.sup.6 --R.sup.12
 wherein G.sup.6 is NH, NH(lower alkyl) and R.sup.12 is hydrogen or lower
 alkyl.
 In Formula III, Q.sup.1 and Q.sup.2 preferably independently represent
 hydrogen, methyl, or ethyl. Particularly preferred compounds of Formula
 III are those where N--V.sup.2 --Y.sup.2 --A.sup.2 represents
 N-cyclopropylmethyl. Other more preferred compounds of Formula III include
 those where one of Q.sup.1 and Q.sup.2 is methyl or ethyl and the other is
 hydrogen.
 Still other more preferred compounds of Formula III are those where
 N--V.sup.2 --Y.sup.2 --A.sup.2 represents N-cyclopropylmethyl, Q.sup.1 is
 methyl or ethyl, and --V.sup.1 --Y.sup.1 --A.sup.1 represents
 ##STR27##
 hereinafter Formula III-a,
 wherein
 R.sub.b is hydrogen or methyl;
 t is 1, 2 or 3, more preferably 1;
 R.sub.x is hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl(C.sub.1 -C.sub.6)alkyl
 where phenyl is optionally mono- or disubstituted independently with
 C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, halogen, or hydroxy; and
 R.sub.y is hydrogen, C.sub.1 -C.sub.6 alkyl, (C.sub.3 -C.sub.6)cycloalkyl;
 or
 NR.sub.x R.sub.y represents pyrrolidinyl, N--(C.sub.1
 -C.sub.6)alkylpyrrolidin-2-yl, piperidinyl, morpholinyl, or N--(C.sub.3
 -C.sub.6)alkylpiperazinyl.
 Particularly preferred compounds of Formula III include those where
 N--V.sup.2 --Y.sup.2 --A.sup.2 represents N-cyclopropylmethyl, Q.sup.1 is
 methyl, and --V.sup.1 --Y.sup.1 --A.sup.1 represents III-a where R.sub.b
 is hydrogen, and t is 1. Particularly preferred R.sub.x and R.sub.y groups
 are independently hydrogen or C.sub.1 -C.sub.2 alkyl, or where NR.sub.x
 R.sub.y 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]pyrimidine
 4-(N-(2-Piperidinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-t
 rimethylphenyl)pyrrolo[2,3-b]pyridine
 4-(N-(2-Morpholinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-t
 rimethylphenyl)pyrrolo[2,3-b]pyridine
 4-(N-(2-Piperazinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-t
 rimethylphenyl)pyrrolo[2,3-b]pyridine
 4-(N-(2-Morpholinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-t
 rimethylphenyl)pyrrolo[2,3-b]pyrimidine
 4-(N-(2-Piperazinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-t
 rimethylphenyl)pyrrolo[2,3-b]pyrimidine
 4-(N-(2-Methylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-t
 rimethylphenyl)pyrrolo[3,2-e]pyrimidine
 4-(N-(2-Dimethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6
 -trimethylphenyl)pyrrolo[3,2-e]pyrimidine
 4-(N-(2-Ethylmethylamino)ethyl-N-cyclopropylmethyl)-amino-2,5-dimethyl-7-(2
 ,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine
 4-(N-(2-Ethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-tr
 imethylphenyl)pyrrolo[3,2-e]pyrimidine
 4-(N-(2-Diethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-
 trimethylphenyl)pyrrolo[3,2-e]pyrimidine
 4-(N-(2-Piperazinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-t
 rimethylphenyl)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--
 In certain situations, the compounds of Formula I may contain one or more
 asymmetric carbon atoms, so that the compounds can exist in different
 stereoisomeric forms. These compounds can be, for example, racemates or
 optically active forms. In these situations, the single enantiomers, i.e.,
 optically active forms, can be obtained by asymmetric synthesis or by
 resolution of the racemates. Resolution of the racemates can be
 accomplished, 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. Conversely,
 if the product is a free base, an addition salt, particularly a
 pharmaceutically acceptable addition salt, may be produced by dissolving
 the free base in a suitable organic solvent and treating the solution with
 an acid, in accordance with conventional procedures for preparing acid
 addition salts from base compounds.
 Non-toxic pharmaceutical salts include salts of acids such as hydrochloric,
 phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic,
 methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic,
 alkanoic such as acetic, HOOC--(CH.sub.2)n-ACOOH where n is 0-4, and the
 like. Those skilled in the art will recognize a wide variety of non-toxic
 pharmaceutically acceptable 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 may be employed to prepare non-toxic
 pharmaceutically acceptable addition salts and acylated prodrugs of the
 compounds encompassed by Formula I.
 By "alkyl", "lower alkyl", or C.sub.1 -C.sub.6 alkyl in the present
 invention is meant straight or branched chain alkyl groups having 1-6
 carbon atoms optionally forming a 3 to 6 atoms carbocycle, 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 C.sub.0 -C.sub.6 alkylene is meant a direct bond or a C.sub.1 -C.sub.6
 alkylene group, optionally forming a 3 to 6 atoms carbocycle, such as
 methylene, ethylidene, propylidene, butylidene, pentylidene,
 cyclopentylidene, hexylidene, cyclohexylidene.
 By "alkoxy", "lower alkoxy", or C.sub.1 -C.sub.6 alkoxy in the present
 invention is meant straight or branched chain alkoxy groups having 1-6
 carbon atoms optionally forming a 3 to 6 atoms carbocycle, such as, for
 example, methoxy, ethoxy, propoxy, isopropoxy, cyclopropylmethoxy,
 n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy,
 neopentoxy, cyclopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy,
 cyclohexoxy.
 By "alkanoyl", "lower alkanoyl", or C.sub.1 -C.sub.6 alkanoyl in the
 present invention is meant straight or branched chain alkanoyl groups
 having 1-6 carbon atoms optionally forming a 3 to 6 atoms carbocycle, such
 as, for example, acetyl, propionyl, isopropionyl, cyclopropionyl,
 butanoyl, pentanoyl, cyclopentanoyl, hexanoyl, cyclhexanoyl.
 CONH represents an amide functional group, i.e.,
 ##STR28##
 The term "heterocycle" or "heterocycloalkyl" means a monocyclic or bicyclic
 hydrocarbon group which in which one or more of the ring carbon atoms has
 been replaced with a heteroatom, e.g., 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 aminoalkyl substituted pyrrolo[3,2-e]pyridine and
 pyrrolo[2,3-b]pyrimidine derivatives of the invention with CRF.sub.1
 receptors is shown in the examples below. This interaction results in the
 pharmacological activities of these compounds as illustrated in relevant
 animal models.
 As the compounds of Formula I are effective CRF.sub.1 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 disturbance
 and stress.
 The compounds of general Formula I may be administered orally, topically,
 parenterally, by inhalation or spray or rectally in dosage unit
 formulations containing conventional non-toxic pharmaceutically acceptable
 carriers, adjuvants and vehicles. The term parenteral as used herein
 includes subcutaneous injections, intravenous, intramuscular, intrasternal
 injection or infusion techniques. In addition, there is provided a
 pharmaceutical formulation comprising a compound of general Formula I and
 a pharmaceutically acceptable carrier. One or more compounds of general
 Formula I may be present in association with one or more non-toxic
 pharmaceutically acceptable carriers and/or diluents and/or adjuvants and
 if desired other active ingredients. The pharmaceutical compositions
 containing compounds of general Formula I may be in a form suitable for
 oral use, for example, as tablets, troches, lozenges, aqueous or oily
 suspensions, dispersible powders or granules, emulsion, hard or soft
 capsules, or syrups or elixirs.
 Compositions intended for oral use may be prepared according to any method
 known to 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
 preserving agents in order to provide pharmaceutically elegant and
 palatable preparations. Tablets contain the active ingredient in admixture
 with non-toxic pharmaceutically acceptable 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 time delay material such as glyceryl
 monostearate or glyceryl distearate may be employed.
 Formulations for oral use may 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
 oil medium, for example peanut oil, liquid paraffin or olive oil.
 Aqueous suspensions contain the active materials in admixture with
 excipients suitable for the manufacture of aqueous suspensions. Such
 excipients are suspending agents, for example sodium
 carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,
 sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;
 dispersing or wetting agents may be a naturally-occurring phosphatide, for
 example, lecithin, or condensation products of an alkylene oxide with
 fatty acids, for example polyoxyethylene stearate, or condensation
 products of ethylene oxide with long chain aliphatic alcohols, for example
 heptadecaethyleneoxycetanol, or condensation products of ethylene oxide
 with partial esters derived from fatty acids and a hexitol such as
 polyoxyethylene sorbitol monooleate, or condensation products of ethylene
 oxide with partial esters derived from fatty acids and hexitol anhydrides,
 for example polyethylene sorbitan monooleate. 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 arachid oil, olive oil, sesame oil or coconut
 oil, or in a mineral oil such as liquid paraffin. The oily suspensions may
 contain a thickening agent, for example beeswax, hard paraffin or cetyl
 alcohol. Sweetening agents such as those set forth above, and flavoring
 agents may be added to provide palatable oral preparations. These
 compositions may be preserved by the addition of an anti-oxidant such as
 ascorbic acid.
 Dispersible powders and granules suitable for preparation of an aqueous
 suspension by the addition of water provide the active ingredient in
 admixture with a dispersing or wetting agent, suspending agent and one or
 more preservatives. Suitable dispersing or wetting agents and suspending
 agents are exemplified by those already mentioned above. Additional
 excipients, for example sweetening, flavoring and coloring agents, may
 also be present.
 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 arachid oil, or a mineral oil, for example liquid paraffin or
 mixtures of these. Suitable emulsifying agents may be naturally-occurring
 gums, for example gum acacia or gum tragacanth, naturally-occurring
 phosphatides, for example soy bean, lecithin, and esters or partial esters
 derived from fatty acids and hexitol, anhydrides, for example sorbitan
 monooleate, and condensation products of the said partial esters with
 ethylene oxide, for example polyoxyethylene sorbitan monooleate. The
 emulsions may also contain sweetening and flavoring agents.
 Syrups and elixirs may be formulated with sweetening agents, for example
 glycerol, propylene glycol, sorbitol or sucrose. Such formulations may
 also contain a demulcent, a preservative and flavoring and coloring
 agents. The pharmaceutical compositions may be in the form of a sterile
 injectable aqueous or oleaginous suspension. This suspension may be
 formulated according to the known art using those suitable dispersing or
 wetting agents and suspending agents which have been mentioned above. The
 sterile injectable preparation may also be sterile injectable solution or
 suspension in a non-toxic parentally acceptable diluent or solvent, for
 example as a solution in 1,3-butanediol. Among the acceptable vehicles and
 solvents that may be employed are water, Ringer's solution and isotonic
 sodium chloride solution. In addition, sterile, fixed oils are
 conventionally employed as a solvent or suspending medium. For this
 purpose any bland fixed oil may be employed including synthetic mono-or
 diglycerides. In addition, fatty acids such as oleic acid find use in the
 preparation of injectables.
 The compounds of general Formula I may 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 at ordinary temperatures but liquid at the rectal
 temperature and will therefore melt in the rectum to release the drug.
 Such materials are cocoa butter and polyethylene glycols.
 Compounds of general Formula I may be administered parenterally in a
 sterile medium. The drug, depending on the vehicle and concentration used,
 can either be 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 the order of from about 0.1 mg to about 140 mg per
 kilogram of body weight per day are useful in the treatment of the
 above-indicated conditions (about 0.5 mg to about 7 g per patient per
 day). The amount of active ingredient that may be combined with the
 carrier materials to produce a single dosage form will vary depending upon
 the host treated and the particular mode of administration. Dosage unit
 forms will generally contain between from about 1 mg to about 500 mg of an
 active ingredient.
 It will be understood, however, that the specific dose level for any
 particular patient will depend upon a variety of factors including the
 activity of the specific compound employed, the age, body weight, general
 health, sex, diet, time of administration, route of administration, and
 rate of excretion, drug combination and the severity of the particular
 disease undergoing therapy.
 Preparation of Aminoalkyl Substituted Pyrrolo[3,2-e]pyridine and Pyrrolo[2
 3-b]pyrimidine Analogues
 An illustration of the preparation of compounds of the present invention is
 given in Scheme I, Scheme II and Scheme III. Those having skill in the art
 will recognize that the starting materials may be varied and additional
 steps employed to produce compounds encompassed by the present invention.
 ##STR29##
 wherein Ar, Q.sup.1, Q.sup.2, R.sup.1 and R.sup.3 are as defined above for
 Formula I; and R.sup.14, R.sup.15 and R.sup.16 are encompassed by the
 definition of X for Formula I.
 ##STR30##
 wherein Ar, Q.sup.1, Q.sup.2, R.sup.1 and R.sup.3 are as defined above for
 Formula I; and R.sup.15 and R.sup.16 are encompassed by the definition of
 X for Formula I.
 ##STR31##
 wherein Ar, Q.sup.1, Q.sup.2 and R.sup.1 are as defined above for Formula
 I; and R.sup.15, R.sup.16 and R.sup.17 are encompassed by the definition
 of X for Formula I.
 The disclosures of all articles and references mentioned in this
 application, including patents, are incorporated herein by reference.

The preparation of the compounds of the present invention is illustrated
 further by the following Examples, which are not to be construed as
 limiting the invention in scope or spirit to the specific procedures and
 compounds described in them.
 Commercial reagents are used without further purification. THF refers to
 tetrahydrofuran. Room or ambient temperature refers to 20 to 25.degree. C.
 Concentration implies the use of a rotary evaporator. TLC refers to thin
 layer chromatography. Mass spectral data are obtained either by CI or APCI
 methods.
 EXAMPLE 1
 A.
 4-(N-Cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo
 [2,3-b]pyridine
 ##STR32##
 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
 dropwise addition of N,N-diisopropylethylamine (6.6 mL). After heating for
 0.5 hour the reaction is cooled to ambient temperature and poured into
 aqueous potassium carbonate solution. The product is extracted with
 dichloromethane, dried over sodium sulfate, filtered and concentrated. The
 concentrate is re-dissolved in THF (100 mL) and mixed with borane-methyl
 sulfide complex (10M, 10.3 mL). The mixture is heated to reflux for 8
 hours and quenched at room temperature with a large excess of methanol
 (about 100 mL). Re-heat mixture to reflux for 1 hour, then concentrate
 under reduced pressure. More methanol (another 50 mL) is added to the
 gummy residue and the solution is re-concentrated to yield a white solid.
 B.
 4-(N-(2-Chloroethyl)-N-cyclopropylmethyl)amino-3.
 6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine
 ##STR33##
 A solution containing the product from Example 1A (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). Add borane-methyl sulfide complex (10M, 3.4 mL) and stir at
 ambient temperature for 15 minutes then for 1 hour at reflux temperature.
 The solution is cooled back to room temperature, quenched with a large
 excess of methanol (50 mL) and re-heated to reflux for 1 hour. The
 solution is then concentrated.
 C.
 4-(N-(2-Dimethylamino)ethyl-N-cyclopropylmethyl)-amino-3,6-dimethyl-1-(2,4
 ,6-trimethylphenyl)pyrrolo[2,3-b]pyridine (Compound 1)
 ##STR34##
 A steel bomb containing the product from Example 1B (3.8 g), dimethylamine
 (8 mL) and N-methylpyrrolidinone (20 mL) is sealed and heated to
 80.degree. 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
 The following compounds are prepared essentially according to the
 procedures set forth 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-l-(2,4,6
 -trimethylphenyl)pyrrolo[2,3-b]pyridine (Compound 3)
 c)
 4-(N-(2-Ethylmethylamino)ethyl-N-cyclopropylmethyl)-amino-3,6-dimethyl-1-(
 2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine (Compound 4)
 d)
 4-(N-(2-Ethylamino)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-t
 rimethylphenyl)pyrrolo[2,3-b]pyridine (Compound 5)
 e)
 4-(N-(2-Diethylamino)ethyl-N-cyalopropylmethyl)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-3,6-dimethyl-1-(2,4,6-
 trimethylphenyl)pyrrolo[2,3-b]pyridine (Compound 7)
 g)
 4-(N-(2-Morpholinyl)ethyl-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-trimeth
 ylphenyl)pyrrolo[2,3-b]pyridine (Compound 11)
 ##STR35##
 A solution containing the product from Example 1B (500 mg) and sodium azide
 (22 mg) in N-methylpyrrolidinone (5 mL) is heated to 120.degree. 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 (10 mL) solution of the crude
 product and 10% palladium on carbon (about 200 mg) is hydrogenated for 8
 hours at approximately 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
 ##STR36##
 Dissolve tert-butylnitrite (0.65 g) in acetonitrile (10 mL) and add
 copper(II)chloride (0.68 g). Then
 4-amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine (1.33
 g) is added portionwise to the greenish-brown solution and the mixture 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)
 ##STR37##
 Combine the compound from Example 4A (200 mg) and piperazine (0.58 g) in
 N-methylpyrrolidinone (2 mL) and heat the solution to 120.degree. C. for
 12 hours. Pour mixture into water and extract with ethyl acetate. Wash
 extract with aqueous ammonium chloride then water. Dry extract over sodium
 sulfate, filter and concentrate.
 EXAMPLE 5
 A.
 4-(N-Cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo
 [3,2-e]pyrimidine
 ##STR38##
 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 to 110.degree. C. in a
 sealed tube for 4 hours. Dilute mixture with ethyl acetate and wash with
 water, aqueous ammonium chloride and brine. Dry over sodium sulfate,
 filter and concentrate to give a tan colored solid: MS 335 (M+H).
 B.
 4-(N-(2-Pyrrolidinyl)ethyl-N-cyclopropylmethyl)-amino-2,5-dimethyl-7-(2,4,
 6-trimethylphenyl)pyrrolo3,2-e]pyrimidine (Compound 13)
 ##STR39##
 To a solution of the compound from Example 5A (130 mg) in
 N,N-dimethylformamide (1 mL) at 0.degree. C., under a blanket of nitrogen,
 is added sodium hydride (60%, 70 mg). After stirring the solution for 0.5
 hours, 2-dimethylaminoethyl chloride hydrochloride (135 mg) is added. The
 mixture is then heated to 40.degree. C. for 2 hours, then quenched with
 ice and water. Dilute with ethyl acetate and wash with water, brine, dry
 over sodium sulfate, filter and concentrate. Purify by preparative TLC
 using 10% methanol and 0.5% ammonium hydroxide in dichloromethane as
 eluent to obtain 100 mg of product: MS 432 (M+H).
 EXAMPLE 6
 The following compounds are prepared essentially according to the
 procedures set forth 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]pyrimidine (Compound 14)
 b)
 4-(N-(2-Dimethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,
 6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine (Compound 15)
 c)
 4-(N-(2-Ethylmethylamino)ethyl-N-cyclopropylmethyl)-amino-2,5-dimethyl-7-(
 2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine (Compound 16)
 d)
 4-(N-(2-Ethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-t
 rimethylphenyl)pyrrolo[3,2-e]pyrimidine (Compound 17)
 e)
 4-(N-(2-Diethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6
 -trimethylphenyl)pyrrolo[3,2-e]pyrimidine (Compound 18)
 f)
 4-(N-(2-Piperidinyl)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-
 trimethylphenyl)pyrrolo[3,2-e]pyrimidine (Compound 19)
 g)
 4-(N-(2-Morpholinyl)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-
 trimethylphenyl)pyrrolo[3,2-e]pyrimidine (Compound 20)
 h)
 4-(N-(2-Piperazinyl)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-
 trimethylphenyl)pyrrolo[3,2-e]pyrimidine (Compound 21)
 i)
 4-(N-(2-(4-Methylpiperazinyl))ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl
 -7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine (Compound 22)
 EXAMPLE 7
 The pharmaceutical utility of compounds of this invention are indicated by
 the following assays for human CRF.sub.1 receptor activity.
 Assay for Recombinant Human CRF.sub.1 Receptor Binding Activity
 CRF receptor binding is performed using a modified version of the assay
 described by Grigoriadis and De Souza (Methods in Neurosciences, Vol. 5,
 1991). Membrane pellets containing CRF.sub.1 receptors are re-suspended in
 50 mM Tris buffer pH 7.7 containing 10 mM MgCl.sub.2 and 2 mM EDTA and
 centrifuged for 10 minutes at 48000 g. Membranes are washed again and
 brought to a final concentration of 1500 mg/ml in 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 .sup.125 I-CRF (SA 2200
 Ci/mmol, final concentration of 100 pM) and 50 mL of drug. Binding is
 carried out at room temperature for 2 hours. Plates are then harvested on
 a Brandel 96 well cell harvester and filters are counted for gamma
 emissions on a Wallac 1205 Betaplate liquid scintillation counter. Non
 specific binding is defined by 1 mM cold CRF. IC.sub.50 values are
 calculated with the non-linear curve fitting program RS/1 (BBN Software
 Products Corp., Cambridge, Mass.). The binding affinity for the compounds
 of Formula I expressed as IC.sub.50 value, generally ranges from about 0.5
 nanomolar to about 10 micromolar.
 Alternatively, the binding activity of the compounds of formula I to the
 human CRF.sub.1 receptor can be measured as follows:
 Assay for Human CRF Receptor Binding Activity in IMR32 Cells
 [.sup.125 I]Sauvagine Binding to CRF.sub.1 Receptors Endogenously Expressed
 in IMR-32 Cells: IMR-32 human neuroblastoma cells are grown to 80%
 confluence in EMEM containing Earle's Balanced Salts and 2 mM 1-glutamine
 with 10% FBS, 25 mM HEPES, 1 mM Sodium Pyruvate, and nonessential amino
 acids. At this time, flasks of cells are treated with 2.5 .mu.M
 5-bromo-2'-deoxyuridine (Br-dU) for 10 days. Media is changed every 3-4
 days across the 10 day period. Cells are harvested using No-Zyme (JRH
 Biosciences) and rinsed with PBS. For membrane preparation, cells are
 homogenized in wash buffer (50 mM Tris HCl, 10 mM MgCl.sub.2, 2 mM EGTA,
 pH 7.4) and centrifuged at 48,000.times.g for 10 minutes at 4.degree. C.
 Pellets are re-suspended, homogenized and centrifuged two additional
 times. The receptor binding assay is performed using assay buffer (50 mM
 Tris HCl, 10 mM MgCl.sub.2, 2 mM EGTA, pH 7.4, 0.1% BSA, 0.1 mM bacitracin
 (22.0 mg/100 mL)), 150 .mu.g protein/tube, and [.sup.125 I]Sauvagine (NEN;
 100 pM for competition analysis and 10 pM-1 nM for saturation analysis) to
 yield a final volume of 200 uL. Nonspecific binding is defined using 2
 .mu.M r/h CRF or 9-41 alpha-helical CRF. Cells are incubated for 2 hours
 at room temperature. The assay is terminated by rapid vacuum filtration
 (Tomtec: Deepwell 3) through GFC filters presoaked in 1% PEI using
 ice-cold 50 mM Tris HCl and dry thoroughly by air. Specific Binding:
 70-80%; Kd (nM): 0.30 nM; Bmax (fmole/mg protein): 40-50. IC.sub.50 values
 are calculated with the non-linear curve fitting program RS/1 (BBN
 Software Products Corp., Cambridge, Mass.).
 The binding affinity for the compounds of Formula I expressed as IC.sub.50
 value, generally ranges from about 0.5 nanomolar to about 10 micromolar.
 The invention and the manner and process of making and using it, are now
 described in such full, clear, concise and exact terms as to enable any
 person skilled in the art to which it pertains, to make and use the same.
 It is to be understood that the foregoing describes preferred embodiments
 of the present invention and that modifications may be made therein
 without departing from the spirit or scope of the present invention as set
 forth in the claims. To particularly point out and distinctly claim the
 subject matter regarded as invention, the following claims conclude this
 specification.