Nitrogen substituted imidazo[4,5-C]pyrazoles as corticotropin releasing hormone antagonists

Corticotropin releasing factor (CRF) antagonists of Formulae (I) or (II): ##STR1## and their use in treating 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.

FIELD OF THE INVENTION
 This invention relates to novel nitrogen substituted imidazo[4,5-c]pyrazole
 compounds and pharmaceutical compositions, and to methods 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. In particular, the present invention relates to novel
 imidazopyrimidines and imidazopyridines, pharmaceutical compositions
 containing such compounds and their use in treating psychiatric disorders,
 neurological diseases, immunological, cardiovascular or heart-related
 diseases and colonic hypersensitivity associated with psychopathological
 disturbance and stress.
 BACKGROUND OF THE INVENTION
 Corticotropin releasing hormone or factor (herein referred to as CRH or
 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 a-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 (Ro15-1788), 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 (FG7142) enhanced the actions of CRF [K. T. Britton et
 al., Psychopharmacology 94:306 (1988)].
 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)].
 Several publications describe corticotropin releasing factor antagonist
 compounds and their use to treat psychiatric disorders and neurological
 diseases. Examples of such publications include DuPont Merck PCT
 application US94/11050, Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO
 95/33727 and Pfizer EP 778277 A1.
 European Patent Application Number 190457 A1 discloses 3-methyl-imidazo
 [4,5-c] pyrazole derivatives which have the general formula shown below.
 The compounds have an intense depressant activity on the central nervous
 system, including anticonvulsant, sedative, analgesic and hypothermizing.
 ##STR2##
 Similar imidazo[4,5-c]pyrazole derivatives are disclosed in Tetrahedron,
 Vol. 46, pp. 5777-5788 (1990).
 European Patent Application Publication Number 407102A discloses
 angiotensin II antagonists having the general formula:
 ##STR3##
 PCT Patent Application WO 91/11999 discloses angiotensin II antagonists
 having the general formula shown below. These compounds also have utility
 as treatments for cognitive dysfunctions, depression, anxiety and
 dysphoric mental states.
 ##STR4##
 Insofar as is known, novel nitrogen substituted imidazo[4,5-c]pyrazoles,
 which are described in detail below, have not been previously reported as
 corticotropin releasing factor antagonist compounds useful in 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.
 SUMMARY OF THE INVENTION
 In accordance with 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 formulae (I) and (II) (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 formulae
 (I) and (II), and methods of using such compounds for the suppression of
 CRF hypersecretion, and/or for the treatment-of anxiogenic disorders.
 According to yet 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, and 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 Alzheimer'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 (ADH); 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,
 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.
 According to a still further aspect of the invention, the compounds
 provided by this invention (and especially labelled compounds of this
 invention) are also useful as standards and reagents in determining the
 ability of a potential pharmaceutical to bind to the CRF receptor.
 DETAILED DESCRIPTION OF THE INVENTION
 [1] Thus, in a first embodiment, the present invention provides novel
 compounds of Formulae (I) and (II):
 ##STR5##
 or isomers thereof, stereoisomeric forms thereof, or mixtures of
 stereoisomeric forms thereof, and pharmaceutically acceptable salt forms
 thereof, wherein:
 R.sup.1 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6
 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 haloalkyl, where such
 haloalkyl is substituted with 1-6 halogens, C.sub.3 -C.sub.6 cycloalkyl,
 C.sub.4 -C.sub.8 cycloalkylalkyl, C1-C6 alkoxy, aryl, heteroaryl or
 heterocyclyl;
 R.sup.2 is C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3
 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.4 -C.sub.12
 cycloalkylalkyl, where each group can be optionally substituted with 1 to
 3 substituents independently selected at each occurrence from C.sub.1
 -C.sub.6 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl,
 C.sub.3 -C.sub.6 cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen,
 cyano, NR.sup.6 R.sup.7, OR.sup.7, thiol, S(O).sub.n R.sup.9, COR.sup.7,
 CO.sub.2 R.sup.7, OC(O)R.sup.9, NR.sup.8 COR.sup.7, NR.sup.8 CONR.sup.6
 R.sup.7, NR.sup.8 CO.sub.2 R.sup.9, CONR.sup.6 R.sup.7 ;
 or
 S(O).sub.n R.sup.9, COR.sup.7, CO.sub.2 R.sup.7, CONR.sup.6 R.sup.7 ;
 or
 C.sub.1 -C.sub.4 haloalkyl, where C.sub.1 -C.sub.4 haloalkyl may be
 substituted with 1-6 halogens;
 or
 aryl or aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl or heteroaryl(C.sub.1
 -C.sub.4 alkyl), heterocyclyl, or heterocyclyl(C.sub.1 -C.sub.4 alkyl),
 wherein C.sub.1 -C.sub.4 alkyl in aryl(C.sub.1 -C.sub.4 alkyl),
 heteroaryl(C.sub.1 -C.sub.4 alkyl) or heterocyclyl(C.sub.1 -C.sub.4 alkyl)
 is optionally substituted with substituents selected from C.sub.1 -C.sub.8
 alkyl, COR.sup.7, CO.sub.2 R.sup.7, S(O).sub.n R.sup.9, cyano and aryl;
 n is independently at each occurrence 0, 1, or 2;
 R.sup.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2
 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 haloalkyl, where such haloalkyl is
 substituted with 1-6 halogens, C.sub.3 -C.sub.6 cycloalkyl, C.sub.2
 -C.sub.10 alkoxyalkyl, C.sub.1 -C.sub.6 hydroxyalkyl, cyano, OR.sup.6,
 thiol, S(O).sub.n R.sup.9, NR.sup.6 R.sup.7, aryl, or heteroaryl;
 R.sup.4 is phenyl, pyridyl, pyrimidyl, triazinyl, furanyl, naphthyl,
 quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl,
 pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,
 isoxazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl or pyrazolyl, where each
 R.sup.4 is attached via an unsaturated carbon atom and each R.sup.4 may be
 optionally substituted with 1 to 4 R.sup.5 groups;
 R.sup.5 is independently at each occurrence selected from C.sub.1 -C.sub.10
 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3
 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, where C.sub.1
 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl,
 C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl are
 optionally substituted with 1-3 substituents independently selected at
 each occurrence from C.sub.1 -C.sub.4 alkyl, nitro, halogen, cyano,
 NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.9,
 COR.sup.7, OR.sup.7, CONR.sup.6 R.sup.7, NR.sup.8 CONR.sup.6 R.sup.7,
 CO.sub.2 R.sup.7, thiol, or S(O).sub.n R.sup.9 ;
 or
 nitro, halogen, cyano, C.sub.1 -C.sub.4 haloalkyl optionally substituted
 with 1-6 halogens, NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2
 R.sup.9, COR.sup.7, OR.sup.7, CONR.sup.6 R.sup.7, NR.sup.8 CONR.sup.6
 R.sup.7, CO.sub.2 R.sup.7, thiol, or S(O).sub.n R.sup.9 ;
 R.sup.6 and R.sup.7 are independently at each occurrence selected from:
 (1) H;
 (2) C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10
 alkynyl, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, or
 C.sub.4 -C.sub.12 cycloalkylalkyl, each optionally substituted with 1-6
 substituents independently selected at each occurrence from C.sub.1
 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halogen, C.sub.1 -C.sub.4
 haloalkyl, cyano, nitro, OR.sup.12, thiol, S(O).sub.n R.sup.9, COR.sup.12,
 CO.sub.2 R.sup.12, NR.sup.8 COR.sup.12, NR.sup.8 CONR.sup.11 R.sup.12,
 NR.sup.8 CO.sub.2 R.sup.9, NR.sup.11 R.sup.12, and CONR.sup.11 R.sup.12 ;
 (3) aryl, aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl or heteroaryl(C.sub.1
 -C.sub.4 alkyl), heterocyclyl, or heterocyclyl(C.sub.1 -C.sub.4 alkyl;
 R.sup.8 is independently at each occurrence selected from H, C.sub.1
 -C.sub.4 alkyl, C3-C8 alkenyl, C.sub.3 -C.sub.6 cycloalkyl, or C.sub.4
 -C.sub.7 cycloalkylalkyl;
 or
 phenyl or phenyl (C1-C4 alkyl), each optionally substituted with 1-3
 substitutents selected from C1-C4 alkyl, halogen, C1-C4 haloalkyl
 optionally substituted with 1-6 halogens, C1-C4 alkoxy, OH;
 R.sup.9 is independently at each occurrence selected from H, C.sub.1
 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl,
 C.sub.4 -C.sub.7 cycloalkylalkyl;
 or
 phenyl or phenyl(C1-C4 alkyl), each optionally substituted with 1-3
 substitutents selected from C1-C4 alkyl, halogen, C1-C4 haloalkyl
 optionally substituted with 1-6 halogens, C1-C4 alkoxy, OH;
 R.sup.10 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.2
 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12
 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl,
 heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl, heterocyclyl(C.sub.1
 -C.sub.4 alkyl), where C1-C4 haloalkyl is optionally substituted with 1 to
 6 halogens;
 R.sup.11 and R.sup.12 are independently at each occurrence selected from H,
 C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.7
 cycloalkylalkyl, or C.sub.1 -C.sub.4 haloalkyl optionally substituted with
 1-6 halogens;
 or
 phenyl or phenyl(C1-C4 alkyl), each optionally substituted with 1-3
 substitutents selected from C1-C4 alkyl, halogen, C1-C4 haloalkyl
 optionally substituted with 1-6 halogens, C1-C4 alkoxy, OH;
 aryl is phenyl or naphthyl, each optionally substituted with 1 to 5
 substituents independently selected at each occurrence from R.sup.13 ;
 heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl,
 isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl,
 oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl,
 pyrazolyl, triazolyl, tetrazolyl, 2,3-dihydrobenzofuranyl,
 2,3-dihydrobenzothienyl, or indazolyl, each optionally substituted with 1
 to 4 substituents independently selected from at each occurrence R.sup.13
 ;
 heterocyclyl is saturated or partially saturated heteroaryl, optionally
 substituted with 1 to 3 substituents independently selected at each
 occurrence from R.sup.13 ;
 R.sup.13 is independently at each occurrence selected from C.sub.1
 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl,
 C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, where
 C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10
 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl
 are optionally substituted with 1-3 substituents independently selected at
 each occurrence from C.sub.1 -C.sub.4 alkyl, nitro, halogen, cyano,
 NR.sup.8 R.sup.9, NR.sup.8 COR.sup.9, NR.sup.8 CO.sub.2 R.sup.9,
 COR.sup.9, OR.sup.9, CONR.sup.8 R.sup.9, NR.sup.8 CONR.sup.8 R.sup.9,
 CO.sub.2 R.sup.9, thiol, or S(O).sub.n R.sup.9
 or
 nitro, halogen, cyano, C.sub.1 -C.sub.4 haloalkyl optionally substituted
 with 1-6 halogens, NR.sup.8 R.sup.9, NR.sup.8 COR.sup.9, NR.sup.8 CO.sub.2
 R.sup.9, COR.sup.9, OR.sup.9, CONR.sup.8 R.sup.9, NR.sup.8 CONR.sup.8
 R.sup.9, CO.sub.2 R.sup.9, thiol, or S(O).sub.n R.sup.9 ;
 [2] In a preferred embodiment, the present invention provides novel
 compounds of Formulae (I) and (II) wherein: R.sup.4 is phenyl, pyridyl or
 pyrimidyl, each optionally substituted by 1 to 4 R.sup.5 groups.
 [3] In a more preferred embodiment, the present invention provides novel
 compounds of Formula (I) and (II), wherein: R.sup.1 is selected from H,
 C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 haloalkyl, where such haloalkyl
 is substituted with 1-6 halogens, C.sub.3 -C.sub.6 cycloalkyl, or aryl.
 [4] In an even more preferred embodiment, the present invention provides
 novel compounds of Formulae (I) and (II), wherein: R.sup.1 is selected
 from H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 haloalkyl, where such
 haloalkyl is substituted with 1-6 halogens, C.sub.3 -C.sub.6 cycloalkyl,
 or aryl and R.sup.4 is phenyl, pyridyl or pyrimidyl, each optionally
 substituted by 1 to 4 R.sup.5 groups.
 [5] In an even further preferred embodiment, the present invention provides
 novel compounds of Formula (I) and (II), wherein the compound is selected
 from the group:
 1-(2-chloro-4-trifluoromethyl)phenyl-5-ethyl-3-methyl-4-[1-(1-methyl)butane
 ]imidazo[4,5-c]pyrazole;
 1-(2-chloro-4-trifluoromethyl)phenyl-5-ethyl-4-[1-(1-ethyl)butane]-3-methyl
 imidazo[4,5-c]pyrazole;
 4-(n-butyl)-1-(2-chloro-4-bromo)phenyl-5-ethyl-3-methylimidazo[4,5-c]pyrazo
 le;
 1-(2-chloro-4-bromo)phenyl-5-ethyl-3-methyl-4-[1-(1-methyl)butane]imidazo[4
 ,5-c]pyrazole;
 1-(2-chloro-4-bromo)phenyl-5-ethyl-4-[1-(1-ethyl)butane]3-methylimidazo[4,5
 -c]pyrazole;
 5-ethyl-3-fluoromethyl-4-[1-(1-methyl)butane]-1-(2,4,6-trichloro)phenylimid
 azo[4,5-c]pyrazole;
 5-ethyl-4-[1-(1-methyl)butane]-1-(2,4,6-trichloro)phenylimidazo[4,5-c]pyraz
 ole;
 1-(2,6-dichloro-4-bromo)phenyl-5-ethyl-4-[1-(1-ethyl)butane]-3-methylimidaz
 o[4,5-c]pyrazole;
 1-(2,4-dichloro)phenyl-5-ethyl-4-[1-(1-ethyl)butane]-3-methylimidazo[4,5-c]
 pyrazole;
 1-(2,4-dichloro)phenyl-5-ethyl-3-methyl-4-[1-(1-methyl)butane]imidazo[4,5-c
 ]pyrazole;
 1-(2,4-dichloro)phenyl-5-ethyl-3-methyl-4-[1-(1,3-dimethyl)butane]imidazo[4
 ,5-c]pyrazole;
 1-(2,6-dichloro-4-bromo)phenyl-5-ethyl-3-methyl-4-[1-(1-methyl)butane]imida
 zo[4,5-c]pyrazole;
 5-ethyl-4-[-1-(1-ethyl)butane]-3-methyl-1-(2,4,5-trichloro)phenylimidazo[4,
 5-c]pyrazole;
 5-ethyl-3-methyl-4-[1-(1-methyl)butane]-1-(2,4,5-trichloro)phenylimidazo[4,
 5-c]pyrazole;
 5-ethyl-4-[1-(1-methyl)pentane]-3-methyl-1-(2,4,6-trichloro)phenylimidazo[4
 ,5-c]pyrazole;
 1-(2-bromo-4-isopropyl)phenyl-5-ethyl-4-[1-(1-ethyl)butane]-3-methylimidazo
 [4,5-c]pyrazole;
 1-(2-bromo-4-isopropyl)phenyl-5-ethyl-3-methyl-4-[1-(1-methyl)butane)imidaz
 o[4,5-c]pyrazole;
 1-(2-bromo-4,6-dichloro)phenyl-5-ethyl-4-[1-(1-ethyl)butane]-3-methylimidaz
 o[4,5-c]pyrazole;
 1-(2-bromo-4,6-dichloro)phenyl-5-ethyl-3-methyl-4-[1-(1-methyl)butane]imida
 zo[4,5-c]pyrazole;
 4-(n-butyl)-1-(2,6-dichloro-4-bromo)phenyl-5-ethyl-3-methylimidazo[4,5-c]py
 razole;
 1-(2,6-dichloro-4-bromo)phenyl-5-ethyl-3-methyl-4-[1-(3-methyl)butane]imida
 zo(4,5-c]pyrazole;
 1-(2,6-dichloro-4-bromo)phenyl-5-ethyl-4-[1-(2-ethyl)butane]-3-methylimidaz
 o[4,5-c]pyrazole;
 4-benzyl-1-(2,6-dichloro-4-bromo)phenyl-5-ethyl-3-methylimidazo[4,5-c]pyraz
 ole; and
 1-(2,6-dichloro-4-bromo)phenyl-4-(3,4-difluorobenzyl)-5-ethyl-3-methylimida
 zo[4,5-c]pyrazole
 or a pharmaceutically acceptable salt form thereof.
 [6, 7, 8, 9, 10] In another preferred embodiment, the present invention
 provides a pharmaceutical composition comprising a pharmaceutically
 acceptable carrier and a therapeutically effective amount of compounds of
 Formulae (I) and (II).
 [11, 12, 13, 14, 15] In yet another preferred embodiment, the present
 invention provides a method of treating 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 feeding disorder,
 drug addiction, drug or alcohol withdrawal symptoms, inflammatory
 diseases, cardiovascular or heart-related diseases, fertility problems,
 human immunodeficiency virus infections, hemorrhagic stress, obesity,
 infertility, head and spinal cord traumas, epilepsy, stroke, ulcers,
 amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of
 which can be effected or facilitated by antagonizing CRF, including but
 not limited to disorders induced or facilitated by CRF, in mammals,
 comprising: administering to the mammal a therapeutically effective amount
 of compounds of Formulae (I) and (II).
 The compounds herein described may have asymmetric centers. Compounds of
 the present invention containing an asymmetrically substituted atom may be
 isolated in optically active or racemic forms. It is well known in the art
 how to prepare optically active forms, such as by resolution of racemic
 forms or by synthesis from optically active starting materials. Many
 geometric isomers of olefins, C.dbd.N double bonds, and the like can also
 be present in the compounds described herein, and all such stable isomers
 are contemplated in the present invention. Cis and trans geometric isomers
 of the compounds of the present invention are described and may be
 isolated as a mixture of isomers or as separated isomeric forms. All
 chiral, diastereomeric, racemic forms and all geometric isomeric forms of
 a structure are intended, unless the specific stereochemistry or isomeric
 form is specifically indicated. All processes used to prepare compounds of
 the present invention and intermediates made therein are considered to be
 part of the present invention.
 The term "substituted," as used herein, means that any one or more
 hydrogens on the designated atom is replaced with a selection from the
 indicated group, provided that the designated atom's normal valency is not
 exceeded, and that the substitution results in a stable compound. When a
 substitent is keto (i.e., .dbd.O), then 2 hydrogens on the atom are
 replaced. Keto substituents are not present on aromatic moieties.
 The present invention is intended to include all isotopes of atoms
 occurring in the present compounds. Isotopes include those atoms having
 the same atomic number but different mass numbers. By way of general
 example and without limitation, isotopes of hydrogen include tritium and
 deuterium. Isotopes of carbon include C-13 and C-14.
 When any variable (e.g., R.sup.6) occurs more than one time in any
 constituent or formula for a compound, its definition at each occurrence
 is independent of its definition at every other occurrence. Thus, for
 example, if a group is shown to be substituted with 0-2 R.sup.6, then said
 group may optionally be substituted with up to two R.sup.6 groups and
 R.sup.6 at each occurrence is selected independently from the definition
 of R.sup.6. Also, combinations of substituents and/or variables are
 permissible only if such combinations result in stable compounds.
 When a bond to a substituent is shown to cross a bond connecting two atoms
 in a ring, then such substituent may be bonded to any atom on the ring.
 When a substituent is listed without indicating the atom via which such
 substituent is bonded to the rest of the compound of a given formula, then
 such substituent may be bonded via any atom in such substituent.
 Combinations of substituents and/or variables are permissible only if such
 combinations result in stable compounds.
 As used herein, "alkyl" is intended to include both branched and
 straight-chain saturated aliphatic hydrocarbon groups having the specified
 number of carbon atoms. Examples of alkyl include, but are not limited to,
 methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl,
 and s-pentyl. "Haloalkyl" is intended to include both branched and
 straight-chain saturated aliphatic hydrocarbon groups having the specified
 number of carbon atoms, substituted with 1 or more halogen (for example
 -C.sub.v F.sub.w where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl
 include, but are not limited to, trifluoromethyl, trichloromethyl,
 pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents an alkyl group
 as defined above with the indicated number of carbon atoms attached
 through an oxygen bridge. Examples of alkoxy include, but are not limited
 to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy,
 n-pentoxy, and s-propoxy, "Cycloalky" is intended to include saturated
 ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. Alkenyl" is
 intended to include hydrocarbon chains of either a straight or branched
 configuration and one or more unsaturated carbon-carbon bonds which may
 occur in any stable point along the chain, such as ethenyl and propenyl.
 "Alkynyl" is intended to include hydrocarbon chains of either a straight
 or branched configuration and one or more triple carbon-carbon bonds which
 may occur in any stable point along the chain, such as ethynyl and
 propynyl.
 "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and
 iodo; and "counterion" is used to represent a small, negatively charged
 species such as chloride, bromide, hydroxide, acetate, and sulfate.
 As used herein, "carbocycle" or "carbocyclic residue" is intended to mean
 any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered
 bicyclic or tricyclic, any of which may be saturated, partially
 unsaturated, or aromatic. Examples of such carbocycles include, but are
 not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
 cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane,
 [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,
 fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
 As used herein, the term "heterocycle" or "heterocyclic system" is intended
 to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to
 10-membered bicyclic heterocyclic ring which is saturated partially
 unsaturated or unsaturated (aromatic), and which consists of carbon atoms
 and from 1 to 4 heteroatoms independently selected from the group
 consisting of N, O and S and including any bicyclic group in which any of
 the above-defined heterocyclic rings is fused to a benzene ring. The
 nitrogen and sulfur heteroatoms may optionally be oxidized. The
 heterocyclic ring may be attached to its pendant group at any heteroatom
 or carbon atom which results in a stable structure. The heterocyclic rings
 described herein may be substituted on carbon or on a nitrogen atom if the
 resulting compound is stable. A nitrogen in the heterocycle may optionally
 be quaternized. It is preferred that when the total number of S and O
 atoms in the heterocycle exceeds 1, then these heteroatoms are not
 adjacent to one another. It is preferred that the total number of S and O
 atoms in the heterocycle is not more than 1. As used herein, the term
 "aromatic heterocyclic system" is intended to mean a stable 5- to
 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic
 heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4
 heterotams independently selected from the group consisting of N, O and S.
 It is preferred that the total number of S and O atoms in the aromatic
 heterocycle is not more than 1.
 Examples of heterocycles include, but are not limited to, acridinyl,
 azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,
 benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
 benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,
 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,
 decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
 dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,
 imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl,
 indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,
 isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,
 methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
 oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,
 phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,
 phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,
 pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,
 pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,
 pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,
 pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,
 quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
 tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,
 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl,
 thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
 thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,
 1,3,4-triazolyl, and xanthenyl. Preferred heterocycles include, but are
 not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
 pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl,
 oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,
 and isatinoyl. Also included are fused ring and spiro compounds
 containing, for example, the above heterocycles.
 The term "amino acid" as used herein means an organic compound containing
 both a basic amino group and an acidic carboxyl group. Included within
 this term are natural amino acids (e.g., L-amino acids), modified and
 unusual amino acids (e.g., D-amino acids), as well as amino acids which
 are known to occur biologically in free or combined form but usually do
 not occur in proteins. Included within this term are modified and unusual
 amino acids,such as those disclosed in, for example, Roberts and Vellaccio
 (1983) The Peptides, 5: 342-429, the teaching of which is hereby
 incorporated by reference. Natural protein occurring amino acids include,
 but are not limited to, alanine, arginine, asparagine, aspartic acid,
 cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine,
 leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine,
 tyrosine, tryptophan, proline, and valine. Natural non-protein amino acids
 include, but are not limited to arginosuccinic acid, citrulline, cysteine
 sulfinic acid, 3,4-dihydroxyphenylalanine, homocysteine, homoserine,
 ornithine, 3-monoiodotyrosine, 3,5-diiodotryosine,
 3,5,5'-triiodothyronine, and 3,3',5,5'-tetraiodothyronine. Modified or
 unusual amino acids which can be used to practice the invention include,
 but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an
 N-Cbz-protected amino acid, 2,4-diaminobutyric acid, homoarginine,
 norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine,
 .beta.-phenylproline, tert-leucine, 4-aminocyclohexylalanine,
 N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine,
 N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic
 acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and
 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid,
 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.
 The phrase "pharmaceutically acceptable" is employed herein to refer to
 those compounds, materials, compositions, and/or dosage forms which are,
 within the scope of sound medical judgment, suitable for use in contact
 with the tissues of human beings and animals without excessive toxicity,
 irritation, allergic response, or other problem or complication,
 commensurate with a reasonable benefit/risk ratio.
 As used herein, "Pharmaceutically acceptable salts" refer to derivatives of
 the disclosed compounds wherein the parent compound is modified by making
 acid or base salts thereof. Examples of pharmaceutically acceptable salts
 include, but are not limited to, mineral or organic acid salts of basic
 residues such as amines; and alkali or organic salts of acidic residues
 such as carboxylic acids. The pharmaceutically acceptable salts include
 the conventional non-toxic salts or the quaternary ammonium salts of the
 parent compound formed, for example, from non-toxic inorganic or organic
 acids. For example, such conventional non-toxic salts include those
 derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric,
 sulfamic, phosphoric, and nitric; and the salts prepared from organic
 acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
 malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,
 phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic,
 fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and
 isethionic.
 The pharmaceutically acceptable salts of the present invention can be
 synthesized from the parent compound which contains a basic or acidic
 moiety by conventional chemical methods. Generally, such salts can be
 prepared by reacting the free acid or base forms of these compounds with a
 stoichiometric amount of the appropriate base or acid in water or in an
 organic solvent, or in a mixture of the two; generally, nonaqueous media
 like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are
 preferred. Lists of suitable salts are found in Remington's Pharmaceutical
 Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418,
 the disclosure of which is hereby incorporated by reference.
 Since prodrugs are known to enhance numerous desirable qualities of
 pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc . .
 . ) the compounds of the present invention may be delivered in prodrug
 form. Thus, the present invention is intended to cover prodrugs of the
 presently claimed compounds, methods of delivering the same and
 compositions containing the same. "Prodrugs" are intended to include any
 covalently bonded carriers which release an active parent drug of the
 present invention in vivo when such prodrug is administered to a mammalian
 subject. Prodrugs the present invention are prepared by modifying
 functional groups present in the compound in such a way that the
 modifications are cleaved, either in routine manipulation or in vivo, to
 the parent compound. Prodrugs include compounds of the present invention
 wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that,
 when the prodrug of the present invention is administered to a mammalian
 subject, it cleaves to form a free hydroxyl, free amino, or free
 sulfhydryl group, respectively. Examples of prodrugs include, but are not
 limited to, acetate, formate and benzoate derivatives of alcohol and amine
 functional groups in the compounds of the present invention.
 "Stable compound" and "stable structure" are meant to indicate a compound
 that is sufficiently robust to survive isolation to a useful degree of
 purity from a reaction mixture, and formulation into an efficacious
 therapeutic agent.
 "Substituted" is intended to indicate that one or more hydrogens on the
 atom indicated in the expression using "substituted" is replaced with a
 selection from the indicated group(s), provided that the indicated atom's
 normal valency is not exceeded, and that the substitution results in a
 stable compound. When a substituent is keto (i.e., .dbd.O) group, then 2
 hydrogens on the atom are replaced.
 "Therapeutically effective amount" is intended to include an amount of a
 compound of the present invention or an amount of the combination of
 compounds claimed effective to inhibit HIV infection or treat the symptoms
 of HIV infection in a host. The combination of compounds is preferably a
 synergistic combination. Synergy, as described for example by Chou and
 Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in
 this case, inhibition of HIV replication) of the compounds when
 administered in combination is greater than the additive effect of the
 compounds when administered alone as a single agent. In general, a
 synergistic effect is most clearly demonstrated at suboptimal
 concentrations of the compounds. Synergy can be in terms of lower
 cytotoxicity, increased antiviral effect, or some other beneficial effect
 of the combination compared with the individual components.
 The term "therapeutically effective amount" of a compound of this invention
 means an amount effective to antagonize abnormal level of CRF or treat the
 symptoms of affective disorder, anxiety or depression in a host.
 Synthesis
 The novel substituted bicyclic imidazo[4,5-c]pyrazoles of Formulae (I) and
 (II) of this invention can be prepared by one of the general schemes
 outlined below, in particular Schemes 1-2.
 Compounds of Formula (I) of this invention may be prepared as shown in
 Scheme 1.
 ##STR6##
 An appropriate hydrazine (R.sup.4 NHNH.sub.2), either as the free base or
 as the corresponding mineral acid salt, may be condensed with
 acrylonitrile compounds of formula R.sup.3 (NH.sub.2)C.dbd.C(CN)H to
 afford pyrazole compounds of formula (III). These cyclizations are
 preferrably conducted in aqueous media and at elevated temperatures up to
 boiling. When R.sup.3 is hydrogen, 2-halogenoacrylonitrile compounds of
 formula CH.sub.2.dbd.CH(CN)Hal or 2,3-dihalogenopropionitrile compounds of
 formula Hal'CH.sub.2 CH(CN)Hal may be cyclized with the hydrazines of
 formula R.sup.4 NHNH.sub.2. Hal and Hal' may be independently selected
 from chlorine, bromine or iodine. One skilled in the art of heterocyclic
 chemistry will readily understand the optimal combinations of conversions
 necessary to prepare a number of compounds of formula (III) with R.sup.3
 and R.sup.4 variations and can refer to the review of Potts, K. T.
 (Comprehensive Heterocyclic Chemistry, Katritzky, A. R., et.al., Eds.,
 Pergamon Press, Oxford, 1984, 5, pg. 111-157) or Vicentini, et.al.
 (Tetrahedron, 1990, 46, 5777).
 Compounds of formula (III) may be readily condensed with compounds of
 formula (R.sup.1 CO).sub.2 O or R.sup.1 COCl to provide amides of formula
 (IV). The condensations may be conducted neat or in the optional presence
 of cosolvent. The reactions are preferrably run at room temperature where
 R.sup.1 is methyl and at elevated temperature up to the boiling point of
 the anhydride or cosolvent used where R.sup.1 is larger than methyl.
 Amides of formula (IV) may then be converted, in the presence of a
 reducing agent, to the substituted amino pyrazoles of formula (V).
 Reducing agents include, but are not limited to, lithium aluminum hydride
 and borane. Reactions are generally run in ethereal solvents, for example
 tetrahydrofuran and diethyl ether. The reductions are carried out for a
 period of time between 1 hour and 4 days, and at room temperature or
 elevated temperature up to reflux in order to effect the reaction. If
 borane is used, it may be employed as a complex, for example, but not
 limited to, borane-methyl sulfide complex, borane-piperidine complex,
 borane-pyridine complex, and borane-tetrahydrofuran complex.
 In preparation for ring closure to the imidazole, compounds of formula (V)
 may be nitrosated in the presence of acid and a suitable nitrosating agent
 such as, but not limited to, isoamyl nitrite in an alcoholic solvent such
 as methanol, ethanol, or isopropanol. The reactions are generally
 conducted at room temperature and afford compounds of formula (VI) in high
 yield and purity after filtration or column chromatography. Cyclization to
 imidazopyrazoles of formula (VII) may be accomplished by refluxing
 precursors of formula (VI) in the presence of a base such as, but not
 limited to, pyridine or other non-nucleophilic organic base for a period
 of time between 1 hour and 3 days and at a temperature ranging from room
 temperature up to the boiling point of the base or co-solvent employed.
 Cosolvents such as, but not limited to, tetrahydrofuran may be used,
 however, it may be preferrable to conduct the cyclizations in the absence
 of cosolvent. Compounds of formula (VII) are expected to exist as a
 mixture of imidazole tautomers, and one skilled in the art will
 immediately recognize this.
 Finally, treatment of compounds of formula (VII) with a base and a compound
 of formula R.sup.2 -X wherein X represents a leaving group may afford the
 desired imidazopyrazole compounds of formula (I). Leaving groups may
 include, but are not limited to, bromo, chloro, iodo, cyano, alkoxy,
 methanesulfonyl, and p-toluenesulfonyl. Possible bases include, but are
 not limited to, the sodium, lithium or potassium
 bis(trimethylsilyl)amides, sodium or potassium hydride, alkyl lithiums and
 alkyl grignards and inorganic bases such as sodium, potassium and lithium
 hydroxide. The reactions are optionally conducted at room temperature or
 at elevated temperatures up to the boiling point of a cosolvent. A wide
 variety of inert solvents may be employed, for example, dimethylformamide,
 dimethylsulfoxide, toluene, tetrahydrofuran, diethyl ether, and methylene
 chloride. The reactions may be successfully performed in glass reaction
 vessels or polypropylene wells, and one skilled in the art of organic
 chemistry will readily understand the optimal combinations of above
 conditions for effecting this transformation, or can consult the text of
 Larock, R. C. (Comprehensive Organic Transformations, VCH Publishers, New
 York, 1989). Although regiomeric alkylation products are conceivably
 possible from tautomers of formula (VII), the experimental conditions
 taught herein will selectively provide the desired regiomer represented by
 compounds of formula (I).
 Alternatively, compounds of formula (I) may be formed from compounds of
 formula (VII) by treatment with a base and subsequent addition to the
 carbon-carbon double bond of an .alpha., .beta.-unsaturated carboxylic
 acid derivative, ketone, aldehyde, or nitrile; a process commonly accepted
 as the Michael reaction. Bases and optional inert cosolvents may be
 selected from those identified (vide supra). One skilled in the art of
 organic synthesis will readily appreciate the utility of the Michael
 reaction, and may consult the teachings of House, H. O. (Modern Synthetic
 Reactions, W. A. Benjamin, Inc., Menlo Park, Calif., 1972, p 595).
 As shown in Scheme 2, compounds of formula (I) where R.sup.3 is OH or SH
 may be transformed into compounds of formula (I) where R.sup.3 is OR.sup.6
 or SR.sup.6 or compounds of formula (II) where G is O or S and the
 pyrazole nitrogen is substituted as R.sup.10.
 ##STR7##
 Reactions to afford compounds of formula (I) where R.sup.3 is OR.sup.6 or
 SR.sup.6 may be preferably conducted with oxophilic alkylating agents such
 as, but not limited to, the trialkyloxonium tetrafluoroborates and/or
 thiophilic alkylating agents such as, but not limited to, dialkyl
 sulfates. Reactions to afford compounds of formula (II), where G is O or S
 and the pyrazole nitrogen is 10 substituted (Scheme 2) as R.sup.10 are
 more preferably effected by treatment of compounds of formula (I, R.sup.3
 is OH or SH) with a base such as, but not limited to, potassium hydroxide
 in a solvent such as acetone or other inert solvent with a reagent
 R.sup.10 -X where X is a leaving group (vide supra). These product
 compounds arise via the tautomeric nature of compounds of formula (I)
 where R.sup.3 is OH or SH.
 In the described manner then, the novel substituted bicyclic
 imidazo[4,5-c]pyrazoles of formula (I) and (II) of this invention can be
 prepared by one of the general schemes outlined above. See Schemes 1-2.
 Compounds of Formula (II) may also be prepared as outlined in Scheme 3.
 ##STR8##
 Imidazoles of Formula (a) (where X=halogen, NH.sub.2, alkylamino (1-6
 carbons), dialkylamino (2-12 carbons), alkylthio (1 to 6 carbons) or
 alkylsulfonyl (1 to 6 carbons) may be reacted with a compound of the
 formula R.sup.10 NHNH.sub.2, in the presence or absence of a base, in an
 inert solvent to give intermediates of formula (b). Bases may include, but
 are not limited to, alkali metal hydrides (preferably sodium hydride),
 alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or
 sodium ethoxide), alkaline earth metal hydrides, alkali metal
 dialkylamides (preferably lithium di-isopropylamide), alkali metal
 bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide),
 trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or
 triethylamine) or aromatic amines (preferably pyridine). Inert solvents
 may include, but are not limited to, lower alkanenitriles (1 to 6 carbons,
 preferably acetonitrile), dialkyl ethers (preferably diethyl ether),
 cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane),
 N,N-dialkylformamides (preferably dimethylformamide),
 N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides
 (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably
 dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene)
 or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably
 dichloromethane). Preferred reaction temperatures range from -20 to
 100.degree. C.
 Intermediates (b) may then be treated with a boronic acid or a boronic acid
 ester of the formula R.sup.4 B(OH).sub.2 or R.sup.4 B(OR.sup.a) (OR.sup.b)
 (where R.sup.a and R.sup.b are lower alkyl(1 to 6 carbons) or together
 R.sup.a and R.sup.b are lower alkylene (2 to 12 carbons) in the presence
 of a metal catalyst with or without a base in an inert solvent to give
 compounds of Formula (II). Metal catalysts include, but are not limited to
 salts or phosphine complexes of Cu, Pd or Ni (e.g. Cu(OAc).sub.2,
 PdCl.sub.2 (PPh.sub.3).sub.2, NiCl.sub.2 (PPh.sub.3).sub.2). Bases may
 include, but are not limited to, alkaline earth metal carbonates, alkaline
 earth metal bicarbonates, alkaline earth metal hydroxides, alkali metal
 carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali
 metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6
 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth
 metal hydrides, alkali metal dialkylamides (preferably lithium
 di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably
 sodium bis(trimethylsilyl)amide), trialkyl amines (preferably
 N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines
 (preferably pyridine). Inert solvents may include, but are not limited to,
 lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl
 ethers (preferably diethyl ether), cyclic ethers (preferably
 tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably
 dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide),
 cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
 (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene
 or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens
 (preferably dichloromethane). Preferred reaction temperatures range from
 -80.degree. C. to 150.degree. C.
 Alternatively, compounds of Formula (II) may be prepared as outlined in
 Scheme 4.
 ##STR9##
 Imidazoles of Formula (a) (where X is defined above) may be treated with
 compounds of the formula R.sup.4 NHNH.sub.2 to yield intermediates (c) in
 the presence or absence of a base in an inert solvent. Bases may include,
 but are not limited to, alkaline earth metal carbonates, alkaline earth
 metal bicarbonates, alkaline earth metal hydroxides, alkali metal
 carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali
 metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6
 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth
 metal hydrides, alkali metal dialkylamides (preferably lithium
 di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably
 sodium bis(trimethylsilyl)amide), trialkyl amines (preferably
 N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines
 (preferably pyridine). Inert solvents may include, but are not limited to,
 lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl
 ethers (preferably diethyl ether), cyclic ethers (preferably
 tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably
 dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide),
 cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
 (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene
 or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens
 (preferably dichloromethane). Preferred reaction temperatures range from
 -80.degree. C. to 150.degree. C.
 Intermediates (c) may then be treated with a reagent of the Formula
 R.sup.10 X to give compounds of Formula (II) in the presence or absence of
 a base in an inert solvent. Bases may include, but are not limited to,
 alkaline earth metal carbonates, alkaline earth metal bicarbonates,
 alkaline earth metal hydroxides, alkali metal carbonates, alkali metal
 bicarbonates, alkali metal hydroxides, alkali metal hydrides (preferably
 sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably
 sodium methoxide or sodium ethoxide), alkaline earth metal hydrides,
 alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali
 metal bis(trialkylsilyl)amides (preferably sodium
 bis(trimethylsilyl)amide), trialkyl amines (preferably
 N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines
 (preferably pyridine). Inert solvents may include, but are not limited to,
 lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl
 ethers (preferably diethyl ether), cyclic ethers (preferably
 tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably
 dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide),
 cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides
 (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene
 or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens
 (preferably dichloromethane). Preferred reaction temperatures range from
 -80.degree. C. to 150.degree. C.