| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | March 19, 2002 |
| PATENT TITLE |
Azolo triazines and pyrimidines |
| PATENT ABSTRACT | Corticotropin releasing factor (CRF) antagonists of formula I or II: ##STR1## and their use in treating anxiety, depression, and other psychiatric, neurological disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | October 26, 2000 |
| PATENT REFERENCES CITED |
Arch. Pharm. (Weinheim) 320, 487-491 (1987). Psychopharmacology (Britton, Lee, Koob) 94:306-311 (1988). Life Sciences (Britton, Koob, Rivier, Vale) 31:363-367 (1982). Bull. Soc. Chim, Belg. (Maquestiau, Taghret, Eynde) vol. 101/No. 2/1992. Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide (De Souza, Nemeroff) 221-224 no year. J. Med. Chem. (Senga, et al.) 25:243-249 (1982). Comprehensive Organic Synthesis (Trost, Fleming) 3:481-520, no year. Comprehensive Organic Synthesis (Trost, Fleming) 7:762-769, no year. Synapse (Battaglia, Webster, De Souza) 1:572-581 (1987). Science (Nemeroff, et al.) 226:1342 (1984). Remington's Pharmaceutical Sciencs (Gennaro, ed.) 17th ed. pp. 1418-1419, no year. Brain Research Reviews (Dunn, Berridge) 15:71-100 (1990). Proc. Natl. Acad. Sci. (Rivier, Spiess, Vale) 80:4851-4855 (1983). Recent Progress in Hormone Research (Vale, et al.) 39:245-271 (1983). Journal of Neuroscience (De Souza, et al.) vol. 5, NO. 12, pp. 3189-3203 (1985). Perspectives on Behavorial Medicine (Koob) 2:39-52 (1985). Biol. Psychiatry (France, et al.) 23:86-88 (1988). Hormones and Behavior (Berridge, Dunn) 21:393-401 (1987). Hospital Practice (De Souza) pp. 59-71 (1988). Arch. Gen. Psychiatry (Sapolsky) 46:1047-1051 (1989). Psychopharmacology (Britton, et al.) 86:170-174 (1985). Biol. Psychiatry (Arato, et al.) 25:355-359 (1989). Regulatory Peptides (Berridge, Dunn) 16:83-93 (1986). Neuropsychopharmacology (Grigoriadis, et al.) vol. 2, No. 1, pp. 53-60 (1989). Psychopharmacology (Swerdlow, Geyer, Vale, Koob) 88:147-152 (1986). Am. J. Psychiatry (Banki, et al.) 144:873-877 (1987). Arch, Gen. Psychiatry (Nemeroff, et al.) 45:577-579 (1988). New Eng. J. Med. (Gold, et al.) vol. 314, No. 21, pp. 1329-1335 (1986). Life Sciences (Morley, et al.) 41:527-544 (1987). Psychiological Reviews (Blalock) vol. 69, No. 1, pp. 1-33 (1989). Journal f. prakt. Chemie. (Joshi, Dubey) Band 321. Heft 2, pp. 341-344 (1979). Journal of Medicinal Chemistry (Springer, et al.) vol. 19, No. 2, pp. 291-296 (1976). J. Heterocyclic Chem. (O'Brien, et al.) 22:601-634 (1985). J. Med. Chem. (Senga, Novinson Wilson) 24:610-613 (1981). Science (Vale, et al.) 213:1394-1397 (1981). CHEMICAL ABSTRACTS, vol. 67, No. 28, 1967, abstract # 108663r. CHEMICAL ABSTRACTS, vol. 74, No. 28, 1971. abstract # 22867t. CHEMICAL ABSTRACTS, vol. 74, No. 28, 1971, abstract # 22872r. CHEMICAL ABSTRACTS, vol. 68, No. 28, 1968, abstract # 114635v. Corticotropin Releasing Factor: Basic and Clinical Studies of a Neuropeptide (De Souza, Nemeroff) p. 221-224 (1990). Comprehensive Organic Synthesis (Trost, Fleming) 3:481-520 (1991). Comprehensive Organic Synthesis (Trost, Fleming) 7:762-769 (1991). Remington's Pharmaceutical Sciences (Gennaro, ed.) 17.sup.th ed. pp. 1418-1419 (1985). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A compound which is a compound of Formula (50) ##STR48## and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, selected from the group consisting of: a compound of Formula (50) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is Me and R.sup.4e is H; a compound of Formula (50) wherein R.sup.3 is --NHCH (Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; a compound of Formula (50) wherein R.sup.3 is NHCH(Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is F and R.sup.4e is H; and a compound of Formula (50) wherein R.sup.3 is NHCH(Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is OMe and R.sup.4e is H. 2. A compound of Formula (50) ##STR49## and pharmaceutically acceptable salt forms thereof, wherein R.sup.3 is NHCH(Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is F and R.sup.4e is H. 3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2. 4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2. 5. A method of treating anxiety in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1. 6. A method of treating anxiety in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 2. 7. A method of treating depression in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1. 8. A method of treating depression in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 2. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION This invention relates a 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, by administration of certain [1,5-a]-pyrazolo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5-triazines, [1,5-a]-pyrazolo-pyrimidines and [1,5-a]-1,2,3-triazolo-pyrimidines. BACKGROUND OF THE INVENTION 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 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 0778 277 A1. Insofar as is known, [1,5-a]-pyrazolo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5-triazines, [1,5-a]-pyrazolo-pyrimidines and [1,5-a]-1,2,3-triazolo-pyrimidines, have not been previously reported as corticotropin releasing factor antagonist compounds useful in the treatment of psychiatric disorders and neurological diseases. However, there have been publications which teach some of these compounds for other uses. For instance, EP 0 269 859 (Qstuka, 1988) discloses pyrazolotriazine compounds of the formula ##STR2## where R.sup.1 is OH or alkanoyl, R.sup.2 is H, OH, or SH, and R.sup.3 is an unsaturated heterocyclic group, naphthyl or substituted phenyl, and states that the compounds have xanthine oxidase inhibitory activity and are useful for treatment of gout. EP 0 594 149 (Ostuka, 1994) discloses pyrazolotriazine and pyrazolopyrimidine compounds of the formula ##STR3## where A is CH or N, R.sup.0 and R.sup.3 are H or alkyl, and R.sup.1 and R.sup.2 are H, alkyl, alkoxyl, alkylthio, nitro, etc., and states that the compounds inhibit androgen and are useful in treatment of benign prostatic hypertrophy and prostatic carcinoma. U.S. Pat. No. 3,910,907 (ICI, 1975) discloses pyrazolotriazines of the formula: ##STR4## where R1 is CH.sub.3, C.sub.2 H.sub.5 or C.sub.6 H.sub.5, X is H, C.sub.6 H.sub.5, m-CH.sub.3 C.sub.6 H.sub.4, CN, COOEt, Cl, I or Br, Y is H, C.sub.6 H.sub.5, o-CH.sub.3 C.sub.6 H.sub.4, or p-CH.sub.3 C.sub.6 H.sub.4, and Z is OH, H, CH.sub.3, C.sub.2 H.sub.5, C.sub.6 H.sub.5, n-C.sub.3 H.sub.7, i-C.sub.3 H.sub.7, SH, SCH.sub.3, NHC.sub.4 H.sub.9, or N(C.sub.2 H.sub.5).sub.2, and states that the compounds are c-AMP phosphodiesterase inhibitors useful as bronchodilators. U.S. Pat. No. 3,995,039 discloses pyrazolotriazines of the formula: ##STR5## where R.sup.1 is H or alkyl, R.sup.2 is H or alkyl, R.sup.3 is H, alkyl, alkanoyl, carbamoyl, or lower alkylcarbamoyl, and R is pyridyl, pyrimidinyl, or pyrazinyl, and states that the compounds are useful as bronchodilators. U.S. Pat. No. 5,137,887 discloses pyrazolotriazines of the formula ##STR6## where R is lower alkoxy, and teaches that the compounds are xanthine oxidase inhibitors and are useful for treatment of gout. U.S. Pat. No. 4,892,576 discloses pyrazolotriazines of the formula ##STR7## where X is O or S, Ar is a phenyl, naphthyl, pyridyl or thienyl group, R.sub.6 -R.sub.8 are H, alkyl, etc., and R.sub.9 is H, alkyl, phenyl, etc. The patent states that the compounds are useful as herbicides and plant growth regulants. U.S. Pat. No. 5,484,760 and WO 92/10098 discloses herbicidal compositions containing, among other things, a herbicidal compound of the formula ##STR8## where A can be N, B can be CR.sub.3, R.sub.3 can be phenyl or substituted phenyl, etc., R is --N(R.sub.4)SO.sub.2 R.sub.5 or --SO.sub.2 N(R.sub.6)R.sub.7 and R.sub.1 and R.sub.2 can be taken together to form ##STR9## where X, Y and Z are H, alkyl, acyl, etc. and D is O or S. U.S. Pat. No. 3,910,907 and Senga et al., J. Med. Chem., 1982, 25, 243-249, disclose triazolotriazines cAMP phosphodiesterase inhibitors of the formula ##STR10## where Z is H, OH, CH.sub.3, C.sub.2 H.sub.5, C.sub.6 H.sub.5, n-C.sub.3 H.sub.7, iso-C.sub.3 H.sub.7, SH, SCH.sub.3, NH(n-C.sub.4 H.sub.9), or N(C.sub.2 H.sub.5).sub.2, R is H or CH.sub.3, and R.sub.1 is CH.sub.3 or C.sub.2 H.sub.5. The reference lists eight therapeutic areas where inhibitors of cAMP phosphodiesterase could have utility: asthma, diabetes mellitus, female fertility control, male infertility, psoriasis, thrombosis, anxiety, and hypertension. WO95/35298 (Otsuka, 1995) discloses pyrazolopyrimidines and states that they are useful as analgesics. The compounds are represented by the formula ##STR11## where Q is carbonyl or sulfonyl, n is 0 or 1, A is a single bond, alkylene or alkenylene, R.sup.1 is H, alkyl, etc., R.sup.2 is naphthyl, cycloalkyl, heteroaryl, substituted phenyl or phenoxy, R.sup.3 is H, alkyl or phenyl, R.sup.4 is H, alkyl, alkoxycarbonyl, phenylalkyl, optionally phenylthio-substituted phenyl, or halogen, R.sup.5 and R.sup.6 are H or alkyl. EP 0 591 528 (Otsuka,1991) discloses anti-inflammatory use of pyrazolopyrimidines represented by the formula ##STR12## where R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl, or phenyl, R.sub.5 is SR.sub.6 or NR.sub.7 R.sub.8, R.sub.6 is pyridyl or optionally substituted phenyl, and R.sub.7 and R.sub.8 are H or optionally substituted phenyl. Springer et al, J. Med. Chem., 1976, vol. 19, no. 2, 291-296 and Springer U.S. Pat. Nos. 4,021,556 and 3,920,652 disclose pyrazolopyrimidines of the formula ##STR13## where R can be phenyl, substituted phenyl or pyridyl, and their use to treat gout, based on their ability to inhibit xanthine oxidase. Joshi et al., J. Prakt. Chemie, 321, 2, 1979, 341-344, discloses compounds of the formula ##STR14## where R.sup.1 is CF.sub.3, C.sub.2 F.sub.5, or C.sub.6 H.sub.4 F, and R.sup.2 is CH.sub.3, C.sub.2 H.sub.5, CF.sub.3, or C.sub.6 H.sub.4 F. Maquestiau et al., Bull. Soc. Belg., vol.101, no. 2, 1992, pages 131-136 discloses a pyrazolo[1,5-a]pyrimidine of the formula ##STR15## Ibrahim et al., Arch. Pharm. (weinheim) 320, 487-491 (1987) discloses pyrazolo[1,5-a]pyrimidines of the formula ##STR16## where R is NH2 or OH and Ar is 4-phenyl-3-cyano-2-aminopyrid-2-yl. Other references which disclose azolopyrimidines inclued EP 0 511 528 (Otsuka, 1992), U.S. Pat. No. 4,997,940 (Dow, 1991), EP 0 374 448 (Nissan, 1990), U.S. Pat. No. 4,621,556 (ICN,1997), EP 0 531 901 (Fujisawa, 1993), U.S. Pat. No. 4,567,263 (BASF, 1986), EP 0 662 477 (Isagro, 1995), DE 4 243 279 (Bayer, 1994), U.S. Pat. No. 5,397,774 (Upjohn, 1995), EP 0 521 622 (Upjohn, 1993), WO 94/109017 (Upjohn, 1994), J. Med. Chem., 24, 610-613 (1981), and J. Het. Chem., 22, 601 (1985). SUMMARY OF THE INVENTION In accordance with one 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 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 hear 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, benzodiazepine, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in a mammal. 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 clonic hypersensitivity associated with psychopathological disturbance and stress in a mammal. According to another aspect, the present invention provides novel compounds of Formulae (1) and (2) (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 (1) and (2), 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 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. |
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