| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | July 4, 2000 |
| PATENT TITLE |
Tetrahydropteridines for treatment of neurological disorders |
| PATENT ABSTRACT | Corticotropin releasing factor (CRF) antagonists of formula I: and their use in treating anxiety, depression, and other psychiatric and neurological disorders are disclosed |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | May 16, 1997 |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
I claim: 1. A CRF antagonist compound of formula I: ##STR22## or a pharmaceutically accetable salt thereof, wherein: A is N; X is H, OR.sup.1, S(O).sub.n R.sup.1, NR.sup.1 R.sup.2, CR.sup.1 R.sup.2 R.sup.3, phenyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl); n is 0, 1 or 2; R.sup.1 is C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkoxyalkyl, C.sub.3 -C.sub.12 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, aryl-(C.sub.1 -C.sub.12 alkyl), C.sub.3 -C.sub.12 dialkylaminoalkyl, C.sub.2 -C.sub.13 cyanoalkyl, C.sub.2 -C.sub.5 carboalkoxy-(C.sub.1 -C.sub.12 alkyl), phenyl (optionally substituted with 1-4 (groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl), or heteroaryl (optionally substituted at one to all valence-allowed positions with groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl); R.sup.2 and R.sup.3 are independently chosen from H, C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkoxyalkyl, C.sub.3 -C.sub.12 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, aryl-(C.sub.1 -C.sub.12 alkyl), C.sub.3 -C.sub.12 dialkylaminoalkyl, C.sub.2 -C.sub.13 cyanoalkyl, C.sub.1 -C.sub.4 carboalkoxy, C.sub.2 -C.sub.12 carboalkoxyalkyl, C(.dbd.O)CH.sub.3, phenyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl), or heteroaryl (optionally substituted at one to all valence-allowed positions with groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl); R.sup.4 is H, C.sub.1 -C.sub.12 alkyl, allyl, propargyl or benzyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, nitro, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl); R.sup.1 and R.sup.4 may also optionally be taken together, along with the other four interconnected atoms, to form a ring of 5-9 total atoms, the structural sequence between the X group and the ring nitrogen atom consisting of the group (CH.sub.2).sub.p W(CH.sub.2).sub.q ; p and q are independently 0, 1 or 2; W is CH.sub.2, C(CH.sub.3).sub.2, C(.dbd.O), O, S or NCH.sub.3 ; R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently chosen from H, straight-chained C.sub.1 -C.sub.4 alkyl, allyl, propargyl, phenyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl) or benzyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl); R.sup.9 is phenyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.2 -C.sub.5 carboalkoxy or cyano), pyridyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.2 -C.sub.5 carboalkoxy or cyano), or pyrimidyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.2 -C.sub.5 carboalkoxy or cyano); R.sup.10 is H, C.sub.1 -C.sub.4 alkyl or cyano; R.sup.11 is H, C.sub.1 -C.sub.4 alkyl or halogen; R.sup.12 is H, C.sub.1 -C.sub.4 alkyl or phenyl; aryl is phenyl, biphenyl or naphthyl; and heteroaryl is pyridyl, pyrimidinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl. 2. A compound of claim 1 wherein: X is OR.sup.1, NR.sup.1 R.sup.2, CR.sup.1 R.sup.2 R.sup.3, R.sup.1 is C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkoxyalkyl, C.sub.3 -C.sub.12 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, aryl-(C.sub.1 -C.sub.12 alkyl), C.sub.3 -C.sub.12 dialkylaminoalkyl, or phenyl (optionally substituted with 1-4 groups independently chosen from halogen, haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl); R.sup.4 is H or C.sub.1 -C.sub.4 alkyl; R.sup.5 and R.sup.6 are either H or C.sub.1 -C.sub.4 alkyl; R.sup.9 is phenyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.2 -C.sub.5 carboalkoxy or cyano), 3-pyridyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.2 -C.sub.5 carboalkoxy or cyano), or 5-pyrimidyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.2 -C.sub.5 carboalkoxy or cyano); R.sup.10 is CH.sub.3 ; and R.sup.11 is H. 3. A compound of claim 2 wherein: X is NR.sup.1 R.sup.2 or CR.sup.1 R.sup.2 R.sup.3 ; R.sup.1 is C.sub.1 -C.sub.6 alkyl or C.sub.2 -C.sub.8 alkoxyalkyl; R.sup.2 and R.sup.3 are independently H, C.sub.1 -C.sub.6 alkyl or C.sub.2 -C.sub.8 alkoxyalkyl; R.sup.4 is H; R.sup.5 and R.sup.6 are H; R.sup.7 and R.sup.8 are independently H or CH.sub.3 ; and R.sup.9 is phenyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, C.sub.2 -C.sub.5 carboalkoxy or cyano). 4. A compound of claim 3 selected from: 8-(2-bromo-4-isopropylphenyl)-4-(ethylbutylamino)-2-methyl-5,6,7,8-tetrahyd ropteridine; 8-(2-chloro-4,6-dimethoxyphenyl)-4-(ethylbutylamino)-2-methyl-5,6,7,8-tetra hydropteridine; 4-(ethylbutylamino)-2-methyl-8-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydropt eridine; and 4-(1-methoxy-2-butyl)amino-2-methyl-8-(2,4,6-trimethylphenyl)-5,6,7,8-tetra hydropteridine. 5. A composition comprising a therapeutically effective amount of compound of claim 1 and a pharmaceutically suitable carrier. 6. A composition comprising a therapeutically effective amount of compound of claim 2 and a pharmaceutically suitable carrier. 7. A composition comprising a therapeutically effective amount of compound of claim 3 and a pharmaceutically suitable carrier. 8. A composition comprising a therapeutically effective amount of compound of claim 4 and a pharmaceutically suitable carrier. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION This invention relates to compounds and pharmaceutical compositions, and to methods of using same in the treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders. 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 secret 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 aid 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 huran depression [R. M. Sapolsky, Arch. Gen. Psychiatry 45:1047 (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 (a-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 published patent applications disclose corticotropin releasing factor antagonist compounds. Among these are DuPont Merck PCT application US94/11050, Pfizer WO 95/33750, Pfizer WO 95/34563, and Pfizer WO 95/33727. U.S. Pat. No. 5,424,311 discloses antiviral use of azaquinoxalines of the formula: ##STR1## in which V, W, Y and Z are CH, CR1, or N; X can be oxygen, sulfur or NR.sup.2 ; R.sup.1 can be alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, or alkylamino; R.sup.2, R.sup.3, R.sup.4 and R.sup.5 can be hydrogen, alkyl, aryl or heteroaryl. U.S. Pat. No. 5,283,244 discloses glutamate receptor antagonizing activity of fused pyrazine derivatives of the the formula: ##STR2## wherein Z represents C or N; R1 represents a diazole or triazole substituent; and the other R groups represent hydrogen or various substituents such as alkyl, phenyl, or heterocycle. SUMMARY OF THE INVENTION This invention is a method of treating an 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, or inflammatory disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a CRF antagonist compound of formula I: ##STR3## or a pharmaceutically accetable salt or prodrug thereof, wherein: A is N or C-R.sup.11 ; X is H, OR.sup.1, S(O).sub.n R.sup.1, NR.sup.1 R.sup.2, CR.sup.1 R.sup.2 R.sup.3, phenyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, nitro, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl) or heteroaryl (optionally substituted at one to all valence-allowed positions with groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, nitro, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy. SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl); n is 0, 1 or 2; R.sup.1 is C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkoxyalkyl, C.sub.3 -C.sub.12 cycloalkyl, C.sub.4 -C.sub.12 cyzloalkylalkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, aryl-(C.sub.1 -C.sub.12 alkyl), C.sub.3 -C.sub.12 dialkylaminoalkyl, C.sub.2 -C.sub.13 cyanoalkyl, C.sub.2 -C.sub.5 carboalkoxy-(C.sub.1 -C.sub.12 alkyl), phenyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, nitro, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl), or heteroaryl (optionally substituted at one to all valence-allowed positions with groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, nitro, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl); R.sup.2 and R.sup.3 are independently chosen from H, C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkoxyalkyl, C.sub.3 -C.sub.12 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, aryl-(C.sub.1 -C.sub.12 alkyl), C.sub.3 -C.sub.12 dialkylaminoalkyl, C.sub.2 -C.sub.13 cyanoalkyl, C.sub.1 -C.sub.4 carboalkoxy, C.sub.2 -C.sub.12 carboalkoxyalkyl, C(.dbd.O)CH.sub.3, phenyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, nitro, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl), or heteroaryl (optionally substituted at one to all valence-allowed positions with groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, nitro, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl); R.sup.4 is H, C.sub.1 -C.sub.12 alkyl, allyl, propargyl or benzyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, nitro, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl); R.sup.1 and R.sup.4 may also optionally be taken together, along with the other four interconnected atoms, to form a ring of 5-9 total atoms, the structural sequence between the X group and the ring nitrogen atom consisting of the group (CH.sub.2).sub.p W(CH.sub.2).sub.q ; p and q are independently 0, 1 or 2; W is CH.sub.2, C(CH.sub.3).sub.2, C(.dbd.O), O, S or NCH.sub.3 ; R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently chosen from H, C.sub.1 -C.sub.4 alkyl, allyl, propargyl, phenyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, nitro, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl) or benzyl (optionally substituted with 1-4 groups independently chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, nitro, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, (cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl); R.sup.4, R.sup.5 and R.sup.6 may also be taken together, along with the two interconnecting atoms, to constitute either an imidazole or tetrazole ring, the imidazole ring being optionally substituted with 1-2 groups chosen independently from C.sub.1 -C.sub.4 alkyl or phenyl; R.sup.5 and R.sup.6 may also be taken together to be O, S or NR.sup.12 ; R.sup.9 is phenyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, nitro, C.sub.2 -C.sub.5 carboalkoxy or cyano), pyridyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, nitro, C.sub.2 -C.sub.5 carboalkoxy or cyano), or pyrimidyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, nitro, C.sub.2 -C.sub.5 carboalkoxy or cyano); R.sup.10 is H, C.sub.1 -C.sub.4 alkyl or cyano; R.sup.11 is H, C.sub.1 -C.sub.4 alkyl or halogen; R.sup.12 is H, C.sub.1 -C.sub.4 alkyl or phenyl; aryl is phenyl, biphenyl or naphthyl; and heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzotihienyl, benzthiazolyl, isoxazolyl or pyrazolyl. Compounds of formula I, other than those in which R5 and R6 are taken together and are O, S or NR12, are novel. This invention includes the novel compounds of formula I and pharmaceutical compositions containing them. Preferred compounds for use in the method of this invention are compounds of formula (I) wherein: X is OR.sup.1, NR.sup.1 R.sup.2, CR.sup.1 R.sup.2 R.sup.3 or phenyl (optionally substituted at the 2-position with CF.sub.3, nitro, halogen or cyano); R.sup.1 is C.sub.3 -C.sub.12 alkyl , C.sub.2 -C.sub.12 alkoxyalkyl, C.sub.3 -C.sub.12 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, aryl-(C.sub.1 -C.sub.12 alkyl), C.sub.3 -C.sub.12 dialklaminoalkyl, or phenyl (optionally substituted with 1-4 groups independently chosen from halogen, haloalkyl, nitro, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.5 carboalkoxy, cyano, OH, C.sub.1 -C.sub.4 alkoxy, SH, C.sub.1 -C.sub.4 alkylthio, NH.sub.2, C.sub.1 -C.sub.4 alkylamino, C.sub.2 -C.sub.8 dialkylamino, or phenyl); R.sup.4 is H or C.sub.1 -C.sub.4 alkyl; R.sup.5 and R.sup.6 are either H or C.sub.1 -C.sub.4 alkyl; R.sup.4, R.sup.5 and R.sup.6 may also be taken together, along with the two interconnecting atoms, to constitute a tetrazole ring; R.sup.9 is phenyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, nitro, C.sub.2 -C.sub.5 carboalkoxy or cyano), 3-pyridyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C., alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, nitro, C.sub.2 -C.sub.5 carboalkoxy or cyano), or 5-pyrimidyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, nitro, C.sub.2 -C.sub.5 carboalkoxy or cyano); R.sup.10 is CH.sub.3 ; and R.sup.11 is H. More preferred compounds in this invention are of the formula (I) wherein: A is N; X is NR.sup.1 R.sup.2 or CR.sup.1 R.sup.2 R.sup.3 ; R.sup.1 is C.sub.1 -C.sub.6 alkyl or C.sub.2 -C.sub.8 alkoxyalkyl; R.sup.2 and R.sup.3 are independently H, C.sub.1 -C.sub.6 alkyl or C.sub.2 -C.sub.8 alkoxyalkyl; R.sup.4 is H; R.sup.5 and R.sup.6 are H; R.sup.7 and R.sup.8 are independently H or CH.sub.3 ; and R.sup.9 is phenyl (optionally substituted with 1-4 groups chosen from halogen, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfonyl, C.sub.2 -C.sub.6 dialkylamino, nitro, C.sub.2 -C.sub.5 carboalkoxy or cyano). Specifically preferred because of their biological activity are the following compounds: 8-(2-bromo-4-isopropylphenyl)-4-(ethylbutylamino)-2-methyl-5,6,7,8-tetrahyd ropteridine; 8-(2-chloro-4,6-dimethoxyphenyl)-4-(ethylbutylamino)-2-methyl-5,6,7,8-tetra hydropteridine; 4-(ethylbutylamino)-2-methyl-8-(2,4,6-trimethylphenyl)-5,6,7,8-tetrahydropt eridine; and 4-(1-methoxy-2-butyl)amino-2-methyl-8-(2,4,6-trimethylphenyl)-5,6,7,8-tetr ahydropteridine |
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