| PATENT ASSIGNEE'S COUNTRY | USA |
| UPDATE | 07.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 04.07.00 |
| 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 | 16.05.97 |
| PATENT REFERENCES CITED | This data is not available for free |
| 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. DETAILED DESCRIPTION OF THE INVENTION Many compounds of this invention have one or more asymmetric centers or planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric isomers of olefins, C.dbd.N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. The compounds 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. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated. The term "alkyl" includes both branched and straight-chain alkyl having the specified number of carbon atoms. "Alkenyl" includes 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, propenyl, and the like. "Alkynyl" includes 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, propynyl and the like. "Haloalkyl" is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted with 1 or more halogen; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, including mono-,bi- or polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. "Halo" or "halogen" includes fluoro, chloro, bromo, and iodo. The term "substituted", as used herein, means that one or more hydrogen 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. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant 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. The term "appropriate amino acid protecting group" means any group known in the art of organic synthesis for the protection of amine or carboxylic acid groups. Such amine protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1991) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Any amine protecting group known in the art car be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl. 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, modified and unusual 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. 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, ornithine, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, .beta.-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methylnorleucine, 3,4-dehydroproline, N,N-methylaminoglycine, 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 term "amino acid residue" as used herein means that portion of an amino acid (as defined herein) that is present in a peptide. The term "peptide" as used herein means a compound that consists of two or more amino acids (as defined herein) that are linked by means of a peptide bond. The term "peptide" also includes compounds containing both peptide and non-peptide components, such as pseudopeptide or peptide mimetic residues or other non-amino acid components. Such a compound containing both peptide and non-peptide components may also be referred to as a "peptide analog". The term "peptide bond" means a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of one amino acid and the amino group of a second amino acid. The term "pharmaceutically acceptable salts" includes acid or base salts of the compounds of formulas (I) and (II). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the compounds of the invention 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. "Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug of formula (I) or (II) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) and (II) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or 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 formulas (I) and (II); and the like. 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 Synthesis of compounds of Formula (I) wherein A.dbd.N may begin with amidine compounds of Formula (II) (Scheme I), which are available commercially or synthetically from heating a nitrile compound and an ammonium salt. Compound (II) may then be condensed with a malonate ester (using conditions such as sodium in ethanol) to give a dihydroxy-pyrimidine compound of Formula (III). Nitration at the 5-position may be accomplished through the use of such conditions, as concentrated nitric acid with or without the presence of another acid such as concentrated sulfuric or glacial acetic. The hydroxy groups of the nitrated compound of Formula (IV) may then be converted into leaving groups (Y), which include chloro, bromo, toluenesulfonate, or methanesulfonate. The dichloro compound (Formula (V), Y.dbd.Cl) may be prepared from the dihydrox by a reagent such as phosphorus oxychloride, with or without the assistance of a catalyst such as diethylaniline. The bis(toluenesulfonate) compound (Formula (V), Y.dbd.OSO.sub.2 C.sub.6 H.sub.4 CH.sub.3), may be prepared from the dihydroxy compound by treatment with a reagent such as toluenesulfonic anhydride. Careful addition one equivalent of a suitable form of a compound X--H to the compound of Formula (V) results in replacement of one of the Y groups with X. This is of particular utility when the X group represents a nucleophilic atom, such as nitrogen, sulfur or oxygen. Conditions which will facilitate this transformation include the optional presence of bases such as sodium hydride, triethylamine, diisopropylethylamine or potassium carbonate, in solvents such as tetrahydrofuran, dimethylformamide, dimethylsulfoxide, methylene chloride, acetonitrile or ethanol, at appropriate temperatures. ##STR4## Alternatively, in the case where X represents a group without a corresponding nucleophilic compound X--H being available, one may condense a compound of Formula (II) with an appropriately-substituted ketoester (using conditions similar to those for the malonate condensation) to obtain a compound of Formula (VII) Nitration conditions similar to those described above may then be used to prepare the nitro compound (VIII). Conversion of the pyrimidone group to the desired Y group may then be accomplished using the same conditions as described above for the transformation of (IV) to (V). A third alternative involves treatment of the compound of Formula (V) with a compound R.sup.9 --NH.sub.2. Conditions may be found for each Y group so that one Y group is replaced by R.sup.9 --NH, and the other is hydrolyzed to the pyrimidone (compound Formula (IX)). For example, for Y.dbd.Cl, this conversion may be effected by slow addition of a dimethylsulfoxide solution of one equivalent of R.sup.9 --NH.sub.2 to a dimethylsulfoxide solution of compound (V), followed by aqueous workup. The pyrimidione of Formula (IX) may be converted to Y-bearing compound (Formula (X)) using the conditions described above for (IV) to (V). The Y group can then be replaced with X analogously to the transformation of (V) to (VI) to give a compound of Formula (XI). Alternatively, the compound of Formula (VI) may be converted to the compound of Formula (XI) by treatment with the compound R.sup.9 --NH.sub.2. Suitable conditions for this reaction include treatment with excess sodium hydride in refluxing toluene or heating the two compounds together in an alcoholic solvent (ethanol, propanol, butanol, ethylene glycol, ethoxyethoxyethanol) or other polar, aprotic solvents (such as dimethylformamide, 1,4-dioxane, dimethoxyethane or diglyme) without a base to effect the coupling. Scheme II shows the appending of the second ring onto the pyrimidine ring. The nitro group in the compound of Formula (XI) can be reduced to an amino group using conditions such as sodium dithionite, catalytic hydrogenation, iron or zinc. The compound of Formula (XII) may be treated with a base such as sodium hydride (in solvents such as dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, etc.), followed by a reagent of the general formula Y--CR.sup.7 R.sup.8 --CO.sub.2 R, where Y is halogen or psuedohalogen, and the structure of R is only important if removal of the group prior to cyclization is desired. ##STR5## Cyclization of the compound of Formula (XIV) may be accomplished by heating in a solvent such as ethanol, dimethylformamide, etc. as temperatures ranging anywhere from ambient to the boiling point of the solvent. An additive such as an acid source (such as toluenesulfonic acid, aqueous hydrochloric, etc.), a base (triethylamine, sodium hydroxide, etc.) or a physical catalyst (such as molecular sieves) may be added, in quantities ranging from catalytic to stoichiometric to excess. In practice, the cyclization of (XIII) often is very facile, particularly in the case where R is lower alkyl, and will occur spontaneously in the reaction medium of the alkylation of compound (XII). Cyclized compound (XIV) may be alkylated with the R.sup.4 group by first treatment with a base such as sodium hydride in a solvent such as dimethylformamide or dimethylsulfoxide, then an alkylating reagent (such as a halogen- or psuedohalogen-bearing compound) which provides the R.sup.4 group, to provide the compound of Formula (XV). At this point, compounds derived from bromoacetate alkylation of compound (XII) can be alkylated with appropriate R.sup.7 and R.sup.8 by treatment with a strong base such as sodium hydride, lithium diisopropylamide or sodium hexamethyldisilazide, and then alkylating agents bearing the R.sup.7 or R.sup.8 groups, thus resulting in the compound of Formula (XV). Compound (XV) is a key intermediate which may be used to generate variations of Formula (I). For example, the carbonyl group of compound (XV) may be reduced with reagents such as lithium aluminum hydride, borane (complexed with tetrahydrofuran or other suitable ligands) or diisobutylaluminum hydride, which will generate a compound of Formula (XVI). The carbonyl group may be substituted with R.sup.5 and R.sup.6 groups using appropriately-substituted organolithium or organomagnesium reagents, to prepare compounds of Formula (XVII). The carbonyl group of compound (XV) may be converted to thiocarbonyl by treatment with reagents such as Lawesson's Reagent or phosphorus pentasulfide in appropriate solvents (toluene, benzene, etc.). The thioamide group of compound (XVIII) may be converted to amidine using the method of Robba et al. (Tetrahedron Letters 1992, 33, 2803-2804), which involves treatment with an amine of formula R.sup.11 --NH.sub.2 and a catalyst such as a mercury (II) salt. This will result in the synthesis of a compound of Formula (XIX). Compounds of Formula (I) composed of a fused pyridine ring (A=CH) may be prepared using very similar technology to that presented in Scheme II. In this case, however, the starting material is not of the structure (XI), but rather of structural formula (XXV) (Scheme III). ##STR6## This compound may be prepared starting with a lactone compound of Formula (XX), which are available by dimerization of a ketoester R.sup.10 C(.dbd.O)CH.sub.2 CO.sub.2 Et according to the method of Arndt (Org. Syn., Coll. Vol. III, p. 231), followed by deacylation according to the method of Collie et al. (J. Chem. Soc. 1907, 91, p. 787 and references therein). The ring oxygen atom may be replaced with nitrogen by treatment with conc. aq. ammonium hydroxide, according to the method of Wang (J. Heterocyclic Chem. 1970, 1, 389-392). Compound (XXI) may be nitrated similarly to the transformation of compound (III) to give compound (XXII). The hydroxy groups of compound (XXII) may be converted to leaving groups Y using the techniques discussed above for the conversion of compound (IV) to (V). The C.sup.4 Y group may be selectively replaced with a nucleophilic X group, and the other Y group in compound (XXIV) may be replaced with NHR.sup.9 by treatment with a compound R.sup.9 NH.sub.2, either with no solvent or an appropriate solvent (such as a high-boiling alcohol) at temperatures sufficiently elevated to effect coupling. Compound (XXV) may then be employed in the same general way as for compounds may be achieved using a compound of Formula (I). ##STR7## Further functionalization of this class of compounds may be achieved using a compound of Formula (XXVI) (Scheme IV), which represents some pyridine or pyridine compound (either uncyclized, like compounds (XI) or (XXV), or a cyclized compound) bearing a leaving group Y. The Y group may be replaced with phenyl or pyridyl using coupling reactions employing a phenyl (or pyridyl) compound of Formula (XXVII) (or (XXIX)) and an appropriate palladium catalyst. For example, arylboronic acids (Z.dbd.B (OH).sub.2) may be coupled to a heterocyclic halide using catalytic amounts of tetrakis(triphenylphosphine)palladium, which is the method of Suzuki, et al. (Synthetic Communications 1981, 11, p. 513-519). Other appropriate reagents for this coupling reaction includes organomagnesium (Z.dbd.MgBr or MgCl) reagents (with nickel (II) chloride catalysis according to the method of Sugimori et al., Synthetic Communications 1991, 21, p. 481-487) or organozinc (Z.dbd.ZnCl) reagents (according to the method of Negishi et al., J. Org. Chem. 1977, 42, p. 1821-1823). Other carbon substituents may be introduced into compound (XXVI) by treatment with a sodium salt (generated by the use of a base such as sodium ethoxide or sodium hydride) of an active methylene or methine reagent (i.e. where B and D are groups which stabilize adjacent anions, such as keto, carboalkoxy, cyano, alkyl- or aryl-sulfonyl, etc.). The resulting compounds of Formula (XXXI) may be further modified by conversion of the B and D groups into R.sup.2 and R.sup.3 groups. Those skilled in the art of organic synthesis should readily understand possible variations of these conversions to prepare a number of different R.sup.1, R.sup.2 and R.sup.3 group substituents. Preparation of compounds of Formula (I) wherein the R.sup.1 and R.sup.4 groups are taken together to form a ring may be accomplished beginning from a compound of Formula (XXXIII) (Scheme V), where X' is meant to designate a group NHR, OH, SH or CHR.sup.2 R.sup.3. This compound may be treated with a base (such as sodium hydride) in an appropriate solvent, followed by a reagent bearing reactive terminii on both ends (for example, a dihaloalkane, a haloester, etc.). The X' and amide NH groups will couple with such a reagent under these conditions to form the third ring of compound (XXXIV). The amide group may then be modified as described above to give then final product of Formula (XXXV). Compounds of Formula (I) wherein the R.sup.4, R.sup.5 and R.sup.6 groups are taken together to form a heteroaromatic ring may be prepared using the strategy displayed in Scheme VI. ##STR8## Compound (XIV) may be converted to amidine (XXXVI), using the conditions described above for the preparation of compound (XIX). The amidine is treated with an .alpha.-halo- or .alpha.-hydroxyketone, under conditions such as refluxing alcohol, to afford the imidazole compound (XXXVII). Compound (XIV) may be converted to fused tetrazole compound (XXXVIII) using the conditions of Duncia et al. (J. Org. Chem. 1991, 56, P. 2395). ##STR9## The experimental methods listed below for Examples 1, 17, 24, 42, 131, 143, 155, and 248 may be used in the preparation of all the compounds shown in Tables I (pyrimidines) and II (pyridines). |
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