Corticotropin releasing factor (CRF), synonymous with corticotropin releasing hormone (CRH), is a 41 amino acid peptide that coordinates the overall response of the body to stress. As an agonist of CRF receptors (e.g., CRF1 and CRF2), CRF is well known as the primary physiological secretagogue controlling hypothalamic-pituitary-adrenal (HPA) axis activity which mediates the endocrine stress response. CRF also plays a central role in the autonomic and behavioral responses to stress. Variation in physiological levels of CRF has been correlated with various disorders including depression and anxiety.
Antagonists of CRF receptors have been shown to effectively ameliorate behavioral stress responses in animal models. It is well established that systemic administration of CRF1 receptor antagonists leads to anxiolytic and antidepressant effects in rodents. Animal model evidence also shows that CRF1 antagonists can help alleviate the symptoms of drug withdrawal, stress-induced seizures, and certain inflammations. 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. Eating disorders, such as anorexia nervosa, have also been linked to elevated levels of CRF.
Though widely dispersed throughout the central nervous system, CRF receptors are also found in peripheral systems including glandular, vascular, gastrointestinal, and immune system tissues. Accordingly, CRF antagonists are believed to have potential in treating numerous other disorders outside the central nervous system. Some CRF-related disorders of peripheral systems include, for example, hypertension, tachycardia, congestive heart failure, stroke, irritable bowel syndrome, post-operative ileus, and colonic hypersensitivity. Studies have indicated that CRF1 antagonists may also be useful as hair growth stimulators.
Pyrazolo[1,5-a]-1,3,5-triazine derivatives have been identified as potent CRF1 antagonists and are currently being studied as therapeutic agents for treatment of various CRF-related disorders, including many of those mentioned above. Numerous pyrazolotriazine CRF1 antagonists have been reported in, for example, U.S. Pat. Nos. 6,124,289; 6,191,131; 6,313,124; 6,060,478; 6,136,809; and 6,358,950, as well as WO 02/72202 and WO 98/08847.
Preparation of pyrazolo[1,5-a]-1,3,5-triazine compounds typically involves a multi-step procedure including two ring-forming reactions to produce the bicyclic core. Syntheses of various pyrazolo[1,5-a]-1,3,5-triazine compounds are reported in the above references as well as in WO 01/23388; U.S. Pat. Nos. 4,824,834, 3,910,907, 5,137,887, 4,892,576, and 5,484,760; EP 594149; He et al., J. Med. Chem., 2000, 43, 449; Senga, et al., J. Med. Chem., 1982, 25, 243; Bruni, et al., J. Heterocycl. Chem., 1995, 32, 291; Kobe, et al., J. Het. Chem., 1974, 991; Kobe, et al., J. Het. Chem. 1974, 199; Novinson, et al., J. Het. Chem., 1974, 691; and Albert, et al., J. Het. Chem. 1973, 885. Ring-forming and other reactions are reported in Beyer, et al., Ber., 1960, 93, 2209 and Cusmano, et al., Gazz. Chim. Ital., 1952, 82, 373.
Numerous active pyrazolo[1,5-a]-1,3,5-triazine compounds include a multi-substituted aryl or heteroaryl group attached to the 8-position of the bicyclic core. Introduction of the 8-subsituent often involves the use of an aryl or heteroaryl acetonitrile derivative. Methods for preparing aryl or heteroaryl acetonitrile derivatives from the corresponding halomethyl compound and cyanide are reported in JP 2001302658; CN 1088574; and Nishida, et al., Technol. Rep. Yamaguchi Univ., 1988, 4(2), 145. Other references reporting reactions that can be used in the preparation of aryl or heteroaryl acetonitrile derivatives include, for example, Nagel, et al., J. Org. Chem., 1977, 42, 3626 and Stogryn, J. Org. Chem., 1972, 37, 673 (n-BuLi metallation of aryl bromides and condensation with DMF to form aldehydes); Li, et al., Tetrahedron Lett. 2001, 1175 (sodium borohydride reduction of benzyl aldehydes to benzyl alcohols); J. Org. Chem., 1970, 35, 3195, J. Org. Chem., 1971, 36, 3044, Tetrahedron 1971, 27, 5979 (chlorination of benzyl alcohol with mesyl chloride and base); J. Am. Chem. Soc., 1951, 73, 2239, J. Am. Chem. Soc., 1953, 75, 2053 (conversion of benzyl chloride to cyanide derivative); and Repic, Principles of Process Research and Chemical Development in the Pharmaceutical Industry, Wiley, 1998, p. 38.
In view of the importance of pyrazolo[1,5-a]-1,3,5-triazine derivatives in the treatment of CRF-related disorders such as anxiety and depression, improved methods for their synthesis are needed. Such improvements can include, for example, enhanced enantiomeric and/or diastereomeric selectivity in individual reaction steps, enhanced chemical purity, increased yields, employment of lower cost starting materials, employment of less toxic starting materials, lowered energy consumption (e.g., avoidance of reactions conducted at very high or low temperatures or pressures), reduction in the number of synthetic steps, and improved scale-up conditions. The processes and intermediates discussed herein help fulfill these and other needs.