| PATENT ASSIGNEE'S COUNTRY | USA |
| UPDATE | 09.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 26.09.00 |
| PATENT TITLE |
Aryloxy- and arylthio- fused pyridines and pyrimidines and derivatives |
| PATENT ABSTRACT | Novel compounds and pharmaceutical compositions thereof, and methods of using same in treating anxiety, depression, and other psychiatric and neurological disorders. The novel compounds provided by this invention are those of the following formulae: ##STR1## wherein R.sup.1, R.sup.13, X, Y, Z, G and Q are as defined herein. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 20.03.97 |
| PATENT REFERENCES CITED |
Chalmers et al. TiPS vol. 17, pp. 166-172, Apr. 1996. Higashino et al. (heterocycles (1981), 15(1), 483-7). Higashino et al. (Fukusokan Kagaku Toronkai Koen Yoshishu, 12th (1979), 171-5). Higashino et al. (Chem. Pharm. Bull. (1980), 28(1), 337-43. Higashino et al. Yakugaku Zasshi (1979), 99(10), 1031-6). Stratakis et al. (Chapter 13), 1997. Rivier et al., Proc. Nat'l. Acad. Sci., vol. 80, p. 4851 (1983). W. Vale et al., Science, vol. 213, p. 1394 (1981). W. Vale et al., Recent Progress in Hormone Research, vol. 39, p. 245 (1983). G.F. Koob, Persp. Behav. Med., vol. 2, p. 39 (1985). E.B. DeSouza et al., Journal of Neuroscience, vol. 5, p. 3189 (1985). J.E. Blalock, Physiological Reviews, vol. 69, p. 1 (1989). J.E. Morley, Life Science, vol. 41, p. 527 (1987). E.B. DeSouza, Hospital Practice, vol. 23, p. 59, (1988). C.B. Nemeroff et al., Science, vol. 226, p. 1342 (1984). C.M. Banki et al., American Journal of Psychiatry, vol. 144, p. 873 (1987). R.D. France et al., Biol. Psychiatry, vol. 23, p. 86 (1988). M. Arato et al., Biol. Psychiatry, vol. 25, p. 355 (1989). C.B. Nemeroff et al., Arch. Gen. Psychiatry, vol. 45, p. 577 (1988). P.W. Gold et al., American Journal of Psychiatry, vol. 141, p. 619 (1984). F. Holsboer et al., Psychoneuroendocrinology, vol. 9, p. 147 (1984). P.W. Gold et al., New England Journal of Medicine, vol. 314, p. 1129 (1986). R.M. Sapolsky, Arch. Gen. Psychiatry, vol. 46, p. 1047 (1989). Grigoriadis et al., Neuropsychopharmacology, vol. 2, p. 53 (1989). D.R. Britton et al., Life Science, vol. 31, p. 363 (1982). C.W. Berridge and A.J. Dunn, Regul. Peptides, vol. 16, p. 83 (1986). C.W. Berridge and A.J. Dunn, Horm. Behav., vol. 21, p. 393 (1987). C.W. Berridge and A.J. Dunn, Brain Research Reviews, vol. 15, p. 71 (1990). K.T. Britton et al., Psychopharmacology, vol. 86, p. 170 (1985). K.T. Britton et al., Psychopharmacology, vol. 94, p. 306 (1988). N.R. Swerdlow et al., Psychopharmacology, vol. 88, p. 147 (1986). G.F. Koob and K.T. Britton, Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, p. 221 (1990). Tanji et al., Chem. Pharm. Bull., vol. 39, p. 3037-3040 (1991). Settimo et al., Il Farmaco, Ed. Sc., vol. 35, p. 308-323 (1980). Biagi et al., Il Farmaco, vol. 49, p. 183-186 (1994). Thompson et al., J. Med. Chem., vol. 34, p. 2877-2882 (1991). Kelley et al., J. Med. Chem., vol. 31, pp. 606-612 (1990). Kelley et al., J. Med. Chem., vol. 33, pp. 1360-1363 (1990). Kelley et al., J. Heterocyclic Chem., vol. 28, p. 1099 (1991). Khairy et al., J. Heterocyclic Chem., vol. 22, p. 853 (1985). Remington's Pharmaceutical Sciences, 17.sup.th ed., Mack Publishing Co., Easton, PA, p. 1418 (1985). P.J. Munson and D. Rodbard, Anal. Biochem., vol. 107, p. 220 (1980). G. Battaglia et al., Synapse, vol. 1, p. 572 (1987). Kaiwar et al., J. Chem. Soc., Perkin Trans. 1, pp. 2281-2287 (1995). Kohda et al., Biological Pharm. Bull., vol. 18, No. 3, pp. 424-430 (1995). Buck et al., Tetrahedron, vol. 50, No. 30, pp. 9195-9206 (1994). Chae et al., J. Med. Chem., vol. 37, pp. 342-347 (1994). Krenitsky et al., J. Med. Chem., vol. 32, pp. 1471-1475, (1989). Ronisvalle et al., Il Farmaco, vol. 44, No. 4, pp. 383-390 (1989). Harnden et al., J. Med. Chem., vol. 32, pp. 1738-1743, (1989). Ukena et al., FEBS Letters, vol. 215, No. 2, pp. 203-208 (May 1987). Drawbaugh et al., J. Med. Chem., vol. 19, No. 11, pp. 1342-1345 (1976). Israel et al., J. Het. Chem., vol. 8, No. 6, pp. 1019-1023 (1971). Chem. Abstr., vol. 123, No. 25, Dec. 18, 1995, p. 1249, col. 2, the Abstract No. 340767a, Reese C., EP664, 294, Jan. 19, 1994. Chem. Abstr., vol. 120, No. 21, May 23, 1994, p. 398, col. 1, the abstract No. 263837g, Shibata, T., JP 9401793, Jun. 18, 1992. Chem. Abstr., vol. 117, No. 1, Jul 6, 1992, p. 799, col. 1, the abstract No. 7889q, El-Bayouki, K.A.M., An Quim. 1991, 87(7), 899-902. Chem. Abstr., vol. 111, No. 9, Aug. 28, 1989, p. 736, the abstract No. 77826, Bois-Choussy, M., Eur. J. Med. Chem. 1988, 23(6), 539-546 (Fr). Chem. Abstr., vol. 101, No. 9, Aug. 27, 1984, p. 647, col. 2, the abstract No. 72754a, S.S. Pharmaceutical Co., JP 84 62,595, Apr. 10, 1984. Chem. Abstr., vol. 96, No. 15, Apr. 12, 1982, p. 705, col. 1, the abstract No. 122819b, S.S. Pharmaceutical Co., JP 81, 131, 587, Oct. 15, 1981. Chem. Abstr., vol. 96, No. 9, Mar. o1, 1982, p. 616, col. 2, the abstract No. 69024k, S.S. Pharmaceutical Co., JP 81, 131, 586, Oct. 15, 1981. Chem. Abstr., vol. 89, No. 13, Sep. 25, 1978, pp. 357-358, col. 2, the Abstract No. 102934n, Breter, H., Biocheim. Biophys. Acta, 1978, 518(2), 205-15 (Eng). Chem. Abstr., vo. 87, No. 3, Jul. 18, 1977, p. 639, col. 7, the abstract No. 23126f, Arya, V.P., Indian J. Chem., Sect. B 1976, 14B(10), 756-8 (Eng). Chem. Abstr., vol. 77, No. 19, Nov. 6, 1972, p. 6 col. 2, the abstract No. 121989c, Niebch, G., Z. Naturforsch. B 1972, 27(6), 675-82 (Ger). Chalmers et al., TIPS, vol. 17, pp. 166-172. Higashino et al., Heterocycles, vol. 15(1), p. 483-7 (1981). Higashino et al., Fukusokan Kagaku Toronkai Koen Yoshishu, 12.sup.th, p. 171-5 (1979). Higashino et al., Chem Pharm. Bull., vol. 28(1), pp. 337-43 (1980). Higashino et al., Yakugaku Zasshi, vol. 99(10), p. 1031-6 (1979). Stratakis et al., Endocrinology: Basic and Clinical Principles, Chapter 13, Humana Press Inc., NJ (1997). LaRock, Comprehensive Organic Transformations, VCH Publishers, NY, p. 411 (1989). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed: 1. A compound of formula I: ##STR22## or a pharmaceutically acceptable salt thereof, wherein: Q is O or S(O)n; Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl, each optionally substituted with 1 to 4 R.sup.5 groups; R.sup.1 is independently at each occurrence H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, halo, CN, C.sub.1 -C.sub.4 haloalkyl, --NR.sup.9 R.sup.10, NR.sup.9 COR.sup.10, --OR.sup.11, SH or --S(O).sub.n R.sup.12 ; R.sup.2 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.6 cycloalkyl, halo, CN, --NR.sup.6 R.sup.7, NR.sup.9 COR.sup.10, C.sub.1 -C.sub.4 haloalkyl, --OR.sup.7, SH or --S(O).sub.n R.sup.12 ; R.sup.3 is H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl or C.sub.4 -C.sub.12 cycloalkylalkyl each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13, --NR.sup.6 R.sup.7, --CONR.sup.6 R.sup.7, heteroaryl and heterocyclyl, where the heteroaryl or heterocyclyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ; R.sup.5 is independently at each occurrence C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, --NO.sub.2, halo, --CN, C.sub.1 -C.sub.4 haloalkyl, --NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, --COR.sup.7 --OR.sup.7, --CONR.sup.6 R.sup.7, --CO(NOR.sup.9)R.sup.7, CO.sub.2 R.sup.7, or --S(O).sub.n R.sup.7, where C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl and C.sub.4 -C.sub.12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.4 alkyl, --NO.sub.2, halo, --CN, --NR.sup.6 R.sup.7, --NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, --COR.sup.7 --OR.sup.7, --CONR.sup.6 R.sup.7, CO.sub.2 R.sup.7, --CO(NOR.sup.9)R.sup.7, or --S(O).sub.n R.sup.7 ; R.sup.6 and R7 are independently at each occurrence H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.4 alkyl)-, heteroaryl or heteroaryl(C.sub.1 -C.sub.4 alkyl)-; or NR.sup.6 R.sup.7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; R.sup.8 is independently at each occurrence H or C.sub.1 -C.sub.4 alkyl; R.sup.9 and R.sup.10 are independently at each occurrence selected from H, C.sub.1 -C.sub.4 alkyl, or C.sub.3 -C.sub.6 cycloalkyl; R.sup.11 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, or C.sub.3 -C.sub.6 cycloalkyl; R.sup.12 is C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 haloalkyl; R.sup.13 is C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl or .sub.C.sub.4 -C.sub.12 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.4 alkyl)-, heteroaryl or heteroaryl (C.sub.1 -C.sub.4 alkyl)-; R.sup.13a is C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl or C.sub.4 -C.sub.12 cycloalkylalkyl; aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13a, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13a, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, NR.sup.8 CO.sub.2 R.sup.13a, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13a, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13a, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13a, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13a, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13a, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13a, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ; n is independently at each occurrence 0, 1 or 2; and provided that when R.sup.3 is alkyl, Q-Ar is other than unsubstituted phenoxy. 2. A compound of claim 1, wherein aryl is phenyl or naphthyl, each substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13a, COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13a, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13a, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7. 3. A compound of claim 2, wherein aryl is phenyl substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13a, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13a, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13a, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7. 4. A compound of claim 3, wherein aryl is phenyl substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, halo, and --COR.sup.7. 5. A compound of claim 2 selected from the group: a) 3-Bromo-5-methoxy-.alpha.,.alpha.-dimethyl-4-[(5-methyl-3-(1-propylbutyl)- 3H-1,2,3-triazolo[4,5-d]pyrimidin-7-yl)-oxy]benzenemethanol; b) 7-[2-Bromo-6-methoxy-4-(1-methylethyenyl)phenoxy]-5-methyl-3-(1-propylbuty l)-3H-1,2,3-triazolo[4,5-d]pyrimidine; c) 7-[2-Bromo-6-methoxy-4-(1-methylethyl)phenoxy]5-methyl-3-(1-propylbutyl)-3 H-1,2,3-triazolo[4,5-d]pyrimidine; d) 3-(1-Ethylpropyl)-5-methyl-7-(2,4,6-trimethylphenoxy)-3H-1,2,3-triazolo[4, 5-d]pyrimidine; and e) 7-[2-Bromo-6-methoxy-3-(1-methoxypropyl)-5-methyl-4-(1-methylethyl)phenoxy ]-3H-1,2,3-triazolo[4,5-d]pyrimidine. 6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1. 7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2. 8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 3. 9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4. 10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 5. 11. A method of treating anxiety or depression in a mammal comprising administering to the mammal a therapeutically effective amount of a CRF antagonist compound of claim 2. 12. A method of treating anxiety or depression in a mammal comprising administering to the mammal a therapeutically effective amount of a CRF antagonist compound of claim 3. 13. A method of treating anxiety or depression in a mammal comprising administering to the mammal a therapeutically effective amount of a CRF antagonist compound of claim 4. 14. A method of treating anxiety or depression in a mammal comprising administering to the mammal a therapeutically effective amount of a CRF antagonist compound of claim 5. 15. A method of treating anxiety or depression in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula I: ##STR23## or a pharmaceutically acceptable salt thereof, wherein: Q is O or S(O)n; Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl, each optionally substituted with 1 to 4 R.sup.5 groups; R.sup.1 is independently at each occurrence H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, halo, CN, C.sub.1 -C.sub.4 haloalkyl, --NR.sup.9 R.sup.10, NR.sup.9 COR.sup.10, --OR.sup.11, SH or --S(O).sub.n R.sup.12 ; R.sup.2 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.6 cycloalkyl, halo, CN, --NR.sup.6 R.sup.7, NR.sup.9 COR.sup.10, C.sub.1 -C.sub.4 haloalkyl, --OR.sup.7, SH or --S(O).sub.n R.sup.12 ; R.sup.3 is H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl or C.sub.4 -C.sub.12 cycloalkylalkyl each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13, --NR.sup.6 R.sup.7, --CONR.sup.6 R.sup.7, aryl, heteroaryl and heterocyclyl, where the aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ; R.sup.5 is independently at each occurrence C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, --NO.sub.2, halo, --CN, C.sub.1 -C.sub.4 haloalkyl, --NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, --COR.sup.7 --OR.sup.7, --CONR.sup.6 R.sup.7, --CO(NOR.sup.9)R.sup.7, CO.sub.2 R.sup.7, or --S(O).sub.n R.sup.7, where C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl and C.sub.4 -C.sub.12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.4 alkyl, --NO.sub.2, halo, --CN, --NR.sup.6 R.sup.7, --NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, --COR.sup.7 --OR.sup.7, --CONR.sup.6 R.sup.7, CO.sub.2 R.sup.7, --CO(NOR.sup.9)R.sup.7, or --S(O).sub.n R.sup.7 ; R.sup.6 and R7 are independently at each occurrence H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.4 alkyl)-, heteroaryl or heteroaryl(C.sub.1 -C.sub.4 alkyl)-; or NR.sup.6 R.sup.7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; R.sup.8 is independently at each occurrence H or C.sub.1 -C.sub.4 alkyl; R.sup.9 and R.sup.10 are independently at each occurrence selected from H, C.sub.1 -C.sub.4 alkyl, or C.sub.3 -C.sub.6 cycloalkyl; R.sup.11 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, or C.sub.3 -C.sub.6 cycloalkyl; R.sup.12 is C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 haloalkyl; R.sup.13 is C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl or C.sub.4 -C.sub.12 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.4 alkyl)-, heteroaryl or heteroaryl (C.sub.1 -C.sub.4 alkyl)-; R.sup.13a is C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl or C.sub.4 -C.sub.12 cycloalkylalkyl; aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13a, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13a, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13a, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13a, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13a, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13a, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13a, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13a, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13a, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ; and n is independently at each occurrence 0, 1 or 2. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION This invention relates to novel 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 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 (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)]. DuPont Merck PCT application US94/11050 describes corticotropin releasing factor antagonist compounds of the formula: ##STR2## and their use to treat psychiatric disorders and neurological diseases. Included in the description are fused pyridines and pyrimidines of the formula: ##STR3## where: Z is CR.sup.2 or N; A is CR.sup.30 or N; D is CR.sup.28 or N; and R.sup.3 can be aryloxy or arylthio. Pfizer WO 95/33750 describes corticotropin releasing factor antagonist compounds useful in the treatment of CNS and stress disorders. The description includes compounds of the formulae: ##STR4## where A is CR.sub.7 or N; B is OCHR.sub.1 R.sub.2 or SCHR.sub.1 R.sub.2 ; R.sub.1 is substituted or unsubstituted alkyl; R.sub.2 is substituted or unsubstituted alkyl, aryl or heteroaryl; R.sub.3 is methyl, halo, cyano, methoxy, etc.; R.sub.4 is H, substituted or unsubstituted alkyl, halo, amino, nitro, etc.; R.sub.5 is substituted or unsubstituted aryl or heteroaryl; R.sub.6 is H or substituted or unsubstituted alkyl; R.sub.7 is H, methyl, halo, cyano, etc.; R.sub.16 and R.sub.17 taken together form an oxo (.dbd.O) group; and G is .dbd.O, .dbd.S, .dbd.NH, .dbd.NCH.sub.3, hydrogen, methyl, methoxy, etc. Pfizer WO 95/34563 describes corticotropin releasing factor antagonist compounds, including compounds of the formula: ##STR5## where A, B and the R groups have definitions similar to those in WO 95/33750. Pfizer WO 95/33727 describes corticotropin releasing factor antagonist compounds of the formula: ##STR6## where A is CH.sub.2 and Z can be a heteroaryl moiety. Ganguly et al., U.S. Pat. No. 4,076,711 describes triazolo[4,5-d]pyrimidines of the formula: ##STR7## where X is halo, --NR.sub.1 R or alkoxy, with R1 and R each being H or alkyl; Y is alkyl, cycloalkyl, hydroxycycloalkyl, phenyl, bicycloalkyl or phenylalkyl or bicycloalkylalkyl; and Q is H or Y. The patent states that the compounds are useful in the treatment of psoriasis. Tanji et al., Chem. Pharm. Bull. 39(11)3037-3040(1991), describes triazolo[4,5-d]pyrimidines of the formula: ##STR8## where halo is I, Br or Cl, Ph is phenyl and Me is methyl. No utility for the compounds is described. Settimo et al., Il Farmaco, Ed. Sc., 35 (4), 308-323 (1980) describes 8-azaadenines (triazolo[4,5-d]pyrimidines) of the formula: ##STR9## where R1 is H or benzyl and R2 is p-methylphenyl. Biagi et al., Il Farmaco, 49 (3), 183-186 (1994), describes N(6)-substituted 2-n-butyl-9-benzyl-8-azaadenines of the formula: ##STR10## where R.sup.2 can be alkyl, phenyl, or benzyl. The paper states that the compounds have affinity for adenosine receptors. Thompson et al., J. Med. Chem., 1991, 34, 2877-2882, describes N.sup.6, 9-disubstituted adenines of the formula: ##STR11## where Ph is phenyl or (when C-2 is unsubstituted) 2-fluorophenyl. The paper states that the compounds have selective affinity for the A.sub.1 adenosine receptor. Kelley et al., J. Med. Chem. 1990, 31, 606-612, describes the compound ##STR12## where R.sup.6 is NHC.sub.6 H.sub.5 and R.sup.9 is CH.sub.2 C.sub.6 H.sub.5, and reports that the compound was inactive when tested for anticonvulsant activity. The paper reports that various 6-(alkylamino)-9-benzyl-9H-purine analogs of the above compound exhibited anticonvulsant activity. Kelley et al., J. Med. Chem. 1990, 33, 1360-1363, describes 6-anilino-9-benzyl-2-choro-9H-purines of the formula: ##STR13## where Bz is benzyl or (when R.sup.4 is H) p-methylbenzyl and R.sup.4 is H or alkyl, alkoxy, halo, cyano, nitro, etc. Tests of the compounds for antirhinoviral activity are reported. Kelley et al., J. Heterocyclic Chem., 28, 1099 (1991), describes 6-substituted-9-(3-formamidobenzyl)-9H-purines of the formula: ##STR14## where R1 is NH2 or NHCHO. The compound where R1 is NHCHO was tested for benzodiazepine receptor binding and was inactive, although various analogs were active. Khairy et al., J. Heterocyclic Chem., 22, 853 (1985), describes synthesis of certain 9-aryl-9H-purin-6-amines of the formula: ##STR15## where the R groups are H, methyl, ethyl, isopropyl, chloro or fluoro. Hoechst EP 298467 (1989) describes azapurine derivatives, including compounds of the structure: ##STR16## where Q is O, S, SO, SO.sub.2 or NH.sub.2 ; X is O, S, SO or SO.sub.2 ; Z is H, halogen, CF.sub.3, 1-3C alkoxy or alkylthio; R.sup.2 is alkyl or alkoxy; R.sup.3 is OR.sup.2. These compounds are claimed to be useful for treating virus diseases, autoimmune diseases and cancers. SS Pharmaceutical Co. Jp 59062595 (1984) and Jp 56131587 (1981) describe triazolopyrimidine derivatives, including compounds of the structure: where Q is O, S, SO.sub.2 ; R is amino or substituted amino, alkoxy, benzyloxy, halogen, or phenylhydrazino. These compounds are claimed to be useful as anticancer agents. ##STR17## Fuji Jp 6019444 (1985) describe aza-indenes, including compounds of the structure: ##STR18## where Q is O, S; R.sup.1, R.sup.2 and R.sup.3 are H, alkyl, aryl, aralkyl, amino, hydroxyl, alkoxy, carbamoyl, aryloxy, alkoxy carbonyl, cyano, halogen, alkylthio, arylthio, carboxyl, or mercapto, provided that at least one of the substituents is mercapto. These compounds are claimed to be useful as light-sensitizing agents, providing high photographic speed and contrast to silver halide emulsions. SUMMARY OF THE INVENTION This invention is a class of novel compounds which are CRF receptor antagonists and which can be represented by formula I or formula II: ##STR19## or a pharmaceutically acceptable salt or pro-drug form thereof, wherein: X is N or CR.sup.1 ; Y is N or CR.sup.2 ; Z is NR.sup.3, O, or S(O).sub.n ; G is O or S; Q is O or S(O)n Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl, each optionally substituted with 1 to 4 R.sup.5 groups; R.sup.1 is independently at each occurrence H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, halo, CN, C.sub.1 -C.sub.4 haloalkyl, --NR.sup.9 R.sup.10, NR.sup.9 COR.sup.10, --OR.sup.11, SH or --S(O).sub.n R.sup.12 ; R.sup.2 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.6 cycloalkyl, halo, CN, --NR.sup.6 R.sup.7, NR.sup.9 COR.sup.10, C.sub.1 -C.sub.4 haloalkyl, --OR.sup.7, SH or --S(O).sub.n R.sup.12 ; R.sup.3 is H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl or C.sub.4 -C.sub.12 cycloalkylalkyl each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13, --NR.sup.6 R.sup.7, --CONR.sup.6 R.sup.7, aryl, heteroaryl and heterocyclyl, where the aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ; R.sup.5 is independently at each occurrence C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, --NO.sub.2, halo, --CN, C.sub.1 -C.sub.4 haloalkyl, --NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, --COR.sup.7 --OR.sup.7, --CONR.sup.6 R.sup.7, --CO(NOR.sup.9)R.sup.7, CO.sub.2 R.sup.7, or --S(O).sub.n R.sup.7, where C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl and C.sub.4 -C.sub.12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.4 alkyl, --NO.sub.2, halo, --CN, --NR.sup.6 R.sup.7, --NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, --COR.sup.7 --OR.sup.7, --CONR.sup.6 R.sup.7, CO.sub.2 R.sup.7, --CO(NOR.sup.9)R.sup.7, or --S(O).sub.n R.sup.7 ; R.sup.6 and R7 are independently at each occurrence H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.4 alkyl)-, heteroaryl or heteroaryl(C.sub.1 -C.sub.4 alkyl)-; or NR.sup.6 R.sup.7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; R.sup.8 is independently at each occurrence H or C.sub.1 -C.sub.4 alkyl; R.sup.9 and R.sup.10 are independently at each occurrence selected from H, C.sub.1 -C.sub.4 alkyl, or C.sub.3 -C.sub.6 cycloalkyl; R.sup.11 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, or C.sub.3 -C.sub.6 cycloalkyl, R.sup.12 is C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 haloalkyl; R.sup.13 is C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.4 alkyl)-, heteroaryl or heteroaryl(C.sub.1 -C.sub.4 alkyl)-; aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ; n is independently at each occurrence 0, 1 or 2; provided that in formula I, when X and Z are each N and Y is CR.sup.2, then R.sup.1 and R.sup.2 cannot be mercapto groups. Included in this invention is the method of treating 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, or fertility problem in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula I or II. Also included in this invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of any one of the above-described compounds. The compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor. DETAILED DESCRIPTION OF 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 poly-cyclic 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 "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 The novel substituted fused pyrimidines of the present invention are prepared by one of the general schemes outlined below wherein Ar, Q, G, X, Y, Z, R.sub.1, R.sub.2, R.sub.3 and R.sub.13 are as above and L represents a suitable leaving group such as halo, methanesulfonate, p-toluenesulfonate, or triflate. ##STR20## Compounds of the type III (Scheme 1) are prepared by condensing the alkali metal salts of compounds of the type I, where Q=O or S, with compounds of the type II made according to literature procedures [Ashley and Harris, J Chem Soc., 677(1944); Albert et al., J Chem Soc., 3832(1954)] in solvents such as acetonitrile at temperatures between 0 and 50.degree. C. Compounds of the type IV are obtained from compounds of the type III by treatment with primary amines such as 4-aminoheptane in solvents such as dioxane at temperatures between 25 and 100.degree. C. These amino adducts are converted into compounds of the type V by reduction with hydrogen in the presence of catalysts such as platinum on carbon at atmospheric or elevated pressure or by reducing agents such as sodium dithionite, or iron in acetic acid. Compounds of the type VI are prepared from compounds of the type V through diazotization and cyclization with an alkali metal nitrite in the presence of an acid in water with or without an organic cosolvent such as cyclic ethers or aromatic hydrocarbons. Compounds of type VII are prepared by the condensation of compounds of the type V with phosgene, thiophosgene, carbonyldiimidazole, thiocarbonyldiimidazole, urea, thiourea, guanidine and the like, in the presence or absence of solvents such as high-boilng ethers or aromatic hydrocarbons and at temperatures between 100-200.degree. C. ##STR21## Compounds of the type VIII are prepared by condensation of the compounds of the type V with reagents such as acids, acid chlorides, anhydrides, amides or ortho esters in the presence or absence of solvents such as ethers or aromatic hydrocarbons at temperatures between 0 to 200.degree. C. Compounds of the type VII, where R.sup.13 =H, are alkylated with reagents such as alkyl halides and the like, in the presence or absence of bases such as sodium hydroxide, in solvents such as tetrahydrofuran or DMF and at temperatures between 0 to 100.degree. C. to yield compounds of the type VIII. Alternatively, compounds of the type VII are prepared from compounds of the type X (Scheme 2). These diamino pyrimidines, X, are made from the dichloroaminopyrimidines of type IX which are synthesized from compounds of type II by treatment with reducing agents such as, but not limited to sodium dithionite, iron or zinc in the presence of acid, or catalytic hydrogenation (see: LaRock, Comprehensive Organic Transformations, VCH Publishers, N.Y., 1989, 411). The diamino compounds, X, are converted into compounds of the type XII using the same procedure as described for the preparation of compounds of the type VII from compounds of the type V, and then condensing compounds of the type XII with salts of the compounds of the type I in solvents such as DMF or 2-ethoxyethanol at temperatures between 25 and 200.degree. C. Alternatively, compounds of the type VIII are prepared from compounds of the type X by first converting them into compounds of the type XIII using the same method as described for the preparation of compounds of the type VIII from compounds of the type V and then condensing compounds of the type XIII thus obtained with salts of the compounds of the type I under the conditions described for the conversion of compounds of the type I into compounds of the type II. Alternatively, compounds of type VI are prepared from compounds of type X by diazotization and cyclization, as previously described for compounds of compound type V to compounds of type VI, to give compounds of type XI. Subsequent treatment with the salts of the compounds of the type I with compounds of type XI, as previously described, provides these tiazolo adducts of type VI. The compounds of the present invention and their synthesis are further illustrated by the following examples and preparations. |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
|
Want more information ? Interested in the hidden information ? Click here and do your request. |