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(12) United States Patent (10) Patent No.: US 7419,980 B2 Trybulski Et Al

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(12) United States Patent (10) Patent No.: US 7419,980 B2 Trybulski Et Al USOO741998OB2 (12) United States Patent (10) Patent No.: US 7419,980 B2 Trybulski et al. (45) Date of Patent: Sep. 2, 2008 (54) FUSED-ARYLAND HETEROARYL 5,502,047 A 3/1996 Kavey ........................ 514, 183 DERVATIVES AND METHODS OF THEIR 6,703,389 B2 3/2004 Wong et al. .............. 514,239.2 USE 2002/0107249 A1 8/2002 Wong et al. .............. 514,238.5 2004/00 19101 A1 1/2004 Karlstadt et al. ............ 514,464 (75) Inventors: Eugene John Trybulski, Huntingdon 2004.0143008 A1 7/2004 Deecher et al. ............. 514,521 Valley, PA (US); Paige Erin Mahaney, 2004/0152710 A1 8/2004 Deecher et al. ........ 514/255.04 Pottstown, PA (US); Lori Krim Gavrin, 2004/0180879 A1 9, 2004 Deecher et al. .......... 514,225.8 Philadelphia, PA (US); Joseph Peter Sabatucci, Collegeville, PA (US); Gary Paul Stack, Ambler, PA (US) FOREIGN PATENT DOCUMENTS (73) Assignee: Wyeth, Madison, NJ (US) DE 2556474 C2 8, 2004 (*) Notice: Subject to any disclaimer, the term of this EP O 310 268 A2 4, 1956 patent is extended or adjusted under 35 EP OO65 757 B1 1, 1985 U.S.C. 154(b) by 636 days. EP O 208 235 B1 1/1990 EP O3O3961 B1 4f1994 (21) Appl. No.: 10/963,064 EP 1266 659 A1 12/2002 GB 1243955 * 8/1971 (22) Filed: Oct. 12, 2004 JP 10218866 A2 8, 1998 O O WO WO 91.18602 A1 12, 1991 (65) Prior Publication Data WO 92/06082 A1 4, 1992 US 2005/O192283 A1 Sep. 1, 2005 WO 94.21610 A1 9, 1994 WO WO97/35586 A1 10, 1997 Related U.S. Application Data WO 97,44329 A1 11, 1997 (60) Provisional application No. 60/570,056, filed on May WO WO99/446O1 A1 9, 1999 11, 2004, provisional application No. 60/561,447. WO WOOO,59851 A1 10, 2000 filed on Apr. 12, 2004, provisional application No. WO WOO1 O1973 A2 1/2001 60/510,811, filed on Oct. 14, 2003. WO WO 02/064543 A2 8, 2002 WO WO 02/064543 A3 8, 2002 (51) Int. Cl. WO WO O2/O78691 A1 10, 2002 A 6LX 3L/2197 (2006.01) A6 IK 3/4965 (2006.01) CO7D 40/00 (2006.01) CO7D 403/00 (2006.01) (Continued) CO7D 405/00 (2006.01) OTHER PUBLICATIONS CO7D 409/00 (2006.01) CO7D 4II/00 (2006.01) Gray, et al., Do O2-Adrenoceptors Play an Integral Role in the CO7D 413/00 (2006.01) Antinociceptive Mechanism of Action of Antidepressant Com CO7D 417/00 (2006.01) pounds, Euro. J. of Pharm. 378, 161-168 (1999).* CO7D 49/00 (2006.01) CO7D 24I/04 (2006.01) (Continued) C07D 295/00 (2006.01) Primary Examiner James O. Wilson (52) U.S. Cl. ............................ 514/252.13: 514/252.14; Assistant Examiner Erich A Leeser 514/253.01: 514/253.09: 514/253.1: 514/253.11; (74) Attorney, Agent, or Firm Thomas C. McKenzie 514/254.01: 514/254.05; 514/254.1: 514/255.05; 544/360; 544/373; 544/374; 544/379; 544/391; (57) ABSTRACT 544/397: 544/403:544/405 (58) Field544/373, of Classification 374,379,391,397, Search 403, ................. 405; 514/252.13, 544/360, A. present invention is directed- 0 to fit and Era. 514/252.14, 253.01, 253.09, 253.1, 253.11, erivatives, compositions containing these derivatives, an 5147254.01254.05 254.1255.05 methods of their use for the prevention and treatment of See application file for completes searchs history.s conditions ameliorated by monoamine reuptake including, interalia, vasomotor symptoms (VMS), sexual dysfunction, (56) References Cited gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromylagia syndrome, nervous system disor U.S. PATENT DOCUMENTS ders, and combinations thereof, particularly those conditions 3.454,554. A 7/1969 Biel et al. ................... 260/239 selected from the group consisting of major depressive dis 4,221,919 A 9, 1980 Grimova et al. ............. 562/.465 order, vasomotor symptoms, stress and urge urinary inconti 4,229,449 A 10/1980 Melloni et al. ...... 514,239.2 nence, fibromyalgia, pain, diabetic neuropathy, and combi 4,310,524. A 1/1982 Wiech et al. ................ 514,217 nations thereof. 4,535,186 A 8, 1985 Husbands et al. ........... 564,336 4,826,844 A 5/1989 Husbands et al. ........... 514,252 13 Claims, 2 Drawing Sheets US 7419,980 B2 Page 2 FOREIGN PATENT DOCUMENTS Kronenberg, F. et al., “Thermoregulatory Physiology of Menopausal Hot Flashes: A Review.” Can. J. Physiol. Pharmacol., 1987, 65:1312 WO WOO3,O37334 A1 5, 2003 1324. WO WOO3,053426 A1 T 2003 Loprinzi, C.L. et al., “Venlafaxine in management of hot flashes in WO WOO3,O77897 A1 9, 2003 Survivors of breast cancer: a randomized controlled trial. Lancet, WO WO 2004/O16272 A1 2, 2004 Dec. 16, 2000, 356(9247): 2059-2063. Loprinizi, C. L. etal. "Pilot Evaluation of Venlafaxine Hydrochloride OTHER PUBLICATIONS for the Therapy of Hot Flashes in Cancer Survivors,” Journal of U.S. Appl. No. 60/557.651, filed Mar. 30, 2004, Kim et al. Clinical Oncology, Jul. 1998, 16(7): 2377-2381. U.S. Appl. No. 60/557,831, filed Mar. 30, 2004, Kim et al. Mackinnon et al., “O-Adrenoceptors: more Subtypes but fewer func U.S. Appl. No. 60/569,863, filed May 11, 2004, Kim et al. tional differences. TIPS, 1994, 15: 119-123. U.S. Appl. No. 60/569,861, filed May 11, 2004, Vu. Merchenthaler et al., “The effect of estrogens and antiestrogens in a U.S. Appl. No. 10/963,458, filed Oct. 12, 2004, Mahaney et al. rat model for hot flush.” Maturitas, 1998, 30(3): 307-316. U.S. Appl. No. 10/962,881, filed Oct. 12, 2004, Mahaney. Morin, S. M., “Atomoxetine Selectively Induces Fos Expression in U.S. Appl. No. 10/962,897, filed Oct. 12, 2004, Deecher et al. the Rat Prefrontal Cortex.” Presented at Society for Neuroscience U.S. Appl. No. 10/963,111, filed Oct. 12, 2004, Trybulski et al. Annual Meeting (SFN); Nov. 2-7, 2002, Orlando, FL. U.S. Appl. No. 10/962,880, filed Oct. 12, 2004, Trybulski et al. Pacholczyk, T. et al., “Expression cloning of a cocaine-and antide U.S. Appl. No. 10/962.971, filed Oct. 12, 2004, Mahaney et al. pressant-sensitive human noradrenaline transporter,” Nature, 1991, U.S. Appl. No. 10/962,899, filed Oct. 12, 2004, Mahaney et al. 350(6316): 350-4. Clinical Trial: “Phase III Randomized Study of Panek, D.U. et al., “Effect of continuous intraventricular estrogen or Medroxyprogesterone Versus Venlafaxine in Women With catechol estrogen treatment on catecholamine turnover in various Symptomic Hot Flashes', www.clinicaltrials.gov sponsored by the brain regions.” J. Pharmacol. Exp. Ther:, 1986, 236(3), 646-652. National Institutes of Health, Study ID Nos. CDRO000069217; NCCTG-N99C7: NCI-PO2-0204, 2003, 6 pages. Prasad, P.D., et al., “Functional expression of the plasma membrane Acs, N. et al., “Estrogen improves impaired musculocutaneous vas serotonin transporter but not the vesicular monoamine transporter in cular adrenergic reactivity in pharmacologically ovariectomized rats: human placental trophoblasts and choriocarcinoma cells. Placenta, a potential peripheral mechanism for hot flashes?”. Endocrinology, 1996, 17(4): 201-7. 2001 15: 68-73. Quella, S. K. et al., “Pilot evaluation of Venlafaxine for the treatment Barlow, D. H., “Venlafaxine for hot flushes.' Lancet, Dec. 16, 2000, of hot flashes in men undergoing androgen ablation therapy for 356(9247): 2025-2026. prostate cancer.” The Journal of Urology, Jul. 1999, 162: 98-102. Barton, D. et al., “Hot Flashes—Aetiology and Management.” Drugs Reneric, J-Ph. et al., “Idazoxan and 8-OH-DPAT modify the behav and Aging, 2001, 18(8): 597-606. ioral effects induced by either NA, or 5-HT, or dual NA/5-HT Berendsen, H. H. G., “Hot Flushes and serotonin.” Journal of the reuptake inhibition in the rat forced Swimming test.” British Menopause Society, Mar. 2002, 8(1): 30-34. Nueropsychopharmacology, Apr. 2001, 24(4): 379-390. Berendsen, H. H. G., “Effect of tibolone and raloxifene on the tail Rosenberg, J. et al., “Hypothesis: pathogenesis of postmenopausal temperature of oestrogen-deficient rats.” European Journal of Phar hot flush.” Medical Hypotheses, 1991, 35: 349-350. macology, 2001, 419(1): 47-54. Shaw, C. R. “The perimenopausal hot flash: epidemiology, physiol Berendsen, H. H. G., “The role of serotonin in hot flushes.” ogy, and treatment.” Nurse Practitioner, Mar. 1997. 22:55-56,61-66. Maturitas, 2000, 36(3): 155-164. Stearns, V. et al., “Hot flushes.” Lancet, Dec. 7, 2002, 360(9348): Bundgaard, H., “Means to enhance penetration; Prodrugs as a means 1851-1861. to improve the delivery of peptide drugs.” Advanced Drug Deliver Stearns.V. et al., “Paroxetine controlled release in the treatment of Reviews, 1992, 8, 1-38. menopausal hot flashes,” JAMA, 2003, 289:2827-2834. Bundgaard, H. et al., “Glycolamide Esters as Biolabile Prodrugs of Stearns, V. et al., “A pilot trial assessing the efficacy of paroxetine Carboxylic Acid Agents: Synthesis, Stability, Bioconversion, and hydrochloride (Paxil) in controlling hot flashes in breast cancer Sur Physicochemical Properties,” J. of Pharmaceutical Sciences, Apr. vivors. Ann Oncol., 2000, 11:17-22. 1988, 77(4):285-298. Waldinger et al., “Treatment of hot flushes with mirtazapine: four Casper, R. F. et al., “Neuroendocrinology of menopausal flushes: an case reports.” Maturitas, 2000, 36(3): 165-168. hypothesis of flush mechanism.” Clinical Endocrinology, 1985, 22: Wilen, S.H. Tables of Resolving Agents and Optical Resolutions, pp. 293-312. 268-298, E.L. Eliel, Ed., University of Notre Dame Press, Notre Fink, G. et al., “Oestrogen and mental state.” Nature, 1996, Dame, IN 1972. 383(6598): 306.
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