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(12) United States Patent (10) Patent No.: US 6,319,953 B1 Carlson Et Al

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(12) United States Patent (10) Patent No.: US 6,319,953 B1 Carlson Et Al USOO6319953B1 (12) United States Patent (10) Patent No.: US 6,319,953 B1 Carlson et al. (45) Date of Patent: *Nov. 20, 2001 (54) TREATMENT OF DEPRESSION AND WO95/08549 3/1995 (WO). ANXETY WITH FLUOXETINE AND AN WO95/18124 7/1995 (WO). NK-1 RECEPTOR ANTAGONST WO 96/O5181 2/1996 (WO). WO 96/18643 6/1996 (WO). (75) Inventors: Emma Joanne Carlson, Puckeridge; WO 96/19233 6/1996 (WO). Nadia Melanie Rupniak, Bishops WO 96/24353 8/1996 (WO). Stortford, both of (GB) WO 98/15277 4/1998 (WO). OTHER PUBLICATIONS (73) Assignee: Merck Sharp & Dohme Ltd., Aguiar, M., et al., Physiology& Behavior, 1996, 60(4) Hoddesdon (GB) 1183-1186. (*) Notice: Subject to any disclaimer, the term of this Barden, N., et al., J. Neurochem., 1983, 41, 834-840. Bristow, L., et al., Eur: J. Pharmacol., 1994, 253, 245-252. patent is extended or adjusted under 35 Brodin, E., et al., Neuropharmacology, 1987, 26(6) U.S.C. 154(b) by 0 days. 581-590. This patent is Subject to a terminal dis Brodin, E., et al., Neuropeptides, 1994, 26, 253-260. claimer. Culman, J., et al., J. Physiol. Pharmacol., 1995, 73, 885-891. Cutler, et al., J. Psychopharmacol, 1994, 8, A22, 87. (21) Appl. No.: 09/457,241 Elliott, P. J., Exp. Brain Res. UK, 1988, 73, 354-356. (22) Filed: Dec. 8, 1999 F-D-C Reports-Prescription Pharmaceuticals and Bio technology, Dec. 8, 1997, 59(49), 10. Related U.S. Application Data File, S. E., Pharm. Biochem. Behavior, 1997, 58, 3, 747-752. (60) Division of application No. 08/994,063, filed on Dec. 19, Kramer, et al., Science, 1998, 281, 1640-1645. 1997, now Pat. No. 6,117,855, which is a continuation-in part of application No. PCT/GB97/02748, filed on Oct. 7, Lowe, J., et al., Drug News Perspect, 1992, 5(4), 223. 1997. Malek-Ahmadi, NeuroScience and Behavioral Reviews, 1992, 16, 365-359. (30) Foreign Application Priority Data Rimon, R., et al., Biological Psychiatry, 1984, 19(4), Oct. 7, 1996 (GB) .................................................. 962O88O 509-516. Aug. 4, 1997 (GB) ..... ... 9716458 Roccon, et al., Pharmacological Research, 1995, 31, 191. Aug. 4, 1997 (GB) .................................................. 97.16460 Rupniak, N., et al., Eur: J. Pharmacol., 1994, 265, 179-183. Shaikh, M., et al., Brain Research, 1993, 625, 283-294. (51) Int. Cl." ...................... A61K 31/135; A61K 31/675; Shirayama, Y., et al., Brain Research, 1996, 739, 70–78. A61K 31/535; A61K 31/44; A61K 31/445 Siegel, R., et al., Neurochem. Int., 1984, 6(6), 783-789. (52) U.S. Cl. ......................... 514/649; 514/90; 514/236.2; Siegel, A., et al., Aggressive Behavior, 1995, 21, 49-62. 514/278; 514/329 Teixeira, R., et al., European J. Pharm., 1996, 311, 7-14. (58) Field of Search .......................... 514/649, 90, 236.2, Vassout, et al., Neuropeptides, 1994, 26 (Suppl. 1), 38. 514/278, 329 Wahlestedt, Science, 1998, 281, 1624–1625. Wall Street Journal, Aug. 13, 1998, B1, Col. 2. (56) References Cited Primary Examiner William R. A. Jarvis U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm J. Eric Thies; David L. Rose 5,162,339 11/1992 Lowe, III. (57) ABSTRACT 5,538,982 7/1996 Hagan et al.. 5,612,337 3/1997 Baker et al. The present invention relates to the treatment or prevention 5,719,147 2/1998 Dorn et al. of depression and/or anxiety by the administration of a 5,728.695 3/1998 Harrison et al. combination of a specific class of NK-1 receptor antagonists FOREIGN PATENT DOCUMENTS and fluoxetine. O 577 394 1/1994 (EP). 8 Claims, 2 Drawing Sheets U.S. Patent US 6,319,953 B1 UOICUU 9/. US 6,319,953 B1 1 2 TREATMENT OF DEPRESSION AND considered in International (PCT) patent specification No. ANXETY WITH FLUOXETINE AND AN WO 96/24353 (published Aug. 15, 1996) which claims NK-1 RECEPTOR ANTAGONST methods for the treatment of psychiatric disorders using a combination of a tachykinin antagonist and a Serotonin CROSS REFERENCE TO RELATED agonist or Selective Serotonin reuptake inhibitor. However, APPLICATIONS the disclosure of WO 96/24353 does not provide any teach ing as to whether the claimed combination has any efficacy This application is a division of Ser. No. 08/994,063, filed and in particular there is no direction towards Specific Dec. 19, 1997, U.S. Pat. No. 6,117,855, which is a combinations which might potentiate the antidepressant or continuation-in-part of PCT Application No. PCT/GB97/ anxiolytic effects of the individual therapeutic agents. There 02748, filed Oct. 7, 1997, which claims priority from Great is no clear direction from WO 96/24353 to which class of Britain Application No. 9620880.6, filed Oct. 7, 1996, Great tachykinin antagonist (e.g. NK-1, NK-2 or NK-3 receptor Britain Application No. 9716458.6 filed Aug. 4, 1997, and antagonists) would be of use in the claimed combinations, Great Britain Application No. 9716460.2, filed Aug. 4, 1997. nor how a perSon of ordinary skill in the art might identify This invention relates to the treatment or prevention of 15 Suitable compounds for use in combination with a Serotonin depression and/or anxiety by the administration of a com agonist or a Selective Serotonin reuptake inhibitor. bination of a Specific class of NK-1 receptor antagonists and Furthermore, there is no teaching which would enable a an antidepressant or anti-anxiety agent. The present inven perSon of ordinary skill in the art to identify those com tion also provides preclinical Screens for anxiolytic and pounds with Sustained activity following oral administration antidepressant activity of NK-1 receptor antagonists. for use in the claimed combinations. At best, WO 96/24353 Major depression is characterised by feelings of intense merely recites m one document that which was already Sadness and despair, mental Slowing and loss of recognised in the art, namely that tachykinin antagonists concentration, pessimistic worry, agitation, and Self might be of use in the treatment of psychiatric disorders and deprecation. Physical changes also occur, especially in that Serotonin agonists and Selective Serotonin reuptake Severe or "melancholic' depression. These include insomnia 25 inhibitors are effective in the treatment of psychiatric dis or hyperSomnia, anorexia and weight loss (or Sometimes orders. overeating), decreased energy and libido, and disruption of There therefore remains a need for an effective combina normal circadian rhythms of activity, body temperature, and tion of an antidepressant and/or an anti-anxiety agent with a many endocrine functions. NK-1 receptor antagonist, which combination provides an Treatment regimens commonly include the use of tricy unexpected and advantageous antidepressant or anxiolytic clic antidepressants, monoamine oxidase inhibitors, Some effect. Such combinations may for example provide an psychotropic drugs, lithium carbonate, and electroconvul enhanced antidepressant or anxiolytic effect. They may also sive therapy (ECT) (see R. J. Baldessarini in Goodman & provide for a rapid onset of action to combat depression Gilman's The Pharmacological Basis of Therapeutics, 9th and/or anxiety thereby enabling prescription on an "as Edition, Chapter 19, McGraw-Hill, 1996 for a review). More 35 needed” basis. recently, new classes of antidepressant drugs are being CNS-penetrant NK-1 receptor antagonists have been developed including Selective Serotonin reuptake inhibitors found to provide an unexpected effect relevant to the treat (SSRIs), specific monoamine reuptake inhibitors and ment and prevention of depression and/or anxiety when used 5-HT1A receptor agonists, antagonists and partial agonists. in combination with an antidepressant or anti-anxiety agent. Anxiety is an emotional condition characterised by feel 40 While not being bound to any particular theory of operation, ingS Such as apprehension and fear accompanied by physical an enhanced effect at treating or preventing a psychological Sympoms Such as tachycardia, increased respiration, Sweat StreSS response in an animal assay is observed with the ing and tremor. It is a normal emotion but when it is Severe combination of drugs than would be expected from either and disabling it becomes pathological. drug alone. In particular, combination therapy of a CNS Anxiety disorders are generally treated using benzodiaz 45 penetrant NK-1 receptor antagonist Selected from the com epine Sedative-antianxiety agents. Potent benzodiazepines pounds of formulae (I), (II), (III), (IV) and (V), and a are effective in panic disorder as well as in generalised Selective Serotonin reuptake inhibitor or a 5-HT1A receptor anxiety disorder, however, the risks associated with drug agonist or antagonist effectively inhibits Separation-induced dependency may limit their long-term use. 5-HT1A receptor Vocalisations in guinea-pig pups. This is indicative of effi partial agonists also have useful anxiolytic and other psy 50 cacy in the treatment of depression and/or anxiety. Such chotropic activity, and less likelihood of Sedation and depen unexpected results would not have been predicted based on dance (see R. J. Baldessarini in Goodman & Gilman's The the disclosures in the art. Pharmacological Basis of Therapeutics, 9th Edition, Chap DETAILED DESCRIPTION OF THE DRAWING ter 18, McGraw-Hill, 1996 for a review). 55 Neurokinin 1 (NK-1; Substance P) receptor antagonists A more complete understanding of the present invention are being developed for the treatment of a number of may be obtained by reading the following description in physiological disorders associated with an exceSS or imbal conjunction with the appended figures. ance of tachykinins, and in particular Substance P. Examples FIG. 1 depicts a Summary of the data from a test of of Such conditions include disorders of the central nervous 60 combinaitons of a CNS-penetrant NK-1 receptor antagonist System Such as anxiety, depression and psychosis (see, for with the anti-anxiety agent, buSpirone, in a guinea-pig instance, International (PCT) patent specification Nos.
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