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(12) United States Patent (10) Patent No.: US 8,637,087 B2 Sandage, Jr

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(12) United States Patent (10) Patent No.: US 8,637,087 B2 Sandage, Jr USOO8637087B2 (12) United States Patent (10) Patent No.: US 8,637,087 B2 Sandage, Jr. et al. (45) Date of Patent: Jan. 28, 2014 (54) TREATMENT OF INTERSTITIAL CYSTITIS (56) References Cited USING (6AR, 10AR)-A-TETRAHYDROCANNABINOL-11-OIC U.S. PATENT DOCUMENTS ACDS 3,536,809 A 10/1970 AppleZweig .................. 424/435 3,598,123 A 8, 1971 Zaffaroni ....... ... 424/435 (75) Inventors: Bobby W. Sandage, Jr., Acton, MA 3,845,770 A 11/1974 Theeuwes ... ... 424/427 (US); Glenn L. Cooper, Wayland, MA 3,916,899 A 11/1975 Theeuwes ...... ... 424/427 (US) 4,008,719 A 2f1977 Theeuwes et al. ..... ... 424/427 4,876,276 A 10, 1989 Machoulam et al. ......... 514/454 4,880,830 A 11/1989 Rhodes ......................... 424/470 (73) Assignee: JB Therapeutics Inc., Newton Center, 4,973,603 A 11/1990 Burnstein ...... A61K 31/35 MA (US) 5,338,753 A 8/1994 Burstein et al. ............... 514.454 6,162,829 A 12/2000 Burstein ........ 514,570 (*) Notice: Subject to any disclaimer, the term of this 6,355,650 B1 3/2002 Burstein ........ ... 514,290 patent is extended or adjusted under 35 6,448,288 B1 9/2002 Burstein et al. ............... 514.454 U.S.C. 154(b) by 0 days. (Continued) (21) Appl. No.: 12/624,313 OTHER PUBLICATIONS (22) Filed: Nov. 23, 2009 Russo, Future of Cannabis and Cannabinoids in Therapeutics. Jour nal of Canabis Therapeutics: The Official Journal of International (65) Prior Publication Data Association for Cannabis. (2003);3(4):163.* US 2011/0318425A1 Dec. 29, 2011 (Continued) Related U.S. Application Data Primary Examiner — Savitha Rao (63) Continuation of application No. 12/070.342, filed on Feb. 15, 2008, now abandoned, and a continuation of (74) Attorney, Agent, or Firm — Medlen & Carroll, LLP application No. 1 1/299,688, filed on Dec. 13, 2005, now abandoned. (57) ABSTRACT (60) Provisional application No. 60/658,578, filed on Mar. The present invention relates to non-psychoactive derivatives 7, 2005, provisional application No. 60/635,005, filed of tetrahydrocannabinol, which are useful in treating intersti on Dec. 13, 2004. tial cystitis and relieving symptoms thereof. The invention uses (6aR.10aR)-A-tetrahydrocannabinol-11-oic acids (51) Int. C. (hereinafter referred to as (6aR.10aR)-A-THC-1 1-oic acid), A6 IK3I/352 (2006.01) as well as pharmaceutical compositions containing the (6aR, A6 IK3I/437 (2006.01) 10aR)-A-THC-11-oic acids, for treatment of interstitial cys A6IP 23/00 (2006.01) titis in a mammal. The invention further covers methods of (52) U.S. C. formulating and administering the compounds and pharma USPC ........... 424/618; 424/725; 514/455; 514/304; ceutical compositions as therapeutic agents in the treatment 514/317; 514/305; 514/424; 514/291; 514/256; of interstitial cystitis, with particularly preferred administra 514/217: 514/56; 514/454 tion routes being oral and via intravesicular instillation. (58) Field of Classification Search None See application file for complete search history. 7 Claims, 9 Drawing Sheets Hor Qu >so O ch CHOR O dr" US 8,637,087 B2 Page 2 (56) References Cited Mukerji G.Yiangou Y. Agarwal SK, Anand P. Increased cannabinoid receptor 1-immunoreactive nerve fibers in overactive and painful U.S. PATENT DOCUMENTS bladder disorders and their correlation with symptoms. Urology. Jun. 2010;75(6):1514.e15-20. Epub Mar. 25, 2010. 2004/004891.0 A1 3f2004 Bove et al. .................... 514,381 2004.0054.007 A1 3, 2004 Burstein et al. 514,568 Sanchez Freire V. Burkhard FC, Kessler TM, Kuhn A. Draeger A. 2004/0225.011 A1 11/2004 Burstein et al. ............... 514.454 Monastyrskaya K. MicroRNAs may mediate the down-regulation of 2006.0128794 A1 6/2006 Sandage ....................... 514.454 neurokinin-1 receptor in chronic bladder pain syndrome. Am J 2008.OO97195 A1 4/2008 Urquhart. 600,429 Pathol. Jan. 2010;176(1):288-303. Epub Dec. 11, 2009. 2008. O182892 A1 7/2008 Sandage ....................... 514.454 Tyagi V. Philips BJ, Su R. Smaldone MC, Erickson VL, Chancellor MB, Yoshimura N. Tyagi P. Differential expression of functional OTHER PUBLICATIONS cannabinoid receptors in human bladder detrusor and urothelium. J Morissette et al. Advanced Drug Delivery Reviews 2004, 56, 275 Urol. Apr. 18, 2009, 1(4):1932-8. Epub Feb. 23, 2009. 3OO.* Merriam FV. Wang ZY. Guerios SD, Bjorling DE., Cannabinoid Vippagunta, Sudha R. "Crystalline Solids.” Advanced Drug Delivery receptor 2 is increased in acutely and chronically inflamed bladder of Reviews 48(2001): 3-26.* rats. Neurosci Lett. Nov. 7, 2008:445(1): 130-4. Epub Aug. 31, 2008. Provisional U.S. Appl. No. 60/625,005, filed Dec. 13, 2004. Hayn MH, Ballesteros I, de Miguel F. Coyle CH, Tyagi S. Yoshimura Provisional U.S. Appl. No. 60/658,578, filed Mar. 7, 2005. N. Chancellor MB, Tyagi P. Functional and immunohistochemical Corey, E. J. and Samuelsson, B. (1984) One-step conversion of pri characterization of CB1 and CB2 receptors in rat bladder. Urology. mary alcohols in the carbohydrate series to the corresponding carboxylic tert-butyl esters, The Journal of Organic Chemistry Nov. 2008:72(5):1174-8. Epub May 12, 2008. 49(24), 4735-4735. Wiley JL, Ajulemic acid. IDrugs. Dec. 2005;8(12):1002-11. Review. Corey, E. J. and Venkateswarlu, A. (1972) Protection of hydroxyl Dinis P. Charrua A. Avelino A. Yaqoob M. Bevan S. Nagy I, Cruz F. groups as tert-butyldimethylsilyl derivatives, J. Am. Chem. Soc. , Anandamide-evoked activation of vanilloid receptor 1 contributes to 94(17), 61.90-6191. the development of bladder hyperreflexia and nociceptive transmis Mechoulam, R. et al. (1990) Synthesis of the individual, pharmaco sion to spinal dorsal horn neurons in cystitis. J Neurosci. Dec. 15, logically distinct, enantiomers of a tetrahydrocannabinol derivative, 2004:24(50): 11253-63. Tetrahedron. Asymmetry I (5), 315-318. Krenn H. Daha LK. Oczenski W. Fitzgerald RD . A case of can Pellegata, R. etal. (1985) An Improved Procedure for the Synthesis of nabinoid rotation in a young woman with chronic cystitis. J Pain Oleuropeic Acid. I. Synth. Commun. I5(2), 165-170. Symptom Manage. Jan. 2003:25(1):3-4. No abstract available. Daly DM, Collins VM. Chapple CR. Grundy D. The afferent system Jaggar SI, Hasnie FS, Sellaturay S. Rice AS., The anti-hyperalgesic and its role in lower urinary tract dysfunction. Curr Opin Urol. Jul. actions of the cannabinoidanandamide and the putative CB2 receptor 2011:21(4):268-74. Review. agonist palmitoylethanolamide in visceral and Somatic inflammatory PooniaMK, KaurG, Chintamaneni M. Changela I., New insights into pain. Pain. May 1998:76(1-2): 189-99. molecular targets for urinary incontinence. Indian J Pharmacol. Oct. 2010:42(5):261-6. * cited by examiner U.S. Patent Jan. 28, 2014 Sheet 2 of 9 US 8,637,087 B2 CYSTOMETROGRAMS VEHICLE i.V. AA O.2596 INFUSION 50 O 50 AAP.75 O.2596 mg/kgy) INFUSION 120) O IP-751 (3 mg/kg. i.v.) 50 120, . 50 AA O.25% INFUSION (min) IP-751 (10 mg/kg i.v.).50 AA O.2596 INFUSION Fig. 2 U.S. Patent Jan. 28, 2014 Sheet 3 of 9 US 8,637,087 B2 SUMMARY INTERCONTRACTION INTERVALS MAXIMUM VOIDING PRESSURE 20 6O x U.S. Patent Jan. 28, 2014 Sheet 4 of 9 US 8,637,087 B2 SUMMARY (96 OF CONTROL) INTERCONTRACTION INTERVALS MAXIMUMWOIDING PRESSURE x 150 — 1 5 O O Z£100 1 O O S. 50 5 O O S. O sistical is O Omg 1 mg 3 mg 10mg Omg 1 mg 3 mg 10mg CT.3 (mg/kg i.v.) BASELINE PRESSURE 150 PRESSURE THRESHOLD- - O 100 S. Ll 50 O & S O Omg 1 mg 3 mg 10mg Omg 1 mg 3 mg 10mg *P(0.05, ONE-WAY ANOVA Fig. 4 U.S. Patent Jan. 28, 2014 Sheet 5 of 9 US 8,637,087 B2 SUMMARY C number Control (min) AA 0.25% (min) MVP number Control (min) AA0.25% (min) Cremophor 6 128 16 5.11+ 0.6* Cremophor || 6 40.1 - 4.5 43.25.5 1 mg/kg 5 13.7+ 1.7 6,171.3** 1 mg/kg 5 37.6+06 41.4.13 3mg/kg 5 12.2+2.9 5, 18+ 1.2 3mg/kg 5 36.4+2.4 43.5 +3.9 10 mg/kg 6 11.8+1.6 13.22+2.7 10 mg/kg 6 32.5 + 1.5 38.0 + 40 PT number Control (min) AA 0.25% (min) BP number Control (min) AA 0.25% (min) Cremophor 6 750.9 6,408 Cremophor || 6 3.30.6 3,706 1 mg/kg 5 9.407 6.905 1 mg/kg 5 3.504 3.90.6 3mg/kg 5 8,705 8.10.4 3mg/kg 5 400.3 4.90.3 10 mg/kg 6 78+ O.7 96 - 0.7 10 mg/kg 6 3.60.5 4.6+06 *P<0.01, P(0.05, PAIREDT-TEST % OF CONTROL ICI (%) MVP (%) PT (%) BP (%) Cremophor 42.96.O. 107.24.O 87.1 6.7 1208 10.8 1 mg/kg 45.27.6 110.0+2.6 74.66.8 1112-9.8 3 mg/kg 51.1 - 18.5 119.17.O. 94.14.2 1254. 124 10 mg/kg 112.4+ 13.O. 116.599 1272 + 12.6* 1311 13.5 *P&O.05, (ONE-WAY ANOVA) Fig.5 U.S. Patent Jan. 28, 2014 Sheet 6 of 9 US 8,637,087 B2 EFFECTS OF i.v. ADMINISTRATION OF P751 ON CYCLOPHOSPHAMIDE INDUCED CYSTITIS IP751 10 mg/kg i.v.
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