USOO7678.363B2 (12) United States Patent (10) Patent No.: US 7,678,363 B2 Barlow et al. (45) Date of Patent: Mar. 16, 2010 (54) METHODS OF TREATING PSYCHIATRIC 5,093,333 A 3, 1992 Saab CONDITIONS COMPRISING 5,110,828 A 5/1992 Bromidge et al. ADMINISTRATION OF MUSCARINC 5,124,460 A 6/1992 Humphrey AGENTS IN COMBINATION WITH SSRIS 5,132,316 A 7/1992 Hadley et al. 5,137,895 A 8/1992 Munson, Jr. et al. (75) Inventors: Carrolee Barlow, Del Mar, CA (US); 4. S.4-1 1 YE Rabarti al. et al. Todd A.Carter, San Diego, CA (US); 5,260.314 A 1 1/1993 Sauerberg et al. Kym I Lorrain San Diego, CA (US); 5,262.427 A 1 1/1993 Nielson et al. Jammieson C. Pires, San Diego, CA 5,278,170 A 1/1994 Orlek et al. (US); Andrew Morse, San Diego, CA 5,286,864 A 2f1994 Walther et al. (US); Dana Gitnick, San Marcos, CA 5,314,901 A 5/1994 Bromidge et al. (US); Kai Treuner, San Diego, CA 5,324,724 A 6/1994 Orlek et al. (US); Alex Broadhead, San Diego, CA RE34,653 E 7, 1994 Tsukamoto et al. (US) 5,340,821 A 8, 1994 Abe et al. 5,356,912 A 10, 1994 Nielsen et al. 5,356,914 A 10/1994 Bromidge et al. (73) Assignee: BrainCells Inc, San Diego, CA (US) 5,362,739 A 11/1994 Orlek et al. 5,362,860 A 11, 1994 H tal. (*) Notice: Subject to any disclaimer, the term of this 5,384,408 A 1/1995 E. patent is extended or adjusted under 35 5,403,931 A 4, 1995 Tsukamoto et al. U.S.C. 154(b) by 409 days. 5,407,938 A 4, 1995 Fisher et al. 5,412,096 A 5/1995 Tsukamoto et al. (21) Appl. No.: 11/467,527 5,424.301 A 6/1995 Huang et al. 5,451,587 A 9, 1995 Walther et al. (22) Filed: Aug. 25, 2006 5,468.875 A 11, 1995 Sabb et al. 5,508.405 A 4/1996 Walther et al. (65) Prior Publication Data 5,510,478 A 4, 1996 Sabb 5,512,574 A 4/1996 Husbands et al. US 2007/OO49.576A1 Mar. 1, 2007 5,527,813 A 6/1996 Sauerberg et al. 5,534,520 A 7/1996 Fisher et al. Related U.S. Application Data 5,534,522 A 7/1996 Ando et al. 5,541,194 A 7/1996 Orlek et al. (60) Provisional application No. 60/71 1,846, filed on Aug. 5,545,740 A 8/1996 Hughes et al. 26, 2005, provisional application No. 60/727,127, 5,571,819 A 1 1/1996 Sabb filed on Oct. 14, 2005, provisional application No. 5,571,826. A 1 1/1996 Sauerberg et al. 60/738,133, filed on Nov. 17, 2005, provisional appli- 5,574,043 A 11/1996 Sauerberg et al. cation No. 60/803,826, filed on Jun. 2, 2006. 5,578,602 A 1 1/1996 Sauerberg et al. 5,580,880 A 12/1996 Handa et al. (51) Int. Cl. 5,599,937 A 2f1997 Glaset al. A6 IK 49/00 (2006.01) 5,605.908 A 2f1997 Merritt et al. A61 K 43/00 (2006.01) (Continued) AOIN 43/00 (2006.01) CO7C 213/OO (2006.01) FOREIGN PATENT DOCUMENTS (52) U.S. Cl. ................... 424/9.1: 514/183: 514/214.03; EP O32325 A1 T, 1989 564/347 (Continued) (58) Field of Classification Search ....................... None See application file for complete search history. OTHER PUBLICATIONS (56) References Cited Drugbank accession No. DB00472.* U.S. PATENT DOCUMENTS (Continued) 4,067,971 A 1/1978 Francis et al. Primary Examiner John D. Ulm 4,710,508 A 12/1987 Bergmeier et al. Assistant Examiner Stacey MacFarlane 4.786,648 A 1 1/1988 Bergmeier et al. (74) Attorney, Agent, or Firm Sughrue Mion, PLLC 4,855,290 A 8, 1989 Fisher et al. 4.866,077 A 9/1989 Bogeso et al. (57) ABSTRACT 4,870,081 A 9, 1989 Orlek et al. The instant disclosure describes methods for treating diseases 4,925,858 A 5/1990 Bogeso et al. and conditions of the central and peripheral nervous system 3. 38. St. et al. by stimulating or increasing neurogenesis. The disclosure 497,975 A 1 1/1990 Hadley et al. includes compositions and methods based on muscarinic 498 is 58 A 1/1991 Fisher et al. receptor modulation, Such as via inhibition of acetylcholine 4992.457 A 2f1991 Schulman et al. esterase (AChE) activity, alone or in combination with 4,996.210 A 2, 1991 Tsukamoto et al. another neurogenic agent to stimulate or activate the forma 5,041,455 A 8/1991 Sauerberg et al. tion of new nerve cells. 5,041,549 A 8, 1991 Tsukamoto et al. 5,043,345 A 8/1991 Sauerberg et al. 2 Claims, 15 Drawing Sheets US 7,678,363 B2 Page 2 U.S. PATENT DOCUMENTS WO WO99, 17771 A1 4f1999 WO WO99.5O247 A1 10, 1999 5,641,791 A 6/1997 Sauerberg et al. WO WOO1/O5763 A2 1, 2001 5,646.289 A 7/1997 Alt et al. WO WOO1,76571 A2 10, 2001 5,650,174 A 7, 1997 Muhammad et al. WO WOO1,83472 A1 11, 2001 RE35,593 E 8, 1997 Orlek et al. WO WO O2/OO3684 * 10/2002 5,665,745. A 9/1997 Alt et al. WO WOO2/O78629 A2 10, 2002 5,668,174 A 9, 1997 Kawagishi et al. WO WOO3,O28650 A2 4/2003 5,672,709 A 9/1997 Alt et al. WO WOO3/031412 A1 4, 2003 5,675,007 A 10/1997 Keogh et al. WO WOO3,057672 A2 7, 2003 5,756,501 A 5/1998 Sabb WO WOO3,057698 A2 7, 2003 5,773,458 A 6, 1998 Sabb et al. WO WOO3,059882 A1 T 2003 5,773,619 A 6, 1998 Bromidge et al. WO WOO3,091220 A1 11, 2003 5,808,075 A 9/1998 Bromidge et al. WO WO2004/034963 A2 4/2004 5,834,458. A 1 1/1998 Mitch WO WO2004/087158 A2 10, 2004 5,852,029 A 12/1998 Fisher et al. WO WO2004/089942 A2 10, 2004 5,902,814 A 5/1999 Gordon et al. WO WO2004/101603 A2 11/2004 RE36,374 E 11/1999 Bogeso et al. WO WO2005/041979 A1 5, 2005 5,981,545 A 11/1999 Jenkins et al. WO WO2005, O72713. A 8, 2005 6,051,581 A 4/2000 Gordon et al. WO WO2006/067494. A 6, 2006 6,103,734. A 8/2000 Ibanez WO WO2006/067496 A 6, 2006 6,174,886 B1 1/2001 Pineiro et al. 6,235,745 B1 5/2001 Megens OTHER PUBLICATIONS 6,237,645 B1 5/2001 Pountey 6,297.262 B1 10/2001 Sams-Dodd et al. Bromidge, Steven M., et al. “Design of R-(Z)-(+)-O- 6,468,560 B2 10/2002 Sauer et al. (Methoxyimino)-1-azabicyclo 2.2.2]octane-3-acetonitrile (SB 6,528,529 B1 3/2003 Brann et al. 202026), a Functionally Selective AZabicyclic Muscarinic M1 6,596,869 B2 7/2003 Hughes et al. Agonist Incorporating the N-Methoxy Imidoyl Nitrile Group as a 6,911,452 B2 6/2005 Schlienger Novel Ester Bioisostere”. J. Med. Chem. (1997) 19:40(26):4268 6,911.477 B2 6, 2005 Villalobos et al. 4280. 6.951,849 B2 10/2005 Kelly et al. Brown, Jason, et al. “Enriched environment and physical activity 2001/0003588 A1 6, 2001 Sauer et al. stimulate hippocampal but not olfactory bulb neurogenesis'. Eur 2001/0018074 A1 8/2001 Napper et al. Neurosci. (2003) 17(10):2042-2046. 2001/0036949 A1 11/2001 Coe et al. Cameron, H.A., et al. "Adult neurogenesis is regulated by adrenal 20O2/O127 271 A1 9, 2002 Van-Schie steroids in the dentate gyrus'. Neuroscience (1994) 61 (2):203-209. 2002/0150618 A1 10/2002 Napper et al. Cao, Y, et al. “Synthesis and biological characterization of 1-methyl 2003/0100545 A1 5/2003 Kelly et al. 1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives aS 2003/0129246 A1 7/2003 Napper et al. muscarinic agonists for the treatment of neurological disorders'. J. 2003. O144285 A1 7/2003 Brann et al. Med. Chem (2003) 46(20):4273-4286. 2003. O157169 A1 8, 2003 Sauer et al. Camps, P. et al. “Cholinergic Drugs in Pharmacotherapy of 2003/0176418 A1 9/2003 Skjaerbaek et al. Alzheimer's Disease'. Minireviews in Medicinal Chemistry (2002) 2005/O113357 A1 5/2005 Anderson et al. 2:11-25. 2005. O130961 A1 6, 2005 Davis et al. Eglen, Richard M., et al. “Selective Muscarinic Receptor Agonistand 2005/0209226 A1 9/2005 Skjaerbaek et al. Antagonists'. Pharmacol. Toxicol. (1996)78:59-68. 2007/00999.47 A1 5, 2007 Dean et al. Eisch, Amelia, J., et al. "Drug dependence and addiction II: Adult neurogenesis and drug addiction'. Am J Psychiatry (2004) FOREIGN PATENT DOCUMENTS 161(3):426. Fisher, Abraham "Muscarinic Receptor Agonists in Alzheimer's EP 311313 A2 12/1989 Disease—More Than Just Symptomatic Treatment?', CNS Drugs EP 370415 A1 5, 1990 (1999) 12(3): 197-214. EP 384285 A2 8, 1990 Fujimoto, J.M., et al. Intracerebroventricular Physostigmine-In EP 384288 A2 8, 1990 duced Analgesia: Enhancement by Naloxone, f-Funaltrexamine and EP 429.344 A1 5, 1991 Nor-Binaltorphimine and Antagonism by Dynorphin A (1-17)".