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(12) United States Patent (10) Patent No.: US 8,697,689 B2 Cid-Nunez Et Al

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(12) United States Patent (10) Patent No.: US 8,697,689 B2 Cid-Nunez Et Al USOO8697689B2 (12) United States Patent (10) Patent No.: US 8,697,689 B2 Cid-Nunez et al. (45) Date of Patent: Apr. 15, 2014 (54) INDOLE AND BENZOMORPHOLINE 5,260,293 A 11/1993 Baker et al. DERVATIVES AS MODULATORS OF 5,280,026 A 1/1994 Brown et al. 5,332,750 A 7, 1994 Mederski et al. METABOTROPIC GLUTAMATE RECEPTORS 5,356,911 A 10, 1994 Muller-Gliemann et al. 5,366,981 A 11/1994 Vecchietti et al. (75) Inventors: Jose Maria Cid-Nunez, Toledo (ES); 5,371,074 A 12/1994 Dunlap et al. Andres Avelino Trabanco-Suarez, 5,374,513 A 12/1994. Ohzeki et al. 5,378,720 A 1/1995 Hlasta et al. Toledo (ES) 5,407,948 A 4/1995 Fey et al. (73) Assignees: Janssen Pharmaceuticals, Inc., 5,418,243 A 5/1995 Angerbauer et al. Titusville, NJ (US); Addex Pharma SA, (Continued) Geneva (CH) FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this BE 841390 11, 1976 patent is extended or adjusted under 35 CA 1019323 1Of 1977 U.S.C. 154(b) by 0 days. (Continued) (21) Appl. No.: 13/123,984 OTHER PUBLICATIONS (22) PCT Filed: Oct. 15, 2009 Vippagunta et al., “Crystalline Solids' Advanced Drug Delivery (86). PCT No.: PCT/EP2009/0074.04 Reviews, vol. 48, pp. 3-26 (2001).* S371 (c)(1), (Continued) (2), (4) Date: Jul. 28, 2011 (87) PCT Pub. No.: WO2010/043396 Primary Examiner — Kahsay T Habte PCT Pub. Date: Apr. 22, 2010 (74) Attorney, Agent, or Firm — Baker & Hostetler LLP (65) Prior Publication Data (57) ABSTRACT US 2011/0275624 A1 Nov. 10, 2011 The present invention relates to novel compounds, in particu (30) Foreign Application Priority Data lar novel indole and benzomorpholine derivatives according to Formula (I) wherein all radicals are as defined in the appli Oct. 16, 2008 (EP) ..................................... O8166832 cation and claims. The compounds according to the invention are positive allosteric modulators of metabotropic recep (51) Int. Cl. CO7D 403/04 (2006.01) tors—subtype 2 (“mCluR2’) which are useful for the treat CO7D 413/04 (2006.01) ment or prevention of neurological and psychiatric disorders CO7D 413/4 (2006.01) associated with glutamate dysfunction and diseases in which A6 IK3I/443.3 (2006.01) the mGluR2 subtype of metabotropic receptors is involved. In A6 IK3I/4439 (2006.01) particular, such diseases are central nervous system disorders (52) U.S. Cl. selected from the group of anxiety, Schizophrenia, migraine, USPC ......... 514/230.5: 514/344; 54.4/105:546/261 depression, and epilepsy. The invention is also directed to (58) Field of Classification Search pharmaceutical compositions as well as to the use of Such USPC ................. 544/105: 514/230.5, 344; 546/261 compounds or compositions for the prevention and treatment See application file for complete search history. of such diseases in which mGluR2 is involved. (56) References Cited (I) U.S. PATENT DOCUMENTS 4,051,244. 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