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(12) United States Patent (10) Patent No.: US 9,114,138 B2 Cid-Nunez Et Al

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(12) United States Patent (10) Patent No.: US 9,114,138 B2 Cid-Nunez Et Al USOO9114138B2 (12) United States Patent (10) Patent No.: US 9,114,138 B2 Cid-Nunez et al. (45) Date of Patent: Aug. 25, 2015 (54) 1',3'-DISUBSTITUTED-4-PHENYL-3,4,5,6- (58) Field of Classification Search TETRAHYDRO-2H, 1'H-14' CPC .......................... A61K 31/4545; CO7D 401/04 BPYRIDINYL-2'-ONES USPC ........................................... 546/194; 514/318 (75) Inventors: Jose Maria Cid-Nunez, Toledo (ES); See application file for complete search history. Andres Avelino Trabanco-Suarez, (56) References Cited Toledo (ES); Gregor James MacDonald, Beerse (BE); Guillaume U.S. PATENT DOCUMENTS Albert Jacques Duvey, Geneva (CH): 4,051,244. A 9/1977 Mattioda et al. Robert Johannes Lutjens, Geneva 4,066,651 A 1/1978 Brittain et al. (CH); Terry Patrick Finn, Geneva (CH) (Continued) (73) Assignees: Janssen Pharmaceuticals, Inc., FOREIGN PATENT DOCUMENTS Titusville, NJ (US); Addex Pharma SA, BE 841390 11, 1976 Geneva (CH) CA 1019323 1Of 1977 (*) Notice: Subject to any disclaimer, the term of this (Continued) patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 287 days. Adam, Octavian R. “Symptomatic Treatment of Huntington Dis (21) Appl. No.: 12/677,618 ease” Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Apr. 2008, vol. 5, 181-197.* (22) PCT Filed: Sep. 12, 2008 Hook V. Y.H. “Neuroproteases in Peptide Neurotransmission and Neurodegenerative Diseases Applications to Drug Discovery (86). PCT No.: PCT/EP2008/007551 Research” Biodrugs 2006, 20, 105-119.* 371 1 Conn, P.J. “Activation of metabotropic glutamate receptors as a novel S (c)(1), approach for the treatment of schizophrenia.” Trends in Pharmaco (2), (4) Date: Jun. 3, 2010 logical Sciences 2008 vol. 30 No. 1 25-31.* Eric R. Marcotte "Animal models of schizophrenia: a critical review” Psychiatry Neurosci 2001:26(5):395-410.* (87) PCT Pub. No.: WO2009/033704 Patani et al. "Bioisosterism: A Rational Approach in Drug Design” s Chemical Reviews 1996, 96, 3147-3176.* PCT Pub. Date: Mar. 19, 2009 Wakefield, Basil 'Fluorinated Pharmaceuticals' Innovations in Phar (65) Prior Publication Data maceutical Technology 2003, 74, 76-78. Online"http://web.archive. org/web/20030905122408/http://www.iptonline.com/articles/pub US 2010/O24O688A1 Sep. 23, 2010 lic/IPTFOUR74NP.pdf.” (accessed via Wayback machine Nov. 20, 2009 showing web availability as of Sep. 2003).* (30) Foreign Application Priority Data (Continued) Primary Examiner – David KO Dell Sepep. 14, 2007 (EP)EP) ..................................... O7116390 (74) Attorney, Agent, or Firm — Baker & Hostetler LLP (51) Int. Cl. (57) ABSTRACT CO7D40 L/04 (2006.01) The present invention relates to novel compounds, in particu A6 IK3 L/4545 (2006.01) lar novel pyridinone derivatives according to Formula (I) CO7D 49.3/10 (2006.01) I A 6LX3/5377 (2006.01) O (I) A6 IK 45/06 (2006.01) CO7D 2II/86 (2006.01) R2 -R C07D 491/107 (2006.01) A6 IK3I/444 (2006.01) 2 A6 IK9/20 (2006.01) N A6 IK9/00 (2006.01) Air A6 IK 47/10 (2006.01) R3 3. % 3:08: wherein all radicals are as defined in the application and claims. The compounds according to the invention are posi A6 IK 47/44 (2006.01) tive allosteric modulators of metabotropic receptors—Sub (52) U.S. Cl. type 2 (“mCluR2’) which are useful for the treatment or CPC ........... A6IK3I/4545 (2013.01); A61 K9/0014 prevention of neurological and psychiatric disorders associ (2013.01); A61 K9/0019 (2013.01); A61 K9/08 ated with glutamate dysfunction and diseases in which the (2013.01); A61 K9/10 (2013.01); A61 K9/2009 mGluR2 subtype of metabotropic receptors is involved. In (2013.01); A61 K9/2013 (2013.01); A61 K particular, such diseases are central nervous system disorders 9/2018 (2013.01); A61 K9/2059 (2013.01); selected from the group of anxiety, Schizophrenia, migraine, A61 K3I/444 (2013.01); A61 K3I/5377 depression, and epilepsy. The invention is also directed to (2013.01); A61K 45/06 (2013.01); A61 K47/10 pharmaceutical compositions and processes to prepare Such (2013.01); A61 K47744 (2013.01); C07D compounds and compositions, as well as to the use of Such 21 1/86 (2013.01); C07D401/04 (2013.01); compounds for the prevention and treatment of such diseases C07D491/107 (2013.01); Co 7D493/10 in which mGluR2 is involved. (2013.01) 11 Claims, No Drawings US 9,114,138 B2 Page 2 (56) References Cited 6,433,014 B1 8, 2002 Acher et al. 6,455,528 B1 9, 2002 Adachi et al. 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