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(12) United States Patent (10) Patent No.: US 9,469,601 B2 Vacher Et Al

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(12) United States Patent (10) Patent No.: US 9,469,601 B2 Vacher Et Al USOO94.69601 B2 (12) United States Patent (10) Patent No.: US 9,469,601 B2 Vacher et al. (45) Date of Patent: Oct. 18, 2016 (54) AMINOCYCLOBUTANE DERIVATIVES, FOREIGN PATENT DOCUMENTS METHOD FOR PREPARING SAME AND THE EP 0 747 348 A1 12/1996 USE THEREOF AS DRUGS EP O747348 A1 * 12, 1996 ............. CO7B 57/OO WO WO 98.07447 A1 2, 1998 (71) Applicant: PIERRE FABRE MEDICAMENT, WO WO 99.12537 A1 3, 1999 Boulogne-Billancourt (FR) WO WO 99.52848 A1 10, 1999 WO WOOOO3716 A1 1, 2000 WO WOOO, 51607 A1 9, 2000 (72) Inventors: Bernard Vacher, Castres (FR); Elodie WO WO 03/06165.6 A1 T 2003 Blanc, Semalens (FR); Ronan WO WO O3,063797 A2 8, 2003 Depoortere, Castres (FR) WO WO 2006/081179 A1 8, 2006 WO WO 2008/092.955 A1 8, 2008 WO WO 2009/O29618 A1 3, 2009 (73) Assignee: PIERRE FABRE MEDICAMENT, WO WO 2009/06961.0 A1 6, 2009 Boulogne-Billancourt (FR) WO WO 2009/092324 A1 T 2009 WO WO 2010/036937 A1 4/2010 (*) Notice: Subject to any disclaimer, the term of this WO WO 2010/037533 A1 4, 2010 patent is extended or adjusted under 35 (Continued) U.S.C. 154(b) by 0 days. OTHER PUBLICATIONS (21) Appl. No.: 14/649,448 Aarts et al., “Novel Treatment of Excitotoxicity: Targeted Disrup (22) PCT Filed: Dec. 4, 2013 tion of Intracellular Signalling from Glutamate Receptors,” Bio chemical Pharmacology, vol. 66, 2003, pp. 877-886. (86). PCT No.: PCT/EP2013/075481 (Continued) S 371 (c)(1), (2) Date: Jun. 3, 2015 Primary Examiner — Jean Cornet (87) PCT Pub. No.: WO2014/086825 (74) Attorney, Agent, or Firm — Birch, Stewart, Kolasch PCT Pub. Date: Jun. 12, 2014 & Birch, LLP (65) Prior Publication Data (57) ABSTRACT US 2015/0315132 A1 Nov. 5, 2015 The present inventions concerns derivatives of aminocy (30) Foreign Application Priority Data clobutane, particularly as NMDA receptor antagonists, their application in human therapy and their method of prepara Dec. 4, 2012 (FR)...................................... 12 61621 tion. These compounds correspond to the general formula (1): (51) Int. Cl. AOIN3L/6 (2006.01) A6 IK3I/I65 (2006.01) (1) CD7C 235/40 (2006.01) R1 X2 CD7C 2.3/4 (2006.01) C07C 237/24 (2006.01) C07D 307/00 (2006.01) O E X (52) U.S. Cl. s CPC ........... C07C 235/40 (2013.01); C07C 231/14 (2013.01); C07C 237/24 (2013.01); C07D R-N 307/00 (2013.01); C07C 2101/04 (2013.01) R2 NH, (58) Field of Classification Search CPC. C07C 101/04; C07C 231/14: CO7C 235/40: C07C 237/24: CO7D 307/00 wherein: See application file for complete search history. X represents a hydrogen atom or fluorine atom; X is a hydrogen atom or fluorine atom or chlorine atom; (56) References Cited R1 represents a hydrogen atom or fluorine atom or U.S. PATENT DOCUMENTS chlorine atom or methyl group or methoxy group or cyano group; 6,387,957 B1 5, 2002 Frome 2004/0101582 A1 5, 2004 Wolicki R2 represents independently or together a methyl group or 2004/0204366 A1 10, 2004 Pasternak et al. ethyl group. 2008/0268071 A1 10, 2008 Gant et al. 2010/0267695 A1 10/2010 Hayashibe et al. 2011 0160260 A1 6, 2011 Ho 14 Claims, 1 Drawing Sheet US 9,469,601 B2 Page 2 (56) References Cited Karadottir et al., “NMDA Receptors Are Expressed in Oligodendrocytes and Activated in Ischaemia,” Nature, vol. 438, Dec. 2005, pp. 1162-1166. FOREIGN PATENT DOCUMENTS Mony et al., “Allosteric Modulators of NR2B-Containing NMDA Receptors: Molecular Mechanisms and Therapeutic Potential.” Brit WO WO 2010/112697 A1 10, 2010 ish Journal of Pharmacology, vol. 157, 2009 (published online Jul. WO WO 2010, 142890 A1 12/2010 8, 2009), pp. 1301-1317. Muir, “Glutamate-Based Therapeutic Approaches: Clinical Trials OTHER PUBLICATIONS with Nimda Antagonists,” Current Opinion in Pharmacology, vol. 6, 2006 (available online Dec. 15, 2005), pp. 53-60. Bardin et al., “In the Formalin Model of Tonic Nociceptive Pain, Piepoli et al., “Glutamate Signaling in Chondrocytes and the 8-OH-DPAT Produces 5-HT Receptor-Mediated, Behaviorally Potential Involvement of NMDA Receptors in Cell Proliferation and Specific Analgesia, European Journal of Pharmacology, vol. 421, Inflammatory Gene Expression.” Osteoarthritis and Cartilage, vol. 2001, pp. 109-114. 17, No. 8, 2009, pp. 1076-1083. Beloeil et al., “The Effect of a Peripheral Block on Inflammation Planells-Cases et al., “A Novel N-Methyl-D-aspartate Receptor Induced Prostaglandin E2 and Cyclooxygenase Expression in Rats.” Open Channel Blocker with in Vivo Neuroprotectant Activity.” International Anesthesia Research Society, Anesthesia and Analge Journal of Pharmacology and Experimental Therapeutics, vol. 302, sia, vol. 109, No. 3, Sep. 2009, pp. 943-950. No. 1, 2002, pp. 163-173. Chen et al., “The Chemical Biology of Clinically Tolerated NMDA Salter et al., “NMDA Receptor Expression and Roles in Human Receptor Antagonists,” Journal of Neurochemistry, vol. 97, 2006, Articular Chondrocyte Mechanotransduction.” Biorheology, vol. pp. 1611-1626. 41, 2004, pp. 273-281. Cohen et al., “Ketamine in Pain Management.” Advances in Psy Soltani Rad et al., “A Simple One-Pot Procedure for the Direct chosomatic Medicine, vol. 30, 2011, pp. 139-161. Conversion of Alcohols Into Azides Using TSLM.” Tetrahedron Depoortere et al., “Prepulse Inhibition of the Startle Reflex in Rats: Letters, vol. 48, 2007 (available online Mar. 12, 2007), pp. 3445 Effects of Compounds Acting at Various Sites on the NMDA 3449. Receptor Complex,” Behavioural Pharmacology, vol. 10, No. 1, Wallace et al., “A Randomized, Double-Blind, Placebo-Controlled 1999, pp. 51-62. Trial of a Glycine Antagonist in Neuropathic Pain.” Neurology, vol. Elia et al., “Ketamine and Postoperative Pain—A Quantitative 59, Dec. 2002, pp. 1694-1700. Systematic Review of Randomised Trials.” Pain, vol. 113, 2005, pp. Wilder-Smith et al., “Preoperative Back Pain is Associated With 61-70. Diverse Manifestations of Central Neuroplasticity.” Pain, vol. 97. Finch et al., “Reduction of Allodynia in Patients with Complex 2002, pp. 189-194. Regional Pain Syndrome: a Double-Blind Placebo-Controlled Trial Williams et al., “A New General Method for Preparation of of Topical Ketamine.” Pain, vol. 146, 2009, pp. 18-25. N-Methoxy-N-Methylamides. Application in Direct Conversion of French Preliminary Search Report, dated Aug. 2, 2013, for French an Ester to a Ketone.” Tetrahedron Letters, vol. 36, No. 31, 1995, Application No. 1261621. pp. 5461-5464. Heusler et al., “Differential Ion Current Activation by Human Zarantonello et al., “Novel Analogues of Ketamine and Phencycli 5-HT Receptors in Xenopus Oocytes: Evidence for Agonist dine as NMDA Receptor Antagonists.” Bioorganic & Medicinal Directed Trafficking of Receptor Signalling.” Neuropharmacology, Chemistry Letters, vol. 21, 2011 (Available online Feb. 18, 2011), vol. 49, 2005, pp. 963-976. pp. 2059-2063. International Search Report and Written Opinion of the Interna Zarate et al., “A Randomized Trial of an N-methyl-D-aspartate tional Searching Authority (Forms PCT/ISA/220 and PCT/ISA/ Antagonist in Treatment-Resistant Major Depression.” Arch Gen 210), dated Feb. 21, 2014, for International Application No. PCT/ Psychiatry, vol. 63, Aug. 2006, pp. 856-864. EP2013,075481. International Search Report issued in PCT/EP2013/075481, mailed Johannes et al., “The Prevalence of Chronic Pain in United States on Feb. 21, 2014. Adults: Results of an Internet-Based Survey.” The Journal of Pain, vol. 11, No. 11, Nov. 2010, pp. 1230-1239. * cited by examiner U.S. Patent Oct. 18, 2016 US 9,469,601 B2 2O to Compound la -0. Ketamine US 9,469,601 B2 1. 2 AMINOCYCLOBUTANE DERIVATIVES, neuropathic (or neurogenic) pain is related to a lesion or METHOD FOR PREPARING SAME AND THE to dysfunctioning or disruption of the Somatosensory USE THEREOF AS DRUGS system; it differs from nociceptive pain in that it has a different Semiology; The present invention concerns derivatives of aminocy 5 psychogenic (or idiopathic pain) is pain which exists in clobutane as well as their method of preparation and their the absence of lesions. The physiological mechanisms use in human therapy. of this type of pain are not clearly defined. It is Glutamate receptors of the NMDA subtype (N-methyl generally resistant to analgesics. D-aspartic acid) are ionotropic receptors, mainly permeable Nevertheless, certain pains have characteristics that are to Ca" ions. Physiologically, their activation triggers the 10 common to several types of pain. For example, this is the opening of anion channel and the production of an incoming case for lower back or cancer pain which present in the form current which is only slowly inactivated. Stimulation of this of pain caused by excessive nociception, or in the form of receptor requires the simultaneous presence of glutamate neuropathic pain or, in most cases, a mixture of the two. (endogenous agonist) and glycine or D-serine (endogenous Depression is defined in psychiatry as a mood disorder. It 15 is characterised by a loss of motivation associated or not co-agonists) as well as depolarisation of the plasma mem with different symptoms such as hopelessness, low self brane initiated by non-NMDA currents. The NMDA recep esteem, anxiety, anguish and, in extreme cases, hallucina tors are widely spread throughout the central nervous system tions. It is often multi-factorial and generally has multiple and are also present at the periphery. They are found in the CalSCS. neurones, astrocytes and oligodendrocytes (Karadottir et al., It is reported that approximately 7% of Europeans suffer 2005, Nature, 438, 1162-1166). At the neuronal level, they from depression and that a third of these are resistant to are located mainly in the post-synapse but also in extra clinically used antidepressants. The cost of depression in the synaptic regions along the axons.
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