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(12) United States Patent (10) Patent No.: US 7,776,886 B2 Lindsley Et Al USOO7776886B2 (12) United States Patent (10) Patent No.: US 7,776,886 B2 Lindsley et al. (45) Date of Patent: Aug. 17, 2010 (54) CYCLOPROPYL PIPERIDINE GLYCINE WO WOOO/25786 * 5/2OOO TRANSPORTER INHIBITORS WO WO O2/O62750 8, 2002 WO WO 03/042174 * 5/2003 WO O3,055478 T 2003 (75) Inventors: Craig W. Lindsley, Schwenksville, PA WO WOO3,088908 10, 2003 (US); David D. Wisnoski, Quakertown, WO WO 2005/0466O1 5, 2005 PA (US); Scott E. Wolkenberg, WO WO 2005/094514 10/2005 Jenkintown, PA (US) WO WO 2005,107469 11, 2005 WO WO 2005/110983 11, 2005 (73) Assignee: Merck Sharp & Dohme Corp., WO WO 2006/067529 6, 2006 Rahway, NJ (US) WO WO 2007/041025 4/2007 WO WO 2007/053400 5/2007 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 256 days. Rogers et al (Brain Res, 493:41-50, 1989).* Brinker (Advances in Carbene Chemistry, vol. 3, 2001, pp. 20-21).* (21) Appl. No.: 11/664,190 Zhao et al (Bioorg Med Chem Lett 16:5968-5972, 2006).* Lindsley et al (Chem Med Chem 1:807-811, 2006).* (22) PCT Filed: Sep. 26, 2005 Zhao et al (Bioorg Med Chem Lett 19:1488-1491, 2009).* Thomson et al (Bioorg Med Chem Lett 19:2235-2239, 2009).* (86). PCT No.: Hovgaard etal (Pharm Res 12:387-392, 1995).* Ulbrich et al (J Med Chem37:953-959, 2002).* S371 (c)(1), Williams etal (Foye's Principles of Medicinal Chemistry, pp. 59-61. (2), (4) Date: Mar. 28, 2007 2001).* Patani etal (Chem Rev 96:3147-3176, 1996).* Cockerham et al (Basic Environmental Toxicology, pp. 201-204. (87) PCT Pub. No.: WO2006/039221 1994).* Wolkenberg, S.E., et. al., Discovery of GlyT1 Inhibitors with PCT Pub. Date: Apr. 13, 2006 Improved Pharmacokinetic Properties, Bioorganic & Medicinal Chemistry Letters (2009), doi:10.1016/j.bmcl. 2009.01.015. (65) Prior Publication Data Copending U.S. Appl. No. 1 1/991,727, filed Sep. 25, 2006, U.S. US 2008/O108663 A1 May 8, 2008 National Stage Entry of PCT/GB06/036989, published as WO 2007/ 041025. Copending U.S. Appl. No. 12/084,027, filed Oct. 27, 2006, U.S. Related U.S. Application Data National Stage Entry of PCT/GB06/041699, published as WO 2007/ (60) Provisional application No. 60/614.942, filed on Sep. O53400. 30, 2004. Copending U.S. Appl. No. 12/085.340, filed Nov. 23, 2006, U.S. National Stage Entry of PCT/GB06/050411, published as WO 2007/ 060484. (51) Int. Cl. Copending U.S. Appl. No. 11/922,074, filed Jun. 13, 2006, U.S. A6 IK 3/445 (2006.01) National Stage Entry of PCT/GB06/002156, published as WO 2006/ CO7D 2II/96 (2006.01) 134341. (52) U.S. Cl. ........................ 514/331; 514/233; 546/184 Supplementary Partial European Search Report for EP Application (58) Field of Classification Search ....................... None No. 0580 1197. See application file for complete search history. * cited by examiner (56) References Cited Primary Examiner Brandon J Fetterolf U.S. PATENT DOCUMENTS Assistant Examiner—Craig Ricci (74) Attorney, Agent, or Firm Gerard Devlin; Raynard Yuro 6,303,637 B1 10, 2001 Bao et al. 6,458,790 B2 10, 2002 Palucki 7,071,213 B2 7/2006 Friary (57) ABSTRACT 2006/0276655 A1 12/2006 Blackaby et al. 2007/0105902 A1* 5/2007 Lindsley et al. ............. 514,317 The present invention is directed to cyclopropyl piperidine 2007/02496.06 A1 10/2007 Lindsley et al. compounds that inhibit the glycine transporter GlyT1 and 2007,0254880 A1 1 1/2007 Blackaby et al. which are useful in the treatment of neurological and psychi 2008, 002101.0 A1 1/2008 Lindsley et al. atric disorders associated with glycinergic or glutamatergic 2008/0090796 A1 4/2008 Blackaby et al. neuro-transmission dysfunction and diseases in which the FOREIGN PATENT DOCUMENTS glycine transporter GlyT1 is involved. WO WO 96.25397 8, 1996 13 Claims, No Drawings US 7,776,886 B2 1. 2 CYCLOPROPYL PIPERDINE GLYCINE Kuhse J, 1994, Neuron 12:1291). Depending on the actual TRANSPORTER INHIBITORS Subunit composition, glutamate and glycine activate the NMDA receptor with EC50 values in the high nanomolar to CROSS REFERENCE TO RELATED low micromolar range. In addition, the pore of the NMDA APPLICATIONS receptor is impermeable to magnesium. Under normal resting conditions, extracellular magnesium can bind to a site within This application is a U.S. National Phase application under the pore and produce a magnesium block of the channel. This 35 U.S.C. 371 of PCT Application No. PCT/US2005/034301, magnesium block imparts a strong Voltage dependence to the filed Sep. 26, 2005, which claims priority under 35 U.S.C. channel which allows the NMDA receptor to act as a coinci 119 from U.S. Application No. 60/614,942, filed Sep. 30, 10 dence detector requiring the binding of glutamate, glycine, 2004. and the occurrence of postsynaptic depolarization before con ducting current. Of particular interest is the finding that the BACKGROUND OF THE INVENTION psychotomimetic drugs MK-801, PCP, and ketamine all act as open channel blockers of the NMDA receptor-channel by Schizophrenia is a debilitating psychiatric disorder char 15 binding to a site that overlaps with the magnesium binding acterized by a combination of negative (blunted affect, with site. It is apparent that the rich diversity of NMDA receptor drawal, anhedonia) and positive (paranoia, hallucinations, Subunits and regulatory sites provides for a complex assort delusions) symptoms as well as marked cognitive deficits. ment of physiologically and pharmacologically distinct het While the etiology of schizophrenia is currently unknown, the eromeric receptors making the NMDA receptor an ideal tar disease appears to be produced by a complex interaction of get for the design of novel therapeutic compounds. biological, environmental, and genetic factors. Over 40 years The NMDA receptor plays a critical role in a variety of ago it was found that phencyclidine (PCP) induces a psy neurophysiological phenomena, including but not limited to chotic state in humans that is very similar to that observed in synaptic plasticity, cognition, attention and memory (Bliss T Schizophrenic patients. The finding that the main mode of and Collingridge W. 1993, Nature 361:31: Morris RG Met action of PCP is that of a non-competitive antagonist of the 25 al., 1986, Nature 319:774). Psychotomimetic drugs consti N-methyl-D-aspartate (NMDA) subtype of ionotropic tute a wide class of drugs including psychomotor stimulants glutamate receptor stimulated a series of studies that have led (cocaine, amphetamine), hallucinogens (LSD), and NMDA to the development of the NMDA receptor hypofunction receptor antagonists (PCP, ketamine). Of these, only the model of schizophrenia (Jentsch J D and Roth R. H., 1999 NMDA receptor antagonists appear to elicit a robust induc Neuropsychopharmacology, 20:201). 30 tion of the positive, negative, and cognitive symptoms of Fast glutamatergic transmission in the mammalian central Schizophrenia. Controlled studies of ketamine-induced psy nervous system is primarily mediated by the excitatory amino chosis in human subjects, as well as observations of symp acid glutamate acting on ionotropic glutamate receptors (iG toms from patients abusing PCP as a recreational drug, have luRs). The iGluRs are comprised of three major subclasses, produced a convincing list of similarities between NMDA including the C-amino-3-hydroxy-5-methyl-4-isoxazolepro 35 receptor antagonist-induced psychosis and Schizophrenia pionic acid (AMPA), kainate, and NMDA receptor subtypes (Jentsch JD and Roth RH, 1999 Neuropsychopharmacology, (Hollmann M and Heinemann S, 1994, Annu. Rev. Neurosci. 20:201). NMDA-receptor antagonists faithfully mimic the 17:31). These three subclasses are multimeric ligand-gated symptoms of schizophrenia to the extent that it is difficult to cation channels which open in response to glutamate binding differentiate the two in the clinic. In addition, NMDA recep to induce a depolarizing excitatory post synaptic current. 40 tor antagonists can exacerbate the symptoms in Schizophren Molecular cloning has revealed that the NMDA receptor fam ics, and can trigger the re-emergence of symptoms in stable ily is composed of two primary subunits, NR1 and NR2. In patients. Finally, the finding that NMDA receptor co-agonists addition a novel inhibitory subunit which is developmentally Such as glycine, D-cycloserine, and D-serine produce benefits regulated termed NR3 has been recently described. A high in schizophrenic patients implicates NMDA receptor hypo degree of molecular diversity exists within each set of sub 45 function in this disorder, and indicate that increasing NMDA units. To date, only one NR1 subunit gene has been cloned; receptor activation may provide atherapeutic benefit (Leider however, alternative splicing of the NR1 gene can produce man E et al., 1996, Biol. Psychiatry 39:213, Javitt D C et al., eight different subunits. In contrast, 4 genes have been cloned 1994, Am. J. Psychiatry 151:1234, Heresco-Levy U, 2000, for the NR2 subunit (NR2A, NR2B, NR2C, and NR2D), Int. J. Neuropsychopharmacol. 3:243, Tsai G. et al., 1998, some of which exhibit alternative splicing (Hollmann Mand 50 Biol. Psychiatry 44:1081). A large number of studies in ani Heinemann S, 1994, Annu. Rev. Neurosci. 17:31). These mal models lend support to the NMDA hypofunction hypoth multiple subunits form heteromeric glutamate-gated ion esis of Schizophrenia. Recent generation of a mutant mouse channels. While the precise subunit stoichiometry of the natu expressing only 5% of normal levels of the NMDA NR1 rally occurring receptor remains unknown, both the NR1 and subunit have shown that this decrease in functional NMDA NR2 subunits are required for the expression of functionally 55 receptors induces a state very similar to that observed in other active receptor-channel complexes in mammalian expression animal models of schizophrenia (Mohn A Ret al., 1999, Cell systems.
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