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(12) United States Patent (10) Patent No.: US 8,916,564 B2 Pettersson Et Al

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USOO891.6564B2 (12) United States Patent (10) Patent No.: US 8,916,564 B2 Pettersson et al. (45) Date of Patent: Dec. 23, 2014 (54) SUBSTITUTED PYRIDO 1.2-APYRAZINES 7,812,040 B2 10/2010 Wager FOR THE TREATMENT OF 7,897,632 B2 3/2011 Kimura et al. 7,902,195 B2 3/2011 Hughes et al. NEURODEGENERATIVE AND 7,923.450 B2 4/2011 Baumann et al. NEUROLOGICAL DISORDERS 8,097,621 B2 1/2012 Bell et al. 8,697,673 B2 4/2014 Pettersson et al. (71) Applicant: Pfizer Inc., Groton, CT (US) 2002/0132817 A1 9/2002 Natsugari et al. 2003. O195205 A1 10, 2003 DeNinno et al. (72) Inventors: Martin Youngjin Pettersson, Littleton, 2004/0220186 Al 11/2004 Bell et al. MA (US); Douglas Scott Johnson 2006/0106035 A1 5/2006 Hendrix et al. s g s 2006/011 1372 A1 5, 2006 Hendrix et al. Concord, MA (US); Chakrapani 2007/0031416 A1 2/2007 Shoji et al. Subramanyam, South Glastonbury, CT 2007/0117798 A1 5, 2007 Kimura et al. (US); Christopher John O'Donnell, 2007/01 17839 A1 5/2007 Kimura et al. O O 2007/O155731 A1 7/2007 Butora et al. NRE's reely. 2007. O197581 A1 8, 2007 Asberometal. am Ende, Mystic, CT (US); Michael 2008, OOO9490 A1 1/2008 Williams et al. Eric Green, Boston, MA (US); Nandini 2008/0076.738 A1 3, 2008 Cai et al. Chaturbhai Patel, Waltham, MA (US); 2008. O194591 A1 8, 2008 Entwistle et al. Cory Michael Stiff, New London, CT 2008/02O7900 A1 8/2008 Kimura et al. 2008/0280948 A1 11/2008 Baumann et al. (US); Tuan Phog Tra. Ledyard, CT 2009.0062529 A1 3/2009 Kimura et al. (US); Gregory Wayne Kauffman, East 2009/0163482 A1 6/2009 McHardy et al. Greenwich, RI (US); Antonia 2009, 0215759 A1 8/2009 Baumann et al. Friederike Stepan, Providence, RI (US); 2009,0306054 A1 12/2009 Cai et al. Patrick Robert Verhoest, Newton, MA 2010, OO16373 A1 1/2010 Khilevich et al. (US) s s 2010.0041680 A1 2/2010 Rivkin 2010/0093.731 A1 4/2010 Goetschi et al. 2010, O105904 A1 4/2010 Kimura et al. (73) Assignee: Pfizer Inc., New York, NY (US) 2010, 0120874 A1 5/2010 Baumann et al. (*) Notice: Subject to any disclaimer, the term of this (Continued) patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS EP 1145714 10, 2001 (21) Appl. No.: 14/031,163 GB 1419789 12, 1975 (22) Filed: Sep.19, 2013 (Continued) OTHER PUBLICATIONS (65) Prior Publication Data PCT Search Report and Written Opinion from International Search US 2014/0088.111A1 Mar. 27, 2014 ing Authority for PCT/IB2013/058347 dated Jan. 15, 2014. Related U.S. Application Data (Continued) (60)60) Provisionalya applicauonapplication No.No 61/703.969,909, filedIlled on Sep.Sep Primary Examiner — Douglas MWillis s (74) Attorney, Agent, or Firm — Richard V. Zanzalari (51) Int. Cl. A6 IK3I/4985 (2006.01) (57) ABSTRACT CO7D 47L/04 (2006.01) Compounds and pharmaceutically acceptable salts of the (52) U.S. Cl. compounds are disclosed, wherein the compounds have the CPC .................................... C07D 471/04 (2013.01) structure of Formula I USPC ......... 514/249; 544/349; 548/335.1; 549/429 (58) Field of Classification Search CPC .................................................. A61K 31f4985 I USPC ......... 514/249; 544/349; 548/335.1; 549/429 R7 Q R2a R2b See application file for complete search history. 24. R3 N1 N1 (56) References Cited R4b U.S. PATENT DOCUMENTS X 4 2 R 5,700,810 A 12/1997 Natsugari et al. O R5a R55 6,489,315 B1 12/2002 Natsugari et al. 7,238,721 B2 7/2007 Chen et al. 7,253,180 B2 8, 2007 Chen et al. as defined in the specification. Corresponding pharmaceuti 7,253,195 B2 8, 2007 Chen cal compositions, methods of treatment, methods of synthe 7,342,118 B2 3/2008 Brodney et al. 7,517,532 B2 4/2009 Wai et al. sis, and intermediates are also disclosed. 7,638,629 B2 12/2009 Hannam et al. 7,741,315 B2 6/2010 Vacca et al. 25 Claims, No Drawings US 8,916,564 B2 Page 2 (56) References Cited Gillman, K., et al., “Discovery and Evaluation of BMS-708 163, a Potent Selective and Orally Bioavailabley-Secretase Inhibitor'. ACS U.S. PATENT DOCUMENTS Medicinal Chemistry Letters, Mar. 22, 2010, pp. 120-124; 1(3). Goel, A., et al., “Amberlyst 15-Catalyzed Efficient synthesis of 2010/013 0495 A1 5, 2010 Forsblom et al. 5-Acetyl-4-hydroxy-coumarone and 5-Acetyl-6-hydroxy 2010.0137320 A1 6/2010 Huang et al. coumarone: Crucial Precursors for Several Naturally Occurring 2010/0204230 A1 8, 2010 Blurton et al. 2010/0222320 A1 9, 2010 Fischer et al. 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    Proc. Natl. Acad. Sci. USA Vol. 88, pp. 10936-10940, December 1991 Neurobiology Aniracetam reduces glutamate receptor desensitization and slows the decay of fast excitatory synaptic currents in the hippocampus (non-N-methyl-D-aspartate receptor/synapse) JEFFRY S. ISAACSON*t AND ROGER A. NICOLLtt *Physiology Graduate Program and the Departments of SPharmacology and tPhysiology, University of California, San Francisco, CA 94143-0450 Communicated by Floyd E. Bloom, September 16, 1991 ABSTRACT Aniracetam is a nootropic drug that has been and DL-2-amino-5-phosphonovaleric acid (50 ,uM) were shown to selectively enhance quisqualate receptor-mediated added to the medium to block y-aminobutyric acid type A responses inXenopus oocytes injected with brain mRNA and in (GABAA) receptors and NMDA receptors, respectively. In hippocampal pyramidal cells [Ito, I., Tanabe, S., Kohda, A. & the majority of experiments examining iontophoretic re- Sugiyama, H. (1990) J. Physiol. (London) 424, 533-544]. We sponses, tetrodotoxin (0.5-1 1uM) was included to block have used patch clamp recording techniques in hippocampal sodium-dependent action potentials. Currents were recorded slices to elucidate the mechanism for this selective action. We with an Axopatch 1B amplifier from neurons in the CA1 and find that aniracetam enhances glutamate-evoked currents in CA3 pyramidal cell layers and granule cell layer of the whole-cell recordings and, in outside-out patches, strongly dentate gyrus using the "blind" whole-cell recording tech- reduces glutamate receptor desensitization. In addition, nique (15, 16). Patch electrodes (tip diameter = 2 Ium) aniracetam selectively prolongs the time course and increases contained (in mM) either a CsF (110 CsF, 10 CsCl, 10 Hepes, the peak amplitude of fast synaptic currents.
  • Penile Injection Therapy | Memorial Sloan Kettering Cancer Center

    Penile Injection Therapy | Memorial Sloan Kettering Cancer Center

    PATIENT & CAREGIVER EDUCATION Penile Injection Therapy This information will help you learn to inject medication into your penis. This is called penile injection therapy. Penile injections can help you achieve an erection if you have erectile dysfunction (ED). Read this resource carefully before starting injection therapy. If you do not follow the instructions in this resource, your doctor or APP may stop prescribing your penile injection medications and supplies. About Penile Injection Therapy The tissue that causes you to get an erection (erectile tissue) is a muscle. Going long periods of time without an erection is unhealthy for erectile tissue and may damage it. We believe having erections keeps erectile tissue healthy. A penile injection helps you have an erection. It works best if it’s given about 5 to 15 minutes before you want an erection. Penile Injection Therapy 1/19 Giving Yourself the Injection Your advanced practice provider (APP) will review the instructions below with you. Generally, the training for the injections takes 2 office visits. Please be aware that each visit may take up to 1 hour, so you should plan your schedule on the day of your appointment. Use this resource to help you the first few times you inject on your own. Do not take the following medications within 18 hours of injecting (before or after): Sildenafil (Viagra®) - 20 mg to 100 mg Vardenafil (Levitra®) - 10 mg to 20 mg Avanafil (Stendra®) - 50 mg to 200 mg If you take tadalafil (Cialis®) 10 mg or 20 mg, do not inject within 72 hours (3 days) of taking the medication.
  • PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1

    PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1

    Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
  • Rotenone-Induced Inner Retinal Degeneration Via Presynaptic

    Rotenone-Induced Inner Retinal Degeneration Via Presynaptic

    www.nature.com/scientificreports OPEN Rotenone-induced inner retinal degeneration via presynaptic activation of voltage-dependent sodium and L-type calcium channels in rats Masaaki Sasaoka, Takashi Ota & Masaaki Kageyama* Rotenone, a mitochondrial complex I inhibitor, causes retinal degeneration via unknown mechanisms. To elucidate the molecular mechanisms of its action, we further characterized a rat model of rotenone- induced retinal degeneration. Intravitreal injection of rotenone (2 nmol/eye) damaged mainly the inner retinal layers, including cell loss in the ganglion cell and inner nuclear layers, which were very similar to those induced by 10 nmol/eye N-methyl-D-aspartate (NMDA). These morphological changes were accompanied by the reduced b-wave amplitude of electroretinogram, and increased immunostaining of 2,4-dinitrophenyl, an oxidative stress marker. Rotenone also downregulated expression of neuroflament light-chain gene (Nf) as a retinal ganglion cell (RGC) marker. This efect was prevented by simultaneous injection of rotenone with antioxidants or NMDA receptor antagonists. More importantly, voltage-dependent sodium and L-type calcium channel blockers and intracellular calcium signaling modulators remarkably suppressed rotenone-induced Nf downregulation, whereas none of these agents modifed NMDA-induced Nf downregulation. These results suggest that rotenone-induced inner retinal degeneration stems from indirect postsynaptic NMDA stimulation that is triggered by oxidative stress-mediated presynaptic intracellular calcium signaling via activation of voltage-dependent sodium and L-type calcium channels. Rotenone is a naturally occurring and broad-spectrum pesticide that inhibits the activity of NADH dehydroge- nase in the mitochondrial respiratory chain complex I1. Because of this unique biological activity, rotenone has been used as a versatile tool to study involvement of mitochondrial functions and oxidative stress in neuronal cell death.