DOCSLIB.ORG

8-Substituted 2-Amino

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
8-Substituted 2-Amino (19) TZZ _¥_Z_T (11) EP 2 817 310 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/496 (2006.01) A61K 31/519 (2006.01) 21.03.2018 Bulletin 2018/12 A61K 31/537 (2006.01) A61K 31/5377 (2006.01) A61K 31/55 (2006.01) A61K 31/5513 (2006.01) (2006.01) (2006.01) (21) Application number: 13700849.6 C07D 487/04 C07D 519/00 A61K 31/5386 (2006.01) (22) Date of filing: 22.01.2013 (86) International application number: PCT/EP2013/000189 (87) International publication number: WO 2013/124026 (29.08.2013 Gazette 2013/35) (54) 8-SUBSTITUTED 2-AMINO-[1,2,4]TRIAZOLO[1,5-A]PYRAZINES AS SYK TRYROSINE KINASE INHIBITORS AND GCN2 SERIN KINASE INHIBITORS 8-SUBSTITUIERTE 2-AMINO-[1,2,4-]TRIAZOLO-[1,5-A-]PYRAZINE ALS SYK-TRYROSIN-KINASEHEMMER UND GCN2-SERIN-KINASEHEMMER 2-AMINO-[1,2,4]TRIAZOLO[1,5-A]PYRAZINES SUBSTITUÉES EN 8ÈME POSITION EN TANT QU’INHIBITEURS DE LA TYROSINE KINASE SYK ET EN TANT QU’INHIBITEURS DE LA SÉRINE KINASE GCN2 (84) Designated Contracting States: • KUHN, Daniel AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 64380 Rossdorf (DE) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • ROSS,Tatjana PL PT RO RS SE SI SK SM TR 65760 Eschborn (DE) • BURGDORF, Lars (30) Priority: 21.02.2012 EP 12001153 60385 Frankfurt am Main (DE) (43) Date of publication of application: (56) References cited: 31.12.2014 Bulletin 2015/01 WO-A1-2009/155551 WO-A1-2011/006903 WO-A1-2011/086098 WO-A1-2011/086099 (73) Proprietor: Merck Patent GmbH WO-A1-2012/025186 64293 Darmstadt (DE) • WERMUTH C G: "MOLECULAR VARIATIONS (72) Inventors: BASED ON ISOSTERIC REPLACEMENTS", • DEUTSCH, Carl PRACTICE OF MEDICINAL CHEMISTRY, XX, XX, 64287 Darmstadt (DE) 1996, pages 203-237, XP002190259, Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 817 310 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 817 310 B1 Description BACKGROUND OF THE INVENTION 5 [0001] The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments. [0002] The present invention relates to compounds and to compounds for use in which the inhibition, regulation and/or modulation of signal transduction by kinases, in particular tyrosine kinases, furthermore to pharmaceutical compositions which comprise these compounds, and to compounds for use for the treatment of kinase-induced diseases. 10 Becauseprotein kinases regulate nearly every cellular process, including metabolism, cell proliferation,cell differentiation, and cell survival, they are attractive targets for therapeutic intervention for various disease states. For example, cell- cycle control and angiogenesis, in which protein kinases play a pivotal role are cellular processes associated with numerous disease conditions such as but not limited to cancer, inflammatory diseases, abnormal angiogenesis and diseases related thereto, atherosclerosis, macular degeneration, diabetes, obesity, and pain. 15 One of the key events in the signaling pathway following the activation of mast cells is activation of the tyrosine kinase Syk. Mast cells play a critical role in asthma and allergic disorders by releasing pro-inflammatory mediators and cytokines. Antigen-mediated aggregation of Fc εRJ, the high-affinity receptor for IgE, results in activation of mast cells. This triggers a series of signaling events resulting in the release of mediators, including histamine, proteases, leukotrienes and cytokines. These mediators cause increased vascular permeability, mucus production, bronchoconstriction, tissue deg- 20 radation and inflammation, thus playing key roles in the etiology and symptoms of asthma and allergic disorders. Syk kinase acts as a central initiator of all subsequent signaling leading to mediator release. The critical role of Syk kinase in the signaling path was demonstrated by the complete inhibition of mediator release by a protein containing the SH2 domains of Syk kinase that functioned as an inhibitor of Syk kinase (J. A.Taylor et al, Molec. and Cell Biol, 15: 4149-4157 (1995). 25 Syk (Spleen-Tyrosine-Kinase) is a 72 kDa non-receptor tyrosine kinase belonging to the subfamily of intracellular tyrosine kinases that comprises ZAP70, Pyk2, Abl, Tie2, KDR and HER, among others. Syk is a major regulator of FcR (Fc γRI, II, III, FcεRI, FcαR) and BCR signaling and is expressed throughout hematopoietic lineage, as well as in fibroblasts, osteoclasts, hepatocytes, epithelial and neuronal cells. In addition to the C terminal kinase domain, SYK exhibits two SH2 domains and over 10 autophosphorylation sites 1. 30 [0003] By means of both its SH2 domains SYK is specifically recruited to phosphorylated ITAMsI mmunoreceptor( Tyrosine-based Activation Motifs present in immunoreceptors such as Fc γRI, IIA, IIIA, Fc αR, FcεRI and BCR, expressed by monocytes, macrophages, mast cells, neutrophils and B cells) and specifically mediates immunoreceptor signaling triggered by activation of those receptors in mast cells, B cells, macrophages, monocytes, neutrophils, eosinophils, NK cells, DC cells platelets and osteoclasts1,2. 35 [0004] Upon BCRcross linking,tyrosine residuesat the ITAM motifs of the cytosolictail ofthe Ig α /Igβ are phosphorylated by the Src-family kinase Lyn, generating docking sites for SYK that is thus recruited to the BCR immunocomplex. SYK is then phosphorylated and activated by the Src-family kinase Lyn. Upon activation, SYK will phosphorylate the adaptor protein BLNK allowing its interaction with both BTK and PLC γ2 via their respective SH2 domains. SYK phosphorylated 2+ -and thus activated- BTK will in turn phosphorylate and activate PLC γ2 leading to IP 3 formation, Ca mobilization, PKC 40 and MAPK activation and consequent NFAT, AP-1 and NFκB transcription factor activation, resulting in activation and surface marker expression, cytokine release, survival and proliferation of B cells 3. In mast cells, allergen activated Fc εRI is phosphorylated by LYN and FYN and recruits SYK which is in turn phosphorylated by LYN and further autophospho- rylated, becoming fully activated. Activated SYK phosphorylates the two adaptor molecules NTAL and LAT creating more docking sites for SH2 containing proteins such as PLCγ1, vav, and the p85 regulatory subunit of PI3K, resulting 45 in mast cell degranulation and cytokine production4. Syk’s critical role in signal transduction of mast cells is confirmed by reproducible observation that the 10-15% of basophils (circulating mast cells) from human donors that cannot de- granulate have reduced amounts of Syk protein5,6. In addition, SYK is required for the bone resorption activity of oste- oclasts. Upon stimulation of osteoclasts by αvβ3 integrin, SYK becomes phosphorylated, most likely by c-Src, in a DAP- 12 / FcγRII dependent mechanism, leading to SPL-76 and Vav3 phosphorylation and subsequent cytoskeletal reorgan- 50 isation. SYK deficient osteoclasts are inactive and show defective cytoskeletal reorganisation. In correlation with this, SYK deficient embryos show defective skeletal mass 7,8. [0005] BCR-mediated activation of B-cells in the lymph nodes, as well as FcR-mediated activation of dendritic cells, monocytes, macrophages, neutrophils and mast cells in the joints, are essential components of the cellular patho- physiological mechanisms taking place during rheumaoid arthritis (RA). Moreover, activation of osteoclasts leads to the 55 bone and cartilage destruction which are hallmarks of this pathology 9. SYK signaling should therefore play a pivotal role during the development of arthritis, both at the periphery and on the site of inflammation10. Indeed, an orally available Syk inhibitor R406 -developed by Rigel- induced a significant improvement of clinical scores and significantly reduced serum cytokine concentrations, as well as bone erosion, in a murine model of RA 11,12. Moreover, this inhibitor has shown 2 EP 2 817 310 B1 efficacy (ACR scores improvement) and good tolerability in RA Phase II studies in humans 13,14,15. [0006] In SLE B cells contriubute essentially towards pathogenesis via production of autoanibodies resulting in immune complex formation, stimulation of Fc receptors and finally in an excessive and chronic activation of inflammation. In a murine model of SLE treatment with a Syk inhibitor resulted in a reduction of numbers of class-switched germinal center, 5 marginal zone, newly formed and follicular B cells and therefore in disease mitigating effects 18. Although TCR signals are transmited by the intracellular tyrosine kinase ZAP-70 in thymocytes and naïve T cells, several studies indicate that differentiated effector T cells, such as those involved in the pathophysiology of Multiple sclerosis (MS) or systemic lupus erythematosus (SLE), show a down regulation of the TCRzeta chain and a concomitant upreg- ulation of the TCR/CD3 chain and its interaction with FcR γ. Those studies show that the TCR/CD3/FcRgamma complex 10 in effector cells recruits and activates Syk, instead of ZAP-70, tyrosine kinase. This physiologic switch in TCR signaling occurs exclusively in effector, and not naive or memory T cells 16,17,18. Not surprisingly then, SYK inhibitors have been shown to delay disease progression and to improve survival in murine models of SLE17,18,19,10,21. [0007] SYK inhibitors may also find a use in asthma, allergy, multiple sclerosis and other diseases such as thrombo- cytopenia purpura and T or B cell lymphomas 1,10,14,22-35. 15 Treatment of prediseased NZB/W mice with a Syk inhibitor prevented the development of renal disease demonstrated by reduced glomerular sclerosis, tubular damage, proteinuria and BUN levels 18.
Load more

Recommended publications
  • Neurotransmitter Resource Guide
    NEUROTRANSMITTER RESOURCE GUIDE Science + Insight doctorsdata.com Doctor’s Data, Inc. Neurotransmitter RESOURCE GUIDE Table of Contents Sample Report Sample Report ........................................................................................................................................................................... 1 Analyte Considerations Phenylethylamine (B-phenylethylamine or PEA) ................................................................................................. 1 Tyrosine .......................................................................................................................................................................................... 3 Tyramine ........................................................................................................................................................................................4 Dopamine .....................................................................................................................................................................................6 3, 4-Dihydroxyphenylacetic Acid (DOPAC) ............................................................................................................... 7 3-Methoxytyramine (3-MT) ............................................................................................................................................... 9 Norepinephrine ........................................................................................................................................................................
    [Show full text]
  • THE BIOSYNTHESIS of SOME PHENOLIC ALKALOIDS a Thesis Submitted by GEOFFREY MELVILLE THOMAS for the Degree of DOCTOR of PHILOSOPH
    /1 THE BIOSYNTHESIS OF SOME PHENOLIC ALKALOIDS a thesis submitted by GEOFFREY MELVILLE THOMAS for the degree of DOCTOR OF PHILOSOPHY of THE UNIVERSITY OF LONDON Imperial College, June 1963. London, S. W.7. ABSTRACT A brief review of the biosynthesis of alkaloids, other than those of the Amaryllidaceae and morphine groups, is given. The biosynthesis of these two groups is discussed more fully with particular reference to the evidence for the Barton and Cohen concept of phenol oxidation as a biogenetic mechanism. The incorporation of labelled phenolic precursors, derivatives of norbelladine, has been shown and by means of multiple labelled experiments incorporation as a whole, without degradation, has been proved. Other experiments described have thrown light on the earlier stages of biogenesis. The norlaudanosine derivative, (±) reticuline, has been shown to be incorporated into morphine, and an in vitro synthesis of thebaine from (±) reticuline using a radiochemical dilution method is de-scribed. I am deeply grateful to Professor D. H. R. Barton and Dr. G. W. Kirby for the privilege and pleasure of working under their supervision and for their great help in matters chemical and non-chemical. To the Salters Company I would like to express my sincere thanks for the award of a scholarship and for their interest during the tenure of it. My thanks are also due to Dr. D. W. Turner for advice on counting techniques, Mr. D. Aldrich and his staff for valuable technical assistance, Miss J. Cuckney for microanalyses, Mr. R.H. Young who grew the daffodils and poppies and to my many friends and co-workers at Imperial College.
    [Show full text]
  • Mrx CLINICAL ALERT
    MRx AUGUST 2018 CLINICAL ALERT YOUR MONTHLY SOURCE FOR DRUG INFORMATION HIGHLIGHTS HOT TOPIC: potential to placebo in non-dependent FIRST DRUG COMPRISED adult recreational drug users. EDITORIAL OF ACTIVE MARIJUANA DERIVATIVE APPROVED Cannabidiol oral solution was studied STAFF in 3 randomized, double-blind, placebo- Under Priority review, the United States controlled clinical trials including 516 (US) Food and Drug Administration (FDA) patients with either LGS or Dravet EDITOR IN CHIEF approved cannabidiol oral solution syndrome. Cannabidiol taken with ® Maryam Tabatabai (Epidiolex ) for the treatment of the patient’s current anticonvulsant PharmD seizures associated with Lennox-Gastaut regimen was shown to be effective syndrome (LGS) or Dravet syndrome in in reducing the frequency of seizures patients ≥ 2 years of age. It is the only when compared with placebo. Over EXECUTIVE EDITOR drug approved to treat Dravet syndrome the 12-week treatment period, the Carole Kerzic and the FDA designated it as an Orphan reduction in median number of LGS RPh drug and Rare pediatric disease drug seizures ranged from 37% to 44% with to treat both serious, difficult-to-treat CBD and 17% to 22% with placebo. DEPUTY EDITORS childhood seizure disorders. Dravet For Dravet syndrome, seizure reductions Stephanie Christofferson syndrome is diagnosed in approximately were 39% and 13% with CBD and PharmD 1 in 15,700 individuals in the US and placebo, respectively. Common side is characterized by frequent prolonged effects (≥ 10%) reported with CBD Jessica Czechowski seizures and developmental delays. LGS were increased liver transaminases PharmD involves frequent drop seizures and (particularly with concurrent use of impaired intellectual development.
    [Show full text]
  • The Activation of Α1-Adrenoceptors Is Implicated in the Antidepressant-Like Effect of Creatine in the Tail Suspension Test
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Progress in Neuro-Psychopharmacology & Biological Psychiatry 44 (2013) 39–50 Contents lists available at SciVerse ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp The activation of α1-adrenoceptors is implicated in the antidepressant-like effect of creatine in the tail suspension test Mauricio P. Cunha, Francis L. Pazini, Ágatha Oliveira, Luis E.B. Bettio, Julia M. Rosa, Daniele G. Machado, Ana Lúcia S. Rodrigues ⁎ Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil article info abstract Article history: The antidepressant-like activity of creatine in the tail suspension test (TST) was demonstrated previously by Received 5 September 2012 our group. In this study we investigated the involvement of the noradrenergic system in the Received in revised form 8 January 2013 antidepressant-like effect of creatine in the mouse TST. In the first set of experiments, creatine administered Accepted 18 January 2013 by i.c.v. route (1 μg/site) decreased the immobility time in the TST, suggesting the central effect of this com- Available online 26 January 2013 pound. The anti-immobility effect of peripheral administration of creatine (1 mg/kg, p.o.) was prevented by the pretreatment of mice with α-methyl-p-tyrosine (100 mg/kg, i.p., inhibitor of tyrosine hydroxylase), Keywords: α α Antidepressant prazosin
    [Show full text]
  • Today's Topic
    May 7, 2021 Vol. 1, No. 8 Palliative Care Pharmacy Team: TODAY’S TOPIC: Antidepressant Adverse Drug Reactions: Focus on QT Prolongation Clinical Pharmacy Specialist: Background: Antidepressants have been used for many years to treat mental health conditions such as Maria Felton Lowry, depression and anxiety (not an all-inclusive list). Their mechanisms are somewhat unique to the PharmD, BCPS, BCGP class of antidepressant, for instance, tricyclic antidepressants are thought to delay the inward Assistant Professor sodium current into cardiomyocytes, slowing cardiac depolarization. In contrast, SSRIs directly block potassium channels and disrupt hERG protein expression, both reducing potassium ion flow. University of Pittsburgh Palliative care clinicians use these medications commonly in clinical practice for symptom School of Pharmacy, management and should be aware of their potential side effects. Department of Pharmacy and Therapeutics Importance: Palliative Antidepressants can cause QTc prolongation. As stated in previous weeks, clinically significant QTc Care Clinical Pharmacy prolongation is an absolute QTc > 500 msec, QTc > 25% from baseline, or change of QTc > 60 Specialist msec.1 The degree of QTc prolongation is a modest predictor of the risk of Torsades de Pointes UPMC Palliative and (TdP) and sudden cardiac death.2 Still, it is important for palliative care clinicians be aware of this Supportive Institute risk of commonly prescribed medications in our practice. Cell: 412-627-8473 Known QTc prolongation risk factors: Office: 412-864-2899
    [Show full text]
  • Assessment Report
    19 September 2013 EMA/737723/2013 Committee for Medicinal Products for Human Use (CHMP) Assessment report ABILIFY MAINTENA International non-proprietary name: ARIPIPRAZOLE Procedure No. EMEA/H/C/002755/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8613 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2013. Reproduction is authorised provided the source is acknowledged. Table of contents 1.1. Submission of the dossier .................................................................................... 6 1.2. Manufacturers ................................................................................................... 6 1.3. Steps taken for the assessment of the product ....................................................... 7 2. Scientific discussion ................................................................................ 7 2.1. Introduction ...................................................................................................... 7 2.2. Quality aspects .................................................................................................. 9 2.2.1. Introduction ................................................................................................... 9 2.2.2. Active Substance ..........................................................................................
    [Show full text]
  • Binding Energies of Tyrosine Kinase Inhibitors: Error Assessment of Computational Methods for Imatinib and Nilotinib Binding Clifford Fong
    Binding Energies of Tyrosine Kinase Inhibitors: error assessment of computational methods for imatinib and nilotinib binding Clifford Fong To cite this version: Clifford Fong. Binding Energies of Tyrosine Kinase Inhibitors: error assessment of computational methods for imatinib and nilotinib binding. Computational Biology and Chemistry, Elsevier, 2015, 58, pp.40-54. 10.1016/j.compbiolchem.2015.05.002. hal-01344991 HAL Id: hal-01344991 https://hal.archives-ouvertes.fr/hal-01344991 Submitted on 13 Jul 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Computational Biology and Chemistry, 18 May 2015, doi:10.1016/j.compbiolchem.2015.05.002 Computational Biology and Chemistry 58 (2015) 40–54 Binding Energies of Tyrosine Kinase Inhibitors: error assessment of computational methods for imatinib and nilotinib binding Clifford W. Fong* Eigenenergy, Adelaide, South Australia, Australia * Author to whom correspondence should be addressed; E-Mail: [email protected] The binding energies of imatinib and nilotinib to tyrosine kinase have been determined by quantum mechanical (QM) computations, and compared with literature binding energy studies using molecular mechanics (MM). The potential errors in the computational methods include these critical factors: Errors in X-ray structures such as structural distortions and steric clashes give unrealistically high van der Waals energies, and erroneous binding energies.
    [Show full text]
  • Wednesday, June 12, 2019 4:00Pm
    Wednesday, June 12, 2019 4:00pm Oklahoma Health Care Authority 4345 N. Lincoln Blvd. Oklahoma City, OK 73105 The University of Oklahoma Health Sciences Center COLLEGE OF PHARMACY PHARMACY MANAGEMENT CONSULTANTS MEMORANDUM TO: Drug Utilization Review (DUR) Board Members FROM: Melissa Abbott, Pharm.D. SUBJECT: Packet Contents for DUR Board Meeting – June 12, 2019 DATE: June 5, 2019 Note: The DUR Board will meet at 4:00pm. The meeting will be held at 4345 N. Lincoln Blvd. Enclosed are the following items related to the June meeting. Material is arranged in order of the agenda. Call to Order Public Comment Forum Action Item – Approval of DUR Board Meeting Minutes – Appendix A Update on Medication Coverage Authorization Unit/Use of Angiotensin Converting Enzyme Inhibitor (ACEI)/ Angiotensin Receptor Blocker (ARB) Therapy in Patients with Diabetes and Hypertension (HTN) Mailing Update – Appendix B Action Item – Vote to Prior Authorize Aldurazyme® (Laronidase) and Naglazyme® (Galsulfase) – Appendix C Action Item – Vote to Prior Authorize Plenvu® [Polyethylene Glycol (PEG)-3350/Sodium Ascorbate/Sodium Sulfate/Ascorbic Acid/Sodium Chloride/Potassium Chloride] – Appendix D Action Item – Vote to Prior Authorize Consensi® (Amlodipine/Celecoxib) and Kapspargo™ Sprinkle [Metoprolol Succinate Extended-Release (ER)] – Appendix E Action Item – Vote to Update the Prior Authorization Criteria For H.P. Acthar® Gel (Repository Corticotropin Injection) – Appendix F Action Item – Vote to Prior Authorize Fulphila® (Pegfilgrastim-jmdb), Nivestym™ (Filgrastim-aafi),
    [Show full text]
  • Psychopharmacology '! by Springer-Verlag 1978
    m : t Aoq Psychopharmacolos5y9, tl 3- 116(1978) Psychopharmacology _'! by Springer-Verlag 1978 Effects of LSD and BOL on the Catecholamine Synthesis and Turnover in Various Brain Regions Sven-Ake Persson Departmentof Pharmacology,Universityof Ume_, S-90I87 Ume_, Sweden Abstract. In the rat, lysergic acid diethylamide (LSD) cerebral dopamine (DA) levels (Diaz et al., 1968). 0.5 mg/kg and 2-bromo lysergic acid diethylamide However, increased cerebral DA levels after LSD have - (BOL) 0.5 mg/kg increased the rate of the striatal in also been reported (Smith et al., (1975), Relatively few vivo tyrosine hydroxylation as measured by the DOPA studies on the cerebral catecholamine turnover have accumulation after decarboxylase inhibition. Neither been reported. High doses of LSD increased the LSD nor BOL significantly changed the DOPA accu- disappearance of NA in the rat brain after treatment mulation in the olfactory tubercle, a dopamine-rich with a-methyl-p-tyrosine methylester (a-MT) (And6n part of the limbic system. LSD but not BOL increased et ai., 1968). LSD did not affect the disappearance of the DOPA accumulation in the cerebral cortex and in DA. Da Prada et al. (1975) found that LSD decreased the brain stem. LSD and BOL appeared not to alter the the disappearance of DA in the rat teldiencephalon rate ofa-MT-induced disappearance of DA or of NA in after _t-MT and that LSD also decreased the homova- the whole brain, nor did they change the rate of the a- nillic acid (HVA) level in the striatum and in the eyes, MT-induced disappearance of DA in the striatum.
    [Show full text]
  • Indications for Use Form
    DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service ____________________________________________________________________________________________________________________________ Food and Drug Administration 10903 New Hampshire Avenue Document Control Center – WO66-G609 Silver Spring, MD 20993-0002 W.H.P.M., INC. February 26, 2015 JOHN WAN 5358 IRWINDALE AVENUE IRWINDALE CA 91706 Re: K150162 Trade/Device Name: First Sign® Drug Of Abuse Cup Test First Sign® Drug Of Abuse Dip Card Test Regulation Number: 21 CFR 862.3610 Regulation Name: Methamphetamine test system Regulatory Class: II Product Code: LAF, JXM, DJG Dated: January 19, 2015 Received: January 26, 2015 Dear Mr. John Wan: We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading. If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls.
    [Show full text]
  • Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis Christopher K
    Review pubs.acs.org/CR Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis Christopher K. Prier, Danica A. Rankic, and David W. C. MacMillan* Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States References 5360 1. INTRODUCTION CONTENTS A fundamental aim in the field of catalysis is the development 1. Introduction 5322 of new modes of small molecule activation. One approach 2+ toward the catalytic activation of organic molecules that has 2. Photochemistry of Ru(bpy)3 5323 3. Net Reductive Reactions 5324 received much attention recently is visible light photoredox 3.1. Reduction of Electron-Poor Olefins 5324 catalysis. In a general sense, this approach relies on the ability of 3.2. Reductive Dehalogenation 5326 metal complexes and organic dyes to engage in single-electron- 3.3. Reductive Cleavage of Sulfonium and transfer (SET) processes with organic substrates upon Sulfonyl Groups 5328 photoexcitation with visible light. 3.4. Nitrogen Functional Group Reductions 5329 Many of the most commonly employed visible light 3.5. Radical Cyclizations 5330 photocatalysts are polypyridyl complexes of ruthenium and iridium, and are typified by the complex tris(2,2′-bipyridine) 3.6. Reductive Epoxide and Aziridine Opening 5331 2+ 3.7. Reduction-Labile Protecting Groups 5331 ruthenium(II), or Ru(bpy)3 (Figure 1). These complexes 4. Net Oxidative Reactions 5332 4.1. Functional Group Oxidations 5332 4.2. Oxidative Removal of the PMB Group 5334 4.3. Oxidative Biaryl Coupling 5335 4.4. Oxidative Generation of Iminium Ions 5335 4.5. Azomethine Ylide [3 + 2] Cycloadditions 5338 4.6.
    [Show full text]
  • Doxepin > Printer-Friendly PDF
    Published on British Columbia Drug and Poison Information Centre (BC DPIC) ( http://www.dpic.org) Home > Drug Product Listings > Doxepin > Printer-friendly PDF Doxepin Trade Name: Silenor Manufacturer/Distributor: Paladin Labs www.paladin-labs.com 1-888-376-7830 Classification: Hypnotic ATC Class: N06AA - doxepin Status: active Notice of Compliance (yyyy/mm/dd): 2012/21/13 Date Marketed in Canada (yyyy/mm/dd): 2012/01/08 Presentation: Tablet: 3 mg. DIN: 02398257 Tablet: 6 mg. DIN: 02398265 Comments: Silenor is indicated for the treatment and symptomatic relief of insomnia characterized by frequent nocturnal awakening, and/or early morning awakenings. Keywords: doxepin sleep disorders hypnotics & sedatives Access: public Back to: Please note - this is not a complete list of products available in Canada. For a complete list of drug products marketed in Canada, visit the Health Canada Drug Product Database Status: <Any> ? Search Terms: Apply A (37) | B (20) | C (24) | D (37) | E (40) | F (12) | G (11) | H (9) | I (24) | K (1) | L (26) | M (12) | N (7) | O (12) | P (28) | R (14) | S (27) | T (33) | U (4) | V (13) | W (2) | Z (4) Common Date Marketed in Generic Name Trade Classification Canada Name(s) (yyyy/mm/dd) Co-stimulation modulator Abatacept Orencia 2006/09 for rheumatoid arthritis Abemaciclib Verzenio Protein kinase inhibitor 2019/07/03 Androgen biosynthesis Abiraterone Zytiga 2011/08/08 inhibitor Acamprosate Campral Alcohol abstinence aid 2007/03 Bronchodilator Duaklir Aclidinium + formoterol combination - LAMA plus 2015/07/09 Genuair
    [Show full text]