DOCSLIB.ORG

US8088935.Pdf

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
US8088935.Pdf USO08088935B2 (12) United States Patent (10) Patent No.: US 8,088,935 B2 Pears0n et al. (45) Date of Patent: Jan. 3, 2012 (54) COMPOUNDS AND METHODS FOR THE FOREIGN PATENT DOCUMENTS TREATMENT OF ASTHMA DE 2326227 2, 1974 ES 3983.19 4, 1975 Inventors: James Pearson, Cambridge, MA (US); FR 2196795 3, 1974 (75) FR 2196796 3, 1974 John J. Talley, Somerville, MA (US); FR 2210398 7, 1974 Mark G. Currie, Sterling, MA (US) GB 1297264 11, 1972 GB 1374981 11, 1974 (73) Assignee: Ironwood Pharmaceuticals, Inc., WO O193867 12/2001 Cambridge, MA (US) WO O3O806O7 10, 2003 OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 Wang, 2002, Role of iNOS and eNOS in modulating proximal tubule U.S.C. 154(b) by 1229 days. transport and acid-base balance. Pizza et 1998. Nitric Oxide synthase inhition reduces muscle inflam (21) Appl. No.: 10/587,054 mation. Patrick Vallance 1998. Student BM.J. (22) PCT Fled: Dec. 23, 2004 * cited by examiner (86) PCT NO.: PCT/US2004/043O82 Primary Examiner — Rita Desai S371 (c)(1), (74) Attorney, Agent, or Firm — Heslin Rothenberg Farley (2), (4) Date: Nov. 22, 2006 & Mesiti P.C. (87) PCT Pub. No.: WO2OOS/O63732 (57) ABSTRACT PCT Pub. Date: Jul. 14, 2005 Compounds and methods for the treatment of asthma are disclosed. The methods involve mast cell stabilization (65) Prior Publication Data together with selective inhibition of iNOS. The compounds are combinations of a mast cell inhibiting moiety and an US 2007/O249644 A1 Oct. 25, 2007 inhibitor of iNOS. An example is: Related U.S. Application Data (60) Provisional application No. 60/531,957, filed on Dec. HOOC O O COOH. 23, 2003. (51) Int. C. CO7D 3L/22 (2006.01) A6 IK3I/353 (2006.01) O O ~~ O (52) U.S. Cl. ......................... 549/401; 549/402:514/456 O (58) Field of Classification Search .................. 549/401, 549/402: 514/456 CH O See application file for complete search history. )=NH NH2 (56) References Cited HN U.S. PATENT DOCUMENTS 3,790,580 A 2, 1974 Johnson et al. 2003/O1995.29 A1 10/2003 Garvey et al. 16 Claims, No Drawings US 8,088,935 B2 1. 2 COMPOUNDS AND METHODS FOR THE (1) A neuronal NOS(NOS-1 or nNOS) was originally isolated TREATMENT OF ASTHMA and cloned from nerve tissue in which it is a constitutive enzyme. nNOS produces NO in response to various physi CROSS REFERENCE TO RELATED ological stimuli, such as the activation of membrane recep APPLICATIONS tors, according to a mechanism dependent on calcium and on calmodulin, nNOS-derived NO serves as a neurotransmitter. This application is a 371 filing of PCT International Appli cation No. PCT/US04/43082 filed Dec. 23, 2004, published (2) An inducible NOS(NOS-2 or iNOS) can be induced in in English as WO 2005/063732 on Jul. 14, 2005. PCT/US04/ response to immunological stimuli Such as, for example, 43082 claimed the priority of U.S. Provisional Application 10 cytokines or bacterial antigens in various cells Such as, for 60/531,957 filed Dec. 23, 2033. The disclosures of both are example macrophages, epithelial cells, hepatocytes, glial incorporated herein by reference in their entirety. cells, and other cell types. The activity of this isoform is not regulated by calcium. Once induced, it produces large FIELD OF THE INVENTION 15 amounts of NO over prolonged periods. (3) An endothelial NOS(NOS-3 or eNOS) is constitutive and The invention relates to compounds and methods for the calcium/calmodulin-dependent. It was originally identified in treatment of asthma. The methods involve mast cell stabili vascular endothelial cells, in which it generates NO in zation together with selective inhibition of iNOS. The com response to physiological stimuli such as the activation of pounds are combinations of a mast cell inhibiting moiety and membrane receptors. an inhibitor of iNOS. Nitric oxide produced by eNOS and nNOS plays a critical BACKGROUND OF THE INVENTION role in cellular signaling and acts to control numerous physi ologic functions including vasodilation and bronchodilation Asthma is a chronic airway inflammatory disorder charac 25 in the lung. In the asthmatic lung, eNOS and nNOS are terized by bronchial hyper-reactivity and bronchospasm, downregulated, and thus contribute to edema and bronchoc among other abnormalities. Lungs of asthmatic patients have onstriction. Contemplating the problem of inadequate eNOS increased numbers of inflammatory cells in bronchioalveolar and nNOS activity, in an approach which is the opposite of fluid and in lung tissues. These inflammatory cells include that taken in the present invention, Garvey et al. (US pub eosinophils, basophils, neutrophils, macrophages, and lym 30 lished application 2003/0199529) have attached stimulators phocytes. In asthmatic lungs, the epithelium, including cili of endogenous NO production to mast cell inhibitors. ated columnar epithelial cells, is damaged. IgE-antigen-mast The NO produced in large amounts by the inducible iso cell interactions represent the early molecular and cellular form iNOS is involved in pathological phenomena associated events that cause inflammatory conditions of asthma. 35 with acute and chronic inflammatory processes in a large Mast Cell Stabilizing Agents provide one approach to the variety of tissues and organs. NO is highly reactive and, prophylaxis and/or treatment of asthma. The prototype drug, together with Superoxide, forms peroxynitrite which dam disodium cromoglycate was synthesized in 1965 and was ages tissues. In asthma this results in epithelial cell extrusion, approved in the United States in 1973 as a prophylactic, 40 sloughing, and cessation of cilia function. An excessive pro nonbronchodilating anti-inflammatory drug for the therapy of duction of NO by induction of iNOS thus plays a part in allergic disorder. Cromolyn is an odorless, white, hygro degenerative pathologies with inflammatory components, scopic crystalline powder that is freely soluble in water up to Such as asthma. 5%. Animal and human studies show it to be excreted In conditions in which an overproduction of NO is delete unchanged in bile and urine. When inhaled into the pulmo 45 rious, it would be desirable to reduce the production of NO by nary tree, as for treatment of asthma, only about 8% of a dose administering substances capable of inhibiting iNOS. How is deposited in the lung and absorbed. Peak plasma levels ever, given the important physiological roles played by the occur within 15 minutes, the biologic half-life is 46-99 min constitutive isoforms, selective inhibition of iNOS is utes. Oral administration in humans results in approximately required. 1% being systemically absorbed. Cromolyn toxicity studies 50 show an impressively low order of acute toxicity, and adverse effects tend to be minimal and reversible. Cromolyn has a SUMMARY OF THE INVENTION unique, purely prophylactic action with no intrinsic bron chodilator or antihistaminic activity. Nedocromil was intro 55 In a composition aspect, the invention relates to agents for duced Subsequent to cromolyn. It is the other standard mast treating a pulmonary disorder represented by the structure: cell stabilizer used in the treatment of asthma. Its chemical properties and therapeutic characteristics are similar. Nitric oxide (NO) is a diffusible radical involved in many physiological and pathological processes. It is synthesized in 60 G)--G) Vivo by oxidation of L-arginine. The synthesis is catalyzed by a family of enzymes known as nitric oxide synthases or NO wherein synthases (NOSs), which are referenced in the international A is a mast-cell stabilizer; enzyme nomenclature system under the number 65 E.C.1.14.13.39. Three NOS isoforms, two of which are con L is a covalent linkage; stitutive and one inducible, are known: B is an iNOS inhibitor. US 8,088,935 B2 3 4 Examples of Such agents are compounds of formula I or II G)--G) In a second method aspect, the invention relates to a method for treating a pulmonary disorder comprising co administering a mast-cell stabilizer and an iNOS inhibitor in the form of a salt, in which one of the mast-cell stabilizer and the iNOS inhibitor is a cation or dication, and the other is an anion ordianion. DETAILED DESCRIPTION OF THE INVENTION 15 Agents for treating a pulmonary disorder according to the invention are represented by the structure: II 2O G)--G) In one embodiment, L is chosen from —CONH , CONH- and —(C=O)OCH(R)O(C=O) and the com pound is represented by a structure chosen from: wherein R" and Rare chosen from hydroxy, C.C.C.C.C.s, and C. straight and branched alkoxy, -G-O(C=O)R. R. NHR, OR7 and OX", wherein X" is a pharmaceu tically acceptable cation; 35 losso —O(C=O)R’ is the deshydrogen residue of a carboxylic acid, the parent of which, RCOOH, is an inhibitor of . Grro ro inducible nitric oxide synthase (iNOS); —(C=O)R’ is the deshydroxy residue of a carboxylic acid, the parent of which, RCOOH, is an inhibitor of iNOS; 45 G) Grr. O R is - O R' U, wherein U is chosen from hydrogen, O O G)—o (1,2-dithiolan-3-yl) and phenyl, and R' is a divalent C to r and Coalkane or Oxaalkane residue. O O —NHR is the deshydrogen residue of an amine, the parent of 50 which, RNH is an inhibitor of iNOS; in which A' is a mast-cell stabilizer having a carboxylic acid —OR7 is the deshydrogen residue of an alcohol, the parent of substituent; A is a mast-cell stabilizer having an amine Sub which, ROH, is an inhibitor of iNOS: stituent; A is a mast-cell stabilizer having an alcohol Sub G is a linking moiety cleavable under physiologic conditions.
Load more

Recommended publications
  • Supplementary Information
    Supplementary Information Network-based Drug Repurposing for Novel Coronavirus 2019-nCoV Yadi Zhou1,#, Yuan Hou1,#, Jiayu Shen1, Yin Huang1, William Martin1, Feixiong Cheng1-3,* 1Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA 2Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA 3Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA #Equal contribution *Correspondence to: Feixiong Cheng, PhD Lerner Research Institute Cleveland Clinic Tel: +1-216-444-7654; Fax: +1-216-636-0009 Email: [email protected] Supplementary Table S1. Genome information of 15 coronaviruses used for phylogenetic analyses. Supplementary Table S2. Protein sequence identities across 5 protein regions in 15 coronaviruses. Supplementary Table S3. HCoV-associated host proteins with references. Supplementary Table S4. Repurposable drugs predicted by network-based approaches. Supplementary Table S5. Network proximity results for 2,938 drugs against pan-human coronavirus (CoV) and individual CoVs. Supplementary Table S6. Network-predicted drug combinations for all the drug pairs from the top 16 high-confidence repurposable drugs. 1 Supplementary Table S1. Genome information of 15 coronaviruses used for phylogenetic analyses. GenBank ID Coronavirus Identity % Host Location discovered MN908947 2019-nCoV[Wuhan-Hu-1] 100 Human China MN938384 2019-nCoV[HKU-SZ-002a] 99.99 Human China MN975262
    [Show full text]
  • Lung Inflammation and Atopy Muscarinic Receptor Expression
    The Journal of Immunology Maternal Exposure to Secondhand Cigarette Smoke Primes the Lung for Induction of Phosphodiesterase-4D5 Isozyme and Exacerbated Th2 Responses: Rolipram Attenuates the Airway Hyperreactivity and Muscarinic Receptor Expression but Not Lung Inflammation and Atopy1 Shashi P. Singh,* Neerad C. Mishra,* Jules Rir-sima-ah,* Mathew Campen,* Viswanath Kurup,† Seddigheh Razani-Boroujerdi,* and Mohan L. Sopori2* Airway hyperreactivity (AHR), lung inflammation, and atopy are clinical signs of allergic asthma. Gestational exposure to ciga- rette smoke (CS) markedly increases the risk for childhood allergic asthma. Muscarinic receptors regulate airway smooth muscle tone, and asthmatics exhibit increased AHR to muscarinic agonists. We have previously reported that in a murine model of bronchopulmonary aspergillosis, maternal exposure to mainstream CS increases AHR after acute intratracheal administration of Aspergillus fumigatus extract. However, the mechanism by which gestational CS induces allergic asthma is unclear. We now show for the first time that, compared with controls, mice exposed prenatally to secondhand CS exhibit increased lung inflammation (predominant infiltration by eosinophils and polymorphs), atopy, and airway resistance, and produce proinflammatory cytokines (IL-4, IL-5, IL-6, and IL-13, but not IL-2 or IFN-␥). These changes, which occur only after an allergen (A. fumigatus extract) treatment, are correlated with marked up-regulated lung expression of M1, M2, and M3 muscarinic receptors and phosphodi- esterase (PDE)4D5 isozyme. Interestingly, the PDE4-selective inhibitor rolipram attenuates the increase in AHR, muscarinic receptors, and PDE4D5, but fails to down-regulate lung inflammation, Th2 cytokines, or serum IgE levels. Thus, the fetus is extraordinarily sensitive to CS, inducing allergic asthma after postnatal exposure to allergens.
    [Show full text]
  • The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances
    WHO/PSM/QSM/2006.3 The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances 2006 Programme on International Nonproprietary Names (INN) Quality Assurance and Safety: Medicines Medicines Policy and Standards The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 © World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
    [Show full text]
  • Structural Basis for the Activity of Drugs That Inhibit Phosphodiesterases
    Structure, Vol. 12, 2233–2247, December, 2004, ©2004 Elsevier Ltd. All rights reserved. DOI 10.1016/j.str.2004.10.004 Structural Basis for the Activity of Drugs that Inhibit Phosphodiesterases Graeme L. Card,1 Bruce P. England,1 a myriad of physiological processes, such as immune Yoshihisa Suzuki,1 Daniel Fong,1 Ben Powell,1 responses, cardiac and smooth muscle contraction, vi- Byunghun Lee,1 Catherine Luu,1 sual response, glycogenolysis, platelet aggregation, ion Maryam Tabrizizad,1 Sam Gillette,1 channel conductance, apoptosis, and growth control Prabha N. Ibrahim,1 Dean R. Artis,1 Gideon Bollag,1 (Francis et al., 2001). Cellular levels of cAMP and cGMP Michael V. Milburn,1 Sung-Hou Kim,2 are regulated by the relative activities of adenylyl and Joseph Schlessinger,3 and Kam Y.J. Zhang1,* guanylyl cyclases, which synthesize these cyclic nucleo- 1Plexxikon, Inc. tides, and by PDEs, which hydrolyze them into 5Ј-nucle- 91 Bolivar Drive otide monophosphates. By blocking phosphodiester hy- Berkeley, California 94710 drolysis, PDE inhibition results in higher levels of cyclic 2 Department of Chemistry nucleotides. Therefore, PDE inhibitors may have consid- University of California, Berkeley erable therapeutic utility as anti-inflammatory agents, Berkeley, California 94720 antiasthmatics, vasodilators, smooth muscle relaxants, 3 Department of Pharmacology cardiotonic agents, antidepressants, antithrombotics, Yale University School of Medicine and agents for improving memory and other cognitive 333 Cedar Street functions (Corbin and Francis, 2002; Rotella, 2002; Sou- New Haven, Connecticut 06520 ness et al., 2000). Of the 11 classes of human cyclic nucleotide phos- phodiesterases, the PDE4 family of enzymes is selective Summary for cAMP, while the PDE5 enzyme is selective for cGMP (Beavo and Brunton, 2002; Conti, 2000; Mehats et al., Phosphodiesterases (PDEs) comprise a large family 2002).
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9.254.262 B2 Casado Et Al
    USOO925.4262B2 (12) United States Patent (10) Patent No.: US 9.254.262 B2 Casado et al. (45) Date of Patent: *Feb. 9, 2016 (54) DOSAGE AND FORMULATION 5,290,815 A 3, 1994 Johnson et al. 5.435.301 A 7/1995 Herold et al. (71) Applicant: Almirall, S.A., Barcelona (ES) 5,569,4475,507,281 A 10,4/1996 1996 LeeKuhnel et al. et al. 5575280 A 11/1996 Guote et al. (72) Inventors: Rosa Lamarca Casado, Barcelona (ES); 5,610,163 A 3, 1997 SA et al. Gonzalo De Miquel Serra, Barcelona 5,617.845 A 4/1997 Posset al. (ES) 5,654,314 A 8, 1997 Banholzer et al. 5,676,930 A 10/1997 Jager et al. (73) Assignee: Almirall, S.A., Barcelona (ES) 5,885,8345,685,294 A 1 3/19991/1997 GupteEpstein et al. 5,962,505 A 10, 1999 Bob tal. (*) Notice: Subject to any disclaimer, the term of this 5,964,416 A 10, 1999 E. a patent is extended or adjusted under 35 6,150,415. A 1 1/2000 Hammocket al. U.S.C. 154(b) by 0 days. 6,299,861 B1 10/2001 Banholzer et al. 6,299,863 B1 10/2001 Aberg et al. This patent is Subject to a terminal dis 6,402,055 B1 6/2002 Jaeger et al. claimer. 6.410,563 B1 6/2002 Deschenes et al. 6,423.298 B2 7/2002 McNamara et al. 6,433,027 B1 8/2002 Bozung et al. (21) Appl. No.: 13/672,893 6,455,524 B1 9/2002 Bozung et al.
    [Show full text]
  • PHARMACEUTICAL APPENDIX to the HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2008) (Rev
    Harmonized Tariff Schedule of the United States (2008) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2008) (Rev. 2) 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. ABACAVIR 136470-78-5 ACIDUM GADOCOLETICUM 280776-87-6 ABAFUNGIN 129639-79-8 ACIDUM LIDADRONICUM 63132-38-7 ABAMECTIN 65195-55-3 ACIDUM SALCAPROZICUM 183990-46-7 ABANOQUIL 90402-40-7 ACIDUM SALCLOBUZICUM 387825-03-8 ABAPERIDONUM 183849-43-6 ACIFRAN 72420-38-3 ABARELIX 183552-38-7 ACIPIMOX 51037-30-0 ABATACEPTUM 332348-12-6 ACITAZANOLAST 114607-46-4 ABCIXIMAB 143653-53-6 ACITEMATE 101197-99-3 ABECARNIL 111841-85-1 ACITRETIN 55079-83-9 ABETIMUSUM 167362-48-3 ACIVICIN 42228-92-2 ABIRATERONE 154229-19-3 ACLANTATE 39633-62-0 ABITESARTAN 137882-98-5 ACLARUBICIN 57576-44-0 ABLUKAST 96566-25-5 ACLATONIUM NAPADISILATE 55077-30-0 ABRINEURINUM 178535-93-8 ACODAZOLE 79152-85-5 ABUNIDAZOLE 91017-58-2 ACOLBIFENUM 182167-02-8 ACADESINE 2627-69-2 ACONIAZIDE 13410-86-1 ACAMPROSATE
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • A Abacavir Abacavirum Abakaviiri Abagovomab Abagovomabum
    A abacavir abacavirum abakaviiri abagovomab abagovomabum abagovomabi abamectin abamectinum abamektiini abametapir abametapirum abametapiiri abanoquil abanoquilum abanokiili abaperidone abaperidonum abaperidoni abarelix abarelixum abareliksi abatacept abataceptum abatasepti abciximab abciximabum absiksimabi abecarnil abecarnilum abekarniili abediterol abediterolum abediteroli abetimus abetimusum abetimuusi abexinostat abexinostatum abeksinostaatti abicipar pegol abiciparum pegolum abisipaaripegoli abiraterone abirateronum abirateroni abitesartan abitesartanum abitesartaani ablukast ablukastum ablukasti abrilumab abrilumabum abrilumabi abrineurin abrineurinum abrineuriini abunidazol abunidazolum abunidatsoli acadesine acadesinum akadesiini acamprosate acamprosatum akamprosaatti acarbose acarbosum akarboosi acebrochol acebrocholum asebrokoli aceburic acid acidum aceburicum asebuurihappo acebutolol acebutololum asebutololi acecainide acecainidum asekainidi acecarbromal acecarbromalum asekarbromaali aceclidine aceclidinum aseklidiini aceclofenac aceclofenacum aseklofenaakki acedapsone acedapsonum asedapsoni acediasulfone sodium acediasulfonum natricum asediasulfoninatrium acefluranol acefluranolum asefluranoli acefurtiamine acefurtiaminum asefurtiamiini acefylline clofibrol acefyllinum clofibrolum asefylliiniklofibroli acefylline piperazine acefyllinum piperazinum asefylliinipiperatsiini aceglatone aceglatonum aseglatoni aceglutamide aceglutamidum aseglutamidi acemannan acemannanum asemannaani acemetacin acemetacinum asemetasiini aceneuramic
    [Show full text]
  • Combinations Comprising Antimuscarinic Agents and PDE4 Inhibitors
    (19) & (11) EP 1 891 973 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 27.02.2008 Bulletin 2008/09 A61K 45/00 (2006.01) A61K 31/439 (2006.01) A61K 31/167 (2006.01) A61K 31/137 (2006.01) (2006.01) (2006.01) (21) Application number: 07019644.9 A61P 11/00 A61P 11/06 A61P 11/08 (2006.01) (22) Date of filing: 31.05.2005 (84) Designated Contracting States: • Llenas Calvo, Jesus AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 08021 Barcelona (ES) HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR • Ryder, Hamish Designated Extension States: 08190 La Floresta, Sant Cugat del Vallés AL BA HR LV MK YU (Barcelona) (ES) • Orviz Diaz, Pio (30) Priority: 31.05.2004 ES 200401312 08198 Sant Cugat del Vallés (Barcelona) (ES) (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: (74) Representative: Srinivasan, Ravi Chandran 05747758.0 / 1 761 280 J.A. Kemp & Co. 14 South Square (71) Applicant: Laboratorios Almirall, S.A. Gray’s Inn 08022 Barcelona (ES) London WC1R 5JJ (GB) (72) Inventors: Remarks: • Gras Escardo, Jordi This application was filed on 08 - 10 - 2007 as a 08018 Barcelona (ES) divisional application to the application mentioned under INID code 62. (54) Combinations comprising antimuscarinic agents and PDE4 inhibitors (57) A combination which comprises (a) a PDE4 in- form of a salt having an anion X, which is a pharmaceu- hibitor and (b) an antagonist of M3 muscarinic receptors tically acceptable anion of a mono or polyvalent acid.
    [Show full text]
  • Cyclic AMP-Specific Pdes: a Promising Therapeutic Target For
    Mini-Review • DOI: 10.2478/v10134-010-0012-0 • Translational Neuroscience • 1(2) • 2010 • 101–105 Translational Neuroscience CYCLIC AMP-sPECIFIC PDEs: A PROMISING THERAPEUTIC Mousumi Ghosh TARGET FOR CNS REPAIR Damien D. Pearse* The Miami Project to Cure Paralysis, University of Miami School of Abstract Medicine, Research to date has indicated that cAMPspecific PDEs, particularly the members of PDE4 family, play a crucial Miami, FL 33136, USA. role in the pathogenesis of CNS injury and neurodegeneration by downregulating intracellular levels of cAMP in various cell types. Reduced cAMP signaling results in immune cell activation, inflammation, secondary tissue damage, scar formation and axon growth failure, ultimately leading to an exacerbation of injury, the prevention of endogenous repair and limited functional recovery. Although inhibition of cAMPspecific-PDE activity through the use of drugs like Rolipram has been shown to reverse these deficiencies and mediate neurorepair, an inability to develop selective agents and/or reduce dose-limiting side-effects associated with PDE4 inhibition has hampered their clinical translation. Recent work with more selective pharmacological inhibitors of cAMP-specific PDEs and molecular targeting approaches, along with improved understanding of the basic biology and role of PDEs in pathological processes may enable this promising therapeutic approach to advance clinically and have a similar impact on CNS injury and disease as PDE5 inhibitors have had on the treatment of sexual dysfunction. Keywords Phosphodiesterase • cyclic AMP • Rolipram • CNS repair • SCI • TBI Received 17 March 2010 © Versita Sp. z o.o. accepted 23 March 2010 1. Introduction to date, which vary in cyclic nucleotide PDE7s’ respective proteins has not yet been The second messenger cyclic adenosine specificity, affinity, regulatory control and reported.
    [Show full text]
  • WO 2013/167743 Al 14 November 2013 (14.11.2013) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2013/167743 Al 14 November 2013 (14.11.2013) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/18 (2006.01) A61K 31/708 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/522 (2006.01) A61K 45/06 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/675 (2006.01) A61P 29/00 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, A61K 31/7068 (2006.01) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (21) International Application Number: NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, PCT/EP2013/059752 RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (22) International Filing Date: TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, 10 May 2013 (10.05.2013) ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 12167771 .0 11 May 2012 ( 11.05.2012) EP TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicant: AKRON MOLECULES GMBH [AT/AT]; MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Helmut-Qualtinger-Gasse 2, A-1030 Vienna (AT).
    [Show full text]
  • Aclidinium for Use in Improving the Quality of Sleep in Respiratory Patients
    (19) & (11) EP 2 510 928 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 17.10.2012 Bulletin 2012/42 A61K 31/439 (2006.01) A61P 11/00 (2006.01) A61P 43/00 (2006.01) (21) Application number: 11382114.4 (22) Date of filing: 15.04.2011 (84) Designated Contracting States: • De Miquel Serra, Gonzalo AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 08980, Sant Feliú de Llobregat (ES) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • Sala Peinado, María José PL PT RO RS SE SI SK SM TR 08980, Sant Feliú de Llobregat (ES) Designated Extension States: BA ME (74) Representative: Elzaburu Marquez, Alberto Elzaburu S.L.P. (71) Applicant: Almirall, S.A. Miguel Angel 21, 08022 Barcelona (ES) 28010 Madrid (ES) (72) Inventors: • García Gil, María Esther 08980, Sant Feliú de Llobregat (ES) (54) Aclidinium for use in improving the quality of sleep in respiratory patients (57) The present invention provides aclidinium or any of its steroisomers or mixture of stereoisomers, or a pharma- ceutically acceptable salt or solvate thereof, for improving the quality of sleep in respiratory patients. EP 2 510 928 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 510 928 A1 Description Field of the Invention 5 [0001] The invention relates to a novel use of aclidinium, which can be advantageously used to improve the quality of sleep in respiratory patients. Background of the Invention 10 [0002] Respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are a significant global health program, with an increasing incidence throughout the world.
    [Show full text]