DOCSLIB.ORG

Ep 2146963 B1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Ep 2146963 B1 (19) TZZ _¥_T (11) EP 2 146 963 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 213/64 (2006.01) C07D 233/64 (2006.01) 17.12.2014 Bulletin 2014/51 C07D 233/68 (2006.01) C07D 233/70 (2006.01) C07D 401/10 (2006.01) C07D 401/12 (2006.01) (2006.01) (2006.01) (21) Application number: 08743204.3 C07D 409/06 A61K 31/4164 A61K 31/4178 (2006.01) A61K 31/4412 (2006.01) A61P 9/00 (2006.01) C07D 231/14 (2006.01) (22) Date of filing: 23.04.2008 A61K 45/00 (2006.01) A61K 31/415 (2006.01) A61K 31/417 (2006.01) A61K 31/4196 (2006.01) C07D 213/89 (2006.01) C07D 233/90 (2006.01) C07D 403/10 (2006.01) (86) International application number: PCT/US2008/005219 (87) International publication number: WO 2008/133896 (06.11.2008 Gazette 2008/45) (54) DUAL-ACTING ANTIHYPERTENSIVE AGENTS BLUTDRUCKSENKENDE MITTEL MIT DUALER WIRKUNG AGENTS ANTIHYPERTENSIFS À DOUBLE ACTION (84) Designated Contracting States: • MCKINNELL, Robert Murray AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Half Moon Bay, California 94019 (US) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT • MCMURTRIE, Darren RO SE SI SK TR Foster City, California 94404 (US) Designated Extension States: • OLSON, Brooke AL BA MK RS San Francisco, California 94110 (US) (30) Priority: 24.04.2007 US 925931 P (74) Representative: Scott, Susan Margaret et al Abel & Imray (43) Date of publication of application: 20 Red Lion Street 27.01.2010 Bulletin 2010/04 London WC1R 4PQ (GB) (73) Proprietor: Theravance Biopharma R&D IP, LLC (56) References cited: South San Francisco, CA 94080 (US) EP-A- 0 437 103 EP-A- 0 505 954 US-A- 5 616 599 (72) Inventors: • ALLEGRETTI, Paul • MIDDLEMISS D., ET AL.: "BENZOFURAN BASED Fort Collins, CO 80526 (US) ANGIOTENSIN II ANTAGONISTS RELATED TO • CHOI, Seok-ki GR117289: PART II; AMINOACID AMIDES" Palo Alto, California 94301 (US) BIOORGANIC & MEDICINAL CHEMISTRY • GENDRON, Roland LETTERS, vol. 3, no. 10, 1993, pages 2043-2046, San Francisco, California 94110 (US) XP002514917 • FATHEREE, Paul R. San Francisco, California 94107 (US) Remarks: • JENDZA, Keith Thefile contains technical information submitted after San Francisco, California 94114 (US) the application was filed and not included in this specification 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 2 146 963 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 146 963 B1 Description BACKGROUND OF THE INVENTION 5 FIELD OF THE INVENTION [0001] The present invention relates to novel compounds having angiotensin II type 1 (AT 1) receptor antagonist activity and neprilysin-inhibition activity. The invention also relates to pharmaceutical compositions comprising such compounds, processes and intermediates for preparing such compounds, and finds utility in methods of using such compounds to 10 treat diseases such as hypertension. STATE OF THE ART [0002] The aim of antihypertensive therapy is to lower blood pressure and prevent hypertension-related complications 15 such as myocardial infarction, stroke, and renal disease. For patients with uncomplicated hypertension (that is, no risk factors, target organ damage, or cardiovascular disease), it is hoped that reducing blood pressure will prevent develop- ment of cardiovascular and renal comorbidities, conditions that exist at the same time as the primary condition in the same patient. For those patients with existing risk factors or comorbidities, the therapeutic target is the slowing of comorbid disease progression and reduced mortality. 20 [0003] Physicians generally prescribe pharmacological therapies for patients whose blood pressure cannot be ade- quately controlled by dietary and/or lifestyle modifications. Commonly used therapeutic classes act to promote diuresis, adrenergic inhibition, or vasodilation. A combination of drugs is often prescribed, depending upon what comorbidities are present. [0004] There are five common drug classes used to treat hypertension: diuretics, which include thiazide and thiazide- 25 like diuretics such as hydrochlorothiazide, loop diuretics such as furosemide, and potassium-sparing diuretics such as triamterene; β1 adrenergic receptor blockers such as metoprolol succinate and carvedilol; calcium channel blockers such as amlodipine; angiotensin-converting enzyme (ACE) inhibitors such as captopril, benazepril, enalapril, enalaprilat, lisinopril, quinapril, and ramipril; and AT1 receptor antagonists, also known as angiotensin II type t receptor blockers (ARBs), such as candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan medoxomil, telmisartan, and valsar- 30 tan. Combinations of these drugs are also administered, for example, a calcium channel blocker (amlodipine) and an ACE inhibitor (benazepril), or a diuretic (hydrochlorothiazide) and an ACE inhibitor (enalapril). All of these drugs, when used appropriately, are effective in the treatment of hypertension. Nevertheless, both efficacy and tolerability should be further improved in new drugs targeting hypertension. Despite the availability of many treatment options, the recent National Health And Nutrition Examination Survey (NHANES) demonstrated that only about 50% of all treated patients 35 with hypertension achieve adequate blood pressure control. Furthermore, poor patient compliance due to tolerability issues with available treatments further reduces treatment success. [0005] In addition, each of the major classes of antihypertensive agents have some drawbacks. Diuretics can adversely affect lipid and glucose metabolism, and are associated with other side effects, including orthostatic hypotension, hy- pokalemia, and hyperuricemia. Beta blockers can cause fatigue, insomnia, and impotence; and some beta blockers can 40 also cause reduced cardiac output and bradycardia, which may be undesirable in some patient groups. Calcium channel blockers are widely used but it is debatable as to how effectively these drugs reduce fatal and nonfatal cardiac events relative to other drug classes. ACE inhibitors can cause coughing, and rarer side effects include rash, angioedema, hyperkalemia, and functional renal failure. AT1 receptor antagonists are equally effective as ACE inhibitors but without the high prevalence of cough. 45 [0006] EP 437,103, EP 505,954, US 5,616,599 and Bioorg. & Med. Chem. Lett. 3(10) 2043-2046 all disclose hetero- cyclic compounds having ATI receptor antagonist activity. [0007] Neprilysin (neutral endopeptidase, EC 3.4.24.11) (NEP), is an endothelial membrane bound Zn 2+metallopepti- dase found in many tissues, including the brain, kidney, lungs, gastrointestinal tract, heart, and peripheral vasculature. NEP is responsible for the degradation and inactivation of a number of vasoactive peptides, such as circulating bradykinin 50 and angiotensin peptides, as well as the natriuretic peptides, the latter of which have several effects including vasodilation and diuresis. Thus, NEP plays an important role in blood pressure homeostasis. NEP inhibitors have been studied as potential therapeutics and include thiorphan, candoxatril, and candoxatrilat. In addition, compounds have also been designed that inhibit both NEP and ACE, and include omapatrilat, gempatrilat, and sampatrilat. Referred to as vasopepti- dase inhibitors, this class of compounds are described in Robl et al. (1999) Exp. Opin. Ther. Patents 9(12): 1665-1677. 55 [0008] There may be an opportunity to increase anti-hypertensive efficacy when combining AT 1 receptor antagonism and NEP inhibition, as evidenced by AT1 receptor antagonist/NEP inhibitor combinations described in WO 9213564 to Darrow et al (Schering Corporation); US20030144215 to Ksander et al.; Pu et al., Abstract presented at the Canadian Cardiovascular Congress (October 2004); and Gardiner et al. (2006) JPET 319:340-348; and WO 2007/045663 (Novartis 2 EP 2 146 963 B1 AG) to Glasspool et al. [0009] Recently, WO 2007/056546 (Novartis AG) to Feng et aL has described complexes of an AT 1 receptor antagonist and a NEP inhibitor, where an AT 1 receptor antagonist compound is non-covalently bound to a NEP inhibitor compound, or where the antagonist compound is linked to the inhibitor compound by a cation. 5 [0010] In spite of the advances in the art, there remains a need for a highly efficacious monotherapy with multiple mechanisms of action leading to levels of blood pressure control that can currently only be achieved with combination therapy. Thus, although various hypertensive agents are known, and administered in various combinations, it would be highly desirable to provide compounds having both AT1 receptor antagonist activity and NEP inhibition activity in the same molecule. Compounds possessing both of these activities are expected to be particularly useful as therapeutic 10 agents since they would exhibit antihypertensive activity through two independent modes of action while having single molecule pharmacokinetics. [0011] In addition, such dual-acting compounds are also expected to have utility to treat a variety of other diseases that can be treated by antagonizing the AT1 receptor and/or inhibiting the NEP enzyme. 15 SUMMARY OF THE INVENTION [0012] The present invention provides novel compounds that have been found to possess AT1
Load more

Recommended publications
  • Partial Agreement in the Social and Public Health Field
    COUNCIL OF EUROPE COMMITTEE OF MINISTERS (PARTIAL AGREEMENT IN THE SOCIAL AND PUBLIC HEALTH FIELD) RESOLUTION AP (88) 2 ON THE CLASSIFICATION OF MEDICINES WHICH ARE OBTAINABLE ONLY ON MEDICAL PRESCRIPTION (Adopted by the Committee of Ministers on 22 September 1988 at the 419th meeting of the Ministers' Deputies, and superseding Resolution AP (82) 2) AND APPENDIX I Alphabetical list of medicines adopted by the Public Health Committee (Partial Agreement) updated to 1 July 1988 APPENDIX II Pharmaco-therapeutic classification of medicines appearing in the alphabetical list in Appendix I updated to 1 July 1988 RESOLUTION AP (88) 2 ON THE CLASSIFICATION OF MEDICINES WHICH ARE OBTAINABLE ONLY ON MEDICAL PRESCRIPTION (superseding Resolution AP (82) 2) (Adopted by the Committee of Ministers on 22 September 1988 at the 419th meeting of the Ministers' Deputies) The Representatives on the Committee of Ministers of Belgium, France, the Federal Republic of Germany, Italy, Luxembourg, the Netherlands and the United Kingdom of Great Britain and Northern Ireland, these states being parties to the Partial Agreement in the social and public health field, and the Representatives of Austria, Denmark, Ireland, Spain and Switzerland, states which have participated in the public health activities carried out within the above-mentioned Partial Agreement since 1 October 1974, 2 April 1968, 23 September 1969, 21 April 1988 and 5 May 1964, respectively, Considering that the aim of the Council of Europe is to achieve greater unity between its members and that this
    [Show full text]
  • Ehealth DSI [Ehdsi V2.2.2-OR] Ehealth DSI – Master Value Set
    MTC eHealth DSI [eHDSI v2.2.2-OR] eHealth DSI – Master Value Set Catalogue Responsible : eHDSI Solution Provider PublishDate : Wed Nov 08 16:16:10 CET 2017 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 1 of 490 MTC Table of Contents epSOSActiveIngredient 4 epSOSAdministrativeGender 148 epSOSAdverseEventType 149 epSOSAllergenNoDrugs 150 epSOSBloodGroup 155 epSOSBloodPressure 156 epSOSCodeNoMedication 157 epSOSCodeProb 158 epSOSConfidentiality 159 epSOSCountry 160 epSOSDisplayLabel 167 epSOSDocumentCode 170 epSOSDoseForm 171 epSOSHealthcareProfessionalRoles 184 epSOSIllnessesandDisorders 186 epSOSLanguage 448 epSOSMedicalDevices 458 epSOSNullFavor 461 epSOSPackage 462 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 2 of 490 MTC epSOSPersonalRelationship 464 epSOSPregnancyInformation 466 epSOSProcedures 467 epSOSReactionAllergy 470 epSOSResolutionOutcome 472 epSOSRoleClass 473 epSOSRouteofAdministration 474 epSOSSections 477 epSOSSeverity 478 epSOSSocialHistory 479 epSOSStatusCode 480 epSOSSubstitutionCode 481 epSOSTelecomAddress 482 epSOSTimingEvent 483 epSOSUnits 484 epSOSUnknownInformation 487 epSOSVaccine 488 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 3 of 490 MTC epSOSActiveIngredient epSOSActiveIngredient Value Set ID 1.3.6.1.4.1.12559.11.10.1.3.1.42.24 TRANSLATIONS Code System ID Code System Version Concept Code Description (FSN) 2.16.840.1.113883.6.73 2017-01 A ALIMENTARY TRACT AND METABOLISM 2.16.840.1.113883.6.73 2017-01
    [Show full text]
  • Self-Measured Compared to Office
    Systematic Review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Supplemental Tables and Figures Part 1: Self-Measured Compared to Office-Based Measurement of Blood Pressure in the Management of Adults With Hypertension Table 1.1 Electronic search terms used for the current meta-analysis (Part 1 – Self-Measured Compared to Office-Based Measurement of Blood Pressure in the Management of Adults With Hypertension). PubMed Search (Blood Pressure Monitoring, Ambulatory [mesh] OR self care [mesh] OR telemedicine [mesh] OR patient participation [tiab] OR ambulatory [tiab] OR kiosk [tiab] OR kiosks [tiab] OR self-monitor* [tiab] OR self-measure* [tiab] OR self-care* [tiab] OR self-report* [tiab] OR telemonitor* [tiab] OR tele-monitor* [tiab] OR home monitor* [tiab] OR telehealth [tiab] OR tele-health [tiab] OR telemonitor* [tiab] OR tele-monitor* [tiab] OR telemedicine [tiab] OR patient-directed [tiab] OR Blood pressure monitoring “patient directed” [tiab] OR HMBP [tiab] OR SMBP [tiab] OR home [tiab] OR white coat [tiab] OR concept + Self Care concept ((patient participation [ot] OR ambulatory [ot] OR kiosk [ot] OR kiosks [ot] OR self-monitor* [ot] OR self-measure* [ot] OR self-care* [ot] OR self-report* [ot] OR telemonitor* [ot] OR tele-monitor* [ot] OR home monitor* [ot] OR telehealth [ot] OR tele-health [ot] OR telemonitor* [ot] OR tele- monitor* [ot] OR telemedicine [ot] OR patient-directed [tiab] OR “patient directed” [tiab]
    [Show full text]
  • BMJ Open Is Committed to Open Peer Review. As Part of This Commitment We Make the Peer Review History of Every Article We Publish Publicly Available
    BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] BMJ Open Pediatric drug utilization in the Western Pacific region: Australia, Japan, South Korea, Hong Kong and Taiwan Journal: BMJ Open ManuscriptFor ID peerbmjopen-2019-032426 review only Article Type: Research Date Submitted by the 27-Jun-2019 Author: Complete List of Authors: Brauer, Ruth; University College London, Research Department of Practice and Policy, School of Pharmacy Wong, Ian; University College London, Research Department of Practice and Policy, School of Pharmacy; University of Hong Kong, Centre for Safe Medication Practice and Research, Department
    [Show full text]
  • Multi-Layered Pharmaceutical Composition for Both Intraoral and Oral Administration
    Europäisches Patentamt *EP001260216A1* (19) European Patent Office Office européen des brevets (11) EP 1 260 216 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: A61K 9/24, A61K 9/00, 27.11.2002 Bulletin 2002/48 A61K 9/48 (21) Application number: 02007778.0 (22) Date of filing: 06.04.2002 (84) Designated Contracting States: • Midha, Kamal K. AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Hamilton HM 12, Bermuda (US) MC NL PT SE TR • Hirsh, Mark Designated Extension States: Wellesley, MA 2481 (US) AL LT LV MK RO SI • Lo, Whe-Yong Canton, MA 02021 (US) (30) Priority: 15.05.2001 US 858016 (74) Representative: (71) Applicant: Peirce Management, LLC COHAUSZ DAWIDOWICZ HANNIG & PARTNER Wellesley, MA 02481 (US) Schumannstrasse 97-99 40237 Düsseldorf (DE) (72) Inventors: • Hirsh, Jane C. Wellesley, MA 02481 (US) (54) Multi-layered pharmaceutical composition for both intraoral and oral administration (57) New pharmaceutical composition in unit dos- capable of intraoral administration; and age form 1 are disclosed for both intraoral and oral ad- ministration to a mammalian patient, said unit dosage (b) as a second portion 4 located within said first form configured to be placed intraorally of said patient, portion 3, a therapeutically effective amount of at which comprises: least one pharmaceutically active ingredient capa- ble of oral administration and which is releasable (a) as a first portion 3 , at least one discrete outer and orally ingestible by the patient after the outer layer comprising a therapeutically effective amount layer has disintegrated or has dissolved intraorally.
    [Show full text]
  • ( 12 ) United States Patent
    US010172837B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 172 ,837 B2 Collier et al. ( 45 ) Date of Patent : Jan . 8 , 2019 (54 ) INSULIN SENSITISERS AND METHODS OF ( 56 ) References Cited TREATMENT U . S . PATENT DOCUMENTS (71 ) Applicant: NAIA Metabolic , Inc. , Richmond , CA 2 ,783 , 241 A 2 / 1957 Young et al. (US ) 2 , 835 , 702 A 5 / 1958 Schultz 3 , 157 , 572 A 11/ 1964 Card (72 ) Inventors: Gregory Royce Collier , Barwon Heads 3 ,668 , 248 A 6 / 1972 Whitehead et al . 4 ,990 , 523 A 2 / 1991 Nolan et al . ( AU ) ; Kenneth Russell Walder , Ocean 5 , 225 ,424 A 7 / 1993 Schoenwald et al . Grove ( AU ) ; James Alexander 6 ,214 , 381 B1 4 / 2001 Burklow et al . Campbell , Newtown (AU ) ; 7 , 238 , 470 B2 7 / 2007 Hebebrand et al. 7 , 375 , 111 B2 5 / 2008 Weber et al. Juan - Carlos Molero - Navajas , Ocean 8 , 455 , 432 B2 6 / 2013 Collier et al. Grove (AU ) ; Nicky Konstantopoulos , 9 , 452 , 148 B2 9 / 2016 Collier et al . Richmond (AU ) ; Guy Yeoman 2002 / 0022245 A1 2 /2002 Hebebrand et al. Krippner , Newtown ( AU ) 2002 / 0037861 A1 3 /2002 Plata - Salaman et al. 2002 / 0055458 A1 5 / 2002 Stefansson 2003 /0060489 A1 * 3 /2003 Buckingham . A61K 31 / 00 ( 73 ) Assignee : Naia Metabolic , Inc. , Richmond , CA 514 / 342 (US ) 2004 / 0039031 A1 2 / 2004 Cugnardey et al . 2005 / 0037981 A1 2 /2005 Beavers et al. ( * ) Notice : Subject to any disclaimer , the term of this 2005 /0288339 A1 12 /2005 Takaoka et al . patent is extended or adjusted under 35 2007 / 0110707 A1 5 /2007 Ravi 2007 /0111272 Al 5 / 2007 Ravi U .
    [Show full text]
  • Alphabetical Listing of ATC Drugs & Codes
    Alphabetical Listing of ATC drugs & codes. Introduction This file is an alphabetical listing of ATC codes as supplied to us in November 1999. It is supplied free as a service to those who care about good medicine use by mSupply support. To get an overview of the ATC system, use the “ATC categories.pdf” document also alvailable from www.msupply.org.nz Thanks to the WHO collaborating centre for Drug Statistics & Methodology, Norway, for supplying the raw data. I have intentionally supplied these files as PDFs so that they are not quite so easily manipulated and redistributed. I am told there is no copyright on the files, but it still seems polite to ask before using other people’s work, so please contact <[email protected]> for permission before asking us for text files. mSupply support also distributes mSupply software for inventory control, which has an inbuilt system for reporting on medicine usage using the ATC system You can download a full working version from www.msupply.org.nz Craig Drown, mSupply Support <[email protected]> April 2000 A (2-benzhydryloxyethyl)diethyl-methylammonium iodide A03AB16 0.3 g O 2-(4-chlorphenoxy)-ethanol D01AE06 4-dimethylaminophenol V03AB27 Abciximab B01AC13 25 mg P Absorbable gelatin sponge B02BC01 Acadesine C01EB13 Acamprosate V03AA03 2 g O Acarbose A10BF01 0.3 g O Acebutolol C07AB04 0.4 g O,P Acebutolol and thiazides C07BB04 Aceclidine S01EB08 Aceclidine, combinations S01EB58 Aceclofenac M01AB16 0.2 g O Acefylline piperazine R03DA09 Acemetacin M01AB11 Acenocoumarol B01AA07 5 mg O Acepromazine N05AA04
    [Show full text]
  • Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DIX to the HTSUS—Continued
    20558 Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DEPARMENT OF THE TREASURY Services, U.S. Customs Service, 1301 TABLE 1.ÐPHARMACEUTICAL APPEN- Constitution Avenue NW, Washington, DIX TO THE HTSUSÐContinued Customs Service D.C. 20229 at (202) 927±1060. CAS No. Pharmaceutical [T.D. 95±33] Dated: April 14, 1995. 52±78±8 ..................... NORETHANDROLONE. A. W. Tennant, 52±86±8 ..................... HALOPERIDOL. Pharmaceutical Tables 1 and 3 of the Director, Office of Laboratories and Scientific 52±88±0 ..................... ATROPINE METHONITRATE. HTSUS 52±90±4 ..................... CYSTEINE. Services. 53±03±2 ..................... PREDNISONE. 53±06±5 ..................... CORTISONE. AGENCY: Customs Service, Department TABLE 1.ÐPHARMACEUTICAL 53±10±1 ..................... HYDROXYDIONE SODIUM SUCCI- of the Treasury. NATE. APPENDIX TO THE HTSUS 53±16±7 ..................... ESTRONE. ACTION: Listing of the products found in 53±18±9 ..................... BIETASERPINE. Table 1 and Table 3 of the CAS No. Pharmaceutical 53±19±0 ..................... MITOTANE. 53±31±6 ..................... MEDIBAZINE. Pharmaceutical Appendix to the N/A ............................. ACTAGARDIN. 53±33±8 ..................... PARAMETHASONE. Harmonized Tariff Schedule of the N/A ............................. ARDACIN. 53±34±9 ..................... FLUPREDNISOLONE. N/A ............................. BICIROMAB. 53±39±4 ..................... OXANDROLONE. United States of America in Chemical N/A ............................. CELUCLORAL. 53±43±0
    [Show full text]
  • European Patent Office
    Europäisches Patentamt *EP001021204B1* (19) European Patent Office Office européen des brevets (11) EP 1 021 204 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: A61K 47/32, A61L 25/00 of the grant of the patent: 28.12.2005 Bulletin 2005/52 (86) International application number: PCT/US1998/020091 (21) Application number: 98949505.6 (87) International publication number: (22) Date of filing: 25.09.1998 WO 1999/015210 (01.04.1999 Gazette 1999/13) (54) BIOADHESIVE COMPOSITIONS AND METHODS FOR TOPICAL ADMINISTRATION OF ACTIVE AGENTS BIOLOGISCHE KLEBER UND VERFAHREN ZUR TOPISCHEN VERABREICHUNG VON WIRKSTOFFEN COMPOSITIONS BIOADHESIVES ET METHODES D’ADMINISTRATION LOCALE D’AGENTS ACTIFS (84) Designated Contracting States: • HOUZE, David AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Miami, FL 33186 (US) MC NL PT SE • KANIOS, David Miami, FL 33196 (US) (30) Priority: 26.09.1997 US 61155 P (74) Representative: Isenbruck, Günter (43) Date of publication of application: Isenbruck, Bösl, Hörschler, Wichmann, Huhn 26.07.2000 Bulletin 2000/30 Patentanwälte Theodor-Heuss-Anlage 12 (73) Proprietor: NOVEN PHARMACEUTICALS, INC. 68165 Mannheim (DE) Miami, FL 33186 (US) (56) References cited: (72) Inventors: FR-A- 2 532 546 GB-A- 1 050 070 • MANTELLE, Juan GB-A- 2 046 773 US-A- 4 593 053 Miami, FL 33176 (US) US-A- 5 656 286 Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted.
    [Show full text]
  • SUPPLEMENTARY MATERIAL 1: Search Strategy
    SUPPLEMENTARY MATERIAL 1: Search Strategy Medline search strategy 1. exp basal ganglia hemorrhage/ or intracranial hemorrhages/ or cerebral hemorrhage/ or intracranial hemorrhage, hypertensive/ or cerebrovascular disorders/ 2. ((brain$ or cerebr$ or cerebell$ or intracerebral or intracran$ or parenchymal or intraparenchymal or intraventricular or infratentorial or supratentorial or basal gangli$ or putaminal or putamen or posterior fossa or hemispher$ or pon$ or lentiform$ or brainstem or cortic$ or cortex$ or subcortic$ or subcortex$) adj5 (h?emorrhag$ or h?ematoma$ or bleed$)).tw 3. ((hemorrhag$ or haemorrhag$) adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva)).tw 4. (ICH or ICHs or PICH or PICHs).tw 5. 1 or 2 or 3 or 4 6. exp blood pressure/ 7. exp hypertension/ 8. (blood pressure or bloodpressure).tw 9. ((bp or blood pressure) adj5 (lowering or reduc$)).tw 10. ((strict$ or target$ or tight$ or intens$ or below) adj3 (blood pressure or systolic or diastolic or bp or level$)).tw 11. (hypertension or hypertensive).tw 12. ((manage$ or monitor$) adj3 (hypertension or blood pressure)).tw 13. ((intense or intensive or aggressive or accelerated or profound or radical or severe) adj5 ((bp or blood pressure) adj5 (lowering or reduc$ or decreas$ or decrement or dimin$ or declin$))).tw 14. ((standard or normal or ordinary or guideline or guide line or guideline recommend$ or recommend$ or convention$ or usual or established) adj5 ((bp or blood pressure) adj5 (lowering or reduc$ or decreas$ or decrement or dimin$ or declin$))).tw 15. (antihypertensive adj2 (agent$ or drug$ or medicat$)).tw 1 16. 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 17.
    [Show full text]
  • Harmonized Tariff Schedule of the United States (2004) -- Supplement 1 Annotated for Statistical Reporting Purposes
    Harmonized Tariff Schedule of the United States (2004) -- Supplement 1 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2004) -- Supplement 1 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. Product CAS No. Product CAS No. ABACAVIR 136470-78-5 ACEXAMIC ACID 57-08-9 ABAFUNGIN 129639-79-8 ACICLOVIR 59277-89-3 ABAMECTIN 65195-55-3 ACIFRAN 72420-38-3 ABANOQUIL 90402-40-7 ACIPIMOX 51037-30-0 ABARELIX 183552-38-7 ACITAZANOLAST 114607-46-4 ABCIXIMAB 143653-53-6 ACITEMATE 101197-99-3 ABECARNIL 111841-85-1 ACITRETIN 55079-83-9 ABIRATERONE 154229-19-3 ACIVICIN 42228-92-2 ABITESARTAN 137882-98-5 ACLANTATE 39633-62-0 ABLUKAST 96566-25-5 ACLARUBICIN 57576-44-0 ABUNIDAZOLE 91017-58-2 ACLATONIUM NAPADISILATE 55077-30-0 ACADESINE 2627-69-2 ACODAZOLE 79152-85-5 ACAMPROSATE 77337-76-9 ACONIAZIDE 13410-86-1 ACAPRAZINE 55485-20-6 ACOXATRINE 748-44-7 ACARBOSE 56180-94-0 ACREOZAST 123548-56-1 ACEBROCHOL 514-50-1 ACRIDOREX 47487-22-9 ACEBURIC ACID 26976-72-7
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2002/0010208A1 Shashoua Et Al
    US 2002001 0208A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0010208A1 Shashoua et al. (43) Pub. Date: Jan. 24, 2002 (54) DHA-PHARMACEUTICAL AGENT Related U.S. Application Data CONJUGATES OF TAXANES (63) Continuation of application No. 09/135,291, filed on (76) Inventors: Victor Shashoua, Brookline, MA (US); Aug. 17, 1998, now abandoned, which is a continu Charles Swindell, Merion, PA (US); ation of application No. 08/651,312, filed on May 22, Nigel Webb, Bryn Mawr, PA (US); 1996, now Pat. No. 5,795,909. Matthews Bradley, Layton, PA (US) Publication Classification Correspondence Address: Edward R. Gates, Esq. (51) Int. Cl." ............................................ A61K 31/337 Wolf, Greenfield & Sacks, P.C. (52) U.S. Cl. .............................................................. 514/449 600 Atlantic Avenue Boston, MA 02210 (US) (57) ABSTRACT The invention provides conjugates of cis-docosahexaenoic (21) Appl. No.: 09/846,838 acid and pharmaceutical agents useful in treating noncentral nervous System conditions. Methods for Selectively target 22) Filled: Mayy 1, 2001 ingg pharmaceuticalp agents9. to desired tissues are pprovided. Patent Application Publication Jan. 24, 2002 Sheet 1 of 14 US 2002/0010208A1 1 OO 5 O -5OO - 1 OO-9 -8 -7 -6 -5 -4 LOG-10 OF SAMPLE CONCENTRATION (MOLAR) CCRF-CEM-o- SR ----- RPM-8226----- K-562- - -A - - HL-60 (TB) -g- - MOLT4: ... O Fig. 1 1 OO 5 O -5OO -1 O O -8 -7 -6 -5 -4 -- 9 LOGo OF SAMPLE CONCENTRATION (MOLAR) A549/ATCC-o-NS326. NCEKVX 28. --Q-- NCI-H322M-...-a---Eidsf8::... NC-H522--O-- HOP-62---Fig. 2 a-- NC-H460.-------- Patent Application Publication Jan.
    [Show full text]