DOCSLIB.ORG

Anti-Viral Nucleoside Analogs and Methods for Treating Viral Infections, Especially Hiv Infections

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Anti-Viral Nucleoside Analogs and Methods for Treating Viral Infections, Especially Hiv Infections (19) & (11) EP 2 298 783 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 23.03.2011 Bulletin 2011/12 C07H 19/10 (2006.01) A61K 31/7068 (2006.01) A61P 31/18 (2006.01) (21) Application number: 10155533.2 (22) Date of filing: 18.02.2004 (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • Cheng, Yung-Chi HU IE IT LI LU MC NL PT RO SE SI SK TR WOODBRIDGE, CT 06525 (US) Designated Extension States: • Tanaka, Hiromichi AL LT LV MK YOKOHAMA 224-0028 (JP) • Baba, Masanori (30) Priority: 19.03.2003 US 448554 KAGOSHIMA Fukuoka 891-0103 (JP) (62) Document number(s) of the earlier application(s) in (74) Representative: Dall’Olio, Giancarlo et al accordance with Art. 76 EPC: Invention S.r.l. 04775776.0 / 1 653 976 Via delle Armi 1 40137 Bologna (IT) (71) Applicants: • Yale University Remarks: New Haven, CT 06511 (US) This application was filed on 04-03-2010 as a • Cheng, Yung-Chi divisional application to the application mentioned Woodbridge, CT 06525 (US) under INID code 62. • Tanaka, Hiromichi Yokohama 224-0028 (JP) (54) Anti-viral nucleoside analogs and methods for treating viral infections, especially hiv infections (57) The present invention relates to novel com- n-C≡C-Ra, Formula (XII) or Formula (XIII) with the pro- pounds according to the general Formulae (I, II, III, IV or viso that R4 and R5 are not both H; Ra is H,F,Cl,Br,I or V); wherein B is nucleoside base according to the struc- -C1-C4 alkyl, preferably H or CH3; Y is H, F, C1, Br, I or ture Formula (VI); R is H, F, Cl, Br, I, C1-C4 alkyl (pref- -C1-C4 alkyl, preferably H or CH3; and n is 0,1,2,3,4 or erably CH3), -C≡N, -C≡C-Ra, Formula (VII); X is H, C 1-C4 5, preferably 0, 1 or 2; and their anomers, pharmaceuti- alkyl (preferably CH 3), F,Cl,Br or 1; Z is 0 or CH 2 with the cally acceptable salts, solvates or polymorphs thereof. proviso that Z is CH2 and not O when the compound is according to general formula II, R3 is -C≡C-H and R2 is H or a phosphate, diphosphate, triphosphate or phos- 1 photriester group; R is H, an acyl group, a C 1-C20 alkyl or an ether group; R2 is H, an acyl group, a CI- C20 alkyl or ether group, a phosphate, diphosphate, triphosphate, phosphodiester group or a Formula; (VIII) or Formula (IX) group; Nu is a radical of a biologically active antiviral com- pound such that an amino group or hydroxyl group from said biologically active antiviral compound forms a phos- phate, phosphoramidate, carbonate or urethane group with the adjacent moiety; R8 is H, or a C1-C20 alkyl or ether group, preferably a C1-C12 alkyl group; k is 0-12, preferably, 0-2; R3 is selected from a C1-C4 alkyl (pref- erably CH3), -(CH2)n-C=C-Ra, Formula (X) or Formula (XI); R3a and R3b are independently selected from H, F, C1, Br or I; R4 and R5 are independently selected from H, F, Cl, Br, I, OH, C1-C4 alkyl (preferably CH3),-(CH2) EP 2 298 783 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 298 783 A1 Description Related Applications 5 [0001] This application claims the benefit of provisional application number 60/448,554, filed February 19, 2003, the entirety of which is incorporated by reference herein. Field of the Invention 10 [0002] The present invention relates to novel 2’,3’-dideoxy and didehydro nucleoside analogs and related prodrugs and their use in the treatment of a number of viral infections and disease states, especially including HIV and its related condition AIDS, among numerous others, and in particular, retroviruses. [0003] This work was supported by Public Health Service grant AI-38204 from the National Institutes of Health. The government retains certain rights in the invention. 15 Background of the invention [0004] Human immunodeficiency virus (HIV/AIDS) has become the leading infectious cause of death worldwide sur- passing malaria and tuberculosis. WHO AIDS Epidemic Update, data for December 2002, lists 3.1 million deaths and 20 42 million people currently living with AIDS. The need for new therapeutic agents with better efficacy is evident. Dideoxy nucleosides are an important group of antiviral compounds(16, 26, 27). A member of this group, 3’-Azido-3’-deoxythy- midine (AZT, Retovir, Zidovudine) was the first drug approved for the treatment of HIV. Its dose limiting adverse effect is myelosuppression (14, 36, 39), which may be worsened by the concurrent administration of other drugs that cause bone marrow suppression or that are hepatically metabolized. 2’, 3’- Didehydro-3’-deoxythymidine (D4T, Stavudine, 25 Zerit) was then approved because of better bioavailability and lower acute toxicity (1). D4T is limited by a long-term delayed toxicity, peripheral sensory neuropathy (4) which is related to mitochondrial damage (3, 5, 6, 13, 18, 22, 30, 33, 34). 2’, 3’-Dideoxyinosine (ddI, Didanosine, Videx) and 2’, 3’-dideoxycytidine (ddC, Zalcitabine) are dideoxynucleoside anti HIV compounds that also have peripheral neuropathy as their leading adverse effect. In the search to find anti- HIV nucleoside analogs that had less neuropathy, many classes of compounds were synthesized and assessed for their 30 antiviral activity and cytotoxicity including their impact on mitochondrial DNA. Dideoxynucleosides in the unnatural L conformation represented by β-L-2’, 3’-dideoxy-3’- thiacytidine (3TC, Lamivudine), its 5- fluoro analog (FTC, Emtricitab- ine) and β-L-2’, 3’-dideoxy-2’,3’-didehydro-5- fluorocytidine (LFd4C, Elvucitabine), have been shown by us (2, 11, 12, 23-25) and others (8, 9, 15, 37) to have good antiviral activity and low mitochondrial toxicity. However, even with com- pounds relatively non-toxic to mitochondria there is a lack of a durable response. This condition can be caused by either 35 the rapid emergence of resistant virus or by host changes that cause differences in drug metabolism (10, 19, 35). [0005] One approach to combat this problem is to develop compounds with less toxicity and lack of cross- resistance to other antiviral drugs. When used in combinations these compounds may decrease the dosage of existing drugs needed to achieve the same antiviral effect with less toxicity. Futhermore, these compounds could even delay the onset of resistance, which could be based on the decreased viral load during treatment. In the search for a new antiviral 40 compounds, others have looked at 4’-substituted dThd analogs (29) (32), while we synthesized a series of 4’- substituted D4T analogs. Screening revealed the 4’-ethynyl D4T to be the most active among those tested (17). In the studies described within we describe the structure activity relationship of this class of compounds and characterize 4’-ethynyl D4T in more detail with respect to its mode of action against HIV and its interaction with key cellular enzymes that mediate its activity. 45 Objects of the Invention [0006] It is an object of the invention to provide compounds for the treatment of viral infections or cancer. [0007] It is another object of the invention to provide pharmaceutical compositions which can be used to treat viral 50 infections or cancer. [0008] It is an additional object to provide compounds and pharmaceutical compositions which can be used in com- bination therapy with known anti-viral agents. [0009] It is still a further object of the present invention to provide prodrug forms of compounds according to the present invention which are formulated in combination with other anti-viral agents. 55 [0010] It is another object of the invention to provide therapeutic methods for the treatment of a variety of viruses as otherwise described herein, or cancer. [0011] It is yet another obj ect of the invention to provide methods of synthesizing compounds according to the present invention. 2 EP 2 298 783 A1 [0012] These and/or other objects of the invention may be readily gleaned from the description of the invention which follows. Brief Description of the Figures 5 [0013] Figure 1 depicts a number of preferred compounds according to the present invention. Figure 2 depicts anti- HIV compounds L(-)Fd4C, L(-)SddC, ddC and D4T that are not object of the present invention. 10 Figure 3 depicts preferred dinucleoside compounds according to the present invention. Figure 4 shows the chemical synthesis of TDK-4-152 in Scheme A that are not object of the present invention. Figure 5 shows the chemical synthesis of TDK-4-114 in Scheme B. Figure 5A shows an alternative chemical synthesis of TDK4-114 . Figure 5B shows an alternative preparation of acyloxynucleoside compound intermediates accordingto the invention, 15 which may be used to produced TKD-4-114 of Figure 5A. Figure 6 shows a chemical synthesis of KMA-23-153 that is not object of the present invention. Figure 7A shows the synthesis of 4’ethynyl-2’-deoxynucleosides from 2’-deoxynucleosides according to the meth- odology of Nomura, et al. J. Med. Chem., 42, 2901-2908 (1999) that is not object of the present invention. Note that SiR3 is a tert-butyldimethylsilyl group and SiR’3 is a tert-butyldiphenylsilyl group. X is a halogen atom, such as 20 chlorine and B is a nucleoside base such as uracil, adenine, guanine or cytosine, among others. Figure 7B shows the synthesis of 4’-ethynyl-2’-deoxynucleosides from a blocked sugar precursor according to the methodology of Ohrui, et al., J. Med.
Load more

Recommended publications
  • Screening of Clinically Approved and Investigation
    Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of SARS-CoV-2 Main Protease and Spike Receptor- Binding Domain Bound with ACE2 COVID19 Target Proteins: A Virtual Drug Repurposing Study Serdar Durdagi1,*, Busecan Aksoydan1,2, Berna Dogan1, Kader Sahin1, Aida Shahraki1,3, Necla Birgul-Iyison3 1Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey 2Neuroscience Program, Graduate School of Health Sciences, Bahçeşehir University, Istanbul, Turkey 3Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey Abstract There is an urgent need for new drugs against COVID-19. Since designing a new drug and testing its pharmacokinetics and pharmacodynamics properties may take years, here we used a physics-driven high throughput virtual screening drug re-purposing approach to identify new compounds against COVID- 19. As the molecules considered in repurposing studies passed through several stages and have well- defined profiles, they would not require prolonged pre-clinical studies and hence, they would be excellent candidates in the cases of disease emergencies or outbreaks. While the Spike Protein is the key for the virus to enter the cell through the interaction with ACE2, enzymes such as main protease are crucial for the life cycle of the virus. These proteins are the most attractive targets for the development of new drugs against COVID-19 due to their pivotal roles in the fusion, replication and transcription of the virus. We used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH Chemical Genomics Center (NCGC) Pharmaceutical Collection (NPC) database in our drug repurposing study.
    [Show full text]
  • Screening of Clinically Approved and Investigation Drugs As Potential
    Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of COVID-19 Main Protease: A Virtual Drug Repurposing Study Serdar Durdagi1,*, Busecan Aksoydan1,2, Berna Dogan1, Kader Sahin1, Aida Shahraki1,3 1Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey 2Neuroscience Program, Graduate School of Health Sciences, Bahçeşehir University, Istanbul, Turkey 3Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey Abstract There is an urgent need for a new drug against COVID-19. Since designing a new drug and testing its pharmacokinetics and pharmacodynamics properties may take years, here we used a physics-driven high throughput virtual screening drug re-purposing approach to identify new compounds against COVID-19. As the molecules considered in repurposing studies passed through several stages and have well-defined profiles, they would not require prolonged pre- clinical studies and hence, they would be excellent candidates in the cases of disease emergencies or outbreaks. While the spike protein is the key for the virus to enter the cell though the interaction with ACE2, enzymes such as main protease are crucial for the life cycle of the virus. This protein is one of the most attractive targets for the development of new drugs against COVID-19 due to its pivotal role in the replication and transcription of the virus. We used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH Chemical Genomics Center (NCGC) Pharmaceutical Collection (NPC) database in our drug repurposing study. Both apo and holo forms of target protein COVID-19 main proteases were used in virtual screening.
    [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]
  • WO 2014/184553 Al 20 November 2014 (20.11.2014) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/184553 Al 20 November 2014 (20.11.2014) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/34 (2006.01) A61K 31/535 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/427 (2006.01) A61P 31/18 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/513 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, PCT/GB20 14/05 1478 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 14 May 2014 (14.05.2014) OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (25) Filing Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (26) Publication Language: English ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 1749/MUM/2013 15 May 2013 (15.05.2013) IN kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (71) Applicant: CIPLA LIMITED [—/IN]; Cipla House, Pen UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, insula Business Park, Ganpatrao Kadam Marg, Lower TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Parel, Mumbai-400 013 (IN).
    [Show full text]
  • Repurposing of FDA Approved Drugs
    Antiviral Drugs (In Phase IV) ABACAVIR GEMCITABINE ABACAVIR SULFATE GEMCITABINE HYDROCHLORIDE ACYCLOVIR GLECAPREVIR ACYCLOVIR SODIUM GRAZOPREVIR ADEFOVIR DIPIVOXIL IDOXURIDINE AMANTADINE IMIQUIMOD AMANTADINE HYDROCHLORIDE INDINAVIR AMPRENAVIR INDINAVIR SULFATE ATAZANAVIR LAMIVUDINE ATAZANAVIR SULFATE LEDIPASVIR BALOXAVIR MARBOXIL LETERMOVIR BICTEGRAVIR LOPINAVIR BICTEGRAVIR SODIUM MARAVIROC BOCEPREVIR MEMANTINE CAPECITABINE MEMANTINE HYDROCHLORIDE CARBARIL NELFINAVIR CIDOFOVIR NELFINAVIR MESYLATE CYTARABINE NEVIRAPINE DACLATASVIR OMBITASVIR DACLATASVIR DIHYDROCHLORIDE OSELTAMIVIR DARUNAVIR OSELTAMIVIR PHOSPHATE DARUNAVIR ETHANOLATE PARITAPREVIR DASABUVIR PENCICLOVIR DASABUVIR SODIUM PERAMIVIR DECITABINE PERAMIVIR DELAVIRDINE PIBRENTASVIR DELAVIRDINE MESYLATE PODOFILOX DIDANOSINE RALTEGRAVIR DOCOSANOL RALTEGRAVIR POTASSIUM DOLUTEGRAVIR RIBAVIRIN DOLUTEGRAVIR SODIUM RILPIVIRINE DORAVIRINE RILPIVIRINE HYDROCHLORIDE EFAVIRENZ RIMANTADINE ELBASVIR RIMANTADINE HYDROCHLORIDE ELVITEGRAVIR RITONAVIR EMTRICITABINE SAQUINAVIR ENTECAVIR SAQUINAVIR MESYLATE ETRAVIRINE SIMEPREVIR FAMCICLOVIR SIMEPREVIR SODIUM FLOXURIDINE SOFOSBUVIR FOSAMPRENAVIR SORIVUDINE FOSAMPRENAVIR CALCIUM STAVUDINE FOSCARNET TECOVIRIMAT FOSCARNET SODIUM TELBIVUDINE GANCICLOVIR TENOFOVIR ALAFENAMIDE GANCICLOVIR SODIUM TENOFOVIR ALAFENAMIDE FUMARATE TIPRANAVIR VELPATASVIR TRIFLURIDINE VIDARABINE VALACYCLOVIR VOXILAPREVIR VALACYCLOVIR HYDROCHLORIDE ZALCITABINE VALGANCICLOVIR ZANAMIVIR VALGANCICLOVIR HYDROCHLORIDE ZIDOVUDINE Antiviral Drugs (In Phase III) ADEFOVIR LANINAMIVIR OCTANOATE
    [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]
  • Providing for Duty-Free Treatment for Specified Pharmaceutical Active
    COMMISSION OF THE EUROPEAN COMMUNITIES Brussels, 12.02.1999 COM(1999)2 final Proposal for a COUNCIL Rl;_GULATION (EC) providing for duty-free treatment for specified pharmaceutical active ingredients bearing an international non-proprietary name (INN) from the World Health Organisation and specified products used for the manufacture of finished pharmaceutical products (presented by the Commission) EXPLANATORY MEMORANDUM I. Pursuant to the conclusions r~.:ached in Uruguay Round Record of Discussions (L/4740 of 25 March 1994) on duty-free treatment for pharmaceutical products, the Commission has participated in the second review of the product coverage to include, r by consensus, additional products for duty-free treatment. 2. The outcome of the review is that 272 pharmaceutical active ingredients bearing an "international nonproprietary name" (INN) from the World Health Organisation and 363 products used for the manufacture of finished pharmaceuticals should be added to the list of products already receiving duty-free treatment and also that the list of specified prefixes and suffixes for salts and esters of INNs should be expanded by five names. 3. The Commission proposes in line with other countries granting duty-free treatment for these additional products that the duty-free treatment shall commence from 1 July 1999. 4. For these reasons the Commission proposes that the Council adopt the Regulation contained in the Annex to this Communication. · jt II I il,, i ·'1.· i. 2 Proposal for a COUNCIL REGULATION (EC) providing for duty-free
    [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]
  • WHO Drug Information Vol. 11, No. 3, 1997
    WHO DRUG INFORMATION VOLUME 11- NUMBER 3 • 1997 RECOMMENDED INN LIST 38 INTERNATIONAL NONPROPRIETARY N A M E S F O R P H A R M A C E U T I C A L SUBSTANCES WORLD HEALTH ORGANIZATION • GENEVA Volume 11, Number 3, 1997 World Health Organization, Geneva WHO Drug Information Contents Essential Drugs WHO Model Formulary Antiprotozoal drugs General Policy Issues Drugs used in amoebiasis 144 The dangers of counterfeit and substandard Diloxanide 144 active pharmaceutical ingredients 123 Drugs used in giardiasis Metronidazole 145 Drugs used in leishmaniasis 145 Quality Assurance Issues Meglumine antimoniate & The importance of analytical procedures sodium stibogluconate 146 in regulatory control 128 Pentamidine 147 Amphotericin B 148 Drugs used in trypanosomiasis 148 Reports on Individual Drugs Melarsoprol 148 Simplified treatment for leprosy 131 Pentamidine 149 Should antibiotics be indicated for children Suramin sodium 149 with acute otitis media? 131 Eflornithine 151 Acetylsalicylic acid: confirmed efficacy Drugs used in American trypanosomiasis 151 after stroke 132 Benznidazole 151 Antiretroviral therapy for HIV: latest guidelines 134 Nifurtimox 152 General Information ATC/DDD Classification Biological standardization: report of the 153 Expert Committee 138 (temporary) Recent Publications and Documents Regulatory Matters Drugs for the elderly 155 Irinotecan-associated mortality 141 Rapid examination methods against counterfeit HIV protease inhibitors associated with and substandard drugs 155 diabetes 141 Countering counterfeiting 155 Valvular
    [Show full text]
  • Piperidine Derivatives Useful As Ccr5
    Europäisches Patentamt & (19) European Patent Office Office européen des brevets (11) EP 1 421 075 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 401/04 (2006.01) A61P 31/18 (2006.01) 07.06.2006 Bulletin 2006/23 A61K 31/435 (2006.01) (21) Application number: 02766142.0 (86) International application number: PCT/US2002/027389 (22) Date of filing: 28.08.2002 (87) International publication number: WO 2003/020716 (13.03.2003 Gazette 2003/11) (54) PIPERIDINE DERIVATIVES USEFUL AS CCR5 ANTAGONISTS FOR THE TREATMENT OF HIV PIPERIDIN DERIVATE ALS CCR5 REZEPTOR ANTAGONISTEN ZUR BEHANDLUNG VON HIV DERIVES DE LA PIPERIDINE UTILISES COMME ANTAGONISTES DU CCR5 POUR LE TRAITEMENT DU SIDA (84) Designated Contracting States: (74) Representative: Adams, Harvey Vaughan John et AT BE BG CH CY CZ DE DK EE ES FI FR GB GR al IE IT LI LU MC NL PT SE SK TR Mathys & Squire Designated Extension States: 120 Holborn AL LT LV MK RO SI London EC1N 2SQ (GB) (30) Priority: 29.08.2001 US 315683 P (56) References cited: EP-A- 0 151 824 EP-A- 0 855 999 (43) Date of publication of application: WO-A-01/30348 WO-A-01/77101 26.05.2004 Bulletin 2004/22 WO-A-97/24324 WO-A-98/01425 WO-A-02/081449 US-A- 5 952 349 (73) Proprietor: SCHERING CORPORATION Kenilworth, NJ 07033-0530 (US) • PALANI, A. ET AL.: "Discovery of 4-[(Z)-(4- Bromophenyl)-(ethoxyimino)methyl ]-1’-[(2,4- (72) Inventors: dimethyl-3-pyridinyl)carbonyl]- 4’-methyl-1,4’- • PALANI, Anandan bipiperidine N-Oxide (SCH 351125): An Orally Bridgewater, NJ 08807 (US) Bioavailable Human CCR5 Antagonist for the • MILLER, Michael, W.
    [Show full text]
  • Chemical Structure-Related Drug-Like Criteria of Global Approved Drugs
    Molecules 2016, 21, 75; doi:10.3390/molecules21010075 S1 of S110 Supplementary Materials: Chemical Structure-Related Drug-Like Criteria of Global Approved Drugs Fei Mao 1, Wei Ni 1, Xiang Xu 1, Hui Wang 1, Jing Wang 1, Min Ji 1 and Jian Li * Table S1. Common names, indications, CAS Registry Numbers and molecular formulas of 6891 approved drugs. Common Name Indication CAS Number Oral Molecular Formula Abacavir Antiviral 136470-78-5 Y C14H18N6O Abafungin Antifungal 129639-79-8 C21H22N4OS Abamectin Component B1a Anthelminithic 65195-55-3 C48H72O14 Abamectin Component B1b Anthelminithic 65195-56-4 C47H70O14 Abanoquil Adrenergic 90402-40-7 C22H25N3O4 Abaperidone Antipsychotic 183849-43-6 C25H25FN2O5 Abecarnil Anxiolytic 111841-85-1 Y C24H24N2O4 Abiraterone Antineoplastic 154229-19-3 Y C24H31NO Abitesartan Antihypertensive 137882-98-5 C26H31N5O3 Ablukast Bronchodilator 96566-25-5 C28H34O8 Abunidazole Antifungal 91017-58-2 C15H19N3O4 Acadesine Cardiotonic 2627-69-2 Y C9H14N4O5 Acamprosate Alcohol Deterrant 77337-76-9 Y C5H11NO4S Acaprazine Nootropic 55485-20-6 Y C15H21Cl2N3O Acarbose Antidiabetic 56180-94-0 Y C25H43NO18 Acebrochol Steroid 514-50-1 C29H48Br2O2 Acebutolol Antihypertensive 37517-30-9 Y C18H28N2O4 Acecainide Antiarrhythmic 32795-44-1 Y C15H23N3O2 Acecarbromal Sedative 77-66-7 Y C9H15BrN2O3 Aceclidine Cholinergic 827-61-2 C9H15NO2 Aceclofenac Antiinflammatory 89796-99-6 Y C16H13Cl2NO4 Acedapsone Antibiotic 77-46-3 C16H16N2O4S Acediasulfone Sodium Antibiotic 80-03-5 C14H14N2O4S Acedoben Nootropic 556-08-1 C9H9NO3 Acefluranol Steroid
    [Show full text]