EP1556007A2 - Composes tetracycline substituee servant au traitement du paludisme - Google Patents

Composes tetracycline substituee servant au traitement du paludisme

Info

Publication number
EP1556007A2
EP1556007A2 EP03781398A EP03781398A EP1556007A2 EP 1556007 A2 EP1556007 A2 EP 1556007A2 EP 03781398 A EP03781398 A EP 03781398A EP 03781398 A EP03781398 A EP 03781398A EP 1556007 A2 EP1556007 A2 EP 1556007A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
hydrogen
substituted
alkynyl
alkenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03781398A
Other languages
German (de)
English (en)
Other versions
EP1556007A4 (fr
Inventor
Michael Draper
Mark L. Nelson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Paratek Pharmaceuticals Inc
Original Assignee
Paratek Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Paratek Pharmaceuticals Inc filed Critical Paratek Pharmaceuticals Inc
Priority to EP10171327A priority Critical patent/EP2277504A1/fr
Publication of EP1556007A2 publication Critical patent/EP1556007A2/fr
Publication of EP1556007A4 publication Critical patent/EP1556007A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • R 4 is NR 4 R 4 , alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;
  • R 3 , R 11 and R 12 are each hydrogen, or a pro-drug moiety;
  • R 10 is hydrogen, a prodrug moiety, or linked to R 9 to form a ring;
  • R 5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
  • this invention also pertains to pharmaceutical compositions which include an effective amount of one of the above-described substituted tetracycline compounds and a pharmaceutically acceptable carrier
  • This invention also features a packaged malarial treatment, including one or more of the substituted tetracycline compounds of the invention packaged with instructions for using the compound to treat malaria.
  • this invention pertains to methods of treating or preventing malaria in a subject, by administering an effective amount of a substituted tetracycline compound.
  • tetracycline compounds includes tetracycline family members such as methacycline, sancycline, apicycline, clomocycline, guamecycline, meglucycline, mepylcycline, penimepicycline, pipacycline, etamocycline, penimocycline, etc. as well as other tetracycline compounds having the characteristic naphthacene A-B-C-D ring structure. Additional tetracycline compounds can be found, for example, in U.S. Patent Application Serial No.: 09/234,847, and U.S. Patents Nos.
  • tetracyclines regardless of specific formulation or chemical structure, were found to be highly effective pharmacologically against rickettsiae, a number of gram-positive and gram-negative bacteria, and the agents responsible for lymphogranuloma venereum, including conjunctivitis, and psittacosis.
  • tetracyclines became known as "broad spectrum" antibiotics.
  • the tetracyclines as a class rapidly became widely used for therapeutic purposes.
  • the substituted tetracycline compound of the invention may have anti-microbial gram positive activity, as measured by assays known in the art or the assay described in Example 6.
  • the anti-microbial gram positive activity of the substituted tetracycline compound is greater than about 0.0001 ⁇ g/ml, greater than about 0.05 ⁇ g/ml, greater than about 0.5 ⁇ g/ml, greater than about 1.0 ⁇ g/ml, or greater than about 5.0 ⁇ g/ml. Values and ranges included and/or intermediate of the values set forth herein are also intended to be within the scope of the present invention.
  • the substituted tetracycline compound of the invention has a cytotoxicity which allows the compound to be administered in an effective amount to the subject with out causing prohibitive cytotoxic side effects.
  • the cytotoxicity of the substituted tetracycline compound of the invention is greater than about 10 ⁇ g/ml, about 15 ⁇ g/ml, about 20 ⁇ g/ml, or about 25 ⁇ g/ml as measured by cytoxicity assays known in the art such as the assay described in Example 5.
  • the substituted tetracycline compound of the invention has a MIC which allows it to perform its intended function, e.g., treat or prevent malaria in a subject.
  • the MIC is a measure of the concentration of the compound necessary to inhibit the malaria parasite.
  • the MIC can be tested using methods known in the art as well as the in vitro method described in Example 3 or the in vivo method described in Example 4.
  • the MIC of a substituted tetracycline compound as measured in vivo is about 500 mg/kg or less, about 250 mg/kg or less, about 200 mg/kg or less, about 190 mg/kg or less, about 180 mg/kg or less, about 170 mg/kg or less, about 160 mg/kg or less, about 150 mg/kg or less, about 140 mg/kg or less, about 130 mg/kg or less, about 120 mg/kg or less, about 110 mg/kg or less, about 100 mg/kg or less, about 95 mg/kg or less, about 90 mg/kg or less, about 85 mg/kg or less, about 80 mg/kg or less, about 75 mg/kg or less, about 70 mg/kg or less, about 65 mg/kg or less, about 60 mg/kg or less, about 55 mg/kg or less, about 50 mg/kg or less, about 45 mg/kg or less, about 40 mg/kg or less, about 35 mg/kg or less, about 30 mg/kg or less, about 29 mg/kg or less, about 28 mg
  • This invention provides a method for treating or preventing malaria in a subject by administering to the subject an effective amount of a substituted tetracycline compound, such that malaria is treated or prevented in said subject.
  • X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O;
  • R 2 , R 2 , R 4 , and R 4 are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
  • R 4 is NR 4 R 4 , alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;
  • R 3 , R 1 ' and R 12 are each hydrogen, or a pro-drug moiety
  • R 5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
  • R 6 and R 6 are independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
  • R 7 is hydrogen, alkylamino, dialkylamino, or a malaria interacting moiety;
  • R 9 is hydrogen, or a malaria interacting moiety
  • R is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
  • Y' and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; with the proviso that the compound of formula I is not oxytetracycline, demeclocycline, doxycycline, chlorotetracycline, minocycline, or tetracycline; and pharmaceutically acceptable salts thereof.
  • Examples of compounds of formula I which can be used in the methods of the invention include substituted tetracycline compounds wherein R , R , R , R , and R 12 are hydrogen; R 4 is NR R" and R 4' and R 4" are alkyl (e.g., methyl); and X is CR 6 R 6' .
  • the substituted tetracycline compounds of the invention may also include substituted minocycline derivatives, e.g., wherein R , R , and R are hydrogen, and R is dialkylamino.
  • the substituted tetracycline compound of the invention is substituted at the 7 or 9 position with a malaria interacting moiety.
  • the term "malaria interacting moiety” is a moiety which allows the substituted tetracycline compound of the invention to perform its intended function, e.g., treat or prevent malaria. It may interact with the malaria parasite or allow other portions of the tetracycline molecule to interact with the parasite. It also may allow the molecule to treat malaria by affecting the way the tetracycline compound interacts with the malaria parasite, the subject, or other microbes.
  • the malaria interacting moiety may alter the tetracycline compounds' properties such that the resulting compound is, for example, non- antibacterial.
  • the malaria interacting moiety is a moiety which comprises from about 2 to 40, from about 3 to 30, from about 3 to 20 carbon, nitrogen, oxygen and sulfur atoms.
  • the malaria interacting moiety may further be substituted with hydrogen and other substituents (e.g., halogens) which are not counted amongst the 2 to 40, from about 3 to 30, from about 3 to 20 atoms.
  • the malaria interacting moiety comprises an aryl or heteroaryl moiety.
  • the aryl or heteroaryl moiety can be substituted with any substituent which allows it to perform its intended function.
  • Examples of malaria interacting moieties include aryl groups such as phenyl and heteroaryl groups (e.g., furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, methylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl, isooxazolyl, naphthridinyl, thiazolyl, isothiazolyl, and deazapurinyl).
  • aryl groups such as phenyl and heteroaryl groups (e.g., furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinoliny
  • the aryl group may be substituted or unsubstituted.
  • substituents include, but are not limited, alkyl, alkenyl, alkynyl, aralkyl, alkoxyalkyl, aminoalkyl, amino, nitro, cyano, halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxy, thiol, formyl, acetyl, acyl, alkoxy (e.g., methylene dioxy, methoxy, ethoxy, propoxy, etc.) and heterocyclic (e.g., morpholino, piperazine, etc.).
  • the substituents may be further substituted as appropriate.
  • R a and R b are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, or heterocyclic (R a and R b may optionally be linked to form a ring); g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; n is O, 1, 2, or 3; and X a , X b , X c , X d , and X e are each independently optionally substituted carbon, oxygen, nitrogen, or sulfur. Furthermore, each carbon atom of the malaria interacting moieties shown above may be further substituted with substituents which allow the tetracycline compound to perform its intended function.
  • substituents include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thio, amid
  • the methods of the invention also include the use of substituted tetracycline compounds which are sancycline derivatives, e.g., wherein R 5 , R 6 , and R 6 are hydrogen.
  • sancycline derivatives include tetracycline compounds wherein R 7 is a malaria interacting moiety.
  • malaria interacting moieties which may be used for substituted sancycline compounds of the invention include those described above.
  • other examples of malaria interacting moieties include, but are not limited to, aryl group such as substituted or unsubstituted phenyl or a heteroaryl moieties.
  • substituted sancycline compounds include compounds wherein R 9 is hydrogen or a malaria interacting moiety.
  • the substituted tetracycline compound has a molecular weight of less than 800, less than 600, less than 550, less than 500, or less than 400 grams/mole.
  • alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C 0 for straight chain, C 3 -C 6 for branched chain).
  • cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • C 2 -C 6 includes alkenyl groups containing 2 to 6 carbon atoms.
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure.
  • Lower alkenyl and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.
  • COS-1 and CHO cell suspensions are prepared, seeded into 96-well tissue culture treated black-walled microtiter plates (density determined by cell line), and incubated overnight at 37°C, in 5% CO 2 and approximately 95% humidity. The following day serial dilutions of drug are prepared under sterile conditions and transferred to cell plates. Cell/Drug plates are incubated under the above conditions for 24 hours. Following the incubation period, media/drug is aspirated and 50 ⁇ l of Resazurin is added. Plates are then incubated under the above conditions for 2 hours and then in the dark at room temperature for an additional 30 minutes. Fluorescence measurements are taken (excitation 535 nm, emission 590 n ).

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pain & Pain Management (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Pyridine Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Furan Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne une méthode de traitement ou de prévention du paludisme chez un sujet. Cette méthode consiste à administrer au sujet une quantité efficace d'un composé tétracycline substituée permettant de traiter ou de prévenir le paludisme. Dans une variante, cette invention concerne des compositions pharmaceutiques qui contiennent une quantité efficace d'un composé tétracycline visant à traiter le paludisme chez un sujet ainsi qu'un excipient pharmaceutiquement acceptable. Les composés tétracycline substituée de cette invention peuvent être associés à un ou plusieurs composés antipaludiques et peuvent être utilisés pour traiter ou prévenir un paludisme résistant à un ou plusieurs autres composés antipaludiques.
EP03781398A 2002-10-24 2003-10-24 Composes tetracycline substituee servant au traitement du paludisme Withdrawn EP1556007A4 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP10171327A EP2277504A1 (fr) 2002-10-24 2003-10-24 Composes tetracycline substituee servant au traitement du paludisme

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US42125902P 2002-10-24 2002-10-24
US421259P 2002-10-24
PCT/US2003/033927 WO2004038001A2 (fr) 2002-10-24 2003-10-24 Composes tetracycline substituee servant au traitement du paludisme

Publications (2)

Publication Number Publication Date
EP1556007A2 true EP1556007A2 (fr) 2005-07-27
EP1556007A4 EP1556007A4 (fr) 2008-12-17

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EP10171327A Withdrawn EP2277504A1 (fr) 2002-10-24 2003-10-24 Composes tetracycline substituee servant au traitement du paludisme
EP03781398A Withdrawn EP1556007A4 (fr) 2002-10-24 2003-10-24 Composes tetracycline substituee servant au traitement du paludisme

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP10171327A Withdrawn EP2277504A1 (fr) 2002-10-24 2003-10-24 Composes tetracycline substituee servant au traitement du paludisme

Country Status (6)

Country Link
EP (2) EP2277504A1 (fr)
JP (2) JP2006503898A (fr)
AU (3) AU2003287218C1 (fr)
CA (1) CA2502464A1 (fr)
IL (1) IL209319A0 (fr)
WO (1) WO2004038001A2 (fr)

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WO2002072506A2 (fr) * 2001-03-13 2002-09-19 Paratek Pharmaceuticals, Inc. Composes de 7-pyrollyl tetracycline et procedes d'utilisation associes
KR101148415B1 (ko) 2002-07-12 2012-05-21 파라테크 파마슈티컬스, 인크. 3, 10, 및 12ａ 치환된 테트라시클린 화합물
EA201100956A1 (ru) * 2003-07-09 2012-01-30 Пэрэтек Фамэсьютикэлс, Инк. Замещенные соединения тетрациклина (варианты), фармацевтическая композиция и способ лечения чувствительного к тетрациклину состояния у субъекта
AU2004259661B2 (en) * 2003-07-09 2011-11-10 Paratek Pharmaceuticals, Inc. Prodrugs of 9-aminomethyl tetracycline compounds
EP1753713B1 (fr) * 2004-05-21 2016-07-27 President and Fellows of Harvard College Synthese de tetracyclines et d'analogues de tetracyclines
EP1807387A2 (fr) * 2004-10-25 2007-07-18 Paratek Pharmaceuticals, Inc. Composes de tetracycline substitues
FR2891744B1 (fr) * 2005-10-06 2009-10-09 France Etat Armement Application a la chimioprophylaxie du paludisme d'une association de chloroquine et de doxycycline
AU2007235279B2 (en) 2006-04-07 2012-12-06 President And Fellows Of Harvard College Synthesis of tetracyclines and analogues thereof
US7763735B2 (en) 2006-10-11 2010-07-27 President And Fellows Of Harvard College Synthesis of enone intermediate
ES2463457T3 (es) * 2006-12-21 2014-05-28 Paratek Pharmaceuticals, Inc. Derivados de la tetraciclina para el tratamiento de infecciones bacterianas, virales y parasitarias
EP2213655A1 (fr) * 2007-04-27 2010-08-04 Paratek Pharmaceuticals, Inc. Procédés de purification de composés d'aminoalkyle de tétracycline
PT2271348T (pt) * 2008-03-28 2018-04-16 Paratek Pharm Innc Formulação de comprimido oral de composto de tetraciclina
MX2011001367A (es) 2008-08-08 2011-06-28 Tetraphase Pharmaceuticals Inc Compuestos de tetraciclina sustituidos con fluor en c7.
US9073829B2 (en) 2009-04-30 2015-07-07 President And Fellows Of Harvard College Synthesis of tetracyclines and intermediates thereto
US9315451B2 (en) 2009-05-08 2016-04-19 Tetraphase Pharmaceuticals, Inc. Tetracycline compounds
EP3275861A1 (fr) 2009-08-28 2018-01-31 Tetraphase Pharmaceuticals, Inc. Composés de tétracycline
CN101967108B (zh) * 2010-09-13 2013-06-19 苏春华 一种美他环素的衍生物
BR112014001798B1 (pt) 2011-07-26 2021-07-27 Kbp Biosciences Co., Ltd. Compostos de tetraciclina 9-aminometila substituídos, seu uso e composição farmacêutica
EP2890673B1 (fr) 2012-08-31 2018-11-14 Tetraphase Pharmaceuticals, Inc. Composés de tétracyclines
CN110582486B (zh) 2016-10-19 2024-01-12 四相制药公司 艾若威四环素的结晶形式
CN115380022A (zh) * 2018-04-06 2022-11-22 帕拉特克药品公司 萨瑞环素盐酸盐的制造方法

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