WO2001089447A2 - Compose antifongique de tirazole a substitution propyle, ses sels, et ses procedes de preparation - Google Patents

Compose antifongique de tirazole a substitution propyle, ses sels, et ses procedes de preparation Download PDF

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Publication number
WO2001089447A2
WO2001089447A2 PCT/CN2001/000862 CN0100862W WO0189447A2 WO 2001089447 A2 WO2001089447 A2 WO 2001089447A2 CN 0100862 W CN0100862 W CN 0100862W WO 0189447 A2 WO0189447 A2 WO 0189447A2
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acid
group
butyl
propyl
iso
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PCT/CN2001/000862
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English (en)
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WO2001089447A8 (fr
WO2001089447A3 (fr
Inventor
Chaomei Liu
Qingyan Sun
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Second Military Medical University Of Pla.
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Priority to AU87525/01A priority Critical patent/AU8752501A/en
Publication of WO2001089447A2 publication Critical patent/WO2001089447A2/fr
Publication of WO2001089447A3 publication Critical patent/WO2001089447A3/fr
Publication of WO2001089447A8 publication Critical patent/WO2001089447A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • Antifungal substituted propyl triazole compound, its salt, and preparation methods thereof are antifungal substituted propyl triazole compound, its salt, and preparation methods thereof.
  • This invention relates to the field of medical technology, more particularly to an antifungal substituted propyl triazole compound, its salts, and preparation methods thereof.
  • azole drugs are noticeable in the development of all kinds of antifungal drugs.
  • the main action. mechanism of the drugs is known to inhibit the biosynthesis of ergosterol needed for the constitution of membrane of fungal cell, resulting in an inhibition of the growth of fungi.
  • fluconazole and itraconazole have been widely used in clinical treatment of fungal infections. Fluconazole is not effective against filamentous fungi and resistant strains are increasing constantly because of the wide use of fluconazole in high dose though fluconazole has a high bioavilability. Although itraconazole is active against filamentous fungi, its curative effect cannot be sustained, which may be relative to its high protein-binding and low bioavilability.
  • the first object of this invention is to provide a substituted propyl triazole compound, with wide-spectrum and more potent, lower toxic antifungal activity, and its salts.
  • the second object of this invention is to provide a preparation method of these compounds and its salts.
  • X is selected from hydrogen or alkyl, in which said alkyl can be straight or branched alkyl with 1-4 carbon atoms, e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, sec-butyl.
  • the alkyl is C ⁇ C 2 alkyl, particular preferably methyl.
  • M is hydrogen, hydroxy or ester group, in which said ester group is straight or branched ester group, e.g. formic ester group, acetic ester group, propionic ester group, isopropionic ester group.
  • the ester group is C ⁇ C 3 ester group, particular preferably acetic ester group.
  • Ar is selected from phenyl, naphthyl, thienyl, furyl, pyridyl and pyrimidinyl substituted by halogen, nitro group, trifluoromethyl or trifluoromethoxy group, in which said halogen may be F, Cl, Br or I.
  • halogen may be F, Cl, Br or I.
  • Ar is phenyl, naphthyland thienyl substituted by F, trifluoromethyl or trifluoromethoxy group, particular preferably p-fluorophenyl, 2,4-difluorophenyl. 2-chlorothienyl and naphthyl;
  • L represents hydrochloric acid, hydrobromic acid, methane sulfonic acid, nitric acid, sulfuric acid(include hydrosulfate), phosphoric acid(include hydrophosphate), acetic acid, oxalic acid,maleic acid, citric acid, fumaric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, malic acid, preferably hydrochloric acid, fumaric acid, gluconic acid, lactic acid and methane sulfonic acid.
  • R ⁇ 8 is selected from hydrogen, alkyl, cyano, or ester group.
  • the alkyl group is selected from C ⁇ C 4 straight or branched alkyl group, e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, tert- butyl, sec- butyl.
  • R ⁇ 8 is methyl, ethyl, cyano, or ester group.
  • Ri ⁇ Rg can also be one or two carbonyl group.
  • Z represents N or CH.
  • R represents:
  • alkyl group in which said alkyl group is selected from C ⁇ C 4 straight or branched alkyl group, e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl.
  • the alkyl is C 3 ⁇ C 4 alkyl, particular preferably iso-propyl and tert-butyl.
  • benzyl or substituted benzyl in which substituting groups in benzene ring may be in ortho-, meta- or para-position, the number of substituting groups is one to three, the substituting groups can be as follows: a. C 1 ⁇ C 4 straight or branched alkyl group, e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, preferably C 3 ⁇ C 4 alkyl groups, particular preferably iso-propyl and tert-butyl; b. C ⁇ C 4 straight or branched alkoxy groups, e.g.
  • the substituting groups in the sumstituted benzyl can be same or different, such as 3-chloro-4-aminobenzyl or 2-notro-4-cyanobenzyl etc..
  • substituting groups in benzene ring can be in ortho-, meta- or para-position, the number of substituting groups can be one to three, the substituting groups can be as follows: a. C ⁇ C 4 straight or branched alkyl groups; b. C ⁇ C 4 straight or branched alkoxy groups, e.g. methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, preferably methoxy or ethoxy, particular preferably C ⁇ C 3 alkoxy groups; c. halogen which is selected from one or two of F, Cl, Br or I; d.
  • NC- cyano-
  • e C ⁇ C 4 acyloxy group
  • f nitro- (0 2 N-)
  • g amino- (H 2 N-)
  • h acylamino- HNQR', in which Q is selected from CO or S0 2
  • R' is selected from the group consisting of C ⁇ C 4 straight or branched alkyl groups, C ⁇ C 4 straight or branched alkoxy group; phenyl or substituted phenyl groups, aromatic heterocycle groups.
  • the substituting groups in benzene ring are selected from one or two of F, Cl, Br or I; C ⁇ C 4 straight or branched alkyl groups; C ⁇ C 4 straight or branched alkoxy groups, nitro,trifluoromethyl and trifluoromethoxy groups.
  • the substituting groups in benzene ring can be same or different, such as 3-chloro-4-aminophenyl or 2-notro-4-cyanophenyl etc..
  • the example of aromatic heterocycle groups are. 2-furyl, 2-thiophenyl, 2-pyridyl, 3-pyridyl and 4-pyridyl; i.
  • triazolonyl group which is l,2,4-triazol-3-one substituted in 2- or 5-position, e.g. 2H-l,2,4-triazol- 3-one -4-yl or 4H-l,2,4-triazol-3-one-2-yl.
  • the intermediate 5-chloro-2'-bromoacetylthiophene was prepared according to the method of Liu Chaomei et al (Acta Pharmaceutica Sinica, 1987,22:736).
  • l-(5-chlorothiophen -2-yl)-2- (1H-1,2,4- triazol-l-yl)ethanone was prepared by the reflux of 5-chloro-2'-bromoacetolthiophene and 1,2,4-triazole in acetonitrile for 48 hrs.
  • the Friedel-Crafts reaction was introduced between naphthalene and chloroacetylchloride ( 1 :1.05 molecular ratio) at 50-55 °C in solvent dichloromethane and catalyzed by anhydrous aluminum chloride (A1C1 ) to form l-(chloroactyl)naphthalene.
  • 2-(lH-l,2,4-triazol-l-yl)acetonaphthone was formed by the reaction of l-(chloroactyl)naphthalene and triazole in ethyl acetate as a solvent and K 2 C0 3 as a catalyst.
  • the substitututed propyl triazole compounds ( I ) were synthesized by the ring-opening reaction between intermediate epoxide III , VI , VII with mono-substituted piperazine (or 4-substituted piperidine )in the alkali condition.
  • the preparation method of salts of substituted propyl triazole compounds in this invention is as follows :the substituted propyl triazole compounds ( I ) prepared as above and any excessive acid of acids L were reacted for 1 ⁇ 2 hrs at 0-25 °C. After reaction, the reaction solution was concentrated to give a precipitate, filtered to obtain salts ( II ) .
  • the element analytical data are supplied by Shanghai Institute of Pharmaceutical Industry.
  • the element analytical instrument used in this invention is MOD- 1106 type.
  • the Bruker Spectrospin. AC-P300 type of nuclear magnetic resonance instrument is used and the 1 HNMR data were supplied by instrument center of the Second Military Medical University.
  • the Yamato model MP-21 type of melting point instrument is used (the thermometer is not corrected).
  • Table 1 The structure of some preferable compounds.
  • the chloroform layer was dried for overnight with 5g of anhydrous sodium sulfate and filtered to remove desiccant sodium sulfate. The concentration of chloroform solution gave the crude product. Finally, by recrystallization from a mixture of 8ml of DMF and 6ml of water, obtained 1.65g of pure product, which melting point 181-182 ° C .yields 72.1%.
  • the substituted propyl triazole compound and its salts in this invention were tested for their antifungal activity in vitro by the standard method for antifungal susceptibility testing recommended by National Committee for Clinical Laboratory Standards (NCCLS) in the United States.
  • NCCLS National Committee for Clinical Laboratory Standards
  • the determination of the end-point (MIC80) was according to the concentration of the title compounds which inhibited 80% growth of the selected fungi.
  • the selected fungi were Candida albicans ATCC76615, Cryptococcus neoformans ATCC32609, Candida tropicalis, Candida parapsilosis, Sporothrix schenckii, and Trichophyton rubrum.
  • the key elements of this standard method were as follows:
  • pH buffer morpholinopropane sulfonic acid (0.165 mol/L);
  • the culture time The culture time for most of yeast is two days and for Cryptococcus neoformans is three days.
  • the determination of endpoint The concentrations of the title compounds which inhibited 80% growth of strain were the endpoints.
  • the substituted propyl triazole compound and its salts in this invention showed a wide-spectrum, low toxicity and potent activity against deep fungal infections.lt can be used to prepare the drugs for the treatment of fungal infections.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention porte sur des techniques médicales et en particulier sur un composé antifongique de triazole à substitution propyle, ses sels et des procédés de préparation. Ledit composé et ses sels sont représentés respectivement par les formules (I) et (II) dans lesquelles: X est sélectionné parmi: hydrogène ou un groupe alkyle; M est hydrogène, ou un groupe hydroxy ou ester; Ar est sélectionné parmi: phényle, naphthyle, thiényle, furyle, pyridyle et pyrimidinyle substitué par halogène, un groupe nitro, un groupe trifluorométhyle ou un groupe trifluorométhoxy; l'halogène est F, Cl, Br, ou I; L est acide hydrochlorique, acide hydrobromique, acide méthylsulfonique, acide nitrique, acide sulfurique, acide phosphorique, acide acétique, acide oxalique, acide maléique, acide citrique, acide fumarique, acide gluconique, acide lactique, acide maléique, acide succinique, acide tartarique, acide malique, et spécialement: acide hydrochlorique, acide fumarique, acide gluconique, acide lactique ou acide méthylsulfonique. Y est représenté par la formule (III) dans laquelle: R1∩8 est sélectionné parmi: hydrogène, ou un groupe alkyle, cyano, ou ester, le groupe alkyle étant sélectionné parmi un groupe C1∩C4 alkyle chaîné ou ramifié, par exemple: méthyle, éthyle, n-propyle, iso-propyle, n-butyle, iso- butyle, sec- butyle, tert- butyle, le premier choix étant méthyle, éthyle, cyano, ou un groupe ester; R1∩8R1 peu également être un ou deux groupes carbonyle; Z est sélectionné parmi: N ou CH; R est sélectionné parmi: (1) formacyle; (2) un groupe alkyle; (3) un groupe benzyle ou un groupe benzyle substitué; (4) un groupe phényle ou phényle substitué. Lesdits composés de triazole et leurs sels présentent une activité à large spectre, puissante, et à faible toxicité contre les infections fongiques systémiques. Ces composés et leurs sels peuvent donc servir à préparer des médicaments contre les infections fongiques graves.
PCT/CN2001/000862 2000-05-24 2001-05-24 Compose antifongique de tirazole a substitution propyle, ses sels, et ses procedes de preparation WO2001089447A2 (fr)

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CNB001158538A CN1137102C (zh) 2000-05-24 2000-05-24 取代丙基三唑类抗真菌化合物和其盐类以及制备方法
CN00115853.8 2000-05-24

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003004489A1 (fr) * 2001-07-05 2003-01-16 Gpc Biotech Inc. Compositions et procedes permettant d'inhiber des prenyltransferases
EP2536697A2 (fr) * 2010-02-12 2012-12-26 Daewoong Pharmaceutical Co., Ltd Nouveaux dérivés de triazole antifongiques
US8648198B2 (en) 2011-01-19 2014-02-11 Cold Spring Harbor Laboratory Phenylethanolamine-based NMDA receptor antagonists
EP2746276A1 (fr) 2012-12-19 2014-06-25 Basf Se Nouveaux triazoles substitués et imidazoles et leur utilisation comme fongicides
US9856230B2 (en) 2012-12-21 2018-01-02 University Of Sunderland Enzyme inhibitors
US12103916B2 (en) * 2016-12-08 2024-10-01 University Of Kentucky Research Foundation Antifungal compounds

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1303073C (zh) * 2005-05-31 2007-03-07 中国人民解放军第二军医大学 取代三唑酮苄胺三唑醇类抗真菌化合物及其制备方法
JP6397482B2 (ja) * 2013-04-12 2018-09-26 バイエル・クロップサイエンス・アクチェンゲゼルシャフト 新規トリアゾール誘導体
CN104725447A (zh) * 2015-04-02 2015-06-24 天津理工大学 一种3-S-四羟基-β-D-葡萄糖苷-1,2,4-三唑类化合物
CN105111261A (zh) * 2015-09-08 2015-12-02 天津理工大学 一种3-S-四羟基-β-D-葡萄糖苷-1,2,4-三唑类化合物及其制备方法和应用
CN116041330B (zh) * 2023-02-20 2024-06-04 中国药科大学 一种含苯并氮杂环侧链的三氮唑醇类抗真菌化合物及其制备方法与用途
CN116874430A (zh) * 2023-07-10 2023-10-13 四川农业大学 一种唑类化合物及其合成、制药应用

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003004489A1 (fr) * 2001-07-05 2003-01-16 Gpc Biotech Inc. Compositions et procedes permettant d'inhiber des prenyltransferases
EP2536697A2 (fr) * 2010-02-12 2012-12-26 Daewoong Pharmaceutical Co., Ltd Nouveaux dérivés de triazole antifongiques
JP2013519667A (ja) * 2010-02-12 2013-05-30 ダエウン ファーマシューティカル カンパニー リミテッド 新規抗真菌性トリアゾール誘導体
EP2536697A4 (fr) * 2010-02-12 2014-01-22 Dae Woong Pharma Nouveaux dérivés de triazole antifongiques
US8940768B2 (en) 2010-02-12 2015-01-27 Daewoong Pharmaceutical Co., Ltd. Antifungal triazole derivatives
US8648198B2 (en) 2011-01-19 2014-02-11 Cold Spring Harbor Laboratory Phenylethanolamine-based NMDA receptor antagonists
US9382227B2 (en) 2011-01-19 2016-07-05 Cold Spring Harbor Laboratory Phenylethanolamine-based NMDA receptor antagonists
EP2746276A1 (fr) 2012-12-19 2014-06-25 Basf Se Nouveaux triazoles substitués et imidazoles et leur utilisation comme fongicides
US9856230B2 (en) 2012-12-21 2018-01-02 University Of Sunderland Enzyme inhibitors
US12103916B2 (en) * 2016-12-08 2024-10-01 University Of Kentucky Research Foundation Antifungal compounds

Also Published As

Publication number Publication date
CN1137102C (zh) 2004-02-04
WO2001089447A8 (fr) 2002-05-23
WO2001089447A3 (fr) 2002-04-25
AU8752501A (en) 2001-12-03
CN1324792A (zh) 2001-12-05

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