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WO1996029325A1 - Composes homochiraux destines a la preparation de cetoconazole, de terconazole et medicaments antifongiques associes - Google Patents

Composes homochiraux destines a la preparation de cetoconazole, de terconazole et medicaments antifongiques associes Download PDF

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Publication number
WO1996029325A1
WO1996029325A1 PCT/EP1996/000972 EP9600972W WO9629325A1 WO 1996029325 A1 WO1996029325 A1 WO 1996029325A1 EP 9600972 W EP9600972 W EP 9600972W WO 9629325 A1 WO9629325 A1 WO 9629325A1
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WO
WIPO (PCT)
Prior art keywords
methyl
dichlorophenyl
dioxolane
compounds
imidazol
Prior art date
Application number
PCT/EP1996/000972
Other languages
English (en)
Inventor
Pelayo Camps Garcia
Xavier Farres Torrecabota
David Mauleon Casellas
Germano Carganico
Maria Luisa Garcia Perez
Original Assignee
Laboratorios Menarini S.A.
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 Laboratorios Menarini S.A. filed Critical Laboratorios Menarini S.A.
Priority to AU50039/96A priority Critical patent/AU5003996A/en
Publication of WO1996029325A1 publication Critical patent/WO1996029325A1/fr

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Classifications

    • 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
    • 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
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/24—Radicals substituted by singly bound oxygen or sulfur atoms esterified

Definitions

  • the present invention relates to novel homochiral compounds and the salts and solvates thereof.
  • the present invention also relates to a process for the preparation of the novel homochiral compounds, as well as their use in the preparation of enantiomerically pure ketoconazole, terconazole and related antifungal drugs.
  • the present invention further relates to the compounds (+)-terconazole and (-) terconazole, the pharmaceutically acceptable salts and solvates thereof, the pharmaceutical compositions containing them, having antifungal and antibacterial activities, and their use thereof in human and veterinary therapies.
  • a large number of pharmaceutically active compounds are commercialized as stereoisomeric mixtures. On the other hand, the case in which only one of said stereoisomers is pharmaceutically active is frequent.
  • the undesired enantiomer has a lower activity and it sometimes may cause undesired side-effects.
  • Ketoconazole (1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]piperazine), terconazole (1-[4-[[2(2,4-dichlorophenyl)-2-[(1H-1 , 2 ,4-triazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]-4-(1-methylethyl)piperazine) and other related azole antifungal drugs contain in their structure a substituted 1,3-dioxolane ring, in which carbon atoms C2 and C4 are stereogenic centres, therefore four possible stereoisomers are possible. These compounds are commercialized in the form or cis racemates which show a higher antifungal activity than the corresponding trans racemates.
  • the cis homochiral compounds of the present invention which are intermediates for the preparation of enantiomerically pure antifungal drugs, have been prepared previously in the racemic form and transformed into the different azole antifungal drugs in the racemic form [J. Heeres et al., J . Med . Chem . , 22 , 1003 (1979). J . Med . Chem . , 26, 611 (1983), J . Med . Chem . , 27 , 894 (1984) and US 4,144,346, 4,223,036, 4,358,449 and 4,335,125].
  • Scheme 1 shows the synthesis described for racemic ketoconazole [J. Heeres et al., J . Med . Chem . , 22 , 1003 (1979)].
  • racemic terconazole J. Heeres et al., J. Med . Chem . , 26 , 611 11983)
  • a 1 H- 1 , 2,4-triazol-1-yl substituent in place of 1H-imidazol-1-yl
  • phenol is 1-methylethyl-4-(4- hydroxyphenyl)piperazme instead of 1-acetyl-4-(4-nydroxyphenyl)piperazine.
  • racemic itraconazole J. Heeres et al., J. Med . Chem. , 27 , 894 (1984)] is similar to that of terconazole, differing only in the nature of the phenol used in the last step of the synthetic sequence.
  • the industrial preparation of enantiomerically pure antifungal drugs with a high antifungal activity and less side-effects is however a problem in therapy.
  • the present invention provides novel homochiral compounds which are intermediates for the industrial preparation of already known, enantiomerically pure antifungal drugs such as ketoconazole enantiomers, or of others which have not yet been reported in literature, which are described first in the present invention, such as (+)-terconazole and (-)-terconazoie, which show the cited antifungal action, allowing to attain the same therapeutical effectiveness using lower dosages than those required for racemic terconazole
  • the present invention relates to novel horrochira. compounds for the preparation cf ketoconazole terconazole and related antifungal drugs characterized by the formulae I, II, III or IV,
  • Ar is a phenyl or substituted phenyl group, so that the substituted phenyl group can contain one to three substituents, which can independently be fluorine, chlorine, bromine, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkyloxy;
  • Y is a CH group or a nitrogen atom
  • R is a (C 1 -C 4 )-alkyl, phenyl or substituted phenyl group with one or two substituents, which can independently be: fluorine, chlorine, bromine, (C 1 -C 4 )-alkyl or
  • the present invention also relates to compounds of formula V
  • Ar is 2,4-dichlorophenyl
  • Y is a nitrogen atom
  • Z is a CH(CH 3 ) 2 group.
  • the present invention also provides a process for the preparation of the novel homochiral compounds of formulae I, II, III and IV and their use as intermediates for the preparation of a number of azole antifungal drugs of formula V,
  • Ar and Y have the meanings defined above and Z is a group COCH 3 , CH(CH 3 ) 2 or
  • Preferred compounds of formulae I, II, III or IV are those wherein Ar is 2,4-dichlorophenyl and R is a methyl or 4-methylphenyl group.
  • Preferred compounds of the present invention are those wherein I, II, III or IV are the following:
  • Particularly preferred compounds of the present invention are also those wherein V are the following: - (2R, 4S)-(+)-1-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-1, 2,4-triazol-1-yl]methyl-1,3-dioxolane-4-yl]methoxy]phenyl]-4-(1-methylethyl)piperazine, (+)-terconazole;
  • the homochiral compounds of formulae I, II, III and IV, wherein Ar, Y and R have the meanings defined above are obtained following the synthetic sequence shown in scheme 3, starting from (R)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane, (R)-(+)-2.
  • the homochiral compounds I, II, III and IV are solids which are purified easily by crystailization, which allows also the enncnment in the desired enantiomer, when starting from (R)- or (S)-4- chloromethyl-2,2-dimethyl-1,3-dioxolane with enantiomeric excesses around 90%.
  • the starting compound ( R) - ( + ) - 2 can be obtained starting from (R)-epichlorohydrin following a synthetic process described in literature [S. Hamaguchi, JP 63051382, ( Chem . Abs t . 109:211035)].
  • (R)-(+)-6 can be determined by high performance liquid-liquid chromatography (HPLC) using the chiral stationary phase CHIRALCEL OD-H and hexane:isopropanol mixtures as eluent.
  • the homochiral compounds III can be obtained starting from the corresponding homochiral compounds I isolation of the corresponding compounds II being not necessary.
  • the enantiomerically pure compounds V (+) or ( - ) can be obt a ined , depend i ng on the c onf i gur at ion o f their precursors
  • the compounds of the present invention are formulated m the suitable pharmaceutical formulations, making use of conventional techniques and excipients, such as those described m Remington's Pharmaceutical Science Handbook, Mack Pub. Co., N.Y., USA.
  • suitable pharmaceutical formulations include capsules, tablets, syrups and similar containing 1 to 1,000 mg per unitary dose.
  • Example 7 (2 R ,4S)-(+)-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]piperazine (22, 4 S)-(+)-ketoconazole.
  • Example 8 (S)-(-)-(2.2-dimethyl-1,3-dioxolane-4-yl)methyl benzoate (S)-(-)-6.
  • This compound is prepared following the process used for the preparation of (R)-(+)-6.
  • (S)-(-)-2 (1,23 g, 8.17 mmol) and sodium benzoate (2.10 g, 14.6 mmol) in anhydrous DMSC
  • Example 9 Mixture of (2S , 4 S )-2-(bromomethyl)4-(chloromethyl)--2-(2,4-dichloroohenyl)-1,3-dioxolane, (2S , 4 S) - 4
  • This compound is prepared following the process described above for (2R,4S)-(+)-ketoconazole.
  • HNa 60-65% dispersion in paraffin, 32 mg, 0.80 mmol
  • 1-acetyl-4-(4-hydroxyphenyl)piperazine 153 mg, 0.69 mol
  • the resulting oily residue (790 mg ) is dissolved in a mixture of dioxane (4.9 ml), water (1 ml) and a 50% NaOH aqueous solution (6.5 ml), and the mixture is heated under reflux for 2 hours. The reaction mixture is allowed to cool to room temperature, diluted with water and extracted with CH 2 Cl 2 (3 ⁇ 30 ml).
  • Example 17 (2R,4S)-(+)-1-[4-[[2-(2,4-dichlorophenyl)- 2-[(1H-1,2,4-triazol-1-yl]methyl-1,3-dioxolane-4-yl]methyl]phenyl]-4-(1-methylethyl)piperazine, (2R,4S)-(+)-terconazole.
  • Example 20 (2S,4R) -(-)-1-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-1,2,4-triazol-1-yl]methyl-1,3-dioxolane-4-yl]methoxy]phenyl]-4-(1-methylethyl)piperazine, (2S,4R) - (-)-terconazole.

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

Abstract

La présente invention se rapporte à des nouveaux composés homochiraux qui sont des intermédiaires utilisés pour la préparation, sous une forme énantiomère pure, d'un certain nombre de médicaments antifongiques à base d'azole, de la formule (V). Dans cette formule Ar représente un groupe phényle ou un groupe phényle substitué de sorte qu'il puisse contenir un à trois substituants, lesquels peuvent être indépendamment fluor, chlore, brome, alkyle C1-C4 ou alkyloxy C1-C4; Y représente un groupe CH ou un atome d'azote; Z représente un groupe COCH3, CH(CH3)2 ou (a). L'invention se rapporte également à des composés (+)-terconazole et (-)-terconazole. Ces composés possèdent des activités antifongiques et antibactériennes et on peut les utiliser à des fins thérapeutiques chez l'humain et l'animal.
PCT/EP1996/000972 1995-03-17 1996-03-07 Composes homochiraux destines a la preparation de cetoconazole, de terconazole et medicaments antifongiques associes WO1996029325A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU50039/96A AU5003996A (en) 1995-03-17 1996-03-07 Homochiral compounds for the preparation of ketoconazole, terconazole and related antifungal drugs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ESP9500553 1995-03-17
ES9500553A ES2112151B1 (es) 1995-03-17 1995-03-17 Nuevos compuestos homoquirales para la preparacion de ketoconazol, terconazol y antifungicos relacionados, procedimiento para su fabricacion y utilizacion de los mismos.

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WO1996029325A1 true WO1996029325A1 (fr) 1996-09-26

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998021205A1 (fr) * 1996-11-12 1998-05-22 Sepracor, Inc. HYDROXY-ITRACONAZOLE 2R,4S,R,R ET $i(2S,4R,R,R)
WO1998021204A1 (fr) * 1996-11-12 1998-05-22 Sepracor, Inc. 2R,4S,S,S et 2S,4R,S,S HYDROXY ITRACONAZOLE
WO1998021203A1 (fr) * 1996-11-12 1998-05-22 Sepracor, Inc. 2r,4s,s,r- et 2s,4r,s,r-hydroxy-itraconazole
WO2010013510A1 (fr) * 2008-08-01 2010-02-04 ダイソー株式会社 Procédé de fabrication d'un composé optiquement actif
JP2010527972A (ja) * 2007-05-25 2010-08-19 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ （２ｓ−シス）−２−（ブロモメチル）−２−（４−クロロフェニル）−１，３−ジオキソラン−４−メタノールメタンスルホネート（エステル）の改良された合成
US8980930B2 (en) 2004-06-25 2015-03-17 The Johns Hopkins University Angiogenesis inhibitors
EP3858357A1 (fr) 2020-01-28 2021-08-04 Diaccurate Utilisation de composés d'azole pour stimuler le système immunitaire et d'inhibiteurs des s-pla2gib
CN116854657A (zh) * 2023-07-04 2023-10-10 浙江东亚药业股份有限公司 一种酮康唑中间体顺式溴代酯的制备方法
WO2024105519A1 (fr) * 2022-11-14 2024-05-23 Piramal Pharma Limited Procédé de préparation de lévokétoconazole

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0050298A2 (fr) * 1980-10-16 1982-04-28 Hoechst Aktiengesellschaft 1-(1,3-dioxolan-2-ylméthyl)-azoles, procédé pour leur préparation et leur application
EP0052905A1 (fr) * 1980-11-24 1982-06-02 Janssen Pharmaceutica N.V. Dérivés de (2-aryl-4-phénylthioalkyl-1,3-dioxolan-2-yl-méthyl)azole
US5208331A (en) * 1992-06-18 1993-05-04 Syntex (U.S.A.) Inc. Process for preparing 1,3-dioxolane derivatives
WO1993019061A1 (fr) * 1992-03-18 1993-09-30 Janssen Pharmaceutica N.V. Stereo-isomeres itraconazole et saperconazole
WO1994025452A1 (fr) * 1993-04-30 1994-11-10 Schering Corporation Procede de preparation d'intermediaires de synthese d'agents antifongiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0050298A2 (fr) * 1980-10-16 1982-04-28 Hoechst Aktiengesellschaft 1-(1,3-dioxolan-2-ylméthyl)-azoles, procédé pour leur préparation et leur application
EP0052905A1 (fr) * 1980-11-24 1982-06-02 Janssen Pharmaceutica N.V. Dérivés de (2-aryl-4-phénylthioalkyl-1,3-dioxolan-2-yl-méthyl)azole
WO1993019061A1 (fr) * 1992-03-18 1993-09-30 Janssen Pharmaceutica N.V. Stereo-isomeres itraconazole et saperconazole
US5208331A (en) * 1992-06-18 1993-05-04 Syntex (U.S.A.) Inc. Process for preparing 1,3-dioxolane derivatives
WO1994025452A1 (fr) * 1993-04-30 1994-11-10 Schering Corporation Procede de preparation d'intermediaires de synthese d'agents antifongiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
D.M. ROTSTEIN ET AL.: "Stereoisomers of ketoconazole: preparation and biological activity", JOURNAL OF MEDICINAL CHEMISTRY, vol. 35, no. 15, 24 July 1992 (1992-07-24), WASHINGTON US, pages 2818 - 2825, XP002003770 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998021205A1 (fr) * 1996-11-12 1998-05-22 Sepracor, Inc. HYDROXY-ITRACONAZOLE 2R,4S,R,R ET $i(2S,4R,R,R)
WO1998021204A1 (fr) * 1996-11-12 1998-05-22 Sepracor, Inc. 2R,4S,S,S et 2S,4R,S,S HYDROXY ITRACONAZOLE
WO1998021203A1 (fr) * 1996-11-12 1998-05-22 Sepracor, Inc. 2r,4s,s,r- et 2s,4r,s,r-hydroxy-itraconazole
US6455530B1 (en) 1996-11-12 2002-09-24 Sepracor Inc. 2R,4S,S,S- and 2S,4R,S,S-hydroxyitraconazole
US8980930B2 (en) 2004-06-25 2015-03-17 The Johns Hopkins University Angiogenesis inhibitors
US9642865B2 (en) 2004-06-25 2017-05-09 The Johns Hopkins University Angiogenesis inhibitors
JP2010527972A (ja) * 2007-05-25 2010-08-19 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ （２ｓ−シス）−２−（ブロモメチル）−２−（４−クロロフェニル）−１，３−ジオキソラン−４−メタノールメタンスルホネート（エステル）の改良された合成
WO2010013510A1 (fr) * 2008-08-01 2010-02-04 ダイソー株式会社 Procédé de fabrication d'un composé optiquement actif
EP3858357A1 (fr) 2020-01-28 2021-08-04 Diaccurate Utilisation de composés d'azole pour stimuler le système immunitaire et d'inhibiteurs des s-pla2gib
WO2021151964A1 (fr) 2020-01-28 2021-08-05 Diaccurate Utilisation de composés azole pour stimuler le système immunitaire et en tant qu'inhibiteurs de s-pla2gib
WO2024105519A1 (fr) * 2022-11-14 2024-05-23 Piramal Pharma Limited Procédé de préparation de lévokétoconazole
CN116854657A (zh) * 2023-07-04 2023-10-10 浙江东亚药业股份有限公司 一种酮康唑中间体顺式溴代酯的制备方法

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Publication number Publication date
ES2112151B1 (es) 1999-09-16
AU5003996A (en) 1996-10-08
ES2112151A1 (es) 1998-03-16

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