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WO2010108637A1 - Composé cristallisé - Google Patents

Composé cristallisé Download PDF

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Publication number
WO2010108637A1
WO2010108637A1 PCT/EP2010/001772 EP2010001772W WO2010108637A1 WO 2010108637 A1 WO2010108637 A1 WO 2010108637A1 EP 2010001772 W EP2010001772 W EP 2010001772W WO 2010108637 A1 WO2010108637 A1 WO 2010108637A1
Authority
WO
WIPO (PCT)
Prior art keywords
caspofungin diacetate
crystals
caspofungin
diacetate
suspension
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.)
Ceased
Application number
PCT/EP2010/001772
Other languages
English (en)
Inventor
Karol Horvath
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.)
Xellia Pharmaceuticals ApS
Original Assignee
Axellia Pharmaceuticals ApS
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 Axellia Pharmaceuticals ApS filed Critical Axellia Pharmaceuticals ApS
Publication of WO2010108637A1 publication Critical patent/WO2010108637A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid

Definitions

  • the invention relates to crystalline compounds, in particular a crystalline form of caspofungin diacetate.
  • Caspofungin is the first of a new class of semi-synthetic antifungal agents belonging to the class of echinocandins.
  • the drug is prepared by synthetic derivatisation of pneumocandin B 0 which is obtained by fermentation of the fungus Glarea lozoyensis.
  • Caspofungin inhibits the biosynthesis of ⁇ -(l,3)-D-glucan, an integral component of the fungal cell wall, and it is indicated for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies, as well as empirical therapy for presumed fungal infections in febrile, neutropenic patients.
  • Caspofungin is also used in the treatment of candidemia and some specific Candida infections (intra-abdominal abscesses, periotonitis, pleural cavity infections and oesophagitis). Caspofungin may also be used to treat general invasive candidiasis in adults. Caspofungin is marketed as its diacetate salt by Merck & Co., under the trade name Cancidas®.
  • Caspofungin as a compound is claimed in the patent US 5,378,804 issued to Merck & Co.
  • the drug was prepared in a lengthy synthetic sequence in 0.7% overall yield from pneumocandin B 0 .
  • the first two synthetic steps were the subject of the patent application EP 0 535 967 A2.
  • Reduction of the primary amide was effected in two steps, i.e. dehydration with cyanuric chloride affording an intermediate nitrile which was reduced with sodium borohydride in the presence of cobalt(II) chloride.
  • the aminal side-chain was introduced via substitution of 2-aminoethanethiol for the hemiaminal hydroxy function, oxidation to the sulfone, followed by substitution with 1,2-diaminoethane.
  • caspofungin diacetate A crystalline form of caspofungin diacetate is known in the art.
  • a crystallizing method described by Merck in the prior art is found in the Leonardo et al, J. Org. Chem. 2007, 72, 2335-2343. This article dictates that caspofungin diacetate is crystallised by dissolution of lyophilized material in a mixture of ethanol, water and acetic acid, followed by the addition of ethyl acetate as antisolvent. Seed material is added to induce crystallization.
  • Leonardo et al. teach the following process for the preparation of crystalline caspofungin diacetate:
  • the invention provides for a novel crystalline form of caspofungin diacetate, and a novel method for preparing a crystalline form of caspofungin diacetate.
  • the method according to the invention is a method where a salt is utilized to crystallize the compound out from the solution.
  • the preferred salt according to the invention is sodium chloride. The method and resulting crystalline form described in detail by the following example and comparative study.
  • Lyophilized caspofungin diacetate (Ig) was dissolved in water (30 ml) at room temperature. The pH was adjusted to 5 by the addition of acetic acid. An aqueous solution of sodium chloride (30 g, 10% w/w) was added. A small sample of the solution was withdrawn (2-3 ml), seeded with caspofungin diacetate crystals, and transferred back to the original solution. Crystallization occurred with formation of a suspension. After 30 min, the temperature was lowered to 0-5 0 C, and the suspension was allowed to age for 2 h. The product was isolated by filtration.
  • Lyophilized caspofungin diacetate (1 g) was dissolved in a mixture of absolute ethanol (10 ml) and water (1 ml) at room temperature. The pH was adjusted to 5 by the addition of acetic acid (0.06 g). Ethyl acetate (7 ml) was added, and a suspension was formed. The mixture was stirred for 1 h, and additional ethyl acetate (9 ml) was added. The suspension was allowed to age for 2 h at 0-5 0 C, and the solid material was isolated by filtration and washed with ethyl acetate.
  • Figure 1 shows XRD diffractogram for batch R78.247A.
  • Figure 2 shows DSC thermal events for batch R78.247A.
  • Figure 3 shows XRD diffractogram for batch Ba 322/73.
  • Figure 4 shows DSC thermal events for batch Ba 322/73.
  • Figure 5 shows XRD diffractogram for batch Ba 377/73.
  • Figure 6 shows DSC thermal events for batch Ba 377/73.
  • the differences in XRD diffractogram and melting point between batch Ba377/73 and R322/73 indicates that the method of the invention results in a different crystal form of caspofungin diacetate than that known in the prior art.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention concerne des composés cristallisés, en particulier une forme cristallisée de diacétate de caspofungine et leur préparation.
PCT/EP2010/001772 2009-03-27 2010-03-22 Composé cristallisé Ceased WO2010108637A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16388609P 2009-03-27 2009-03-27
US61/163,886 2009-03-27

Publications (1)

Publication Number Publication Date
WO2010108637A1 true WO2010108637A1 (fr) 2010-09-30

Family

ID=42135925

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/001772 Ceased WO2010108637A1 (fr) 2009-03-27 2010-03-22 Composé cristallisé

Country Status (1)

Country Link
WO (1) WO2010108637A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012041801A1 (fr) * 2010-09-28 2012-04-05 Dsm Sinochem Pharmaceuticals Netherlands B.V. Procédé d'isolement de cyclohexapeptide
EP2559696A4 (fr) * 2010-04-15 2013-10-30 Shanghai Techwell Biopharm Co Méthodes de purification d'un azacyclohexapeptide ou de son sel
WO2014177483A1 (fr) * 2013-05-02 2014-11-06 Dsm Sinochem Pharmaceuticals Netherlands B.V. Procédé pour isoler la caspofungine
US9446091B2 (en) 2011-04-22 2016-09-20 Shanghai Techwell Biopharmaceutical Co., Ltd. Caspofungin or salts thereof with high purity, as well as preparation method and use thereof
WO2020086931A1 (fr) * 2018-10-25 2020-04-30 Cidara Therapeutics, Inc. Polymorphe d'un agent antifongique de type échinocandine
CN112110991A (zh) * 2014-12-24 2020-12-22 上海天伟生物制药有限公司 一种含氮杂环六肽前体的组合物及其制备方法和用途

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0535967A2 (fr) 1991-10-01 1993-04-07 Merck & Co. Inc. Cyclohexapeptides bisaminés
US5378804A (en) 1993-03-16 1995-01-03 Merck & Co., Inc. Aza cyclohexapeptide compounds
US5527959A (en) * 1995-01-23 1996-06-18 Board Of Trustees Operating Michigan State University Crystalline composition of lysine and succinic acid or alkali metal salt thereof
WO1997039763A1 (fr) * 1996-04-19 1997-10-30 Merck & Co., Inc. Compositions contenant un agent antifongique et un tampon acetate
US20020161176A1 (en) * 1999-03-03 2002-10-31 Dalder Brian Weston Formation and anion-exchange of crystalline echinocandin ammonium salts
WO2007057141A1 (fr) 2005-11-15 2007-05-24 Sandoz Ag Procede et intermediaires pour la synthese de la caspofungine
WO2008012310A1 (fr) * 2006-07-26 2008-01-31 Sandoz Ag Préparations à base de caspofungine

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0535967A2 (fr) 1991-10-01 1993-04-07 Merck & Co. Inc. Cyclohexapeptides bisaminés
US5378804A (en) 1993-03-16 1995-01-03 Merck & Co., Inc. Aza cyclohexapeptide compounds
US5527959A (en) * 1995-01-23 1996-06-18 Board Of Trustees Operating Michigan State University Crystalline composition of lysine and succinic acid or alkali metal salt thereof
WO1997039763A1 (fr) * 1996-04-19 1997-10-30 Merck & Co., Inc. Compositions contenant un agent antifongique et un tampon acetate
US20020161176A1 (en) * 1999-03-03 2002-10-31 Dalder Brian Weston Formation and anion-exchange of crystalline echinocandin ammonium salts
WO2007057141A1 (fr) 2005-11-15 2007-05-24 Sandoz Ag Procede et intermediaires pour la synthese de la caspofungine
WO2008012310A1 (fr) * 2006-07-26 2008-01-31 Sandoz Ag Préparations à base de caspofungine

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LEONARD ET AL., J. ORG. CHEM., vol. 72, 2007, pages 2335 - 2343
LEONARD WILLIAM R JR ET AL: "Synthesis of the antifungal beta-1,3-glucan synthase inhibitor CANCIDAS (caspofungin acetate) from pneumocandin B-0", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, EASTON.; US LNKD- DOI:10.1021/JO062008I, vol. 72, no. 7, 1 March 2007 (2007-03-01), pages 2335 - 2343, XP002535918, ISSN: 0022-3263, [retrieved on 20070308] *
LEONARDO ET AL., J. ORG. CHEM., vol. 72, 2007, pages 2335 - 2343

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2559696A4 (fr) * 2010-04-15 2013-10-30 Shanghai Techwell Biopharm Co Méthodes de purification d'un azacyclohexapeptide ou de son sel
WO2012041801A1 (fr) * 2010-09-28 2012-04-05 Dsm Sinochem Pharmaceuticals Netherlands B.V. Procédé d'isolement de cyclohexapeptide
US9056897B2 (en) 2010-09-28 2015-06-16 DSM Sinochem Pharmaceuticals Method for isolating a cyclohexapeptide
US9446091B2 (en) 2011-04-22 2016-09-20 Shanghai Techwell Biopharmaceutical Co., Ltd. Caspofungin or salts thereof with high purity, as well as preparation method and use thereof
DE112012001839B4 (de) 2011-04-22 2019-02-07 Shanghai Techwell Biopharmaceutical Co., Ltd. Caspofungindiacetat mit hoher Reinheit sowie Herstellungsverfahren und Verwendung dafür
WO2014177483A1 (fr) * 2013-05-02 2014-11-06 Dsm Sinochem Pharmaceuticals Netherlands B.V. Procédé pour isoler la caspofungine
CN105164146A (zh) * 2013-05-02 2015-12-16 中化帝斯曼制药有限公司荷兰公司 分离卡泊芬净的方法
EP2992003B1 (fr) 2013-05-02 2017-01-25 DSM Sinochem Pharmaceuticals Netherlands B.V. Procédé pour isoler la caspofungine
US9828411B2 (en) 2013-05-02 2017-11-28 Dsm Sinochem Pharmaceuticals Netherlands B.V. Method for isolating caspofungin
CN112110991A (zh) * 2014-12-24 2020-12-22 上海天伟生物制药有限公司 一种含氮杂环六肽前体的组合物及其制备方法和用途
WO2020086931A1 (fr) * 2018-10-25 2020-04-30 Cidara Therapeutics, Inc. Polymorphe d'un agent antifongique de type échinocandine
US12060439B2 (en) 2018-10-25 2024-08-13 Napp Pharmaceutical Group Limited Polymorph of echinocandin antifungal agent

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