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WO2013095307A1 - Nouveaux sels cristallins de zofénopril, procédé pour les obtenir et leur utilisation à des fins de thérapie - Google Patents

Nouveaux sels cristallins de zofénopril, procédé pour les obtenir et leur utilisation à des fins de thérapie

Info

Publication number
WO2013095307A1
WO2013095307A1 PCT/SI2012/000040 SI2012000040W WO2013095307A1 WO 2013095307 A1 WO2013095307 A1 WO 2013095307A1 SI 2012000040 W SI2012000040 W SI 2012000040W WO 2013095307 A1 WO2013095307 A1 WO 2013095307A1
Authority
WO
WIPO (PCT)
Prior art keywords
zofenopril
salt
salts
following
spacing
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/SI2012/000040
Other languages
English (en)
Inventor
Rudolf RUČMAN
Pavel Zupet
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.)
Silverstone Pharma AG
Original Assignee
Silverstone Pharma AG
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 Silverstone Pharma AG filed Critical Silverstone Pharma AG
Priority to EP12753265.3A priority Critical patent/EP2794560A1/fr
Publication of WO2013095307A1 publication Critical patent/WO2013095307A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry and relates to new salts of zofenopril and polymorph forms thereof.
  • n 1 or 2
  • Ri can be H, a CH 3 or C 2 H 5 group and R 2 is a CH 2 OH group, or
  • the base is an organic diamino compound of formula III:
  • R can be H, an alkyl group having 1 to 6 carbon atoms or a benzyl group
  • m can represent 0 or 1 ,
  • X can represent an OH group or H.
  • zofenopril is used exclusively in the form of a calcium salt.
  • a drawback of this salt is its very low solubility in water and especially its numerous polymorph forms. Under certain conditions, it also happens that one polymorph form turns into another and a mixture of polymorph forms is obtained.
  • Zofenopril is an ACE inhibitor (abr.: Angiotensin Converting Enzyme) and is used in the treatment of cardiovascular diseases, especially for regulating high blood pressure and myocardial infarction. It further has lipophilic and antioxidative properties due to the presence of sulfide function.
  • Patent applications WO 2007/138352A1 and WO 2007/003963A1 disclose a process for producing a calcium salt of zofenopril, which in addition to polymorph form A also contains 6 % of other forms, wherein the solution of a soluble calcium salt, preferably calcium chloride is reacted with a solution of zofenopril acid or other salt of zofenopril.
  • the company Generics Ltd. protected two new polymorph crystal forms E in F in their patent application WO 2009/106894 Al, whereas patent application WO 2009/022168 Al discloses a new anhydrous form D of a calcium salt of zofenopril.
  • Patent application WO 2010/84515 A2 owned by Glenmark discloses a synthesis of zofenopril and its salts: amorphous and crystal forms of a calcium salt and in addition also salts with tert-butyl amine and dicyclohexylamine.
  • Publication MXPA 05013701 A-2007-06,14,6 of the company Menarini describes a pharmaceutical formulation of zofenopril with the diuretic hydrochlorotiazide.
  • Patent US 4,316,906 provides an exhaustive description of a synthesis of zofenopril and related compounds.
  • salts of zofenopril particularly calcium salt
  • their low solubility and bad resorption and in particular their tendency to form numerous polymorph forms as well as uncontrolled mixtures of polymorphic forms.
  • the present invention therefore relates to new salts of zofenopril represented with the above-stated general formula I and their hydrates having 1 to 3 molecules of water.
  • the present invention further relates to a process for the preparation of salts of zofenopril according to the present invention, said method comprising the following steps: a) combining a solution of zofenopril or its soluble salt with organic amino compounds or their salts,
  • pure zofenopril which is an acid
  • its soluble salt such as sodium or potassium salt
  • Ethylenediamine or a substituted ethylenediamine such as ⁇ , ⁇ '- dibenzylethylenediamine or ⁇ , ⁇ '-dimethylethylenediamine, or an amino alcohol such as 2-amino-l-butanol, 2-amino-l ethanol or l,3-diamino-2-propanol are used as organic bases.
  • Amino alcohols are used in a ratio of 1 mol to 1 mol of zofenopril and in case of a reaction with ethylene diamine derivatives in a ratio of 2 mol of zofenopril to 1 mol of ethylenediamine.
  • the reaction is performed at room temperature in a suitable solvent, such as methanol, ethanol, ethyl acetate, acetonitrile or in a mixture of these solvents with water.
  • a suitable solvent such as methanol, ethanol, ethyl acetate, acetonitrile or in a mixture of these solvents with water.
  • a third less polar solvent such as diethyl ether, n- hexane or methyl tert-butyl ether may be added in crystallization.
  • the present invention further relates to pharmaceutical formulations containing salts of zofenopril according to the present invention.
  • Salts of zofenopril prepared according to the present invention are used as active ingredients in the preparation of tablets or other solid forms by use of substances and processes which are common in manufacturing of solid pharmaceutical formulations, such as fillers, disintegrants, lubricants, glidants etc.
  • the salts of zofenopril in a pharmaceutical formulation may also be combined with diuretics such as indapamide, or with calcium ion inhibitors form the group of dihydropiridines (amlodipine, lacidipine).
  • the present invention thus further relates to the use of salts of zofenopril according to the present invention for manufacturing of a medicament for the treatment of arterial hipertension and miocardial infarction.
  • Fig. 1 ⁇ -NMR spectrum of salt of zofenopril with ⁇ , ⁇ '-ethylenediamine - trihydrate
  • Fig. 2 ⁇ -NMR spectrum of salt of zofenopril with N,N'-dimethylethylenediamine
  • Fig. 3 ⁇ -NMR spectrum of salt of zofenopril with N,N'-dibenzylethylenediamine
  • Fig. 4 ⁇ -NMR spectrum of salt of zofenopril with 1,3-diamino-l-propanol - trihydrate
  • Fig. 5 ⁇ -NMR spectrum of salt of zofenopril with (R)-2-amino-l-butanol
  • the X-ray powder diffractogram represented by the following 2 values and relative intensities (only reflexes above 10 % are indicated):
  • the X-ray powder diffractogram represented by the following 2 ⁇ -values and relative intensities (only reflexes above 10 % are indicated):
  • the X-ray powder diffractogram represented by the following 2 lvalues and relative intensities (only reflexes above 10 % are indicated): Position [2 ⁇ °] Spacing [d/A] Relative intensity [%]
  • the X-ray powder diffractogram represented by the following 2(9-values and relative intensities (only reflexes above 10 % are indicated):
  • the X-ray powder diffractogram represented by the following 2 ⁇ -values and relative intensities (only reflexes above 10 % are indicated):
  • the X-ray powder diffractogram represented by the following 2 ⁇ -values and relative intensities (only reflexes above 10 % are indicated):
  • Film coating ingredients hypromellose, titanium dioxide, macrogol 400, macrogol

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux sels de zofénopril sous une forme cristalline exactement définie, des procédés permettant leur préparation et des formulations pharmaceutiques sous forme solide destinées à être utilisées dans le traitement de l'infarctus du myocarde et de l'hypertension artérielle.
PCT/SI2012/000040 2011-12-19 2012-06-19 Nouveaux sels cristallins de zofénopril, procédé pour les obtenir et leur utilisation à des fins de thérapie Ceased WO2013095307A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP12753265.3A EP2794560A1 (fr) 2011-12-19 2012-06-19 Nouveaux sels cristallins de zofénopril, procédé pour les obtenir et leur utilisation à des fins de thérapie

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SIP-201100472 2011-12-19
SI201100472A SI23949A (sl) 2011-12-19 2011-12-19 Nove kristalne soli zofenoprila, postopek za njihovo dobivanje in njihova uporaba v terapiji

Publications (1)

Publication Number Publication Date
WO2013095307A1 true WO2013095307A1 (fr) 2013-06-27

Family

ID=46759025

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SI2012/000040 Ceased WO2013095307A1 (fr) 2011-12-19 2012-06-19 Nouveaux sels cristallins de zofénopril, procédé pour les obtenir et leur utilisation à des fins de thérapie

Country Status (3)

Country Link
EP (1) EP2794560A1 (fr)
SI (1) SI23949A (fr)
WO (1) WO2013095307A1 (fr)

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US431690A (en) 1890-07-08 William z
GB2028327A (en) 1978-08-11 1980-03-05 Squibb & Sons Inc Mercaptoacyl derivatives of substituted prolines
US4316906A (en) 1978-08-11 1982-02-23 E. R. Squibb & Sons, Inc. Mercaptoacyl derivatives of substituted prolines
US6515021B1 (en) 1996-03-14 2003-02-04 Centre International De Recherches Dermatologiques Galderma Bicyclic aromatic compounds
US6521760B1 (en) 1998-08-04 2003-02-18 Menarini Richerche S.P.A. Process for the preparation of zofenopril calcium salt
WO2007003963A1 (fr) 2005-07-01 2007-01-11 Generics [Uk] Limited Zofénopril calcium sous la forme polymorphique c
CN101012192A (zh) 2007-01-30 2007-08-08 广东邦民制药厂有限公司 一种佐芬普利钙的制备方法
CN101053563A (zh) 2006-04-12 2007-10-17 北京德众万全药物技术开发有限公司 佐芬普利口服药物组合物
WO2007138352A1 (fr) 2006-05-26 2007-12-06 Generics (Uk) Limited Zofénopril calcium
WO2009022168A1 (fr) 2007-08-10 2009-02-19 Generics [Uk] Limited Nouvelle forme cristalline
CN101372472A (zh) 2007-08-24 2009-02-25 扬子江药业集团上海海尼药业有限公司 佐芬普利钙盐合成方法
WO2009106894A1 (fr) 2008-02-27 2009-09-03 Generics [Uk] Limited Nouvelles formes cristallines
WO2010084515A2 (fr) 2009-01-23 2010-07-29 Glenmark Generics Limited Procédé pour la préparation de zofénopril et ses sels pharmaceutiquement acceptables

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US431690A (en) 1890-07-08 William z
GB2028327A (en) 1978-08-11 1980-03-05 Squibb & Sons Inc Mercaptoacyl derivatives of substituted prolines
US4316906A (en) 1978-08-11 1982-02-23 E. R. Squibb & Sons, Inc. Mercaptoacyl derivatives of substituted prolines
US6515021B1 (en) 1996-03-14 2003-02-04 Centre International De Recherches Dermatologiques Galderma Bicyclic aromatic compounds
US6521760B1 (en) 1998-08-04 2003-02-18 Menarini Richerche S.P.A. Process for the preparation of zofenopril calcium salt
WO2007003963A1 (fr) 2005-07-01 2007-01-11 Generics [Uk] Limited Zofénopril calcium sous la forme polymorphique c
CN101053563A (zh) 2006-04-12 2007-10-17 北京德众万全药物技术开发有限公司 佐芬普利口服药物组合物
WO2007138352A1 (fr) 2006-05-26 2007-12-06 Generics (Uk) Limited Zofénopril calcium
CN101012192A (zh) 2007-01-30 2007-08-08 广东邦民制药厂有限公司 一种佐芬普利钙的制备方法
WO2009022168A1 (fr) 2007-08-10 2009-02-19 Generics [Uk] Limited Nouvelle forme cristalline
CN101372472A (zh) 2007-08-24 2009-02-25 扬子江药业集团上海海尼药业有限公司 佐芬普利钙盐合成方法
WO2009106894A1 (fr) 2008-02-27 2009-09-03 Generics [Uk] Limited Nouvelles formes cristallines
WO2010084515A2 (fr) 2009-01-23 2010-07-29 Glenmark Generics Limited Procédé pour la préparation de zofénopril et ses sels pharmaceutiquement acceptables

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KUMAR L ET AL: "Salt selection in drug development", PHARMACEUTICAL TECHNOLOGY, ADVANSTAR COMMUNICATIONS,INC, US, vol. 32, no. 3, 1 March 2008 (2008-03-01), pages 128 - 146, XP008127365, ISSN: 1543-2521 *
STEFFEN PAULEKUHN G ET AL: "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 50, no. 26, 27 December 2007 (2007-12-27), pages 6665 - 6672, XP002651069, ISSN: 0022-2623, [retrieved on 20071201], DOI: 10.1021/JM701032Y *

Also Published As

Publication number Publication date
EP2794560A1 (fr) 2014-10-29
SI23949A (sl) 2013-06-28

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