WO2016016907A1 - Nouveaux polymorphes de (1s,2s,3r,5s)-3-[7-{[(1r,2s)-2-(3,4-difluorophényl)cyclopropyl]amino}-5-(propylthio)-3h-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyéthoxy)cyclopentane-1,2-diol - Google Patents

Nouveaux polymorphes de (1s,2s,3r,5s)-3-[7-{[(1r,2s)-2-(3,4-difluorophényl)cyclopropyl]amino}-5-(propylthio)-3h-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyéthoxy)cyclopentane-1,2-diol Download PDF

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Publication number
WO2016016907A1
WO2016016907A1 PCT/IN2015/000305 IN2015000305W WO2016016907A1 WO 2016016907 A1 WO2016016907 A1 WO 2016016907A1 IN 2015000305 W IN2015000305 W IN 2015000305W WO 2016016907 A1 WO2016016907 A1 WO 2016016907A1
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WIPO (PCT)
Prior art keywords
amino
cyclopropyl
difluorophenyl
pyrimidin
triazolo
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PCT/IN2015/000305
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English (en)
Inventor
Srinivasan Thirumalai Rajan
Original Assignee
Msn Laboratories Private Limited
Eswaraiah, Sajja
SATYANARAYANA, Kisara
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Application filed by Msn Laboratories Private Limited, Eswaraiah, Sajja, SATYANARAYANA, Kisara filed Critical Msn Laboratories Private Limited
Publication of WO2016016907A1 publication Critical patent/WO2016016907A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention provides novel polymorphs of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-
  • Ticagrelor is the first reversibly binding oral adenosine diphosphate (ADP) receptor antagonist and is chemically distinct from thienopyridine compounds like clopidogrel. It selectively inhibits P2Y12, a key target receptor for ADP. ADP receptor blockade inhibits the action of platelets in the blood, reducing recurrent thrombotic events.
  • the drug has shown a statistically significant primary efficacy against the widely prescribed clopidogrel (Plavix) in the prevention of cardiovascular (CV) events including myocardial infarction (heart attacks), stroke, and cardiovascular death in patients with ACS.
  • CV cardiovascular
  • U.S. Patent Application No. 2007/0293513 discloses four crystalline forms (polymorphs I, II, III and IV) of the compound of formula I (ticagrelor), processes for their preparation, and characterizes the polymorphs by powder X-ray diffraction (P-XRD) pattern and melting points which were determined using differential scanning calorimetry (DSC).
  • P-XRD powder X-ray diffraction
  • DSC differential scanning calorimetry
  • the '513 application teaches an amorphous form of ticagrelor (Form a), and a process for preparing it.
  • the ticagrelor in substantially amorphous form is produced by a process which comprises freeze drying or spray drying a solution of ticagrelor using a suitable solvent system, for example ethanol/water.
  • the Form a of ticagrelor is prepared by dissolving ticagrelor in a 50% aqueous solution of ethanol, followed by the drop-wise addition of water and then freeze drying the resulting saturated solution using Virtis instrumentation under the following conditions (vacuum 2170 mT, run time 20.2 hours, condensed temperature -52°C, ambient temperature 20.3°C).
  • Polymorphs are distinct solids having the same molecular formula yet having distinct advantageous physical properties compared to other polymorphic forms of the same compound. The difference in the physical properties of different polymorphic forms results from the orientation and intermolecular interactions of adjacent molecules in the bulk solid.
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of polymorphic forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption and solid state NMR spectrum.
  • One polymorphic form may give rise to thermal behavior different from that of another polymorphic form. Thermal behaviour can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) which have been used to distinguish polymorphic forms.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • the present inventors have now surprisingly and unexpectedly found a novel crystalline form of ticagrelor.
  • the novel crystalline form of ticagrelor is consistently reproducible, does not have the tendency to convert to other forms, and is found to be more stable.
  • the novel crystalline form disclosed herein exhibits properties making it suitable for formulating ticagrelor.
  • the first aspect of the present invention is to provide anhydrous crystalline form of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H- [l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l ,2-diol, herein after designated as crystalline form-M.
  • the second aspect of the present invention is to provide crystalline form of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H- [l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol, herein after designated as crystalline form-S.
  • the third aspect of the present invention is to provide process for the preparation of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl) cyclopropyl] amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclo pentane-l,2-diol compound of formula- 1.
  • the fourth aspect of the present invention is to provide a process for the preparation of crystalline form-S of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrirnidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane- 1 ,2-diol compound of formula- 1.
  • Figure-1 Illustrates the PXRD pattern of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
  • Figure-2 Illustrates the DSC endotherm of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
  • Figure-3 Illustrates the IR spectrum of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)- 2-(3 ,4-difluorophenyl)cyclopropyl] amino ⁇ -5-(propylthio)-3H-[ 1 ,2,3 ] -triazolo [4,5- d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
  • Figure-4 Illustrates the thermogravimetric thermogram of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H- [1,2,3] -triazolo [4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
  • Figure-5 Illustrates the PXRD pattern of crystalline form-S of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
  • Figure-6 Illustrates the PXRD pattern of amorphous form of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)- 2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
  • Detailed description of the invention :
  • suitable solvent refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diethyl ether, methyl tert-butyl ether, 1,2- dimethoxy ethane, tetrahydrofuran and the like; "ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, dioxane and the like; "chloro solvents” such as dichloromethane, dichloroethane, chloroform and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobuty
  • the first aspect of the present invention provides crystalline form-M of (1 S,2S,3R,5S)- 3-[7- ⁇ [(lR,2S)-2-(3,4-difiuorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]- triazolo[4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula- 1.
  • the crystalline form-M of the present invention is characterized by its powder X- Ray diffraction pattern having peaks at about 4.2, 6.3, 7.0, 8.7, 10.3, 13.0, 17.7, 18.7, 1 .9,
  • the crystalline form-M of the present invention is further characterized by its X-Ray powder diffraction pattern having additional peaks at about 5.4, 8.4, 13.2, 18.0, 19.2, 21.6, 22.0, 22.6, 23.8, 24.6,
  • the crystalline form-M is further characterized by the PXRD pattern as illustrated in figure- 1 and its differential scanning calorimetric (DSC) thermogram having an endofherms at 113.65°C, 138.32°C & 151.94°C as illustrated in figure-2.
  • DSC differential scanning calorimetric
  • the second aspect of the present invention provides crystalline form-S of
  • the crystalline form-S of the present invention is further characterized by its X- ay powder diffraction pattern having additional peaks at about 5.9, 8.4, 11.0, 12.1, 13.5, 16.8, 18.2, 19.5, 21.5, 22.7, 24.1, 25.2, 28.2, 30.0 and 33.1 ⁇ 0.2 degrees of 2-theta.
  • the crystalline form-S is further characterized by the PXRD pattern as illustrated in figure-5.
  • X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used).
  • intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation.
  • persons skilled in the art of X-ray powder diffraction will realize that the relative intensities of the peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used.
  • the skilled person will also realize that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer.
  • the surface planarity of the sample may also have a small effect.
  • the diffraction pattern data presented herein is not to be construed as absolute and any crystalline form that provides a powder diffraction pattern substantially identical to those disclosed herein fall within the scope of the present disclosure.
  • a measurement error of a diffraction angle in an X-ray powder diffraction pattern is typically ⁇ 0.2° of 2-theta.
  • melting point measured by DSC may occur as a result of variations in sample purity, sample preparation and the measurement conditions (e.g. heating rate). It will be appreciated that alternative readings of melting point may be given by other types of equipment or by using conditions different to those described hereinafter. Hence the melting point and endotherm figures quoted herein are not to be taken as absolute values and such measurement errors are to be taken into account when interpreting the DSC data. As a skilled person will realize, melting point can vary with sample purity and degree of crystallinity of the sample. Even low levels of impurities can affect the measured melting point. Therefore, the melting points disclosed herein may vary by ⁇ 5°C from the values quoted herein.
  • the third aspect of the present invention provides a process for the preparation of crystalline form-M of (l S,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino ⁇ -5-(propylthio)-3H-[l ,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclo pentane- 1 ,2-diol compound of formula- 1 , which comprises of:
  • step-c) adding water to the compound obtained in step-c) at a suitable temperature
  • the suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, ketone solvents, polar aprotic solvents or mixtures thereof; the suitable temperature is 0°C to reflux temperature of the solvent used in step a);
  • the suitable temperature in steps d), e) & h) are 10-50°C, preferably 25-30°C.
  • the suitable temperature in step i) is 25-60°C, preferably 45-50°C.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2 -hydroxy ethoxy)cyclopentane- 1 ,2-diol compound of formula- 1 , which comprises of:
  • step-c) adding water to the compound obtained in step-c) at 25-30°C j
  • the fourth aspect of the present invention provides a process for the preparation of crystalline form-S of (l S,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane- 1 ,2-diol compound of formula- 1 , which comprises of:
  • step-c) adding water to the compound obtained in step-c) at 25-30°C,
  • the crystalline (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimxdin-3-yl]-5-(2-hydroxyethoxy)cyclo pentane- 1 ,2-diol of the present invention can be utilized in the preparation of pharmaceutical compositions useful for the treatment of arterial thrombosis.
  • the PXRD analysis of the crystalline compound of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A 0 and at a continuous scan speed of 0.03°/min.
  • DSC Differential scanning calorimetric
  • Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • the best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention.
  • Example-1 Preparation of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4- difluorophenyl)cyclopropyl] amino ⁇ -5-(propylthio)-3H- [1 ,2,3]-triazoIo [4,5-d] pyrimidin- 3-yI]-5-(2-hydroxyethoxy)cycIopentane-l,2-diol (Forniula-l)
  • the PXRD of the obtained compound is shown in figure- 1, the DSC is shown in figure-2 and IR spectrum is shown in figure-3.
  • the termo gravimetric thermogram of the obtained compound shows anhydrous nature of the compound, which is illustrated in figure-4. Yield: 13.0 gm; Water content: 0.02% w/w.
  • Example-3 Preparation of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4- difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin- 3-yI]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol (Formula-1)
  • Example-5 Preparation of amorphous (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluoro phenyl)cyclopropyl]amino ⁇ -5-(propyIthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5- (2-ydroxyethoxy)cyclopentane-l,2-diol

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Abstract

Cette invention concerne de nouveaux polymorphes de (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophényl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo [4,5-d]pyrimidin-3-yl]-5-(2-hydroxyéthoxy) cyclopentane-1,2-diol représentés par la formule structurale 1 suivante et leur procédé de préparation.
PCT/IN2015/000305 2014-08-01 2015-07-31 Nouveaux polymorphes de (1s,2s,3r,5s)-3-[7-{[(1r,2s)-2-(3,4-difluorophényl)cyclopropyl]amino}-5-(propylthio)-3h-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyéthoxy)cyclopentane-1,2-diol WO2016016907A1 (fr)

Applications Claiming Priority (2)

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IN3795/CHE/2014 2014-08-01
IN3795CH2014 2014-08-01

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001092262A1 (fr) * 2000-06-02 2001-12-06 Astrazeneca Ab Nouvelle forme cristalline et amorphe d'un compose de triazolo(4,5-d)pyrimidine
WO2013079589A1 (fr) * 2011-11-30 2013-06-06 Actavis Group Ptc Ehf Nouvelle forme cristalline du ticagrelor et procédé pour sa préparation
WO2014166337A1 (fr) * 2013-04-07 2014-10-16 杭州领业医药科技有限公司 Forme cristalline de ticagrélor et son procédé de fabrication et son utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001092262A1 (fr) * 2000-06-02 2001-12-06 Astrazeneca Ab Nouvelle forme cristalline et amorphe d'un compose de triazolo(4,5-d)pyrimidine
WO2013079589A1 (fr) * 2011-11-30 2013-06-06 Actavis Group Ptc Ehf Nouvelle forme cristalline du ticagrelor et procédé pour sa préparation
WO2014166337A1 (fr) * 2013-04-07 2014-10-16 杭州领业医药科技有限公司 Forme cristalline de ticagrélor et son procédé de fabrication et son utilisation

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