WO2012090221A1 - Novel salts of imatinib - Google Patents

Novel salts of imatinib Download PDF

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Publication number
WO2012090221A1
WO2012090221A1 PCT/IN2011/000895 IN2011000895W WO2012090221A1 WO 2012090221 A1 WO2012090221 A1 WO 2012090221A1 IN 2011000895 W IN2011000895 W IN 2011000895W WO 2012090221 A1 WO2012090221 A1 WO 2012090221A1
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WO
WIPO (PCT)
Prior art keywords
imatinib
acid
solvent
crystalline
depicted
Prior art date
Application number
PCT/IN2011/000895
Other languages
French (fr)
Inventor
Kumar Kamlesh Laxmi Singh
Chetan Jayantibhai VASAVA
Nikhil Amar SINGH
Gulab Khushalrao PATHE
Original Assignee
Cadila Healthcare Limited
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Priority to IN3250/MUM/2010 priority Critical
Priority to IN3250MU2010 priority
Application filed by Cadila Healthcare Limited filed Critical Cadila Healthcare Limited
Publication of WO2012090221A1 publication Critical patent/WO2012090221A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The present inventiin discloses pharmaceutically acceptable salts of imatinib of Formula (II) wherein in S represent the acid selected from the group consisting of oxalic acid, ptoluene sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, amino acids like lysine, lysine HC1, arginine; which forms a salt with imatinib.

Description

NOVEL SALTS OF IMATINIB

FIELD OF THE INVENTION

The invention relates to imatinib and its pharmaceutically acceptable salts. The invention also relates to improved processes for the preparation of imatinib and its pharmaceutically acceptable salts. The invention also relates to pharmaceutical compositions that includes the therapeutically effective amount of pharmaceutically acceptable salts of imatinib.

BACKGROUND OF THE INVENTION

Imatinib, is chemically known as 4-[(4-methylpiperazin-l -yl)methyl]-N-[4- methyl-3-[[(4-pyridin-3-yl)pyrimidin-2-yl)]amino]phenyl]benzamide and represented by compound of Formula (I). Imatinib is in a class of protein-tyrosine kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply.

Figure imgf000002_0001

(I)

Imatinib acts as tyrosine kinase inhibitor and protein kinase inhibitor. It also acts as single transduction inhibitor. It is highly specific for BCR-ABL, the enzyme associated with chronic myelogenous leukemia and certain forms of acute lymphoblastic leukemia. It inhibits the transmembrane receptor KIT and platelet- derived growth factor (PDGF) receptors. It is used as Antineoplastic. It is used in the treatment of all kind of cancer such as leukemia, solid tumor, gastrointestinal cancer, prostate cancer, neurological cancer, myeloma and glioblastoma. It is also used in the treatment of, pulmonary fibrosis, rheumatoid arthritis and thrombocythemia.

U.S. Patent No. 5,521 , 184 discloses N-phenyl-2-pyrimidine amine compounds including Imatinib.

U.S. Patent No. 6,894,051 discloses mesylate salt of imatinib. The patent discloses that imatinib mesylate salt can exist in needle-shaped a-crystalline form or non-needle-shaped β-crystalline form. It is reported that β-crystalline form has improved properties. The efforts to improve the property of imatinib mesylate salt has work out continuously and various polymorphic forms are reported in several patent applications.

U.S. Patent Application No. 20090264438 discloses several crystalline forms of imatinib mesylate namely designated as Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV and Form XVI.

International (PCT) publication WO 2004/106326 discloses novel crystalline Form HI of imatinib mesylate by using chlorinated solvent.

International (PCT) publication WO 2005/077933 discloses novel a.2 crystalline form of imatinib mesylate. The a2 crystalline form is stable and less hygroscopic in nature and suitable for Formulation development.

International (PCT) publication WO 2006/054314 discloses two crystalline polymorphic forms of imatinib mesylate designated as Form I and Form II. Both the polymorphs are reported as stable form under normal condition.

International (PCT) publication WO 2007/023182 discloses crystalline Form δ and Form ε of imatinib mesylate and international (PCT) publication WO 2007/059963A1 discloses crystalline Form F, G, H, I and K of imatinib mesylate.

Therefore, it is desirous to improve the properties of imatinib for pharmaceutical use.

International (PCT) publication WO 2005/075454 discloses imatinib acid addition salts like tartrate, citrate, maleate, fumarate, succinate, benzoate, besylate, palmoate, formate, malonate, napsylate, salysilate, cyclohexane sulfamate, lactate, mandalate, glutarate, adipate, squarate, vallinate, oxaloacetate, ascorbate and sulfate salts. According to the disclosure, only tartrate, malonate and succinate salt are having higher solubility.

Although imatinib mesylate provides good pharmaceutical activity, it would be beneficial to find other forms of imatinib since, imatinib forms having advantageous properties for pharmaceutical use.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide pharmaceutically acceptable salts of imatinib.

Another object of the present invention is to provide processes for preparing pharmaceutically acceptable salts of imatinib. Yet another object of the present invention is to provide a pharmaceutical composition comprising pharmaceutically acceptable salts of imatinib.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG.l : X-ray diffraction pattern of imatinib maleate crystalline form.

FIG.2: Differential Scanning Calorimetry of imatinib maleate crystalline form.

FIG.3: Infrared spectrum of crystalline imatinib maleate crystalline form.

FIG.4: X-ray diffraction pattern of imatinib phosphate amorphous form.

FIG.5: Differential Scanning Calorimetry of imatinib phosphate amorphous form.

FIG.6: X-ray diffraction pattern of imatinib lysinate crystalline form.

FIG.7: Differential Scanning Calorimetry of imatinib lysinate crystalline form.

FIG.8: Infrared spectrum of crystalline imatinib lysinate crystalline form.

FIG.9: X-ray diffraction pattern of imatinib oxalate crystalline form.

FIG.10: Differential Scanning Calorimetry of imatinib oxalate crystalline form.

FIG.l 1: Infrared spectrum of crystalline imatinib oxalate crystalline form.

FIG.12: X-ray diffraction pattern of imatinib tosylate amorphous form.

FIG.13: X-ray diffraction pattern of imatinib tosylate crystalline form.

FIG.14: Differential Scanning Calorimetry of imatinib tosylate crystalline form.

FIG.15: Infrared spectrum of crystalline imatinib tosylate crystalline form.

FIG.16: X-ray diffraction pattern of imatinib nitrate crystalline form.

FIG.17: Differential Scanning Calorimetry of imatinib nitrate crystalline form.

FIG.18: Infrared spectrum of crystalline imatinib nitrate crystalline form.

FIG.19: X-ray diffraction pattern of imatinib arginate crystalline form.

FIG.20: Differential Scanning Calorimetry of imatinib arginate crystalline form.

FIG.21: Infrared spectrum of crystalline imatinib arginate crystalline form.

FIG.22: X-ray diffraction pattern of imatinib maleate crystalline form as per reference

Example-9.

FIG.23: Differential Scanning Calorimetry of imatinib maleate crystalline form as per reference Example-9.

DETAILED DESCRIPTION OF THE INVENTION

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention that come within the scope of any claims and their equivalents. The present inventors have found that by preparing pharmaceutically acceptable salts of imatinib free base in crystalline form, the formation of impurities can be minimized and better purity and chemical stability can be achieved. The inventors have developed different acid addition salts of imatinib which exhibit improved physiochemical properties like melting point, solubility, toxicology, and improved stability under various stress conditions.

The term "elevated temperature" used herein means, heating the reaction mixture either heterogeneous or homogeneous at a temperature from about 35°C to boiling point of solvent. In particular, from about 35°C to about 100°C. The term "ambient temperature" used herein means, slurrying the reaction mixture either heterogeneous or homogeneous at a temperature from about 0°C to about 35°C of solvent.

"Suitable solvent" means a single or a combination of two or more solvents. The present invention relates to imatinib (I) and its pharmaceutically acceptable salts thereof, to the processes for their preparation and isolation, and to pharmaceutical compositions comprising the same.

Figure imgf000005_0001

(I)

The present inventors have prepared certain salt forms of imatinib and structurally characterized them as described herein. The salts forms are also referred as , pharmaceutically acceptable salts of imatinib. These salts can be oxalate, p-toluene sulfonate, naphthalene sulfonate, benzene sulfonate, nitrate, phosphate, acetate, maleate, fumarate, lysinate, lysinate HC1, arginate salts of imatinib.

In one aspect, the present invention provides pharmaceutically acceptable salts of imatinib of Formu

Figure imgf000005_0002

(II) wherein in S represent the acid selected from the group consisting of oxalic acid, p- toluene sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, amino acids like lysine, lysine HC1, arginine; which forms a salt with imatinib.

The novel pharmaceutically acceptable salts of the invention are expected to provide potential advantages over other reported salts of imatinib. Without limitations these advantages may include improved purity profile, improved pharmacokinetics properties desirable for modified release, immediate release and injectable dosage forms, ease of pharmaceutical processing, discovery of novel polymorphs, improved stability. In summary, a combination of these improved properties of novel salt of imatinib is expected to provide improved overall treatment outcomes.

Accordingly in first aspect, the invention relates to new salts of imatinib, namely imatinib oxalate, imatinib besylate, imatinib nitrate, imatinib tosylate, imatinib napsylate, imatinib phosphate, imatinib maleate, imatinib fumarate, imatinib arginate, imatinib lysinate, imatinib lysinate HC1 compounds or its hydrate. The compound may be isolated and/or purified or it may be part of