WO2009102226A1 - Sel d'acide malonique de la 5-[[4-[2-(méthyl-2-pyridinylamino)éthoxy]phényl]méthyl]-2,4-thiazolidinedione - Google Patents

Sel d'acide malonique de la 5-[[4-[2-(méthyl-2-pyridinylamino)éthoxy]phényl]méthyl]-2,4-thiazolidinedione Download PDF

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Publication number
WO2009102226A1
WO2009102226A1 PCT/PL2009/000015 PL2009000015W WO2009102226A1 WO 2009102226 A1 WO2009102226 A1 WO 2009102226A1 PL 2009000015 W PL2009000015 W PL 2009000015W WO 2009102226 A1 WO2009102226 A1 WO 2009102226A1
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Prior art keywords
methyl
salt
thiazolidinedione
ethoxy
phenyl
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PCT/PL2009/000015
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English (en)
Inventor
Michal Chodynski
Andrzej Kutner
Kinga Leszczynska
Anita Pietraszek
Magdalena Glice
Kataryzna Korczak
Wioleta Maruszak
Original Assignee
Adamed Sp. Z O.O.
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.)
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Application filed by Adamed Sp. Z O.O. filed Critical Adamed Sp. Z O.O.
Publication of WO2009102226A1 publication Critical patent/WO2009102226A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to new acid addition salt of 5-[[4-[2-(methyl-2- piridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione and to its use in medicine.
  • EP-A-O 306 228 discloses a group of thiazolidinedione derivatives with hypoglycemic and antidiabetic activity.
  • One of compounds described in EP-A-O 306 228 is 5-[[4-[2-(methyl-2- pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione also known under international non-proprietary name (INN) rosiglitazone.
  • INN international non-proprietary name
  • EP-A-O 306 228 reveals that rosiglitazone may exist in several tautomeric forms and/or solvated forms. Document also discusses the possibility of formation of pharmaceutically acceptable salts of rosiglitazone with alkali metals via thiazolidinedione moiety.
  • European patent application EP-A-O 658 161 discloses certain acid addition salts of 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4- thiazolidinedione formed by association of hydrogen atom of the acid moiety with any possible salt forming rosiglitazone group, particularly with nitrogen atom of pyridine.
  • rosiglitazone salt is maleic acid salt which is able to form tautomeric forms and/or solvates, especially hydrates.
  • FIG. 1 illustrates rosiglitazone malonate spatial conformation.
  • Fig. 2 illustrates packing of molecules in crystal lattice of rosiglitazone malonate
  • Fig. 3 is the X-ray powder diffraction pattern (XRPD) of the crystalline rosiglitazone malonate.
  • Fig. 4 shows infrared spectrum (KBr) of the crystalline rosiglitazone malonate.
  • the present invention provides malonic acid salt of 5-[[4-[2-(methyl-2- piridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione as a new chemical compound, referred hereinafter as rosiglitazone malonate.
  • the salt according to the present invention is isolated in stoichiometry wherein the molar ratio of 5-[[4-[2-(methyl-2- pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione (rosiglitazone base) to malonic acid is 1:1.
  • the chemical structure of rosiglitazone malonate may be represented by the general formula (I)
  • the invention encompasses all possible isomers, tautomers and/or solvates of the compound represented by formula (I).
  • the invention also provides a process for preparation of rosiglitazone malonate, its isomers, tautomers and/or solvates thereof, which consists in that 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione or the salt thereof, dispersed or dissolved in organic solvent, is reacted with malonic acid or its source.
  • the starting compound for the preparation process may be obtained according to any procedure known in the art, e.g. by the method disclosed in European Patent application EP-A-O 306 228.
  • the salt forming reaction is carried out with the use of a molar ratio of malonic acid to rosiglitazone base in a range from 1:1 to 1.2:1.
  • the suitable reaction solvents are aliphatic ketones, such as acetone; carboxylic acids esters, such as ethyl acetate; ethers, such as tetrahydrofurane, dioxane; nitriles, such as acetonitrile, or mixtures thereof.
  • malonate salt of rosiglitazone is prepared in a process comprising:
  • the most preferred reaction solvent according to the present invention is ethyl acetate.
  • Rosiglitazone malonate is obtained with a high yield.
  • the yield usually exceeds 93% (calculated on the starting rosiglitazone base).
  • the salt according to the invention is isolated from the reaction mixture in a crystalline form which is furthe aspect of the invention.
  • the crystalline salt of rosiglitazone malonate isolated from the reaction mixture is distinguished by very high chemical purity, regardless of the starting rosiglitazone base purity.
  • rosiglitazone malonate is obtained In situ, namely in the same solvent in which rosiglitazone base synthesis is carried out - without isolation from reaction mixture or purification of rosiglitazone base. 2009/000015
  • Rosiglitazone malonate according to the present invention is chemically stable. Under long-term and stress storage conditions neither the impurities nor water content increase was observed.
  • Rosiglitazone malonate according to the present invention consists of the moieties of rosiglitazone base and malonic acid in a molar ratio 1: 1.
  • the chemical structure of the new salt is confirmed by nuclear magnetic resonance 1 H-NMR and 13 C-NMR.
  • Crystallographic data in particular the unit cells dimensions, the volume of each cell, calculated density, and the measurement parameters are collected in Table 1.
  • Fig. 1 Spatial structure of rosiglitazone malonate
  • XRPD X-ray powder diffraction pattern
  • the crystalline rosigiitazone malonate according to invention is characterized by the X-ray powder diffraction pattern (XRPD) substantially as depleted in Fig.3,
  • the new rosiglitazone salt with malonic acid is well tolerated and pharmaceutically accepted (see, Handbook of Pharmaceutical Salts, ed. P. H. Stahl. CG. Wermuth, Verlag Helvetica Chimica Acta, 2002). Due to its advantageous physicochemical and toxicological properties, it may be used in the therapy and prophylaxis in humans. Pharmacological properties of malonate salt are expected to be the same as of rosiglitazone maleate.
  • the present invention accordingly provides rosiglitazone malonate, its isomers, tautomers and/or solvates thereof for use as an active therapeutic substance.
  • the present invention provides the use of rosiglitazone malonate, its isomers, tautomers and/or solvates thereof as the insulin sensitizer increasing glycaemic control, for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
  • the active substance rosiglitazone malonate may be administered to the patient per se, or as a pharmaceutical composition comprising therapeutically effective amount of the active substance together with at least one pharmaceutically acceptable carrier and/or excipient.
  • the present invention also provides a pharmaceutical composition which may be administered to a patient in a need for treatment in an appropriate pharmaceutical dosage form, dependent on the mode of administration.
  • the orally or parenterally administrable pharmaceutical dosage forms are preferred.
  • the active substance dose selection and the treatment regimes depend on the disease progression, age, body weight and condition of the patient, and may be determined by a skilled person basing on the known treatment and prophylaxis regimes appropriate for this kind of diseases.
  • rosiglitazone malonate may range from 1 to 16 mg per day, more preferably from 2 to 8 mg per day (calculated on rosiglitazone base). Rosiglitazone malonate may be administered to the patient either as a single daily dose or in 2 or more divided doses, as monotherapy or in combination with other therapeuticals, such as sulfonylureas, biguanides and/or alpha-glucosidase inhibitors. The components of such combinations may be administered to the patient in the form of one combined fixed-dosage pharmaceutical formulation or in separate formulations one after the other in order and time intervals established by a skilled person.
  • composition according to the present invention may be administered in the pharmaceutical form well-known to those skilled in the art. See: e .g. Remington's Pharmaceutical Sciences, 18 th ed., red. A.R.Gennaro, Mack Publ. Co., 1990, Easton, Pensylwania.
  • the pharmaceutical compositions may be adopted for oral administration, although compositions for administration by other routs, such as parenteral, are also envisaged.
  • the pharmaceutical oral dosage forms comprise solid dosage forms, such as tablets, coated tablets, powders, granules, pellets or capsules; and liquid dosage forms, such as suspensions, elixirs, solutions and syrups.
  • the active substance they contain pharmaceutically acceptable fillers and/or excipients.
  • the pharmaceutically acceptable fillers and/or excipients are the substances or mixtures thereof generally known in the art as not exerting their own pharmacological effect.
  • the suitable fillers for use in the solid dosage forms for the conventional release of the active substance include starch, lactose, microcrystalline cellulose, saccharose, sorbitol, talc, mannitol, mono- or dibasic calcium phosphate, pregelatinized starch, glycine and others.
  • the solid oral dosage forms may further contain excipients facilitating the manufacturing process and imparting required physicomechanical properties to the finished dosage form.
  • excipients may be selected from disintegrants, such as starch and starch derivates, crosscarmellose sodium, microcrystalline cellulose, crosslinked polyvinylpyrrolidone, starch sodium glycolate or other products based on crosslinked polymer; binders, such as polyvinylpyrrolidone, gelatin, natural and synthetic gums, cellulose derivative, e.g. hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose; lubricants, such as sodium lauryl sulphate; glidants, such as colloidal silicon dioxide, stearic acid, magnesium stearate, talc, fumaric acid and others.
  • the tablets optionally may be coated as described for example in
  • the coating formulations preferably contain film coating substance selected to provide the dissolution or fragmentation of the coating in the desired gastrointestinal tract section, together with the pharmaceutical excipients, such as plasticizers, fillers, opacifiers, colourants and polishing agents.
  • the film coating substances are preferably polymers such as cellulose derivatives, acrylic polymers and copolymers, high molecular weight polyethylene glycols, polyvinylpyrrolidone, polyvinyl alcohol and others.
  • Suitable plasticizers can be polyols, such as glycerol; organic esters such as phtalates, sebacates or citrates, and others.
  • parenteral compositions comprising rosiglitazone malonate in the parenteral dosage form, e.g. for intravenous, subcutaneous or intramuscular administration, may also be considered.
  • the parenteral compositions comprise sterile water, water-organic and non-water solutions and suspensions; lyophylisates and tablets suitable for reconstitution ex tempore.
  • suspending agents providing uniform active substance distribution in the liquid phase, such as polysorbates, lecithin, polyoxyethylene and polyoxypropylene copolymers; peptizers, such as phosphates, polyphosphates and citrates, water-soluble polymers, such as carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, hydrogenated oils, gums or gelatin, may be applied.
  • peptizers such as phosphates, polyphosphates and citrates
  • water-soluble polymers such as carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, hydrogenated oils, gums or gelatin
  • parenteral formulations may further contain pharmaceutically acceptable additives, such as solubilizers, preservatives, pH adjusting agents, buffers and tonicity agents.
  • pharmaceutically acceptable additives such as solubilizers, preservatives, pH adjusting agents, buffers and tonicity agents.
  • the present invention provides crystalline rosiglitazone malonate salt distinguished by high stability and polymorphic homogeneity.
  • the invention further provides efficient, reproducible manufacturing process of high chromatographic purity salt of rosiglitazone malonate.
  • the infrared absorption spectra were obtained from KBr pellets on SPECTRUM BX FT-IR system Perkin-Elmer spectrophotometer with Fourier transform.
  • the magnetic nuclear resonance spectra were recorded using GEMINI-200 Varian spectrophotometer.
  • the melting point was measured using differential scanning calorimetry on Mettler Toledo DSC 822 apparatus in alumina crucibles in temperature range of 40-200 0 C starting with the isothermic segment (4O 0 C, 3 minutes) followed by dynamic segment at heating rate 10°C/min.
  • the melting point was determined in two methods: (i) as "extrapolated peak", ie., the intersection of tangent to the peak, and (ii) as "onset”, ie., the intersection of tangents to the base line and to the rising peak line.
  • XRPD X-ray powder diffraction
  • rosiglitazone (10,4 g, 29,1 mmol) and ethyl acetate (250 ml_) were heated to boiling temperature while mixing. Then malonic acid was added (3,1 g, 29,8 mmol) and the reaction mixture was kept under reflux for 5 minutes. Then, the mixture was stirred at room temperature for 60 minutes and directly afterwards reaction mixture was left in fridge (O 0 C) for 4 h. Solid was filtered off, washed with cold ethyl acetate (50 ml_), then dried in vacuum- dryer (5O 0 C, 50 mbar,16 h). Rosiglitazone malonate was obtained with 96% yield (12.9 g)
  • rosiglitazone (1,64 g, 4.59 mmol) and malonic acid (0,48 g, 4.61 mmol) in 35 mL of THF were heated on water bath to reflux while stirring for 0.5 h. Obtained clear solution has been concentrated to about 17 mL and allowed to crystallize at 5 0 C for 16 h. The formed solid was filtered off, washed with cold THF (5 mL) and dried in vacuum-dryer (50 0 C, 50 mbar, 16 h). Rosiglitazone malonate was obtained with 68% yield (1.45 g).
  • Example 6 In 1 L capacity round-bottom flask equipped with stirrer and reflux condenser rosiglitazone malonate (8.0 g, 2.17 mmol) in 620 mL of ethyl acetate was heated to reflux with stirring for 5 minutes. Then water-bath has been removed and reaction mixture was stirred for 5 h at room temperature. The formed solid was filtered off using B ⁇ chner funnel, washed with cold ethyl acetate (-15 0 C, 50 mL) and dried in vacuum-dryer (40 0 C, 50 mbar, 16 h). Rosiglitazone malonate was obtained (5.4 g). Crystallization yield 68%.
  • the components of the core were pressed to round, biconvex tablet cores, 300.00 mg ⁇ 2% each. Cores were coated with Opadry® II coating. Coated tablets with approximated total mass of 309 mg and 10,328 mg of rosiglitazone malonate content (8 mg calculated on the rosiglitazone free base) were obtained.

Abstract

L'invention concerne le sel d'acide malonique de la 5-[[4-[2-(méthyl-2-pyridinylamino)éthoxy]phényl]méthyl]-2,4-thiazolidinedione, ainsi que ses isomères, tautomères et/ou solvates, et leur utilisation pour le traitement et/ou la prévention du diabète sucré, des affections associées au diabète sucré et de certaines de ses complications.
PCT/PL2009/000015 2008-02-12 2009-02-11 Sel d'acide malonique de la 5-[[4-[2-(méthyl-2-pyridinylamino)éthoxy]phényl]méthyl]-2,4-thiazolidinedione WO2009102226A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PL384446A PL384446A1 (pl) 2008-02-12 2008-02-12 Sól 5-[[4-[2-(metylo-2-pirydynyloamino)etoksy]fenylo]metylo]-2,4-tiazolidynodionu z kwasem malonowym i sposób jej wytwarzania
PLPL384446 2008-02-12

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2013068486A1 (fr) 2011-11-08 2013-05-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le diagnostic et le traitement de l'infertilité masculine
CN109053718A (zh) * 2018-08-09 2018-12-21 天津理工大学 一种罗格列酮糖精盐及其制备方法
CN109053717A (zh) * 2018-08-09 2018-12-21 天津理工大学 一种罗格列酮龙胆酸盐及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0306228A1 (fr) * 1987-09-04 1989-03-08 Beecham Group Plc Thiazolidinediones substituées
WO1994005659A1 (fr) * 1992-09-05 1994-03-17 Smithkline Beecham Plc Derives substitues de la thiazolidenedione
WO2003053962A1 (fr) * 2001-12-20 2003-07-03 Smithkline Beecham Plc Sel d'acide malique 5-(4-(2-(n-methyl-n-(2-pyridyl)amino)ethoxy) benzyl) thiazolidine-2, 4-dione et son utilisation contre le diabete sucre
WO2006125402A1 (fr) * 2005-05-24 2006-11-30 Zentiva, A.S. Procede de cristallisation de rosiglitazone et de ses derives a partir de solvants mixtes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0306228A1 (fr) * 1987-09-04 1989-03-08 Beecham Group Plc Thiazolidinediones substituées
WO1994005659A1 (fr) * 1992-09-05 1994-03-17 Smithkline Beecham Plc Derives substitues de la thiazolidenedione
WO2003053962A1 (fr) * 2001-12-20 2003-07-03 Smithkline Beecham Plc Sel d'acide malique 5-(4-(2-(n-methyl-n-(2-pyridyl)amino)ethoxy) benzyl) thiazolidine-2, 4-dione et son utilisation contre le diabete sucre
WO2006125402A1 (fr) * 2005-05-24 2006-11-30 Zentiva, A.S. Procede de cristallisation de rosiglitazone et de ses derives a partir de solvants mixtes

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2013068486A1 (fr) 2011-11-08 2013-05-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le diagnostic et le traitement de l'infertilité masculine
CN109053718A (zh) * 2018-08-09 2018-12-21 天津理工大学 一种罗格列酮糖精盐及其制备方法
CN109053717A (zh) * 2018-08-09 2018-12-21 天津理工大学 一种罗格列酮龙胆酸盐及其制备方法

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