WO2011039107A1 - Method for the preparation of a crystalline form of 1-chloro-4- (beta-d-glucopyranos-1-yl)-2-(4-((s)-tetrahydrofuran-3-yloxy)benzyl)benzene - Google Patents
Method for the preparation of a crystalline form of 1-chloro-4- (beta-d-glucopyranos-1-yl)-2-(4-((s)-tetrahydrofuran-3-yloxy)benzyl)benzene Download PDFInfo
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- WO2011039107A1 WO2011039107A1 PCT/EP2010/064117 EP2010064117W WO2011039107A1 WO 2011039107 A1 WO2011039107 A1 WO 2011039107A1 EP 2010064117 W EP2010064117 W EP 2010064117W WO 2011039107 A1 WO2011039107 A1 WO 2011039107A1
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- VSANEFHLKLICBN-ZAUCCHTLSA-N Cc1ccc(C(CC2O)OC(CO)[C@H]2O)cc1Cc(cc1)ccc1OCC1COCC1 Chemical compound Cc1ccc(C(CC2O)OC(CO)[C@H]2O)cc1Cc(cc1)ccc1OCC1COCC1 VSANEFHLKLICBN-ZAUCCHTLSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- 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
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- 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
- A61P3/04—Anorexiants; Antiobesity agents
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- 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
- A61P3/06—Antihyperlipidemics
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
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- 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
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- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- 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
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/04—Carbocyclic radicals
Definitions
- the invention relates to a method for the preparation for a crystalline form of 1 - chloro-4-( ⁇ -D-glucopyranos-1 -yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]- 5 benzene.
- the invention relates to a crystalline form obtainable by such a method and the use of the crystalline form for preparing medicaments.
- the compounds described therein have a valuable inhibitory effect on the sodium-dependent glucose cotransporter SGLT, particularly SGLT2.
- a crystalline form of the compound A and a method for its preparation are described in the international application WO 2006/1 17359.
- preferred solvents for example methanol, ethanol, isopropanol, ethyl acetate, diethylether, acetone, water and5 mixtures thereof are described for the crystallization process.
- the aim of the present invention is to find an advantageous method for preparing a crystalline form of a compound 1 -chloro-4- ⁇ -D-glucopyranos-1 -yl)-2-[4-((S)- tetrahydrofuran-3-yloxy)-benzyl]-benzene; in particular a robust method with which the crystalline form may be obtained in a high purity, with a low content of certain impurities, and/or which allows the manufacture of the crystalline form in a commercial scale with a low technical expenditure and a high space/time yield.
- Another aim of the present invention is to provide a crystalline form of 1 -chloro-4- ⁇ - D-glucopyranos-1 -yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, in particular in a high purity.
- a further aim of the present invention is to provide a pharmaceutical composition comprising the crystalline form.
- Another aim of the present invention is to provide a use of the crystalline form.
- the present invention relates to a method for preparing a crystalline form of a compound 1 -chloro-4-( ⁇ -D-glucopyranos-1 -yl)-2-[4-((S)-tetrahydrofuran-3- yloxy)-benzyl]-benzene comprising the following steps: (a) dissolving the compound in a mixture of at least two solvents to form a solution wherein the first solvent is selected from the group of solvents consisting of toluene and tetrahydrofuran, and the second solvent is selected from the group of solvents consisting of methanol, ethanol, 1 -propanol and 2-propanol, or
- the first solvent is ethanol and the second solvent is selected from the group of solvents consisting of ethylacetate, n-propylacetate and methylethyl ketone;
- the crystalline form can be obtained in a high purity and in a high yield, in particular at commercially viable scales.
- the method shows a low technical expenditure and a high space/time yield.
- the method yields the crystalline form in a high purity.
- impurities of the formulas IMP.1 and IMP.2 can be depleted to a high degree:
- the present invention relates to the crystalline form of a compound 1 -chloro-4-( ⁇ -D-glucopyranos-1 -yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]- benzene obtainable by a process as described hereinbefore and hereinafter.
- the present invention relates to the crystalline form of a compound 1 -chloro-4-( ⁇ -D-glucopyranos-1 -yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]- benzene having an X-ray powder diffraction pattern that comprises peaks at 18.84, 20.36 and 25.21 degrees 2 ⁇ ( ⁇ 0.1 degrees 2 ⁇ ), wherein said X-ray powder diffraction pattern is made using CuK a i radiation, characterized by a purity above 99 % as measured by HPLC.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising the crystalline form as described hereinbefore and hereinafter.
- the present invention relates to a use of the crystalline form as described hereinbefore and hereinafter for preparing a pharmaceutical composition which is suitable for the treatment or prevention of metabolic disorders, in particular of a metabolic disorder selected from the group consisting of type 1 and type 2 diabetes mellitus, complications of diabetes, metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, oedema and hyperuricaemia.
- a metabolic disorder selected from the group consisting of type 1 and type 2 diabetes mellitus, complications of diabetes, metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, oedema and hyperuricaemia.
- the Figure 1 shows a background corrected X-ray powder diffractogram of the crystalline form of the compound A.
- the Figure 2 shows the thermoanalysis via DSC of the crystalline form of the compound A. Detailed description of the invention
- This crystalline form of the compound A may be identified by means of their characteristic X-ray powder diffraction (XRPD) patterns, in particular as described in the WO 2006/1 17359.
- XRPD characteristic X-ray powder diffraction
- the crystalline form is characterised by an X-ray powder diffraction pattern that comprises peaks at 18.84, 20.36 and 25.21 degrees 2 ⁇ ( ⁇ 0.1 degrees 2 ⁇ ), wherein said X-ray powder diffraction pattern is made using CuK a i radiation.
- said X-ray powder diffraction pattern comprises peaks at 14.69, 18.84, 19.16, 19.50, 20.36 and 25.21 degrees 2 ⁇ ( ⁇ 0.1 degrees 2 ⁇ ), wherein said X-ray powder diffraction pattern is made using CuK a i radiation.
- Said X-ray powder diffraction pattern is even more characterised by peaks at 14.69, 17.95, 18.84, 19.16, 19.50, 20.36, 22.71 , 23.44, 24.81 and 25.21 degrees 2 ⁇ ( ⁇ 0.1 degrees 2 ⁇ ), wherein said X-ray powder diffraction pattern is made using CuK a i radiation.
- the crystalline form of the compound A is characterised by an X- ray powder diffraction pattern, made using CuK a i radiation, which comprises peaks at degrees 2 ⁇ ( ⁇ 0.1 degrees 2 ⁇ ) as contained in the Table 1 of WO 2006/1 17359 or as contained in the Table 1 of the Experiment A of the present application or as shown in the Figure 1 of WO 2006/1 17359 or as shown in the Figure 1 of the present application.
- the crystalline form of the compound A is characterised by a melting point of about 151 °C ⁇ 5°C (determined via DSC; evaluated as onset-temperature; heating rate 10 K/min).
- the above described 2 ⁇ values should be considered accurate to ⁇ 0.1 degrees 2 ⁇ , in particular ⁇ 0.05 degrees 2 ⁇ . That is to say, when assessing whether a given sample of crystals of the compound A is the crystalline form in accordance with the invention, a 2 ⁇ value which is experimentally observed for the sample should be considered identical with a characteristic value described above if it falls within ⁇ 0.1 degrees 2 ⁇ , in particular ⁇ 0.05 degrees 2 ⁇ of the characteristic value.
- the melting point is determined by DSC (Differential Scanning Calorimetry) using a DSC 821 (Mettler Toledo).
- the present invention relates to a method for preparing a crystalline form of the compound A comprising the following steps:
- the first solvent is ethanol and the second solvent is selected from the group of solvents consisting of ethylacetate, n-propylacetate and methylethyl ketone;
- the first solvent is preferably selected from the group of solvents consisting of toluene and tetrahydrofuran.
- the second solvent is preferably selected from the group of solvents consisting of methanol, ethanol, 1 -propanol and 2-propanol; even more preferably from the group of solvents consisting of ethanol, 1 -propanol and 2-propanol.
- the first solvent is ethanol and the second solvent is n-propylacetate or ethylacetate.
- mixtures of at least two solvents are toluene/methanol, toluene/ethanol, toluene/1 -propanol, toluene/2-propanol, tetrahydrofuran/methanol,
- tetrahydrofuran/ethanol tetrahydrofuran/1 -propanol, tetrahydrofuran/2-propanol, ethanol/n-propylacetate, ethanol/ethylacetate, ethanol/methylethylketon.
- Preferred examples of mixtures of at least two solvents are toluene/ethanol, toluene/1 -propanol, toluene/2-propanol, tetrahydrofuran/ethanol, tetrahydrofuran/1 - propanol, tetrahydrofuran/2-propanol, ethanol/n-propylacetate, ethanol/ethylacetate.
- the weight ratio of the first solvent to the second solvent is preferably in the range from about 1 : 10 to 10 : 1 , more preferably from about 1 : 5 to 5 : 1 , even more preferably from about 1 : 2 to 2 : 1 , most preferably about 1 : 1 .
- the weight ratio of the first solvent to the second solvent is preferably in the range from about 1 : 5 to 5 : 1 , more preferably from about 1 : 2 to 2 : 1 , most preferably about 1 : 1 .
- the weight ratio of the first solvent to the second solvent is preferably in the range from about 1 : 10 to 2 : 1 , more preferably from about 1 : 5 to 1 : 1 , even more preferably from about 1 : 4 to 1 : 2.
- the compound A may be employed in an amorphous or crystalline form or as a solution, for example obtained in the synthesis of the compound A.
- the solution obtained in the step (a) is a saturated or nearly saturated solution at the given temperature.
- saturated or nearly saturated are related to the starting material of the compound A as used in step (a).
- a solution which is saturated with respect to the starting material of the compound A may be supersaturated with respect to its crystalline form.
- the weight ratio of the compound A relative to the mixture of solvents is preferably in the range 1 : 8 to 1 : 2, more preferably 1 : 6 to 1 : 3, even more preferably from 1 : 5 to 1 :4.
- the solution may be heated up to the boiling temperature of the solution or to a temperature in the range from about 60°C to 120°C, for example about 100 °C.
- the solution obtained in the step (a) may be filtered, for example over charcoal.
- seeding crystals of the compound A are preferably added to the solution obtained in the step (a), optionally after a filtration step.
- the amount of the seeding crystals relative to the total amount of the compound A may be in the range from up to about 5 weight-%, more preferably from about 0.001 to 1 weight-%.
- the seeding crystals may be obtained for example by a process as described in the WO 2006/1 17359.
- the seeding crystals are preferably added at a temperature in the range from about 30°C to 80°C, most preferably about 60 to 75°C. Alternatively the crystallization may be induced by methods as known in the art, for example by scratching or rubbing.
- the temperature is preferably lowered in order to obtain a high yield of the precipitated crystalline form of the compound A.
- the temperature may be lowered continously or via a predefined cooling ramp.
- An example of a cooling ramp is within about 30min to 60 ⁇ 5°C, then within about 90min to 50 ⁇ 5°C, then within about 60min to 40 ⁇ 5°C, then within about 60min to 25 ⁇ 5°C.
- a preferred final temperature at the end of the step (b) is in the range from about -10°C to 40°C, more preferably from about 0°C to 35°C, most preferably from about 10°C to 30°C.
- the duration of the step (b) may be in the range from about 30 min to 48 hours, preferably from about 3 to 6 hours.
- the step (b) can be carried out with or without stirring.
- the size, shape and quality of the obtained crystals can be varied.
- the obtained crystals are isolated, for example via centrifugation or filtration.
- the obtained crystals are preferably washed with a solvent or a mixture of solvents, wherein the solvent is preferably selected from the group consisting of methanol, ethanol, 1 -propanol, 2-propanol or tert.-butylmethylether.
- the most preferred solvent is ethanol.
- Preferably remaining solvent(s) are advantageously removed from the crystals in a drying step, preferably at a temperature in the range from about 0°C to 100°C, for example from about 50°C to 80°C.
- the temperature, the pressure and the duration of this drying step may be chosen in order to lower the content of one or more solvents below a given value.
- the content of toluene in the crystalline form may be chosen to be equal or below 890 ppm, preferably below 500 ppm, even more preferably below 300 ppm.
- the content of ethanol in the crystalline form may be chosen to be equal or below 5000 ppm, preferably below 2000 ppm, even more preferably below 1000 ppm.
- the compound A may be synthesized by methods as specifically and/or generally described or cited in the international application WO 2005/092877. Furthermore the biological properties of the compound A may be investigated as it is described in the international application WO 2005/092877 which in its enterity is incorporated herein by reference.
- the crystalline form in accordance with the invention is preferably employed as drug active substance in substantially pure form, that is to say, essentially free of other crystalline forms of the compound A. Nevertheless, the invention also embraces the crystalline form as herein defined in admixture with another crystalline form or forms. Should the drug active substance be a mixture of crystalline forms, it is preferred that the substance comprises at least 50% of the crystalline form as described herein.
- the crystalline form of the compound A having an X-ray powder diffraction pattern that comprises peaks at 18.84, 20.36 and 25.21 degrees 2 ⁇ ( ⁇ 0.1 degrees 2 ⁇ ), wherein said X-ray powder diffraction pattern is made using CuK a i radiation is characterized by a purity above 99 % as measured by HPLC.
- the purity is above 99.5 %, even more preferably above 99.7 %, most preferably above 99.8 %.
- the content of the compound of the formula IMP.1 is equal or below 0.15 %, even more preferably equal or below 0.05 % as measured by HPLC.
- the crystalline form as defined hereinbefore is characterized by a content of the compound of the formula IMP.2
- the content of the compound of the formula IMP.2 is equal or below 0.05 % as measured by HPLC.
- the crystalline form is characterized by a content of the compounds of the formulas IMP.1 and IMP.2 as defined above.
- purity and impurity may be determined with methods known to the one skilled in the art.
- the purity and impurity is measured via HPLC.
- the purity is preferably determined as 100% minus the sum of all quantified impurities.
- the HPLC device is equipped with a C18 column, in particular a column with a microparticulate C18 packing used for reversed-phase HPLC, for example prepared by chemically bonding a sterically-protected C18 stationary phase (e.g. diisobutyl n-octadecylsilane) to porous silica microspheres (e.g. with a pore size of about 80A).
- a sterically-protected C18 stationary phase e.g. diisobutyl n-octadecylsilane
- porous silica microspheres e.g. with a pore size of about 80A.
- Advantageous dimensions of the column and microspheres are 4,6 mm (inner dimension) x 50 mm column and 1 .8 ⁇ .
- a UV-detection is preferred, for example at 224 nm.
- Typical parameters for such a HPLC are:
- Eluent B acetonitrile + 0,1 % trifluoroacetic acid
- a preferred solvent for the samples or as blank solution is a 50/50 (v/v) mixture of acetonitrile/water.
- Preferably all solvents including water are HPLC grade.
- the crystalline form according to the invention is suitable for the preparation of pharmaceutical compositions for the treatment and/or preventative treatment of all those conditions or diseases which may be affected by the inhibition of the SGLT activity, particularly the SGLT-2 activity. Therefore, the crystalline form is particularly suitable for the preparation of pharmaceutical compositions for prevention or treatment of diseases, particularly metabolic disorders, or conditions such as type 1 and type 2 diabetes mellitus, complications of diabetes (such as e.g.
- the crystalline form is also suitable for the preparation of pharmaceutical compositions for preventing beta-cell degeneration such as e.g. apoptosis or necrosis of pancreatic beta cells.
- the crystalline form is also suitable for the preparation of pharmaceutical compositions for improving or restoring the functionality of pancreatic cells, and also of increasing the number and size of pancreatic beta cells.
- the crystalline form according to the invention may also be used for the preparation of pharmaceutical compositions usefull as diuretics or antihypertensives and suitable for the prevention and treatment of acute renal failure.
- an abnormal accumulation of fat in the liver may be reduced or inhibited. Therefore according to another aspect of the present invention there is provided a method for preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat in a patient in need thereof characterized in that a pharmaceutical composition according to the present invention is administered.
- Diseases or conditions which are attributed to an abnormal accumulation of liver fat are particularly selected from the group consisting of general fatty liver, nonalcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), hyperalimentation- induced fatty liver, diabetic fatty liver, alcoholic-induced fatty liver or toxic fatty liver.
- the crystalline form according to the invention is suitable for the preparation of pharmaceutical compositions for the prevention or treatment of diabetes, particularly type 1 and type 2 diabetes mellitus, and/or diabetic
- the crystalline form according to the invention is particularly suitable for the prevention or treatment of overweight, obesity (including class I, class II and/or class III obesity), visceral obesity and/or abdominal obesity.
- the dosage required to achieve the corresponding activity for treatment or prevention usually depends on the patient, the nature and gravity of the illness or condition and the method and frequency of administration and is for the patient's doctor to decide. Expediently, the dosage may be from 1 to 100 mg by oral route, in each case administered 1 to 4 times a day.
- the pharmaceutical compositions according to this invention preferably comprise the crystalline form together with one or more inert conventional carriers and/or diluents.
- compositions may be formulated as conventional galenic
- preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
- the following example of synthesis serves to illustrate a method of preparing the compound A and its crystalline form. It is to be regarded only as a possible method described by way of example, without restricting the invention to its contents.
- This method is used for the determination of organic impurities in the compound A.
- the quantification is carried out via external standard solutions.
- the reagents acetonitrile, water, trifluoroacetic acid (TFA)
- TFA trifluoroacetic acid
- the term "compound A xx " denotes the crystalline form of the compound A as obtained with a method according to this invention.
- a solution with a concentration of 0,5 mg/ml of the compound IMP.2 is prepared; e.g. 25 mg of the substance are weighed, dissolved in 2 mL of methanol and diluted with solvent to a total volume of 50 mL.
- a solution with a concentration of 0,5 mg/ml of the compound A xx is prepared, containing approx. 0,5% IMP.2; e.g. 25 mg of the compound A xx are weighed, dissolved in 2 mL of methanol (via ultrasound) and, after addition of 250 ⁇ of solution 1 , diluted with solvent to a total volume of 50 mL.
- approx. 0,5% of the following possible impurities may be added: IMP.1
- a solution with 0,05% of the nominal concentration is prepared. Therefore, 50 ⁇ of a stem solution is diluted with solvent to a total volume of 100 mL
- a solution of the substance to be analyzed is prepared with a concentration of 0,8 mg/mL. Therefore, e.g. 40 mg of the substance are weighed, dissolved in 2 mL of methanol and diluted with solvent to a total volume of 50 mL. This solution is prepared twice.
- a solution of the compound A xx is prepared with a concentration of 0,8 mg/mL.
- a solution of compound A xx with a concentration of 4 g/ml compared to the nominal weighed sample is prepared. Therefore, e.g. 250 ⁇ of the stem solution are diluted with 50 mL. This solution is prepared twice (once from each stem solution).
- the order of elution of the peaks in the chromatogram of the SST-solution should correspond to a example chromatogram.
- the peak assignment is carried out with a example chromatogram or via the relative retention times (RRTs).
- Vx volume to which the dilution is carried out
- VF dilution factor
- the purity of a sample of the compound A is calculated as 100% minus the sum of all quantified impurities.
- room temperature or “ambient temperature” denote a temperature of about 20°C.
- the cartouche may be exchanged during filtration and washed with a fluorobenzene/2-propanole mixture (1 :4; 40kg) after filtration.
- 2-propanole (240kg) is added at a temperature in the range between about 40 to 50°C. If the content of fluorobenzene is greater than 1 % as determined via GC, another 140kg of solvent are distilled off and 2-propanole (140kg) is added. Then the solution is cooled from about 50°C to 40°C within one hour and seeding crystals (50g) are added.
- the solution is further cooled from about 40°C to 20°C within 2 hours.
- Water (450kg) is added at about 20°C within 1 hour and the suspension is stirred at about 20°C for an additional hour before the suspension is filtered.
- the filter cake is washed with 2-propanole/water (1 :1 ; 800kg).
- the product is dried until a water level of ⁇ 0.06%w/w is obtained.
- the second half of the organic phase is processed identically. A total of 410kg (94%yield) of product which has a white to off-white crystalline appearance, is obtained.
- the identity of the product is determined via infrared spectrometry.
- ketone VII.1 (217,4kg) and aluminium chloride (AICI 3 ; 81 ,5kg) in toluene (366,8kg) is added 1 ,1 ,3,3-tetramethyldisiloxane (TMDS, 82,5kg) within 1 hr 30 min (temperature: 18-26°C).
- TMDS 1,3 ,3,3-tetramethyldisiloxane
- a suspension of the D-(+)-gluconic acid-delta-lactone IVa.1 (42,0kg), tetrahydrofuran (277,2kg), 4-methylmorpholine (NMM; 152,4kg) and 4-dimethylaminopyridine (DMAP; 1 ,44kg) is treated with chlorotrimethylsilane (TMSCI; 130,8kg) within 50 min at 13 to 19°C. After completion of the addition stirring is continued for 1 hr 30 min at
- n-heptane 216,4kg
- Water 143kg
- the mixture is heated to 15°C and stirred for 15 min.
- the stirrer is switched off and the mixture is left stand for 15 min.
- the phases are separated and the organic layer is washed in succession two times with water (143kg each).
- solvent is distilled off at 38°C under reduced pressure and n-heptane (130kg) is added to the residue.
- the resulting solution is filtered and the filter is rinsed with n-heptane (63kg) (filter solution and product solution are combined).
- the conversion is determined via HPLC analysis (for information).
- a solution of citric acid in water (938L; concentration: 10 %-weight) is added to the reaction mixture of a volume of about 2500L at -13 to 19°C within 1 hr 25 min.
- the solvent is partially distilled off from the reaction mixture (residual volume: 1816-1905L) at 20 to 30°C under reduced pressure and 2- methyltetrahydrofuran (532kg) is added. Then the stirrer is switched off and the phases are separated at 29°C.
- the pH value of the organic phase is measured with a pH electrode (Mettler Toledo MT HA 405 DPA SC) or alternatively with pH indicator paper (such as pH-Fix 0-14, Macherey and Nagel).
- the measured pH value is 2 to 3.
- Full conversion to the acetale 111.1 is achieved by subsequent distillation at 20 to 32°C under reduced pressure and addition of methanol (409kg).
- the ratio of the sum of the HPLC-area of the alpha-form + beta-form of intermediate 111.1 relative to the area of intermediate llla.1 is greater or equal to 96,0% : 4,0%.
- the ratio of the HPLC-area of the alpha-form of intermediate 111.1 to the beta-form of 111.1 is greater or equal to 97,0% to 3,0%.
- the water content of the mixture is determined via Karl Fischer titration (result: 0,27%).
- reaction mixture is then added within 1 hr 40 min at 10 to 19°C to a preformed mixture of AICI 3 (176kg), methylene chloride (474kg), acetonitrile (340kg), and triethylsilane (205kg).
- AICI 3 176kg
- methylene chloride 474kg
- acetonitrile 340kg
- triethylsilane 205kg
- the resulting mixture is stirred at 18 to 20°C for 70 min.
- water (1263L) is added at 20 to 30°C within 1 hr 30 min and the mixture is partially distilled at 30 to 53°C under atmospheric pressure and the phases are separated.
- Toluene (698kg) is added to the organic phase and solvent is distilled off under reduced pressure at 22 to 33°C.
- the product is then crystallized by addition of seeding crystals (0,5kg) at 31 °C and water (267kg) added after cooling to 20°C.
- the reaction mixture is cooled to 5°C within 55 min and stirred at 3 to 5°C for 12 hrs.
- the product is collected on a centrifuge as colourless, crystalline solid, washed with toluene (348kg) and dried at 22 to 58°C. 21 1 kg (73%) of product are obtained.
- the identity of the product is determined via the HPLC retention time.
- the conversion is determined via HPLC analysis.
- the reaction is regarded as completed when the area of the peak corresponding to the iodide V.1 is smaller than 5,0% of the total area of both peaks, iodide V.1 and the corresponding desiodo compound of iodide V.1 . If the reaction is not completed, additional Turbogrignard solution is added until the criterion is met.
- the result is 0,35%.
- the lactone IV.1 (36g) is added at -15 to -6°C temperature within 15 min.
- the resulting mixture is stirred for further 1 hr at -6 to -7°C.
- the conversion is determined via HPLC analysis (for information).
- a solution of citric acid in water (105mL; concentration: 10 %-weight) is added to the reaction mixture at -15 to 10°C within 30 min.
- intermediate 111.1 relative to the area of intermediate llla.1 is greater or equal to 96,0% : 4,0%. In this particular case the ratio is 99,6% : 0,43%.
- the ratio of the HPLC-area of the alpha-form of intermediate 111.1 to the beta-form of 111.1 is greater or equal to 97,0% to 3,0%. In this particular case the ratio is 98,7%
- reaction mixture is then added within 1 hr 5 min at 20°C to a preformed mixture of AICI 3 (19,8g), methylene chloride (49ml_), acetonitrile (51 mL), and triethylsilane (23g).
- AICI 3 (19,8g)
- methylene chloride 49ml_
- acetonitrile 51 mL
- triethylsilane 23g
- water 156mL
- water is added at 20°C within 25 min and the mixture is partially distilled at 55°C under atmospheric pressure and the phases are separated at 33°C.
- the mixture is heated to 43°C and toluene (90mL) is added and solvent is distilled off under reduced pressure at 41 to 43°C.
- acetonitrile (10mL) is added at 41 °C and the percentage of acetonitrile is determined via GC measurement. In this particular case, the acetonitrile percentage is 27%-weight.
- the product is then crystallized by addition of seeding crystals (0,1 g) at 44°C and the mixture is further stirred at 44°C for 15min.
- the mixture is then cooled to 20°C within 60min and water (142mL) is added at 20°C within 30min.
- the reaction mixture is cooled to 0 to 5°C within 60 min and stirred at 3°C for 16 hrs.
- the product is collected on a filter as colourless, crystalline solid, washed with toluene (80mL) and dried at 20 to 70°C. 20,4g (62,6%) of product are obtained.
- the identity of the product is determined via the HPLC retention time.
- a solution of the compound A (79,0kg) in a mixture of toluene (186,6kg) and ethanol (187,2kg) is heated to reflux until complete dissolution and filtered (hot filtration).
- the filter is washed with toluene (19,6kg) and the washing solution is combined with the product solution.
- the product solution is then cooled to 66°C and seeding crystals (0,1 kg) are added.
- the product solution is then cooled to 22°C using a defined cooling ramp: within 30 min to 57°C, then within 90 min to 50°C, then within 60 min to 41 °C, then within 60 min to 22°C.
- the crystalline form is characterised and a pattern as shown in the Figure 1 is obtained.
- the intensity shown in the Figure 1 is given in units of cps (counts per second) and is background corrected.
- the values "2 ⁇ [°]” denote the angle of diffraction in degrees and the values "d [A]” denote the specified distances in A between the lattice planes.
- Table 1 Indexed * X-ray powder diffraction pattern of the crystalline form (only peaks up to 30° in 2 ⁇ are listed):
- the compound of the formula IMP.1 is added to the crystalline form of the compound A as obtained according to the Experiment A such that the amounts according to the Table 2 are obtained.
- the compound IMP.1 are combined.
- half of this mixture of compounds is recrystallized according to the procedure of the Experiment A on a laboratory scale.
- the crystalline form of compound A is obtained as a white crystalline material.
- the content of the compound of the formula IMP.1 is analyzed via HPLC.
- the other half of this mixture of compounds is recrystallized using a mixture of methanol and water according to the following procedure:
- a sample of raw material of the compound A for example as obtained from a not optimized lab-scale procedure according to Example 5a or 5b, is analyzed via HPLC with respect to their purity.
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Abstract
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JP2012531332A JP5736377B2 (en) | 2009-09-30 | 2010-09-24 | Process for the preparation of the crystalline form of 1-chloro-4- (β-D-glucopyranos-1-yl) -2- [4-((S) -tetrahydrofuran-3-yloxy) benzyl] benzene |
IN2756DEN2012 IN2012DN02756A (en) | 2009-09-30 | 2010-09-24 | |
ES10755201.0T ES2596202T3 (en) | 2009-09-30 | 2010-09-24 | Method for the preparation of a crystalline form of 1-chloro-4- (β-D-glucopyranos-1-yl) -2- [4 - ((S) -tetrahydrofuran-3-yloxy) -benzyl] -benzene |
NZ598318A NZ598318A (en) | 2009-09-30 | 2010-09-24 | Method for the preparation of a crystalline form of 1-chloro-4- (beta-d-glucopyranos-1-yl)-2-(4-((s)-tetrahydrofuran-3-yloxy)benzyl)benzene |
DK10755201.0T DK2483286T3 (en) | 2009-09-30 | 2010-09-24 | PROCESS FOR THE PREPARATION OF A crystal form of 1-chloro-4- (BETA-D-glucopyranos-1-yl) -2- (4 - ((S) -tetrahydrofuran-3-yloxy) benzyl) benzene |
EA201200506A EA020798B1 (en) | 2009-09-30 | 2010-09-24 | Method for the preparation of a crystalline form of 1-chloro-4-(beta-d-glucopyranos-1-yl)-2-[4-((s)-tetrahydrofuran-3-yloxy)benzyl]benzene |
EP10755201.0A EP2483286B1 (en) | 2009-09-30 | 2010-09-24 | Method for the preparation of a crystalline form of 1-chloro-4-(beta-d-glucopyranos-1-yl)-2-(4-((s)-tetrahydrofuran-3-yloxy)benzyl)benzene |
BR112012007092-4A BR112012007092B1 (en) | 2009-09-30 | 2010-09-24 | Method for preparing a crystalline form of a 1-chloro-4- (beta-d-glycopyran-1-yl) -2- [4 - ((s) -tetrahydro-furan-3-yloxy) benzyl) benzene compound |
CA2775961A CA2775961C (en) | 2009-09-30 | 2010-09-24 | Method for the preparation of a crystalline form of 1-chloro-4-(beta-d-glucopyranos-1-yl)-2-(4-((s)-tetrahydrofuran-3-yloxy)benzyl)benzene |
MX2012002942A MX2012002942A (en) | 2009-09-30 | 2010-09-24 | Method for the preparation of a crystalline form of 1-chloro-4- (beta-d-glucopyranos-1-yl)-2-(4-((s)-tetrahydrofuran-3-yloxy)be nzyl)benzene. |
KR1020127008069A KR101811997B1 (en) | 2009-09-30 | 2010-09-24 | Method for the preparation of a crystalline form of 1-chloro-4-(beta-D-glucopyranos-1-yl)-2-(4-((S)-tetrahydrofuran-3-yloxy)benzyl)benzene |
CN201080043252.2A CN102549005B (en) | 2009-09-30 | 2010-09-24 | The preparation method of the crystal formation of the chloro-4-of 1-(β-D-Glucopyranose-1-base)-2-[4-((S)-tetrahydrofuran (THF)-3-base oxygen base)-benzyl]-benzene |
AU2010303123A AU2010303123B2 (en) | 2009-09-30 | 2010-09-24 | Method for the preparation of a crystalline form of 1-chloro-4- (Beta-D-glucopyranos-1-yl)-2-(4-((S)-tetrahydrofuran-3-yloxy)benzyl)benzene |
IL218102A IL218102B (en) | 2009-09-30 | 2012-02-14 | Method for the preparation of a crystalline form of 1-chloro-4-(beta-d-glucopyranos-1-yl)-2-(4-((s)-tetrahydrofuran-3-yloxy) benzyl)benzene |
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EP (1) | EP2483286B1 (en) |
JP (1) | JP5736377B2 (en) |
KR (1) | KR101811997B1 (en) |
CN (1) | CN102549005B (en) |
AR (1) | AR078475A1 (en) |
AU (1) | AU2010303123B2 (en) |
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CL2012000810A1 (en) | 2012-08-31 |
EA020798B1 (en) | 2015-01-30 |
JP5736377B2 (en) | 2015-06-17 |
CA2775961C (en) | 2017-11-07 |
US20110237526A1 (en) | 2011-09-29 |
CN102549005B (en) | 2015-08-26 |
EP2483286B1 (en) | 2016-07-13 |
CA2775961A1 (en) | 2011-04-07 |
IL218102B (en) | 2020-06-30 |
AR078475A1 (en) | 2011-11-09 |
PL2483286T3 (en) | 2017-04-28 |
NZ598318A (en) | 2014-02-28 |
BR112012007092B1 (en) | 2020-03-31 |
ES2596202T3 (en) | 2017-01-05 |
KR20120091024A (en) | 2012-08-17 |
BR112012007092A2 (en) | 2016-08-23 |
AU2010303123A1 (en) | 2012-03-15 |
EP2483286A1 (en) | 2012-08-08 |
EA201200506A1 (en) | 2012-11-30 |
US8802842B2 (en) | 2014-08-12 |
IL218102A0 (en) | 2012-04-30 |
AU2010303123B2 (en) | 2014-02-27 |
MX2012002942A (en) | 2012-04-11 |
JP2013505974A (en) | 2013-02-21 |
TW201127849A (en) | 2011-08-16 |
TWI482778B (en) | 2015-05-01 |
DK2483286T3 (en) | 2016-09-19 |
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