EP2406271A1 - Nouvel hydrate de fluoroglycoside hétéroaromatique cristallisé, ses procédés de fabrication, ses méthodes d'utilisation et ses compositions pharmaceutiques - Google Patents

Nouvel hydrate de fluoroglycoside hétéroaromatique cristallisé, ses procédés de fabrication, ses méthodes d'utilisation et ses compositions pharmaceutiques

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Publication number
EP2406271A1
EP2406271A1 EP09764844A EP09764844A EP2406271A1 EP 2406271 A1 EP2406271 A1 EP 2406271A1 EP 09764844 A EP09764844 A EP 09764844A EP 09764844 A EP09764844 A EP 09764844A EP 2406271 A1 EP2406271 A1 EP 2406271A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
combination
hydrate
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09764844A
Other languages
German (de)
English (en)
Inventor
Harald Berchtold
Norbert Nagel
Bruno Baumgartner
Oliver Plettenburg
Franz Weiberth
Gill Harpal
Yong Yu
Harvey Lieberman
Elisabeth Secord
Boris Gordonov
Tim Doneghan
Steve Byard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Original Assignee
Sanofi SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi SA filed Critical Sanofi SA
Priority to EP09764844A priority Critical patent/EP2406271A1/fr
Publication of EP2406271A1 publication Critical patent/EP2406271A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms

Definitions

  • the invention relates to a crystalline hydrate of a heteroaromatic fluoroglycoside known as 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside.
  • a heteroaromatic fluoroglycoside known as 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside.
  • Heteroaromatic fluoroglycosides have been described in EP1572708 B1 and Published United States Patent Application US 2004/0259819.
  • the aforementioned patent and/or application makes no mention as to the particular physical form of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D- glucopyranoside provided from the procedure disclosed therein or the hydration state or physical purity of the compound provided from the procedure.
  • Another object is to increase the storage stability of the amorphous heteroaromatic fluoroglycoside from EP1572708 B1 which is a crucial parameter for formulating pharmaceuticals.
  • Another object is to provide processes for the preparation of a stable monohydrate form of 4- [(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta- D-glucopyranoside or a tautomer thereof (henceforth referred to as "Form A").
  • the object is achieved by providing a stable crystalline hydrate of the formula I
  • n has a value of from 0.9 to 1.1 or a tautomer thereof.
  • Figure 1 Form A exhibits the XRPD shown.
  • the XRPD was measured in transmission with Cu-K ⁇ 1 radiation at room temperature.
  • Figure 2 shows the Raman spectrum of Form A.
  • Figure 3 shows the DSC thermogram of Form A.
  • Figure 4 shows the TG analysis of Form A.
  • - can have a defined purity required for the approval of a pharmaceutical - is readily detectable and identifiable by customary methods such as XRPD (X- ray powder diffraction), melting point, IR (infrared spectrum), and it has
  • Crystalline active ingredients are generally more stable than amorphous active ingredients. Problems with the degradation of the active ingredients and the degradation products formed are thus avoided.
  • the amorphous form of an active ingredient may also comprise an unwanted content of solvents. These are generally difficult to remove, since recrystallization is not possible.
  • the amorphous form is a more energetic state than a crystalline form and, as such, is more difficult to stabilize. Molecules of an amorphous material may spontaneously rearrange to a lower energy crystalline one leading to a change in activity of the active ingredient. As a consequence there may be significant effect on the reliability of the active ingredient and thus a risk for the patient. It is also difficult to prove that different batches of amorphous active ingredient are identical.
  • a further embodiment of the invention comprises Form A wherein the XRPD, measured with CuKa radiation, has a main peak of 20.27 degrees 2 theta ⁇ 0.2 degrees 2 theta.
  • a further embodiment of the invention comprises Form A wherein the XRPD, measured with CuKa radiation, has at least peaks of the following 2 theta values: 14.88, 20.27, 22.98 ⁇ 0.2 degrees 2 theta.
  • a further embodiment of the invention comprises Form A wherein the XRPD, measured with CuKa radiation, has at least peaks of the following 2 theta values: 5.98, 14.88, 20.27, 22.98, 26.52 ⁇ 0.2 degrees 2 theta.
  • a further embodiment of the invention comprises Form A wherein the XRPD, measured with CuKa radiation, has at least peaks of the following 2 theta values: 5.98, 7.48, 12.09, 14.88, 14.99, 20.27, 20.75, 22.81 , 22.98, 26.52, 27.60, 31.01 ⁇ 0.2 degrees 2 theta.
  • the amount of a compound of formula I necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient.
  • the daily dose is generally in the range from 0.01 mg to 100 mg (typically from 0.05 mg and 50 mg) per day and per kilogram of body weight, for example 0.05-10 mg/kg/day.
  • Single-dose formulations which can be administered orally such as, for example, tablets or capsules may contain, for example, from 1.0 to 1000 mg, typically from 5 from 600 mg.
  • the compounds of formula I may be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier.
  • the carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not harmful for the patient's health.
  • the carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient.
  • Other pharmaceutically active substances may likewise be present, including further compounds of the formula I.
  • the pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients.
  • compositions of the invention are those suitable for oral and peroral (for example sublingual) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case.
  • Coated formulations and coated slow-release formulations also belong within the framework of the invention.
  • Acid- and gastric juice-resistant formulations are possible.
  • Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
  • Suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, cachets, suckable tablets or tablets, each of which contains a defined amount of the compound of formula I; as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil- in-water or water-in-oil emulsion.
  • These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact.
  • the compositions are generally produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary.
  • a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients.
  • Compressed tablets can be produced by tableting the compound in free-flowing form such as, for example, a powder or granules, where appropriate mixed with a binder, glidant, inert diluent and/or one (or more) surface-active/dispersing agent(s) in a suitable machine.
  • Molded tablets can be produced by molding the compound, which is in powder form and is moistened with an inert liquid diluent, in a suitable machine.
  • compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula I with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
  • the compound(s) of the invention (I) can also be administered in combination with further active ingredients.
  • active ingredients suitable for combination products are: All antidiabetics which are mentioned in the Rote Liste 2007, chapter 12; all weight- reducing agents/appetite suppressants which are mentioned in the Rote Liste 2005, chapter 1 ; all lipid-lowering agents which are mentioned in the Rote Liste 2007, chapter 58. They may be combined with the compound of the invention of the formula I in particular for a synergistic improvement in the effect.
  • the active ingredient combination can be administered either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients is present in a pharmaceutical preparation. Most of the active ingredients mentioned hereinafter are disclosed in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
  • Antidiabetics include insulin and insulin derivatives such as, for example, Lantus® (see www.lantus.com) or HMR 1964 or Levemir® (insulin detemir) or those described in WO2005005477 (Novo Nordisk), fast-acting insulins (see US 6,221 ,633), inhalable insulins such as, for example, Exubera ® or oral insulins such as, for example, IN-105 (Nobex) or Oral-lynTM (Generex Biotechnology), GLP-1 derivatives and GLP-1 agonists such as, for example, exenatide, liraglutide or those which have been disclosed in WO98/08871 or WO2005027978, WO2006037811 , WO2006037810 of Novo Nordisk A/S, in WO01/04156 of Zealand or in WO00/34331 of Beaufour-lpsen, pramlintide acetate (Symlin; Amylin Pharmaceuticals), BIM-51077,
  • Antidiabetics also include agonists of the glucose-dependent insulinotropic polypeptide (GIP) receptor as described for example in WO2006121860.
  • GIP glucose-dependent insulinotropic polypeptide
  • the orally effective hypoglycemic active ingredients include preferably sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, inhibitors of glycogen phosphorylase, glucagon antagonists, glucokinase activators, inhibitors of fructose-1 ,6-bisphosphatase, modulators of glucose transporter 4 (GLUT4), inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT),
  • GLP-1 agonists such as, for example, pinacidil, cromakalim, diazoxide or those described in R.D. Carr et al., Diabetes 52, 2003, 2513-2518, in J. B. Hansen et al., Current Medicinal Chemistry 11 , 2004, 1595-1615, in T.M. Tagmose et al., J. Med.
  • potassium channel openers such as, for example, pinacidil, cromakalim, diazoxide or those described in R.D. Carr et al., Diabetes 52, 2003, 2513-2518, in J. B. Hansen et al., Current Medicinal Chemistry 11 , 2004, 1595-1615, in T.M. Tagmose et al., J. Med.
  • DPP-IV dipeptidylpeptidase IV
  • insulin sensitizers inhibitors of liver enzymes involved in stimulating gluconeogenesis and/or glycogenolysis
  • modulators of glucose uptake, of glucose transport and of glucose reabsorption inhibitors of 11 ⁇ -HSD1 , inhibitors of protein tyrosine phosphatase 1 B (PTP1 B), modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1 , SGLT2), compounds which alter lipid metabolism such as antihyperlipidemic active ingredients and antilipidemic active ingredients, compounds which reduce food intake, compounds which increase thermogenesis,
  • PPAR and RXR modulators and active ingredients which act on the ATP-dependent potassium channel of the beta cells.
  • the compound of the formula I or Form A is administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, L-659699.
  • an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, L-659699.
  • the compound of the formula I or Form A is administered in combination with a cholesterol absorption inhibitor such as, for example, ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech, WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497, WO2005021495) or with compounds as described in WO2002066464, WO2005000353 (Kotobuki Pharmaceutical Co.
  • a cholesterol absorption inhibitor such as, for example, ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech, WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497, WO2005021495) or with compounds as described in WO2002066464, WO2005000353 (
  • WO2005044256 or WO2005062824 Merck & Co.
  • WO2005061451 and WO2005061452 AstraZeneca AB
  • WO2006017257 Phenomix
  • WO2005033100 Lipideon Biotechnology AG
  • WO2004097655 WO2004000805, WO2004000804, WO2004000803, WO2002050068, WO2002050060, WO2005047248, WO2006086562, WO2006102674, WO2006116499, WO2006121861 , WO2006122186, WO2006122216, WO2006127893, WO2006137794, WO2006137796, WO2006137782, WO2006137793, WO2006137797, WO2006137795, WO2006137792, WO2006138163.
  • the compound of the formula I or Form A is administered in combination with VytorinTM, a fixed combination of ezetimibe with simvastatin.
  • the compound of the formula I or Form A is administered in combination with a fixed combination of ezetimibe with atorvastatin.
  • the compound of the formula I or Form A is administered in combination with a fixed combination of ezetimibe with fenofibrate.
  • the compound of the formula I or Form A is administered in combination with a fixed combination of fenofibrate with rosuvastatin.
  • the compound of the formula I or Form A is administered in combination with synordia (R), a fixed combination of fenofibrate with metformin.
  • the compound of the formula I or Form A is administered in combination with ISIS-301012, an antisense oligonucleotide able to regulate the apolipoprotein B gene.
  • the compound of the formula I or Form A is administered in combination with a PPAR gamma agonist such as, for example, rosiglitazone, pioglitazone, JTT-501 , G1 262570, R-483 or CS-011 (rivoglitazone).
  • a PPAR gamma agonist such as, for example, rosiglitazone, pioglitazone, JTT-501 , G1 262570, R-483 or CS-011 (rivoglitazone).
  • the compound of the formula I or Form A is administered in combination with CompetactTM, a fixed combination of pioglitazone hydrochloride with metformin hydrochloride.
  • the compound of the formula I or Form A is administered in combination with TandemactTM, a fixed combination of pioglitazone with glimepride.
  • the compound of the formula I or Form A is administered in combination with a fixed combination of pioglitazone hydrochloride with an angiotensin Il agonist such as, for example, TAK-536.
  • the compound of the formula I or Form A is administered in combination with a PPAR alpha agonist such as, for example, GW9578, GW-590735, K- 111 , LY-674, KRP-101 , DRF-10945, LY-518674 or those described in WO2001040207, WO2002096894, WO2005097076.
  • a PPAR alpha agonist such as, for example, GW9578, GW-590735, K- 111 , LY-674, KRP-101 , DRF-10945, LY-518674 or those described in WO2001040207, WO2002096894, WO2005097076.
  • the compound of the formula I or Form A is administered in combination with a mixed PPAR alpha/gamma agonist such as, for example, naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, CKD-501 (lobeglitazone sulfate) or as described in WO 00/64888, WO 00/64876, WO 03/020269 or in J. P. Berger et al., TRENDS in Pharmacological Sciences 28(5), 244-251 , 2005.
  • a mixed PPAR alpha/gamma agonist such as, for example, naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, CKD-501 (lobeglitazone sulfate) or as described in WO 00/64888, WO 00/64876, WO 03/020269 or in J
  • the compound of the formula I or Form A is administered in combination with a PPAR delta agonist such as, for example, GW-501516 or as described in WO2006059744, WO2006084176, WO2006029699, WO2007039172, WO2007039178.
  • a PPAR delta agonist such as, for example, GW-501516 or as described in WO2006059744, WO2006084176, WO2006029699, WO2007039172, WO2007039178.
  • the compound of the formula I or Form A is administered in combination with metaglidasen or with MBX-2044 or other partial PPAR gamma agonists/antagonists.
  • the compound of the formula I or Form A is administered in combination with a fibrate such as, for example, fenofibrate, clofibrate or bezafibrate.
  • the compound of the formula I or Form A is administered in combination with an MTP inhibitor such as, for example, implitapide, BMS-201038, R-103757, AS-1552133 or those described in WO2005085226, WO2005121091 , WO2006010423.
  • an MTP inhibitor such as, for example, implitapide, BMS-201038, R-103757, AS-1552133 or those described in WO2005085226, WO2005121091 , WO2006010423.
  • the compound of the formula I or Form A is administered in combination with a CETP inhibitor such as, for example, torcetrapib or JTT-705 or those described in WO2006002342, WO2006010422, WO2006012093, WO2006073973, WO2006072362, WO2006097169, WO2007041494.
  • a CETP inhibitor such as, for example, torcetrapib or JTT-705 or those described in WO2006002342, WO2006010422, WO2006012093, WO2006073973, WO2006072362, WO2006097169, WO2007041494.
  • the compound of the formula I or Form A is administered in combination with a bile acid absorption inhibitor (see, for example, US 6,245,744, US 6,221 ,897 or WO00/61568), such as, for example, HMR 1741 or those as described in DE 10 2005 033099.1 and DE 10 2005 033100.9, WO2007009655-56.
  • a bile acid absorption inhibitor see, for example, US 6,245,744, US 6,221 ,897 or WO00/61568
  • HMR 1741 such as, for example, HMR 1741 or those as described in DE 10 2005 033099.1 and DE 10 2005 033100.9, WO2007009655-56.
  • the compound of the formula I or Form A is administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine or colesevelam.
  • a polymeric bile acid adsorbent such as, for example, cholestyramine or colesevelam.
  • the compound of the formula I or Form A is administered in combination with an LDL receptor inducer (see US 6,342,512), such as, for example, HMR1171 , HMR1586 or those as described in WO2005097738.
  • an LDL receptor inducer see US 6,342,512
  • the compound of the formula I or Form A is administered in combination with an ABCA1 expression enhancer as described for example in WO2006072393.
  • the compound of the formula I or Form A is administered in combination with an RNAi therapeutic directed against PCSK9 (proprotein convertase subtilisin/kexin type 9).
  • the compound of the formula I or Form A is administered in combination with Omacor® (omega-3 fatty acids; highly concentrated ethyl esters of eicosapentaenoic acid and of docosahexaenoic acid).
  • Omacor® omega-3 fatty acids; highly concentrated ethyl esters of eicosapentaenoic acid and of docosahexaenoic acid.
  • the compound of the formula I or Form A is administered in combination with an ACAT inhibitor such as, for example, avasimibe or SMP-797.
  • the compound of the formula I or Form A is administered in combination with an antioxidant such as, for example, OPC-14117, probucol, tocopherol, ascorbic acid, ⁇ -carotene or selenium.
  • an antioxidant such as, for example, OPC-14117, probucol, tocopherol, ascorbic acid, ⁇ -carotene or selenium.
  • the compound of the formula I or Form A is administered in combination with a vitamin such as, for example, vitamin B6 or vitamin B12.
  • the compound of the formula I or Form A is administered in combination with a lipoprotein lipase modulator such as, for example, ibrolipim (NO-1886).
  • a lipoprotein lipase modulator such as, for example, ibrolipim (NO-1886).
  • the compound of the formula I or Form A is administered in combination with an ATP citrate lyase inhibitor such as, for example, SB-204990.
  • the compound of the formula I or Form A is administered in combination with a squalene synthetase inhibitor such as, for example, BMS-188494, TAK-475 or as described in WO2005077907, JP2007022943.
  • the compound of the formula I or Form A is administered in combination with a lipoprotein(a) antagonist such as, for example, gemcabene (CI-1027).
  • a lipoprotein(a) antagonist such as, for example, gemcabene (CI-1027).
  • the compound of the formula I or Form A is administered in combination with an agonist of GPR109A (HM74A receptor agonist; NAR agonist (nicotinic acid receptor agonist) such as, for example, nicotinic acid or extended release niacin in conjunction with MK-0524A or the compounds described in WO2006045565, WO2006045564, WO2006069242, WO2006124490, WO2006113150, WO2007017261 , WO2007017262, WO2007017265, WO2007015744, WO2007027532.
  • GPR109A HM74A receptor agonist
  • NAR agonist nicotinic acid receptor agonist
  • the compound of the formula I or Form A is administered in combination with an agonist of GPR116 as described for example in WO2006067531 , WO2006067532.
  • the compound of the formula I or Form A is administered in combination with a lipase inhibitor such as, for example, orlistat or cetilistat (ATL-962).
  • a lipase inhibitor such as, for example, orlistat or cetilistat (ATL-962).
  • the compound of the formula I or Form A is administered in combination with insulin.
  • the compound of the formula I or Form A is administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.
  • a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride.
  • the compound of the formula I or Form A is administered in combination with a substance which enhances insulin secretion, such as, for example, KCP-265 (WO2003097064) or those described in WO2007026761.
  • the compound of the formula I or Form A is administered in combination with agonists of the glucose-dependent insulinotropic receptor (GDIR), such as, for example, APD-668.
  • GDIR glucose-dependent insulinotropic receptor
  • the compound of the formula I or Form A is administered in combination with a biguanide such as, for example, metformin.
  • the compound of the formula I or Form A is administered in combination with a meglitinide such as, for example, repaglinide, nateglinide or mitiglinide.
  • a meglitinide such as, for example, repaglinide, nateglinide or mitiglinide.
  • the compound of the formula I or Form A is administered with a combination of mitiglinide with a glitazone, e.g. pioglitazone hydrochloride.
  • the compound of the formula I or Form A is administered with a combination of mitiglinide with an alpha-glucosidase inhibitor.
  • the compound of the formula I or Form A is administered in combination with a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2- quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.
  • a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2- quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidine
  • the compound of the formula I or Form A is administered in combination with an ⁇ -glucosidase inhibitor such as, for example, miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor such as, for example, miglitol or acarbose.
  • the compound of the formula I or Form A is administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
  • the compound of the formula I or Form A is administered in combination with more than one of the aforementioned compounds, e.g. in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
  • the compound of the formula I or Form A is administered in combination with an inhibitor of glycogen phosphorylase, such as, for example, PSN- 357 or FR-258900 or those as described in WO2003084922, WO2004007455, WO2005073229-31 or WO2005067932.
  • an inhibitor of glycogen phosphorylase such as, for example, PSN- 357 or FR-258900 or those as described in WO2003084922, WO2004007455, WO2005073229-31 or WO2005067932.
  • the compound of the formula I or Form A is administered in combination with glucagon receptor antagonists such as, for example, A-770077, NNC-25-2504 or as described in WO2004100875 or WO2005065680.
  • glucagon receptor antagonists such as, for example, A-770077, NNC-25-2504 or as described in WO2004100875 or WO2005065680.
  • the compound of the formula I or Form A is administered in combination with activators of glucokinase, such as, for example, LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50 or those as are described for example in WO2004072031 , WO2004072066, WO2005080360, WO2005044801 , WO2006016194, WO2006058923, WO2006112549, WO2006125972, WO2007017549, WO2007017649, WO2007007910, WO2007007040-42, WO2007006760-61 , WO2007006814, WO2007007886, WO2007028135, WO2007031739, WO2007041365, WO2007041366, WO2007037534, WO2007043638, WO2007053345, WO2007051846, WO2007051845, WO2007053765, WO2007051847.
  • the compound of the formula I or Form A is administered in combination with an inhibitor of gluconeogenesis, such as, for example, FR-225654.
  • the compound of the formula I or Form A is administered in combination with inhibitors of fructose-1 ,6-bisphosphatase (FBPase), such as, for example, CS-917 (MB-06322) or MB-07803 or those described in WO2006023515, WO2006104030, WO2007014619.
  • FBPase fructose-1 ,6-bisphosphatase
  • the compound of the formula I or Form A is administered in combination with modulators of glucose transporter 4 (GLUT4), such as, for example, KST-48 (D.-O. Lee et al.: Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004)).
  • GLUT4 glucose transporter 4
  • the compound of the formula I or Form A is administered in combination with inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), as are described for example in WO2004101528.
  • the compound of the formula I or Form A is administered in combination with inhibitors of dipeptidylpeptidase IV (DPP-IV), such as, for example, vildagliptin (LAF-237), sitagliptin (MK-0431 ), sitagliptin phosphate, saxagliptin (BMS- 477118), GSK-823093, PSN-9301 , SYR-322, SYR-619, TA-6666, TS-021 , GRC-8200, GW-825964X, KRP-104, DP-893, ABT-341 , ABT-279 or another salt thereof, or the compounds described in WO2003074500, WO2003106456, WO2004037169, WO200450
  • the compound of the formula I or Form A is administered in ccoommbbiinnaattiioonn wwiitthh JJaannuummeetTM, a fixed combination of sitagliptin phosphate with metformin hydrochloride.
  • the compound of the formula I or Form A is administered in combination with inhibitors of 11 -beta-hydroxysteroid dehydrogenase 1 (11 ⁇ -HSD1 ), such as, for example, BVT-2733, JNJ-25918646, INCB-13739 or those as are described for example in WO200190090-94, WO200343999, WO2004112782, WO200344000, WO200344009, WO2004112779, WO2004113310, WO2004103980, WO2004112784, WO2003065983, WO2003104207, WO2003104208, WO2004106294, WO2004011410, WO2004033427, WO2004041264, WO2004037251 , WO2004056744, WO2004058730, WO2004065351 , WO2004089367, WO2004089380, WO2004089470-71 , WO2004089896, WO2005016877,
  • the compound of the formula I or Form A is administered in combination with inhibitors of protein tyrosine phosphatase 1 B (PTP1 B), as are described for example in WO200119830-31 , WO200117516, WO2004506446, WO2005012295, WO2005116003, WO2005116003, WO2006007959, DE 10 2004 060542.4, WO2007009911 , WO2007028145, WO2007081755.
  • PTP1 B protein tyrosine phosphatase 1 B
  • the compound of the formula I or Form A is administered in combination with modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1 , SGLT2), such as, for example, KGA-2727, T-1095, SGL-0010, AVE 2268, SAR 7226 and sergliflozin or as are described for example in WO2004007517, WO200452903, WO200452902, PCT/EP2005/005959, WO2005085237, JP2004359630, WO2005121161 , WO2006018150, WO2006035796, WO2006062224, WO2006058597, WO2006073197, WO2006080577, WO2006087997, WO2006108842, WO2007000445, WO2007014895, WO2007080170 or by A. L. Handlon in Expert Opin. Ther. Patents (2005) 15(11 ), 1531 -1540.
  • the compound of the formula I or Form A is administered in combination with modulators of GPR40 as described for example in WO2007013689, WO2007033002.
  • the compound of the formula I or Form A is administered in combination with modulators of GPR119b as described for example in WO2004041274.
  • the compound of the formula I or Form A is administered in combination with modulators of GPR119 as described for example in WO2005061489 (PSN-632408), WO2004065380, WO2007003960-62 and WO2007003964.
  • the compound of the formula I or Form A is administered in combination with modulators of GPR120.
  • the compound of the formula I or Form A is administered in combination with inhibitors of hormone-sensitive lipase (HSL) and/or phospholipases as described for example in WO2005073199, WO2006074957, WO2006087309, WO2006111321 , WO2007042178.
  • HSL hormone-sensitive lipase
  • the compound of the formula I or Form A is administered in combination with inhibitors of acetyl-CoA carboxylase (ACC), such as, for example, those as described in WO199946262, WO200372197, WO2003072197, WO2005044814, WO2005108370, JP2006131559, WO2007011809, WO2007011811 , WO2007013691.
  • ACC acetyl-CoA carboxylase
  • the compound of the formula I or Form A is administered in combination with modulators of xanthine oxidoreductase (XOR).
  • XOR xanthine oxidoreductase
  • the compound of the formula I or Form A is administered in combination with an inhibitor of phosphoenolpyruvate carboxykinase (PEPCK), such as, for example, those as described in WO2004074288.
  • PEPCK phosphoenolpyruvate carboxykinase
  • the compound of the formula I or Form A is administered in combination with an inhibitor of glycogen synthase kinase 3 beta (GSK-3 beta), as described for example in US2005222220, WO2005085230, WO2005111018, WO2003078403, WO2004022544, WO2003106410, WO2005058908, US2005038023, WO2005009997, US2005026984, WO2005000836, WO2004106343, EP1460075, WO2004014910, WO2003076442, WO2005087727 or WO2004046117.
  • GSK-3 beta glycogen synthase kinase 3 beta
  • the compound of the formula I or Form A is administered in combination with an inhibitor of the serum/glucocorticoid-regulated kinase (SGK) as described for example in WO2006072354.
  • SGK serum/glucocorticoid-regulated kinase
  • the compound of the formula I or Form A is administered in combination with an agonist of the RUP3 receptor as described for example in WO2007035355.
  • the compound of the formula I or Form A is administered in combination with an inhibitor of protein kinase C beta (PKC beta), such as, for example, ruboxistaurin.
  • PLC beta protein kinase C beta
  • the compound of the formula I or Form A is administered in combination with an activator of the gene which codes for the ataxia telangiectasia mutated (ATM) protein kinase, such as, for example, chloroquine.
  • ATM ataxia telangiectasia mutated
  • the compound of the formula I or Form A is administered in combination with an endothelin A receptor antagonist such as, for example, avosentan (SPP-301 ).
  • an endothelin A receptor antagonist such as, for example, avosentan (SPP-301 ).
  • the compound of the formula I or Form A is administered in combination with inhibitors of "1-kappaB kinase" (IKK inhibitors), as are described for example in WO2001000610, WO2001030774, WO2004022553 or WO2005097129.
  • the compound of the formula I or Form A is administered in combination with modulators of the glucocorticoid receptor (GR), like those described for example in WO2005090336, WO2006071609, WO2006135826.
  • GR glucocorticoid receptor
  • the compound of the formula I or Form A is administered in combination with CART modulators (see “Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice” Asakawa, A. et al.: Hormone and Metabolic Research (2001 ), 33(9), 554-558); NPY antagonists such as, for example, naphthalene-1 -sulfonic acid ⁇ 4-[(4- aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl ⁇ amide hydrochloride (CGP 71683A);
  • NPY-5 receptor antagonists such as L-152804 or such as described, for example, in
  • NPY-4 receptor antagonists such as described, for example, in WO2007038942; NPY-2 receptor antagonists such as described, for example, in WO2007038943; peptide YY 3-36 (PYY3-36) or analogous compounds, such as, for example, CJC- 1682 (PYY3-36 conjugated with human serum albumin via Cys34), CJC-1643 (derivative of PYY3-36 which conjugates in vivo to serum albumin) or those as are described in WO2005080424, WO2006095166; derivatives of the peptide obestatin such as those described in WO2006096847; CB1 R (cannabinoid receptor 1 ) antagonists (such as, for example, rimonabant, SR147778, SLV-319, AVE-1625, MK-0364 or salts thereof or compounds such as those described for example in EP 0656354, WO 00/15609, WO2001 /64632-64634,
  • MC4 agonists e.g. 1 -amino-1 ,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2-(3a- benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1 -(4- chlorophenyl)-2-oxoethyl]amide; (WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141 or those that are described in WO2005060985, WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720, US20050124652, WO2005051391 , WO2004112793, WOUS20050222014, US20050176728, US20050164914, US200
  • WO2007041061 WO2007041052; orexin receptor antagonists (e.g. 1 -(2-methylbenzoxazol-6-yl)-3-[1 ,5]naphthyridin-4- ylurea hydrochloride (SB-334867-A) or those as are described for example in WO200196302, WO200185693, WO2004085403, WO2005075458,
  • exin receptor antagonists e.g. 1 -(2-methylbenzoxazol-6-yl)-3-[1 ,5]naphthyridin-4- ylurea hydrochloride (SB-334867-A) or those as are described for example in WO200196302, WO200185693, WO2004085403, WO2005075458,
  • histamine H3 receptor agonists e.g. 3-cyclohexyl-1 -(4,4-dimethyl-1 ,4,6,7- tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1 -one oxalic acid salt (WO 00/63208) or those as are described in WO200064884, WO2005082893, WO2006107661 , WO2007003804, WO2007016496, WO2007020213); histamine H1/histamine H3 modulators such as, for example, betahistine or its dihydrochloride;
  • CRF antagonists e.g. [2-methyl-9-(2,4,6-trimethylphenyl)-9H-1 ,3,9-triazafluoren-4- yl]dipropylamine (WO 00/66585)
  • CRF BP antagonists e.g.
  • urocortin urocortin
  • urocortin agonists agonists of the beta-3 adrenoceptor such as, for example, 1 -(4-chloro-3- methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1 H-indol-6-yloxy)ethylamino]ethanol hydrochloride (WO 01/83451 ) or solabegron (GW-427353) or N-5984 (KRP-204), or those as are described in JP2006111553, WO2002038543, WO2007048840-843;
  • MSH melanocyte-stimulating hormone
  • MCH (melanin-concentrating hormone) receptor antagonists such as, for example,
  • CCK-A agonists such as, for example, ⁇ 2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2- cyclohexylethyl)thiazol-2-ylcarbannoyl]-5,7-dinnethylindol-1 -yl ⁇ acetic acid trifluoroacetic acid salt (WO 99/15525) or SR- 146131 (WO 0244150) or SSR-125180) or those as are described in WO2005116034; serotonin reuptake inhibitors (e.g. dexfenfluramine); mixed serotonin/dopamine reuptake inhibitors (e.g. bupropion) or fixed combinations of bupropion with naltrexone; mixed serotoninergic and noradrenergic compounds (e.g. WO 00/71549);
  • serotonin reuptake inhibitors e.g. dexfenfluramine
  • 5-HT receptor agonists e.g. 1 -(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt
  • 5-HT2C receptor agonists such as, for example, lorcaserin hydrochloride (APD-356) or BVT-933 or those as are described in WO200077010, WO200077001 -02,
  • WO2005082859, WO2006077025, WO2006103511 5-HT6 receptor modulators such as, for example E-6837 or BVT-74316 or those as are described in WO2005058858, WO2007054257; bombesin receptor agonists (BRS-3 agonists); galanin receptor antagonists; growth hormone (e.g.
  • growth hormone-releasing compounds tertiary butyl 6-benzyloxy-1 -(2-diisopropyl- aminoethylcarbamoyl)-3,4-dihydro-1 H-isoquinoline-2-carboxylate (WO 01/85695)
  • growth hormone secretagogue receptor antagonists ghrelin antagonists
  • TRH agonists see, for example, EP 0 462 884
  • uncoupling protein 2 or 3 modulators leptin agonists
  • leptin agonists see, for example, Lee, Daniel W.; Leinung, Matthew C; Rozhavskaya- Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity.
  • DA agonists bromocriptine or Doprexin
  • lipase/amylase inhibitors for example WO 00/40569
  • inhibitors of diacylglycerol O-acyltransferases such as for example BAY-74- 4113 or as described for example in US2004/0224997, WO2004094618, WO200058491 , WO2005044250, WO2005072740, JP2005206492, WO2005013907, WO2006004200, WO2006019020, WO2006064189, WO2006082952, WO2006120125, WO2006113919, WO2006134317, WO2007016538; inhibitors of fatty acid synthase (FAS) such as, for example, C75 or those as described in WO2004005277; inhibitors of stearoyl-CoA delta9 desaturase (S)
  • thyroid hormone receptor agonists or partial agonists such as, for example: KB- 2115 or those as described in WO20058279, WO200172692, WO200194293, WO2003084915, WO2004018421 , WO2005092316, WO2007003419, WO2007009913, WO2007039125.
  • the further active ingredient is varenicline tartrate, a partial agonist of the alpha 4-beta 2 nicotinic acetylcholine receptor.
  • the further active ingredient is trodusquemine.
  • the further active ingredient is a modulator of the SIRT1 enzyme.
  • the further active ingredient is leptin; see, for example, "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001 ), 2(10), 1615-1622.
  • the further active ingredient is dexamphetamine or amphetamine.
  • the further active ingredient is fenfluramine or dexfenfluramine.
  • the further active ingredient is sibutramine.
  • the further active ingredient is mazindole or phentermine.
  • the compound of the formula I or Form A is administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, Carob/Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6).
  • bulking agents preferably insoluble bulking agents
  • Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food
  • Caromax® Ingredients GmbH, lndustriepark H ⁇ chst, 65926 Frankfurt/Main). Combination with Caromax® is possible in one preparation or by separate administration of compounds of the formula I and Caromax®. Caromax® can in this connection also be administered in the form of food products such as, for example, in bakery products or muesli bars.
  • the invention furthermore relates to processes for preparing the crystalline compound of the formula I or a tautomer thereof.
  • the invention provides Form A.
  • the starting material i.e. the compound of Formula I
  • the starting material employed for the processes and procedures described herein should be essentially pure. "Essentially pure” means the starting material has an HPLC purity grade of at least 98%. The HPLC purity grade for the starting material is preferably at least 99.8%.
  • Form A is isolated by dissolving an essentially pure hydrate of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside in isopropyl acetate and adding an anti solvent such as n-heptane.
  • an anti solvent such as n-heptane.
  • Alternative antisolvents such as methylcyclohexane may also be used.
  • Form A may be isolated from an aqueous solution of a salt of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]4-deoxy-4-fluoro- beta-D-glucopyranoside.
  • a sodium salt of the pyrazole functionality, or other suitable salt of the pyrazole may be used to prepare the aqueous solution.
  • the pH is adjusted and the free acid is extracted into an organic solvent, preferably isopropyl acetate.
  • an antisolvent such as, for example, n-heptane crystallizes 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4- deoxy-4-fluoro-beta-D-glucopyranosidehydrate i.e. Form A.
  • Alternative antisolvents such as methylcyclohexane may also be used.
  • Form A can be obtained after completely or substantially dehydrating solid essentially pure 4-[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)-1 H-pyrazole-3-yl]i4-deoxy-4-fluoro-beta-D-glucopyranoside hydrate by drying by heating followed by a rehydration process of the resultant solid in a humid environment (relative humidity: 20-90%).
  • Form A may be maintained during drying of wet 4-[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D- glucopyranosidemonohydrate by avoiding dehydration, for example by drying under a humid environment (relative humidity 20-90%).
  • HPLC purity grade of the compound is at least 99.8 %.
  • Form A was precipitated from different solvents at room temperature by adding n- heptane or diisopropylether as antisolvent.
  • Example 1a 0.209 g of compound of the formula Il was dissolved in 12.45 mL of ethanol. The slightly turbid solution was stirred overnight. 75mL of diisopropylether were added to the stirred solution. Since no precipitation appeared, the sample was evaporated at room temperature.
  • Example 1 b 0.212 g of compound of the formula Il was dissolved in 2.50 ml_ of water/methanol 1 :1 (vol/vol) at about 65°C. The solvent was allowed to evaporate from the stirred solution at the same temperature overnight.
  • Samples of the compound of formula Il were dissolved at 65°C in several solvents and transferred to 0oC environment in which they were stirred for 0.5, 19 or 24 hours before vacuum filtration.
  • Example 1 c Rapid cooling of a stirred solution (slightly turbid) of 0.220 g of compound of formula Il in 8.0 ml_ butyl acetate from 65°C to 0oC. Since no precipitation occurred the sample was evaporated at room temperature.
  • Example 1d Rapid cooling of a stirred solution (slightly turbid)) of 0.224 g of compound of formula Il in 13.0 ml_ ethanol from 65°C to 0oC. Since no precipitation occurred the sample was evaporated at room temperature.
  • Example 1 e Rapid cooling of a stirred solution (slightly turbid)) of 0.210 g of compound of formula Il in 1.0 ml_ methyl ethyl ketone from 65°C to 0oC. Since no precipitation occurred, the sample was evaporated at room temperature.
  • the batch was then transferred to a second reactor through a polishing filter fitted with a 0.45 ⁇ m cartridge and the first reactor was rinsed with n-propanol (20kg) and demineralized water (25.5kg).
  • the rinses were charged to this second reactor and the mixture was heated to 45 ⁇ 3°C.
  • Demineralized water (281 kg) was added at a controlled rate maintaining the batch temperature at 42 ⁇ 5°C.
  • the resultant solution was cooled to 29 ⁇ 1 °C and then gradually to 22 ⁇ 1 °C using a jacket cooling profile (4.5°C/hr).
  • the resulting slurry was heated to 36 ⁇ 2°C and maintained at 36 ⁇ 2°C for not less than 80 minutes.
  • the batch was then cooled to 1 ⁇ 3°C using a jacket cooling profile (3°C/hr) and held for not less than 1 hour at 1 ⁇ 3°C.
  • the batch was filtered, washed twice with demineralized water (2 X 160kg), dried under reduced pressure ( ⁇ 100mm Hg) at 60 ⁇ 5°C such that water content was less than 3.0% by KF titration and then allowed to rehydrate to give the product 4- [(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4- fluoro-beta-D-glucopyranosideas the monohydrate form A (22.95kg; molar yield 90.0%).
  • the solution was cooled to 0 ⁇ 2°C over a period of 3.5 hours, filtered, washed with n-heptane (27.0kg) and dried under reduced pressure ( ⁇ 100mm Hg) at a temperature of not more than 50oC such that residual solvent levels for isopropyl acetate and n-heptane were less than 5000 ppm each.
  • the solids were then allowed to rehydrate under humid conditions to give the product 4-[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside as the monohydrate form A (10.90kg; molar yield 93.2%).
  • a 24.8439g sample of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside(a mixture of crystalline hydrates) was transferred into an open crystallization dish to form an 3 cm thick layer.
  • the dish was placed in an open aluminum dessicator and transferred to a vacuum oven.
  • the sample was dried at 60oC under vacuum for 24 hours.
  • the sample was then placed on an analytical balance in the presence of an open vessel containing water and allowed to rehydrate.
  • X-ray powder diffraction experiments were performed with a STOE Stadi-P transmission diffractometer using Cu-Kcci radiation.
  • XRPD X-ray powder diffraction experiments
  • linear position sensitive detectors were used for room temperature powder diffraction. Dry samples were investigated in a flat preparation. The measured data was evaluated and plotted with the software WinXPOW v2.12.
  • thermogravimetric analyses were performed with a METTLER TGA85 1 e (module TGAISDTA85 1 elSF 1 1001042). Open 100 ⁇ L Al-crucibles were used and the measurements were performed in a nitrogen gas flow of 50 mL/min. The measured data was evaluated via the software STARe V8.10.
  • Infra-red absorption spectra were recorded on a FT-IR Spectrometer (Nexus 470, NICOLET). The spectra are evaluated and plotted by the software Omnic V. 6.1 A.
  • Form A exhibits the XRPD shown in Figure 1.
  • the XRPD was measured in transmission with Cu-Kalpha1 radiation at room temperature. The most important 2 theta values are summarized in table 1.
  • the 2 theta values of the peaks can be stated with an accuracy of +/- 0.2 degrees theta.
  • the following tables 2 to 5 show data for the storage stability of Form A. Samples of Form A were packed into LDPE (low density polyethylene) flat bags which are used as primary packaging material. Physical and chemical stability was monitored over a period up to 12 month under different conditions as indicated at each table.
  • LDPE low density polyethylene

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Abstract

Cette invention concerne un nouvel hydrate de fluoroglycoside hétéroaromatique cristallisé, ses procédés de fabrication, ses méthodes d'utilisation et ses compositions pharmaceutiques. L'invention concerne un hydrate cristallisé de formule (I), n étant compris entre 0,9 et 1,1. Le composé est approprié pour être utilisé, par exemple, comme antidiabétique.
EP09764844A 2008-12-08 2009-12-07 Nouvel hydrate de fluoroglycoside hétéroaromatique cristallisé, ses procédés de fabrication, ses méthodes d'utilisation et ses compositions pharmaceutiques Withdrawn EP2406271A1 (fr)

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EP09764844A EP2406271A1 (fr) 2008-12-08 2009-12-07 Nouvel hydrate de fluoroglycoside hétéroaromatique cristallisé, ses procédés de fabrication, ses méthodes d'utilisation et ses compositions pharmaceutiques

Applications Claiming Priority (3)

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EP08291157 2008-12-08
PCT/EP2009/066551 WO2010066690A1 (fr) 2008-12-08 2009-12-07 Nouvel hydrate de fluoroglycoside hétéroaromatique cristallisé, ses procédés de fabrication, ses méthodes d'utilisation et ses compositions pharmaceutiques
EP09764844A EP2406271A1 (fr) 2008-12-08 2009-12-07 Nouvel hydrate de fluoroglycoside hétéroaromatique cristallisé, ses procédés de fabrication, ses méthodes d'utilisation et ses compositions pharmaceutiques

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