WO2012023598A1 - 4-イソプロピルフェニル グルシトール化合物の結晶形及びその製造方法 - Google Patents
4-イソプロピルフェニル グルシトール化合物の結晶形及びその製造方法 Download PDFInfo
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- WO2012023598A1 WO2012023598A1 PCT/JP2011/068736 JP2011068736W WO2012023598A1 WO 2012023598 A1 WO2012023598 A1 WO 2012023598A1 JP 2011068736 W JP2011068736 W JP 2011068736W WO 2012023598 A1 WO2012023598 A1 WO 2012023598A1
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- JAWMENYCRQKKJY-UHFFFAOYSA-N [3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-ylmethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]methanone Chemical compound N1N=NC=2CN(CCC=21)CC1=NOC2(C1)CCN(CC2)C(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F JAWMENYCRQKKJY-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000009056 active transport Effects 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000005250 beta ray Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000003544 deproteinization Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000009207 exercise therapy Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 238000007446 glucose tolerance test Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- GRRNUXAQVGOGFE-NZSRVPFOSA-N hygromycin B Chemical compound O[C@@H]1[C@@H](NC)C[C@@H](N)[C@H](O)[C@H]1O[C@H]1[C@H]2O[C@@]3([C@@H]([C@@H](O)[C@@H](O)[C@@H](C(N)CO)O3)O)O[C@H]2[C@@H](O)[C@@H](CO)O1 GRRNUXAQVGOGFE-NZSRVPFOSA-N 0.000 description 1
- 229940097277 hygromycin b Drugs 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940030980 inova Drugs 0.000 description 1
- 238000010813 internal standard method Methods 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- NVWZNEDLYYLQJC-UHFFFAOYSA-N methyl 2-amino-2-methylpropanoate;hydrochloride Chemical compound Cl.COC(=O)C(C)(C)N NVWZNEDLYYLQJC-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N methyl monoether Natural products COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- PNFGNHGNXRWCQW-UHFFFAOYSA-N n-[2-(dimethylamino)ethyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCCN(C)C PNFGNHGNXRWCQW-UHFFFAOYSA-N 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- CYXKNKQEMFBLER-UHFFFAOYSA-N perhexiline Chemical compound C1CCCNC1CC(C1CCCCC1)C1CCCCC1 CYXKNKQEMFBLER-UHFFFAOYSA-N 0.000 description 1
- 229960000989 perhexiline Drugs 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 150000003904 phospholipids Chemical group 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- JLKDVMWYMMLWTI-UHFFFAOYSA-M potassium iodate Chemical compound [K+].[O-]I(=O)=O JLKDVMWYMMLWTI-UHFFFAOYSA-M 0.000 description 1
- 239000001230 potassium iodate Substances 0.000 description 1
- 235000006666 potassium iodate Nutrition 0.000 description 1
- 229940093930 potassium iodate Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Images
Classifications
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Definitions
- the present invention relates to a crystal form of 4-isopropylphenyl glucitol useful as an active ingredient of a therapeutic drug for diabetes and a method for producing the same.
- Blood glucose level is one of the biomarkers of metabolic syndrome, and diabetes is diagnosed when fasting blood glucose is 126 mg / dL or more. Even if the fasting blood glucose level is normal, a glucose tolerance abnormality (or postprandial hyperglycemia) is diagnosed when the blood glucose level for 2 hours after meal is 140 to 200 mg / dL.
- impaired glucose tolerance increases the risk of cardiovascular disorders (see Non-Patent Documents 1 and 2).
- exercise therapy and drug treatment suppress the transition from impaired glucose tolerance to type 2 diabetes and significantly suppress the onset of hypertension (see Non-Patent Document 3).
- suppressing postprandial hyperglycemia is important for suppressing the onset of diabetes and metabolic syndrome, and the demand for drugs that control postprandial hyperglycemia is increasing.
- ⁇ -glucosidase inhibitors that inhibit saccharide hydrolase and delay sugar absorption from the small intestine have been widely used as postprandial hyperglycemia-improving agents. Development of drugs to improve blood glucose is also underway.
- SGLT1 Sodium-dependent glucose cotransporter 1
- SGLT1 is frequently expressed in the small intestinal epithelium of mammals.
- SGLT1 is known to depend on sodium in the small intestine and to control the active transport of glucose and galactose. Accordingly, pyrazole derivatives that inhibit SGLT1 activity to suppress glucose absorption derived from meals and can be used for prevention or treatment of postprandial hyperglycemia have been reported (see Patent Documents 1 to 6). ).
- sodium-dependent glucose cotransporter 2 (SGLT2) is frequently expressed in the kidney, and glucose once filtered by the glomerulus is reabsorbed via SGLT2 (non-patent document). Reference 4).
- Non-Patent Document 5 As a feature of SGLT2 inhibitor, it has an excellent effect of lowering blood glucose as needed, but it has a low effect of correcting postprandial hyperglycemia like SGLT1 inhibitor. There is also a report on a C-phenyl glucitol derivative that simultaneously inhibits SGLT2 activity in addition to SGLT1 activity (see Patent Document 7).
- a cationic drug having a hydrophilic group such as a tertiary amine and a hydrophobic group such as an aromatic ring in the molecule is hydrophobically bound to a phospholipid, and is taken into a lysosome and accumulated in organs throughout the body. It is known that As typical examples, chloroquine caused retinal damage, and perhexiline had changes in the lungs and cerebellum, causing neuropathy (see Non-Patent Document 6).
- the drug is rapidly excreted from the body after exhibiting a medicinal effect.
- a drug having no problem of persistence in the body is desired.
- pharmaceuticals are required to have physical properties that are easy to handle on an industrial scale and have excellent storage stability.
- An object of the present invention is to provide a crystal of a novel compound that exhibits an SGLT1 inhibitory action with a wide safety range between a medicinal amount, toxicity, and side effect, and is excellent in the above physical properties.
- One embodiment of the present invention provides (1S) -1,5-anhydro-1- [5- (4- ⁇ (1E) -4-[(1-)] having the following physical properties (a) to (c). ⁇ [2- (dimethylamino) ethyl] amino ⁇ -2-methyl-1-oxopropan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-en-1-yl ⁇ benzyl)- Crystal of ethanol solvate of 2-methoxy-4- (propan-2-yl) phenyl] -D-glucitol.
- (1S) -1,5-anhydro-1- [5- (4- ⁇ (1E) -4] is added to ethanol or a mixed solution of ethanol and an organic solvent having a property miscible with ethanol.
- -[(1- ⁇ [2- (dimethylamino) ethyl] amino ⁇ -2-methyl-1-oxopropan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-ene-1- Yl ⁇ benzyl) -2-methoxy-4- (propan-2-yl) phenyl] -D-glucitol is dissolved and crystallized at 0 to 80 ° C., and the resulting crystals are dried at 50 ° C.
- Another embodiment of the present invention is the following (1S) -1,5-anhydro-1- [5- (4- ⁇ (1E) -4-[(1-)] having the following physical properties (a) to (b): ⁇ [2- (dimethylamino) ethyl] amino ⁇ -2-methyl-1-oxopropan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-en-1-yl ⁇ benzyl)- This is a crystal of 2-methoxy-4- (propan-2-yl) phenyl] -D-glucitol (A-form crystal).
- Another aspect of the present invention is to prepare (1S) -1,5-anhydro-1- [5- (4- ⁇ (1E) -4-[(1- ⁇ [2- (dimethyl alcohol)] in water or a phosphate buffer solution.
- a crystal having the following physical properties (a) to (b), wherein an ethanol solvate of (propan-2-yl) phenyl] -D-glucitol is suspended and then dried at 35 ° C. or lower ( A type crystal).
- (A) In powder X-ray diffraction (Cu-K ⁇ ), it has peaks at 2 ⁇ 6.1 degrees, 13.7 degrees, 18.0 degrees and 18.7 degrees; and (b) the melting point is around 110 ° C. is there.
- Another embodiment of the present invention is the following (1S) -1,5-anhydro-1- [5- (4- ⁇ (1E) -4-[(1-)] having the following physical properties (a) to (b): ⁇ [2- (dimethylamino) ethyl] amino ⁇ -2-methyl-1-oxopropan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-en-1-yl ⁇ benzyl)- This is a crystal of 2-methoxy-4- (propan-2-yl) phenyl] -D-glucitol (B-form crystal).
- an organic solvent excluding ethanol
- a crystal having the following physical properties (a) to (b), wherein the ethanol solvate of -D-glucitol is suspended and then dried at room temperature to 100 ° C.
- (B-form crystal) It is a manufacturing method.
- (A) In powder X-ray diffraction (Cu—K ⁇ ), it has peaks at 2 ⁇ 6.4 °, 10.9 °, 16.9 ° and 18.1 °; and (b) the melting point is around 115 ° C. is there.
- Another embodiment of the present invention is the following (1S) -1,5-anhydro-1- [5- (4- ⁇ (1E) -4-[(1-)] having the following physical properties (a) to (b): ⁇ [2- (dimethylamino) ethyl] amino ⁇ -2-methyl-1-oxopropan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-en-1-yl ⁇ benzyl)- This is a crystal of 2-methoxy-4- (propan-2-yl) phenyl] -D-glucitol (C-form crystal).
- (A) In powder X-ray diffraction (Cu—K ⁇ ), it has peaks at 2 ⁇ 10.7 degrees, 17.9 degrees and 19.7 degrees; and (b) the melting point is around 127 ° C.
- Another embodiment of the present invention relates to (1S) -1,5-anhydro-1- [5- (4- ⁇ (1E) -4-[(1- ⁇ [2- (dimethylamino) ethyl] amino ⁇ amino ⁇ - 2-methyl-1-oxopropan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-en-1-yl ⁇ benzyl) -2-methoxy-4- (propan-2-yl) Crystals of phenyl] -D-glucitol (form A crystals) are heated from room temperature to 150 ° C. under reduced pressure, suspended in a mixed solvent of hexane and ethyl acetate, and dried at 35 ° C. or lower.
- a method for producing a crystal (C-type crystal) having the following physical properties (a) to (b): (A) In powder X-ray diffraction (Cu—K ⁇ ), it has peaks at 2 ⁇ 10.7 degrees, 17.9 degrees and 19.7 degrees; and (b) the melting point is around 127 ° C.
- Another embodiment of the present invention is the following (1S) -1,5-anhydro-1- [5- (4- ⁇ (1E) -4-[(1-)] having the following physical properties (a) to (b): ⁇ [2- (dimethylamino) ethyl] amino ⁇ -2-methyl-1-oxopropan-2-yl) amino] -3,3-dimethyl-4-oxobut-1-en-1-yl ⁇ benzyl)- 2-methoxy-4- (propan-2-yl) phenyl] -D-glucitol crystals (dihydrate crystals).
- FIG. 1 shows a powder X-ray diffraction pattern of an ethanol solvate.
- the infrared absorption spectrum (KBr method) of an ethanol solvate is shown.
- the differential thermal analysis / thermal mass measurement curve of an ethanol solvate is shown.
- the powder X-ray diffraction pattern of A-form crystal is shown.
- the differential thermal analysis / thermal mass measurement curve of A-form crystal is shown.
- the powder X-ray diffraction pattern of a B-form crystal is shown.
- the differential thermal analysis / thermal mass measurement curve of a B-form crystal is shown.
- the powder X-ray-diffraction pattern of a C-form crystal is shown.
- the differential thermal analysis / thermal mass measurement curve of a C-form crystal is shown.
- 2 shows a powder X-ray diffraction pattern of dihydrate crystals. 2 shows a differential thermal analysis / thermal mass measurement curve of a dihydrate crystal.
- crystal of the present invention An ethanol solvate of compound (A) (hereinafter sometimes referred to as “crystal of the present invention”) is obtained as a single crystal having a certain quality with good reproducibility, and is a crystal of a drug substance used for the manufacture of a pharmaceutical product. Can be stably supplied, and has excellent storage stability. In addition, the crystal of the present invention can be easily changed to other crystal forms by suspending it in water or an organic solvent (excluding ethanol). These crystal form differences are distinguished in particular by powder X-ray diffraction and differential thermal analysis / thermal mass measurement curves.
- the “crystal of the present invention” means a concept including a mixture of ethanol solvate and anhydride crystal, and a mixed crystal of ethanol solvate and anhydride crystal.
- the ethanol solvate of compound (A) has the following physical properties (a) to (c).
- the melting point is near 111 ° C.
- the temperature is preferably 108 ° C to 114 ° C.
- the powder X-ray diffraction pattern of the ethanol solvate of compound (A) is shown in FIG. 1, the infrared absorption spectrum (KBr method) is shown in FIG. 2, and the differential thermal analysis / thermal mass measurement curve is as shown in FIG. .
- the ethanol solvate of compound (A) is obtained by crystallization from a solution in which compound (A) is dissolved in ethanol or a mixed solution of an organic solvent having a property of being miscible with ethanol and ethanol.
- the raw material compound (A) before recrystallization is amorphous.
- the compound (A) may be dissolved in the solution and crystallized from the solution by a usual method.
- a method is used in which an amorphous compound (A) is heated and dissolved in a mixed solution composed of an organic solvent having a property miscible with ethanol and ethanol, and then cooled.
- Examples of the organic solvent having a property to be mixed with ethanol include hydrocarbons such as heptane, t-butyl methyl ether, and ethyl acetate.
- the concentration for dissolving the compound (A) is 0.5 to 70% by mass, preferably 5 to 50% by mass.
- the mass% is the mass percentage of the ethanol solvate of the compound (A) in the solution or suspension.
- the mixing ratio in a mixed solvent of an organic solvent having a property of being mixed with ethanol and ethanol can be appropriately changed.
- the precipitated ethanol solvate crystals are separated from the solvent by filtration, centrifugation, etc. from the solution, and then dried at 50 ° C. or lower.
- Form A crystals of compound (A) have the following physical properties (a) to (b).
- (A) In powder X-ray diffraction (Cu-K ⁇ ), it has peaks at 2 ⁇ 6.1 degrees, 13.7 degrees, 18.0 degrees and 18.7 degrees; and (b) the melting point is around 110 ° C. Yes, preferably 107 ° C to 113 ° C.
- the powder X-ray diffraction pattern of the A-form crystal of the compound (A) is as shown in FIG. 4, and the differential thermal analysis / thermal mass measurement curve is as shown in FIG.
- the A-form crystal of the compound (A) is obtained by suspending an ethanol solvate of the compound (A) from water or a phosphate buffer solution.
- Examples of phosphoric acid that can be used in the phosphate buffer include phosphoric acid, sodium dihydrogen phosphate and its hydrate (for example, dihydrate), disodium hydrogen phosphate and its hydrate (for example, 12 Hydrate), potassium dihydrogen phosphate and its hydrate, dipotassium hydrogen phosphate and its hydrate, and the like.
- the concentration at which the ethanol solvate of compound (A) is suspended is 0.5 to 30% by mass, preferably 1 to 20% by mass, based on the suspension.
- the suspension temperature is 35 ° C or lower, and is usually 25 ° C.
- the suspension time is not always constant depending on the type of solvent, temperature, and other conditions.
- the suspension temperature is 25 ° C.
- the suspension time is 24 hours or longer, usually 24 hours.
- the suspension conditions may be as long as the suspension state of the compound (A) is not impaired, and the time for conversion to A-type crystals can be shortened by heating.
- the end point of the conversion to the A-form crystal can be confirmed by filtering a part of the crystal from the suspension and measuring the powder X-ray diffraction pattern of the crystal.
- the A-form crystals obtained as described above are separated from the dispersion (suspension) solution by filtration, centrifugation, etc., and then dried at 35 ° C. or lower and usually at room temperature (25 ° C.).
- the drying time is not necessarily constant depending on the drying temperature, the crystal form of the raw material used, the particle diameter, and other conditions, but the end point of the change in the crystal form takes a part of the dry crystal. This can be confirmed by measuring a powder X-ray diffraction pattern or the like.
- Form B crystals of compound (A) have the following physical properties (a) to (b).
- (A) In powder X-ray diffraction (Cu—K ⁇ ), it has peaks at 2 ⁇ 6.4 °, 10.9 °, 16.9 ° and 18.1 °; and (b) the melting point is around 115 ° C. It is preferably 112 ° C to 118 ° C.
- the powder X-ray diffraction pattern of the B-form crystal of the compound (A) is as shown in FIG. 6, and the differential thermal analysis / thermal mass measurement curve is as shown in FIG.
- Form B crystals of compound (A) are mixed with isopropyl ether, an organic solvent (excluding ethanol) and isopropyl ether, which is miscible with ethanol solvate of compound (A), or miscible with hexane or heptane. It is obtained by suspending from a mixed solution of an organic solvent having (excluding ethanol) and hexane or heptane.
- organic solvents having a property of being mixed with hexane or heptane include ethyl acetate, acetone, t-butyl methyl ether, and the like.
- the concentration at which the ethanol solvate of compound (A) is suspended is 0.5 to 30% by mass, preferably 1 to 20% by mass, based on the suspension.
- the suspension temperature is 35 ° C or lower, and is usually 25 ° C.
- the suspension time is not always constant depending on the type of solvent, temperature, and other conditions.
- the suspension temperature is 25 ° C.
- the suspension time is one week or longer, and usually one week.
- the suspension conditions may be as long as the suspension state of the compound (A) is not impaired, and the time for conversion to the B-type crystals can be shortened by heating.
- the end point of the conversion to the B-form crystal can be confirmed by filtering a part of the crystal from the suspension and measuring the powder X-ray diffraction pattern of the crystal.
- the B-form crystals obtained as described above are dried from room temperature to 100 ° C. after being separated from the solvent from the dispersion (suspension) solution by filtration, centrifugation or the like.
- the humidity when drying at room temperature is 20% or less, and usually 11% or less.
- the drying time is not necessarily constant depending on the drying temperature, the crystal form of the raw material used, the particle diameter, and other conditions, but the end point of the change in the crystal form takes a part of the dry crystal. This can be confirmed by measuring a powder X-ray diffraction pattern or the like.
- Form B crystals of Compound (A) can be obtained by subjecting an ethanol solvate of Compound (A) to a state of 25 ° C. and 11% humidity after being separated from the solvent suspension. .
- Form B crystals of Compound (A) can be obtained by subjecting an ethanol solvate of Compound (A) to a state of 60 ° C. and 0% humidity after separation from the solvent suspension. It is done.
- the form B crystal of the compound (A) can be obtained by separating the ethanol solvate of the compound (A) from the suspension of the solvent and then subjecting it to 100 ° C.
- the C-type crystal of the compound (A) has the following physical properties (a) to (b).
- (A) In powder X-ray diffraction (Cu—K ⁇ ), it has peaks at 2 ⁇ 10.7 degrees, 17.9 degrees and 19.7 degrees; and (b) the melting point is around 127 ° C., preferably 124 ° C to 130 ° C.
- the C-form crystal of the compound (A) is obtained by raising the temperature of the A-form crystal of the compound (A) from room temperature to 150 ° C. under reduced pressure, and then suspending it from a mixed solution of hexane and ethyl acetate. .
- the temperature at which the A-form crystal of compound (A) is heated under reduced pressure is room temperature to 150 ° C., preferably room temperature to 120 ° C., more preferably 120 ° C.
- the concentration suspended in a mixed solution of hexane and ethyl acetate is 0.5 to 30% by mass, preferably 1% with respect to the suspension. ⁇ 20% by weight.
- the suspension temperature is 55 to 75 ° C, usually 65 ° C.
- the suspension time is not always constant depending on the type of solvent, temperature, and other conditions. In the case of 65 ° C., the suspension time is 8 hours or longer, usually 8 hours.
- the end point of the conversion to the C-type crystal can be confirmed by filtering a part of the crystal from the suspension and measuring the powder X-ray diffraction pattern of the crystal.
- the C-form crystals obtained as described above are separated from the solvent by distilling the solvent off using a rotary evaporator or by filtering, centrifuging, etc. from the dispersion (suspension) liquid, and at 35 ° C. or lower, usually at room temperature. dry.
- the drying time is not necessarily constant depending on the drying temperature, the crystal form of the raw material used, the particle diameter, and other conditions, but the end point of the change in the crystal form takes a part of the dry crystal. This can be confirmed by measuring a powder X-ray diffraction pattern or the like.
- the crystal of the dihydrate of the compound (A) has the following physical properties (a) to (b).
- (A) In powder X-ray diffraction (Cu—K ⁇ ), it has peaks at 2 ⁇ 17.2 degrees, 17.8 degrees and 20.9 degrees; and (b) the melting point is near 121 ° C., preferably 118 ° C to 124 ° C.
- the concentration at which the ethanol solvate of compound (A) is suspended is 0.5 to 20% by mass, preferably 0.5 to 10% by mass, based on the suspension.
- the suspension temperature is 35 ° C or lower, and is usually 25 ° C.
- the suspension time is not always constant depending on the type of solvent, temperature, and other conditions.
- the suspension temperature is 25 ° C.
- the suspension time is 6 days or longer, usually 6 days.
- the suspension conditions may be as long as the suspension state of the compound (A) is not impaired, and the time for conversion to dihydrate crystals can be shortened by heating.
- the end point of the conversion of the dihydrate into crystals can be confirmed by filtering a part of the crystals from the suspension and measuring the powder X-ray diffraction pattern of the crystals.
- the dihydrate crystals obtained as described above are separated from the solvent from the dispersion (suspension) solution by filtration, centrifugation, etc., and then dried at room temperature.
- the humidity when drying at room temperature is 40% to 85%. It has been confirmed that the dihydrate crystal transitions from the B-type crystal at a humidity of 40% or higher and deliquesces at a humidity of 85% or higher.
- the drying time is not necessarily constant depending on the drying temperature, the crystal form of the raw material used, the particle diameter, and other conditions, but the end point of the change in the crystal form takes a part of the dry crystal. This can be confirmed by measuring a powder X-ray diffraction pattern or the like.
- NMR (nuclear magnetic resonance) spectra were measured at room temperature at 200 MHz (GEMINI 2000/200, Varian Instruments), 300 MHz (INOVA 300, Varian Instruments, JEOL JNM-ECP300, JEOL, JEOL JNM-ECX300, JEOL L) 600 MHz. JNM-ECA600, JEOL).
- the chemical shift value in the present specification is shown as a parts per million ( ⁇ ) value with respect to the internal standard substance (tetramethylsilane).
- Mass spectrum is Waters micromass GCT (EI: electron ionization method), micromass Platform-LC mass spectrometer (ESI: electrospray ionization method) or Shimadzu LCMS-2010EV (ESI: electrospray ionization method / APCI: atmospheric pressure ionization method Du) Measured with
- Powder X-rays were measured with Rigaku RINT 2200 Ultima III.
- Methyl iodide (9.8 mL, 0.156 mol) was added to an acetonitrile suspension (200 mL) of compound (B1) (27.4 g, 0.104 mol) and potassium carbonate (21.7 g, 0.156 mol) at 40 ° C. For 2.5 hours. Methyl iodide (3.5 mL, 0.052 mol) was further added, and the mixture was stirred at the same temperature for 1 hour. Insoluble matter was filtered off, and the filtrate was diluted with ethyl acetate. The organic layer was washed with water, 10% aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate.
- Et 3 SiH (1.1 mL, 7.1 mmol) was added to a solution of this crude product (3.3 g) in chloroform (25 mL) and acetonitrile (25 mL), and the mixture was ice-cooled in a nitrogen atmosphere. Under ice cooling, BF 3 ⁇ OEt 2 (0.9 mL, 7.1 mmol) was added dropwise over 10 minutes, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure.
- intermediate (B) (1.2 g, 1.85 mmol), intermediate (C) (2.59 g, 13.0 mmol), palladium (II) acetate (44 mg, 0.19 mmol), tri-o -A suspension of tolylphosphine (112 mg, 0.37 mmol) and triethylamine (1.3 mL, 9.25 mmol) in acetonitrile (36 ml) was stirred at 120 ° C for 30 minutes under microwave irradiation. The reaction solution was filtered using Celite (registered trademark) and washed with ethyl acetate.
- Celite registered trademark
- Example 1 25 mg of colorless amorphous compound (A) (purity 99.9%) was dissolved in 0.08 mL of ethanol at room temperature and stirred at room temperature for 1 day to obtain crystals. The crystals were dried under reduced pressure at room temperature to obtain 27 mg of colorless crystals (recovery rate 100%).
- Example 2 After dissolving 56 g of colorless amorphous compound (A) (purity 96.0%) in ethanol 135 mL at 66 ° C., 135 mL of heptane was added with stirring and the mixture was cooled and obtained in Example 1 at around 45 ° C. After adding ethanol solvate crystals of Compound (A), the temperature was lowered to 1 ° C. The precipitated crystals were collected by filtration and then dried under reduced pressure at 40 ° C.
- Example 4 2 mL of isopropyl ether / methanol (9/1) was added to 0.10 g of the ethanol solvate of compound (A), suspended, and suspended at 25 ° C. for 1 week. After centrifugation (3000 rpm, 25 ° C., 10 minutes), the supernatant was removed and dried at room temperature to obtain colorless crystals.
- Example 6 10 mL of isopropyl ether / methanol (9/1) was added to 0.40 g of the ethanol solvate of compound (A), suspended, and suspended at 25 ° C. for 3 days. Further, 50 mL of isopropyl ether / methanol (9/1) was added, and then suspended at 25 ° C. for 6 days. After centrifugation (3000 rpm, 25 ° C., 10 minutes), the supernatant was removed and dried at room temperature to obtain colorless crystals. When the powder X-ray diffraction pattern and differential thermal analysis / thermal mass measurement (TG / DTA) of this crystal were measured, it was a dihydrate crystal.
- TG / DTA differential thermal analysis / thermal mass measurement
- Test example 1 (1) Preparation of CHO-K1 cells stably expressing human SGLT1 Plasmid vectors expressing human SGLT1 protein were transfected into CHO-K1 cells using Lipofectamine 2000 (Invitrogen). SGLT1-expressing cells were cultured in the presence of geneticin at a concentration of 500 ⁇ g / mL, resistant strains were selected, and sugar uptake capacity was obtained as an index by the system shown below.
- Method B A plasmid vector expressing human SGLT2 protein was transfected into CHO-K1 cells using Lipofectamine LTX (Invitrogen). SGLT2-expressing cells were cultured in the presence of geneticin at a concentration of 1000 ⁇ g / mL, resistant strains were selected, and sugar uptake capacity was obtained as an index by the system shown below. The results calculated using the stably expressing cells are shown in Table 1 as Method B. (3) Sodium-dependent sugar uptake inhibition test in stably expressing cells The following tests were conducted using the stably expressing cells prepared above.
- pretreatment buffer 140 mM choline chloride, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4
- pretreatment buffer 140 mM choline chloride, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4
- the pretreatment buffer is removed, and the uptake buffer containing the test compound ([ 14 C] methyl ⁇ -D-glucopyranoside containing methyl ⁇ -D-glucopyranoside (1 mM), 140 mM NaCl, 2 mM KCl, 1 mM CaCl 2 , Add 1 ⁇ M MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4) 75 ⁇ L (for SGLT1) or 200 ⁇ L (for SGLT2) and perform uptake reaction at 37 ° C. for 30 minutes (SGLT1) or 60 minutes (SGLT2) It was.
- the test compound [ 14 C] methyl ⁇ -D-glucopyranoside containing methyl ⁇ -D-glucopyranoside (1 mM), 140 mM NaCl, 2 mM KCl, 1 mM CaCl 2 , Add 1 ⁇ M MgCl 2 , 10 mM HEPES / 5 mM Tris, pH
- the cells are washed with a buffer for washing (10 mM methyl ⁇ -D-glucopyranoside, 140 mM choline chloride 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4) 200 ⁇ L (for SGLT1), or 2 mL It was washed twice with (in the case of SGLT2) and dissolved in 75 ⁇ L of 0.25 M NaOH solution (in the case of SGLT1) or 400 ⁇ L (in the case of SGLT2).
- a buffer for washing 10 mM methyl ⁇ -D-glucopyranoside, 140 mM choline chloride 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4
- test compound concentration (IC 50 value) at which the sugar uptake amount was inhibited by 50% relative to the sugar uptake amount (100%) of the control group was calculated using appropriate 6 concentrations of the test compound. .
- the test results are shown in Table 1.
- Test Example 2 Test for confirming inhibitory effect on blood glucose level in streptozotocin diabetic model rats (1) Preparation of diabetic model rats 7-week-old SD / IGS rats (Nippon Charles River Co., Ltd., male) were fasted for about 16 hours and then anesthetized with ether. Under the above, streptozotocin (STZ) 50 mg / kg was administered into the tail vein to prepare a diabetes model rat. Similarly, under ether anesthesia, 1.25 mmol / L citrate physiological saline 1 mL / kg was administered into the tail vein to prepare normal control rats.
- Blood collection was performed using heparin-coated blood collection tubes from the rat tail vein under ether anesthesia, and plasma was collected after centrifugation.
- the plasma glucose concentration was measured using Glucose CII Test Wako (Wako Pure Chemical Industries, Ltd.).
- the blood glucose level increase inhibitory action strength is calculated by calculating the area under the blood glucose level-time curve (AUC) using the trapezoidal method from the blood glucose level from 0 to 1 hour of each drug administration group, and the area of increased blood glucose ( ⁇ AUC) by subtracting basal ) And expressed as a percentage of the drop relative to that of the control group.
- AUC blood glucose level-time curve
- Test example 3 Changes in renal concentrations up to 1 week after oral administration of the compound disclosed in WO2007 / 136116 7% -old SD / IGS rats (Nippon Charles River Co., Ltd., male, non-fasted) were treated with 0.5% CMC. Compounds 4, 10, 33 (1 mg / kg each) prepared in an aqueous solution and compound 11 (0.3 mg / kg) were orally administered. At 24, 72 and 168 hours after drug administration, whole blood was collected from the posterior vena cava under ether anesthesia, and the kidney was removed after confirmation of euthanasia. After washing the tissue surface with physiological saline, the weight was measured, 4 times the amount of purified water was added, and the mixture was homogenized under ice cooling.
- the internal standard substances of compounds 10 and 33 include (1S) -1,5-anhydro-1- [5- (4-ethoxybenzyl) -2-methoxy-4-methylphenyl] -1-thio- D-glucitol and ethyl-D 5 were used, and compound 11 and compound 11 deuterium labeled (trishydroxymethyl-D 6 ; —C (CD 2 OH) 3 ) were used as the internal standard substances of compounds 4 and 11, respectively.
- (1S) -1,5-anhydro-1- [5- (4-ethoxybenzyl) -2-methoxy-4-methylphenyl] -1-thio- D-glucitol and ethyl-D 5 were used, and compound 11 and compound 11 deuterium labeled (trishydroxymethyl-D 6 ; —C (CD 2 OH) 3 ) were used as the internal standard substances of compounds 4 and 11, respectively.
- the compound disclosed in WO2007 / 136116 showed a strong blood glucose lowering action in a glucose tolerance test after oral administration of 1 mg / kg. However, after oral administration of 1 mg / kg, the disappearance rate of the compound from the kidney was slow, and even after 7 days, the compound was not excreted and remained in the kidney (Table 2).
- the compound (A) had a strong hypoglycemic action like the above prior art compounds.
- the continuous administration for 3 days at a dose of 3 mg / kg it was shown that the compound unexpectedly did not remain in the kidney 2 days after administration (Table 3).
- the compound (A) has a property excellent in practicality as a pharmaceutical having no residual in the body and few side effects and toxicity due to continuous administration.
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Abstract
Description
(a)粉末X線回折(Cu-Kα)において、2θ=5.9度、17.1度、17.6度及び21.5度にピークを有する;
(b)赤外線吸収スペクトルにおいて、特性吸収帯が3538cm-1、3357cm-1、2964cm-1、1673cm-1、1634cm-1及び1505cm-1にある;並びに
(c)融点が111℃付近である。
(a)粉末X線回折(Cu-Kα)において、2θ=5.9度、17.1度、17.6度及び21.5度にピークを有する;
(b)赤外線吸収スペクトルにおいて、特性吸収帯が3538cm-1、3357cm-1、2964cm-1、1673cm-1、1634cm-1及び1505cm-1にある;並びに
(c)融点が111℃付近である。
(a)粉末X線回折(Cu-Kα)において、2θ=6.1度、13.7度、18.0度及び18.7度にピークを有する;並びに
(b)融点が110℃付近である。
(a)粉末X線回折(Cu-Kα)において、2θ=6.1度、13.7度、18.0度及び18.7度にピークを有する;並びに
(b)融点が110℃付近である。
(a)粉末X線回折(Cu-Kα)において、2θ=6.4度、10.9度、16.9度及び18.1度にピークを有する;並びに
(b)融点が115℃付近である。
(a)粉末X線回折(Cu-Kα)において、2θ=6.4度、10.9度、16.9度及び18.1度にピークを有する;並びに
(b)融点が115℃付近である。
(a)粉末X線回折(Cu-Kα)において、2θ=10.7度、17.9度及び19.7度にピークを有する;並びに
(b)融点が127℃付近である。
(a)粉末X線回折(Cu-Kα)において、2θ=10.7度、17.9度及び19.7度にピークを有する;並びに
(b)融点が127℃付近である。
(a)粉末X線回折(Cu-Kα)において、2θ=17.2度、17.8度及び20.9度にピークを有する;並びに
(b)融点が121℃付近である。
本発明の他の態様は、イソプロピルエーテルとメタノールとの混合液に、(1S)-1,5-アンヒドロ-1-[5-(4-{(1E)-4-[(1-{[2-(ジメチルアミノ)エチル]アミノ}-2-メチル-1-オキソプロパン-2-イル)アミノ]-3,3-ジメチル-4-オキソブタ-1-エン-1-イル}ベンジル)-2-メトキシ-4-(プロパン-2-イル)フェニル]-D-グルシトールのエタノール溶媒和物を懸濁させた後、室温で乾燥させることを特徴とする下記(a)~(b)の物性を有する結晶(二水和物の結晶)の製造方法である。
(a)粉末X線回折(Cu-Kα)において、2θ=17.2度、17.8度及び20.9度にピークを有する;並びに
(b)融点が121℃付近である。
(a)粉末X線回折(Cu-Kα)において、2θ=5.9度、17.1度、17.6度及び21.5度にピークを有する;
(b)赤外線吸収スペクトルにおいて、特性吸収帯が3538cm-1、3357cm-1、2964cm-1、1673cm-1、1634cm-1及び1505cm-1にある;並びに
(c)融点が111℃付近であり、好ましくは108℃~114℃である。
(a)粉末X線回折(Cu-Kα)において、2θ=6.1度、13.7度、18.0度及び18.7度にピークを有する;並びに
(b)融点が110℃付近であり、好ましくは107℃~113℃である。
(a)粉末X線回折(Cu-Kα)において、2θ=6.4度、10.9度、16.9度及び18.1度にピークを有する;並びに
(b)融点が115℃付近であり、好ましくは112℃~118℃である。
(a)粉末X線回折(Cu-Kα)において、2θ=10.7度、17.9度及び19.7度にピークを有する;並びに
(b)融点が127℃付近であり、好ましくは124℃~130℃である。
(a)粉末X線回折(Cu-Kα)において、2θ=17.2度、17.8度及び20.9度にピークを有する;並びに
(b)融点が121℃付近であり、好ましくは118℃~124℃である。
参考例1 中間体(B)の製造
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.16 - 1.25 (m, 6 H) 2.64 - 2.98 (m, 1 H) 5.21 (s, 1 H) 6.57 (dd, J=8.13, 2.20 Hz, 1 H) 6.88 (d, J=2.20 Hz, 1 H) 7.54 (d, J=8.13 Hz, 1 H).
参考例1-2 化合物(B2)
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (d, J=6.84 Hz, 6 H) 2.87 (quin, J=6.92 Hz, 1 H) 3.88 (s, 3 H) 6.58 - 6.65 (m, 1 H) 6.70 (d, J=1.87 Hz, 1 H) 7.65 (d, J=8.08 Hz, 1 H).
MS ESI/APCI Dual posi : 277[M+H]+.
参考例1-3 化合物(B3)
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, 6 H) 1.84 (s, 3 H) 1.97 (s, 3 H) 2.06 (s, 3 H) 2.10 (s, 3 H) 2.87 (dt, J=13.83, 6.92 Hz, 1 H) 3.32 (s, 3 H) 3.87 (s, 3 H) 4.04 (ddd, J=10.26, 4.74, 2.41 Hz, 1 H) 4.17 - 4.23 (m, 1 H) 4.28 - 4.36 (m, 1 H) 5.25 (dd, J=10.18, 9.40 Hz, 1 H) 5.36 (d, J=10.10 Hz, 1 H) 5.60 (dd, J=10.03, 9.40 Hz, 1 H) 6.74 (d, J=1.55 Hz, 1 H) 6.79 (dd, J=8.08, 1.24 Hz, 1 H) 7.26 - 7.33 (m, 1 H).
MS ESI/APCI Dual posi : 533[M+Na]+.
参考例1-4 化合物(B4)
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J=6.99 Hz, 6 H) 1.77 (s, 3 H) 2.01 (s, 3 H) 2.05 (s, 3 H) 2.07 (s, 3 H) 2.87 (dt, J=13.76, 6.96 Hz, 1 H) 3.80 - 3.87 (m, 1 H) 3.84 (s, 3 H) 4.09 - 4.16 (m, 1 H) 4.22 - 4.29 (m, 1 H) 4.88 - 4.95 (m, 1 H) 5.18 - 5.27 (m, 1 H) 5.32 - 5.38 (m, 2 H) 6.71 (d, J=1.55 Hz, 1 H) 6.83 (dd, J=7.93, 1.55 Hz, 1 H) 7.23 - 7.30 (m, 1 H).
MS ESI/APCI Dual posi : 503[M+Na]+.
MS ESI/APCI Dual nega : 515[M+Cl]-.
参考例1-5 化合物(B5)
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20 (d, J=6.84 Hz, 3 H) 1.23 (d, J=6.84 Hz, 3 H) 1.80 (s, 3 H) 2.01 (s, 3 H) 2.05 (s, 3 H) 2.09 (s, 3 H) 3.31 (quin, J=6.84 Hz, 1 H) 3.77 - 3.82 (m, 1 H) 3.83 (s, 3 H) 4.10 - 4.17 (m, 1 H) 4.22 - 4.30 (m, 1 H) 4.83 (d, J=9.48 Hz, 1 H) 5.17 - 5.38 (m, 3 H) 6.75 (s, 1 H) 7.49 (s, 1 H).
MS ESI/APCI Dual posi : 581[M+Na]+, 583[M+2+Na]+.
参考例1-6 化合物(B6)
1H NMR (300 MHz, CHLOROFORM-d) δ ppm -0.32 (s, 9 H) 0.09 (s, 9 H) 0.18 (s, 9 H) 0.20 (s, 9 H) 1.19 (d, J=6.84 Hz, 3 H) 1.23 (d, J=6.84 Hz, 3 H) 3.26 - 3.44 (m, 3 H) 3.52 - 3.58 (m, 2 H) 3.65 - 3.75 (m, 3 H) 3.76 - 3.83 (m, 1 H) 3.80 (s, 3 H) 4.60 (d, J=8.55 Hz, 1 H) 6.72 (s, 1 H) 7.51 (s, 1 H).
MS ESI/APCI Dual posi : 701[M+Na]+, 703[M+2+Na]+.
参考例1-7 化合物(B7)
1H NMR (300 MHz, METHANOL- d4) δ ppm 1.00 - 1.11 (m, 6 H) 3.10 - 3.27 (m, 2 H) 3.34 - 3.40 (m, 5H) 3.43 - 3.70 (m, 4H) 3.84 (s, 4 H) 4.66 (d, J=9.64 Hz, 1 H) 5.47 (s, 1 H) 6.89 (d, J=1.24 Hz, 1 H) 7.20 (d, J=2.18 Hz, 1 H) 7.22 (d, J=2.18 Hz, 1 H) 7.37 - 7.47 (m, 3 H).
MS ESI/APCI Dual posi : 479[M-H2O+H]+
参考例1-8 中間体(B)の製造
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.04 (d, J=6.84 Hz, 3 H) 1.09 (d, J=6.84 Hz, 3 H) 1.76 (s, 3 H) 2.01 (s, 3 H) 2.05 (s, 3 H) 2.06 (s, 3 H) 2.91 - 3.06 (m, 1 H) 3.80 - 3.88 (m, 4 H) 3.91 (d, J=5.13 Hz, 2 H) 4.06 - 4.18 (m, 1 H) 4.20 - 4.31 (m, 1 H) 4.82 - 4.93 (m, 1 H) 5.15 - 5.43 (m, 3 H) 6.77 (s, 1 H) 6.92 (d, J=8.55 Hz, 2 H) 7.11 (s, 1 H) 7.36 (d, J=8.55 Hz, 2 H).
MS ESI/APCI Dual posi : 671[M+Na]+, 666[M+NH4]+
参考例2 中間体(C)の製造
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (s, 6 H) 1.51 (s, 6 H) 3.73 (s, 3 H) 5.17 - 5.32 (m, 2 H) 6.02 (dd, J=17.56, 10.57 Hz, 1 H) 6.25 (br. s., 1 H).
MS ESI/APCI Dual posi : 214[M+H]+.
参考例2-2 中間体(C)
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 6 H) 1.54 (s, 6 H) 5.16 - 5.36 (m, 2 H) 6.01 (dd, J=17.49, 10.65 Hz, 1 H) 6.14 (s, 1 H).
MS ESI/APCI Dual posi : 200[M+H]+, 222[M+Na]+.
MS ESI/APCI Dual nega : 198[M-H]-.
参考例3 化合物Dの製造
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.08 (d, J=6.84 Hz, 3 H) 1.12 (d, J=6.84 Hz, 3 H) 1.38 (s, 6 H) 1.53 (s, 6 H) 1.77 (s, 3 H) 2.00 (s, 3 H) 2.05 (s, 6 H) 3.06 (quin, J=6.64 Hz, 1 H) 3.78 - 3.83 (m, 1 H) 3.84 (s, 3 H) 3.97 (s, 2 H) 4.07 - 4.18 (m, 1 H) 4.17 - 4.27 (m, 1 H) 4.87 (dd, J=6.76, 2.88 Hz, 1 H) 5.16 - 5.25 (m, 1 H) 5.27 - 5.40 (m, 2 H) 6.18 - 6.33 (m, 2 H) 6.54 (d, J=16.48 Hz, 1 H) 6.77 (s, 1 H) 7.03 (d, J=8.08 Hz, 2 H) 7.10 (s, 1 H) 7.29 (d, J=8.08 Hz, 2 H).
MS ESI/APCI Dual posi : 768[M+H]+, 790[M+Na]+.
MS ESI/APCI Dual nega : 766[M-H]-.
参考例4 化合物(E)の製造
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.05 (d, J=6.84 Hz, 3 H) 1.10 (d, J=6.84 Hz, 3 H) 1.38 (s, 6 H) 1.49 (s, 6 H) 1.77 (s, 3 H) 2.00 (s, 3 H) 2.05 (s, 3 H) 2.06 (s, 3 H) 2.46 (s, 6 H) 2.64 - 2.78 (m, 2 H) 3.04 (quin, J=6.80 Hz, 1 H) 3.38 - 3.49 (m, 2 H) 3.78 - 3.83 (m, 1 H) 3.85 (s, 3 H) 3.87 - 4.04 (m, 2 H) 4.08 - 4.18 (m, 1 H) 4.18 - 4.30 (m, 1 H) 4.87 (d, J=9.48 Hz, 1 H) 5.16 - 5.27 (m, 1 H) 5.28 - 5.44 (m, 2 H) 6.35 (s, 1 H) 6.40 - 6.57 (m, 2 H) 6.77 (s, 1 H) 7.01 (d, J=8.24 Hz, 2 H) 7.13 (s, 1 H) 7.32 (d, J=8.24 Hz, 2 H) 7.40 (s, 1 H).
MS ESI/APCI Dual posi : 838[M+H]+.
MS ESI/APCI Dual nega : 872[M+Cl]-.
参考例5 化合物(A)の製造
1H NMR (600 MHz, METHANOL- d4) δ ppm 1.07 (d, J=5.04 Hz, 3 H) 1.09 (d, J=5.04 Hz, 3 H) 1.36 (s, 6 H) 1.44 (s, 6 H) 2.23 (s, 6 H) 2.41 (t, J=6.88 Hz, 2 H) 3.10 (quin, J=6.76 Hz, 1 H) 3.26 - 3.30 (m, 2 H) 3.38 (d, J=5.96 Hz, 2 H) 3.45 - 3.52 (m, 1 H) 3.54 - 3.60 (m, 1 H) 3.62 - 3.69 (m, 1 H) 3.79 - 3.89 (m, 4 H) 3.99 (s, 2 H) 4.65 (d, J=9.63 Hz, 1 H) 6.39 (d, J=16.51 Hz, 1 H) 6.52 (d, J=16.51 Hz, 1 H) 6.88 (s, 1 H) 7.07 (d, J=8.25 Hz, 2 H) 7.23 (s, 1 H) 7.31 (d, J=8.25 Hz, 2 H).
MS ESI/APCI Dual posi : 670[M+H]+.
MS ESI/APCI Dual nega : 704[M+Cl]-.
Anal. Calcd for C37H55N3O8・1.0H2O : C, 64.6; H, 8.36; N, 6.11. Found : C, 64.5; H, 8.31; N, 6.02.
参考例6 化合物(A)の精製
無色非晶質の化合物(A)(9.88g,純度96.0%)を中性シリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=7:3→1:1)にて精製し、無色非晶質の化合物(A)(6.24g,回収率63%,純度99.5%)を得た。更に、無色非晶質の化合物(A)(6.24g,純度99.5%)を中性シリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=7:3→3:7)にて精製し、無色非晶質の化合物(A)(3.31g,回収率53%,純度99.9%)を得た。
実施例1
無色非晶質の化合物(A)(純度99.9%)25mgをエタノール0.08mLに室温にて溶解させた後、1日間室温で撹拌させ結晶を得た。本結晶を室温で減圧乾燥し、無色の結晶27mg(回収率100%)を得た。この結晶の粉末X線回折パターン及び示差熱分析/熱質量測定(TG/DTA)を測定したところ、化合物(A)のエタノール溶媒和物の結晶であった。
実施例2
無色非晶質の化合物(A)(純度96.0%)56gをエタノール135mLに66℃で溶解した後、撹拌しながらヘプタン135mLを加えて冷却し、45℃付近で、実施例1で得られた化合物(A)のエタノール溶媒和物の結晶を入れた後、1℃まで温度を下げた。析出した結晶をろ取した後に、40℃で減圧乾燥し、無色の結晶46g(回収率82%,純度99.1%)を得た。この結晶の粉末X線回折パターン、示差熱分析/熱質量測定(TG/DTA)及び赤外吸収スペクトルを測定したところ、化合物(A)のエタノール溶媒和物の結晶であった。
1H NMR (600 MHz, METHANOL- d4) δ ppm 1.06 (d, J=5.04 Hz, 3 H) 1.07 (d, J=5.50 Hz, 3 H) 1.15 (t, J=6.88 Hz, 3 H) 1.34 (s, 6 H) 1.43 (s, 6 H) 2.20 (s, 6 H) 2.37 (t, J=6.88 Hz, 2 H) 3.08 (quin, J=6.88 Hz, 1 H) 3.26 (t, J=6.88 Hz, 2 H) 3.28-3.30 (m, 4 H) 3.34 - 3.38 (m, 2 H) 3.43 - 3.49 (m, 1 H) 3.55 (t, J=9.17 Hz, 1 H) 3.58 (q, J=6.88 Hz, 2 H) 3.62 - 3.66 (m, 1 H) 3.78 - 3.85 (m, 4 H) 3.96 (s, 2 H) 4.63 (d, J=9.62 Hz, 1 H) 6.37 (d, J=16.50 Hz, 1 H) 6.50 (d, J=16.50 Hz, 1 H) 6.86 (s, 1 H) 7.05 (d, J=7.80 Hz, 2 H) 7.22 (s, 1 H) 7.29 (d, J=7.79 Hz, 2 H).
MS ESI/APCI Dual posi : 670[M+H]+.
MS ESI/APCI Dual nega : 704[M+Cl]-.
Anal. Calcd for C39H61N3O9・0.6H2O : C, 64.94; H, 8.61; N, 5.83. Found: C, 64.75; H, 8.46; N, 5.82.
実施例3
化合物(A)のエタノール溶媒和物0.10gにリン酸塩緩衝液(リン酸二水素ナトリウム・2水和物とリン酸水素二ナトリウム・12水和物との混合液)(pH6.8)600μLを加え,25℃で24時間懸濁した。遠心分離(3000rpm,25℃,10分)後,上清を取り除き、室温で乾燥し、無色の結晶を得た。この結晶の粉末X線回折パターン及び示差熱分析/熱質量測定(TG/DTA)を測定したところ、A形結晶であった。
実施例4
化合物(A)のエタノール溶媒和物0.10gにイソプロピルエーテル/メタノール(9/1)を2mL加え、懸濁させ、25℃で1週間懸濁した。遠心分離(3000rpm,25℃,10分)後,上清を取り除き、室温で乾燥して無色の結晶を得た。この結晶の粉末X線回折パターン及び示差熱分析/熱質量測定(TG/DTA)を測定したところ、B形結晶であった。
実施例5
化合物(A)のA形結晶1.00gを減圧状態で120℃まで昇温させた後、0.5gを採取し、ヘキサン/酢酸エチル(2/1)を10mL加え、懸濁させ、65℃で8時間懸濁した。懸濁液の溶媒を留去後、室温で乾燥して無色の結晶を得た。この結晶の粉末X線回折パターン及び示差熱分析/熱質量測定(TG/DTA)を測定したところ、C形結晶であった。
実施例6
化合物(A)のエタノール溶媒和物0.40gにイソプロピルエーテル/メタノール(9/1)を10mL加え、懸濁させ、25℃で3日間懸濁した。さらにイソプロピルエーテル/メタノール(9/1)を50mL追加後、25℃で6日間懸濁した。遠心分離(3000rpm,25℃,10分)後,上清を取り除き、室温で乾燥して無色の結晶を得た。この結晶の粉末X線回折パターン及び示差熱分析/熱質量測定(TG/DTA)を測定したところ、二水和物の結晶であった。
試験例1
(1)ヒトSGLT1を安定に発現するCHO-K1細胞の作製
ヒトSGLT1蛋白質を発現するプラスミドベクターを、リポフェクトアミン2000(インビトロジェン社)を用いてCHO-K1細胞にトランスフェクションした。SGLT1発現細胞は、500μg/mLの濃度のジェネティシンの存在下で培養し耐性株を選択し、下記に示す系により糖取り込み能を指標に取得した。
(2)ヒトSGLT2を安定に発現するCHO-K1細胞の作製
方法A(WO2007/136116に記載の方法):ヒトSGLT2カルボキシ末端の最終残基にLeuGluSerArgGlyProValが付加された蛋白質を発現するプラスミドベクターを、リポフェクトアミン2000(インビトロジェン社)を用いてCHO-K1細胞にトランスフェクションした。SGLT2発現細胞は、500μg/mLの濃度のハイグロマイシンBの存在下で培養し耐性株を選択し、下記に示す系により糖取り込み能を指標に取得した。本安定発現細胞を用いて算出された結果を表1に方法Aとして示した。
(3)安定発現細胞におけるナトリウム依存的糖取り込み阻害試験
上記で調製した安定発現細胞を用いて下記試験を行った。
(1)糖尿病モデルラットの作製
7週齢のSD/IGSラット(日本チャールスリバー株式会社,雄性)について約16時間の絶食後、エーテル麻酔下でストレプトゾトシン(STZ)50mg/kgを尾静脈内投与し、糖尿病モデルラットを作製した。同様にエーテル麻酔下、1.25mmol/Lクエン酸生理食塩液1mL/kgを尾静脈内投与し、正常対照ラットを作製した。STZまたは1.25mmol/Lクエン酸生理食塩液投与1週後(8週齢)、経口グルコース負荷試験に供した。
(2)経口グルコース負荷試験
ラットを約16時間の絶食後、薬物投与群には、0.5%カルボキシメチルセルロースナトリウム(CMC)水溶液に溶解した薬物(1mg/kg)を、対照群には0.5%CMC水溶液のみ経口投与した。薬物投与5分後に、グルコース溶液(2g/kg)を経口投与し、薬物投与前(0time)、及び、経口投与0.25、0.5、1、2時間後の計5点で採血した。
(1)WO2007/136116に開示された化合物の経口投与後1週間までの腎臓中濃度推移
7週齢のSD/IGSラット(日本チャールスリバー株式会社、雄性、非絶食)に、0.5%CMC水溶液にて調製した化合物4、10、33(各1mg/kg)、および化合物11(0.3mg/kg)を経口投与した。薬物投与後24、72、168時間にエーテル麻酔下、後大静脈より全採血し、安楽死確認後に腎臓を摘出した。生理食塩液で組織表面を洗浄後、重量を測定し4倍量の精製水を加え氷冷下ホモジナイズした。ホモジネートに内標準物質を含むアセトニトリル/メタノール溶液を加えて除タンパクした後、上清をLC-MS/MS(アプライドバイオシステムズAPI3000)に供した。ポジティブイオンモードのエレクトロスプレーイオン化法にて生成した薬物由来のイオンを選択反応モニタリングにて検出した。得られた抽出イオンクロマトグラムのピーク面積から内標準法にてホモジネート中薬物濃度を算出した。
(2)本発明の化合物(A)の3日間反復経口投与後の腎臓中濃度
7週齢のSD/IGSラット(日本チャールスリバー株式会社、雄性、非絶食)に、0.5%CMC水溶液にて調製した化合物(A)(3mg/kg)を1日1回3日間連続経口投与した。最終日の薬物投与後48時間にイソフルラン麻酔下、後大静脈より全採血し、安楽死確認後に腎臓を摘出した。生理食塩液で組織表面を洗浄後、重量を測定し4倍量の精製水を加え氷冷下ホモジナイズした。ホモジネート中薬物濃度の測定は、上記に示した試験例3の(1)と同じ方法で、内部標準物質に上記の化合物11を用い、LC-MS/MSにより行った。
Claims (6)
- 下記(a)~(c)の物性を有する、(1S)-1,5-アンヒドロ-1-[5-(4-{(1E)-4-[(1-{[2-(ジメチルアミノ)エチル]アミノ}-2-メチル-1-オキソプロパン-2-イル)アミノ]-3,3-ジメチル-4-オキソブタ-1-エン-1-イル}ベンジル)-2-メトキシ-4-(プロパン-2-イル)フェニル]-D-グルシトールのエタノール溶媒和物の結晶。
(a)粉末X線回折(Cu-Kα)において、2θ=5.9度、17.1度、17.6度及び21.5度にピークを有する;
(b)赤外線吸収スペクトルにおいて、特性吸収帯が3538cm-1、3357cm-1、2964cm-1、1673cm-1、1634cm-1及び1505cm-1にある;並びに
(c)融点が111℃付近である。 - エタノール又はエタノールと混和する性質を有する有機溶媒とエタノールとの混合液に、(1S)-1,5-アンヒドロ-1-[5-(4-{(1E)-4-[(1-{[2-(ジメチルアミノ)エチル]アミノ}-2-メチル-1-オキソプロパン-2-イル)アミノ]-3,3-ジメチル-4-オキソブタ-1-エン-1-イル}ベンジル)-2-メトキシ-4-(プロパン-2-イル)フェニル]-D-グルシトールを溶解させた後、0~80℃で結晶化させ、得られた結晶を50℃以下で乾燥させることを特徴とする下記(a)~(c)の物性を有する結晶の製造方法。
(a)粉末X線回折(Cu-Kα)において、2θ=5.9度、17.1度、17.6度及び21.5度にピークを有する;
(b)赤外線吸収スペクトルにおいて、特性吸収帯が3538cm-1、3357cm-1、2964cm-1、1673cm-1、1634cm-1及び1505cm-1にある;並びに
(c)融点が111℃付近である。 - 下記(a)~(b)の物性を有する、(1S)-1,5-アンヒドロ-1-[5-(4-{(1E)-4-[(1-{[2-(ジメチルアミノ)エチル]アミノ}-2-メチル-1-オキソプロパン-2-イル)アミノ]-3,3-ジメチル-4-オキソブタ-1-エン-1-イル}ベンジル)-2-メトキシ-4-(プロパン-2-イル)フェニル]-D-グルシトールの結晶。
(a)粉末X線回折(Cu-Kα)において、2θ=6.1度、13.7度、18.0度及び18.7度にピークを有する;並びに
(b)融点が110℃付近である。 - 水又はリン酸塩緩衝液に、(1S)-1,5-アンヒドロ-1-[5-(4-{(1E)-4-[(1-{[2-(ジメチルアミノ)エチル]アミノ}-2-メチル-1-オキソプロパン-2-イル)アミノ]-3,3-ジメチル-4-オキソブタ-1-エン-1-イル}ベンジル)-2-メトキシ-4-(プロパン-2-イル)フェニル]-D-グルシトールのエタノール溶媒和物を懸濁させた後、得られた結晶を35℃以下で乾燥させることを特徴とする下記(a)~(b)の物性を有する結晶の製造方法。
(a)粉末X線回折(Cu-Kα)において、2θ=6.1度、13.7度、18.0度及び18.7度にピークを有する;並びに
(b)融点が110℃付近である。 - 下記(a)~(b)の物性を有する、(1S)-1,5-アンヒドロ-1-[5-(4-{(1E)-4-[(1-{[2-(ジメチルアミノ)エチル]アミノ}-2-メチル-1-オキソプロパン-2-イル)アミノ]-3,3-ジメチル-4-オキソブタ-1-エン-1-イル}ベンジル)-2-メトキシ-4-(プロパン-2-イル)フェニル]-D-グルシトールの結晶。
(a)粉末X線回折(Cu-Kα)において、2θ=6.4度、10.9度、16.9度及び18.1度にピークを有する;並びに
(b)融点が115℃付近である。 - イソプロピルエーテルと混和する性質を有する有機溶媒(エタノールを除く)とイソプロピルエーテルとの混合液又はヘキサンあるいはヘプタンと混和する性質を有する有機溶媒(エタノールを除く)とヘキサンあるいはヘプタンとの混合液に、(1S)-1,5-アンヒドロ-1-[5-(4-{(1E)-4-[(1-{[2-(ジメチルアミノ)エチル]アミノ}-2-メチル-1-オキソプロパン-2-イル)アミノ]-3,3-ジメチル-4-オキソブタ-1-エン-1-イル}ベンジル)-2-メトキシ-4-(プロパン-2-イル)フェニル]-D-グルシトールのエタノール溶媒和物を懸濁させた後、得られた結晶を室温~100℃で乾燥させることを特徴とする下記(a)~(b)の物性を有する結晶の製造方法。
(a)粉末X線回折(Cu-Kα)において、2θ=6.4度、10.9度、16.9度及び18.1度にピークを有する;並びに
(b)融点が115℃付近である。
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RU (1) | RU2013112368A (ja) |
SG (1) | SG187893A1 (ja) |
TW (1) | TW201219414A (ja) |
WO (1) | WO2012023598A1 (ja) |
ZA (1) | ZA201301034B (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014119787A1 (ja) | 2013-02-04 | 2014-08-07 | 大正製薬株式会社 | 便秘症の予防又は治療薬 |
WO2017221886A1 (ja) * | 2016-06-20 | 2017-12-28 | 大正製薬株式会社 | 腸内環境改善剤 |
JP2020176914A (ja) * | 2019-04-18 | 2020-10-29 | 株式会社島津製作所 | 培地処理システム及び培地処理方法 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5817317B2 (ja) * | 2010-08-20 | 2015-11-18 | 大正製薬株式会社 | 4−イソプロピルフェニルグルシトール化合物を有効成分として含有することを特徴とする糖尿病の予防又は治療剤 |
EP3570740B1 (en) | 2017-01-23 | 2023-08-30 | Naqi Logix Inc. | Apparatus and method for using imagined direction to perform at least one action |
CN110183576B (zh) * | 2019-06-04 | 2021-10-22 | 万华化学(四川)有限公司 | 一种可用于附聚的生产聚丁二烯胶乳的乳化剂、其制备方法及应用 |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002098893A1 (en) | 2001-05-30 | 2002-12-12 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivative, medicinal composition containing the same, medicinal use thereof, and intermediate therefor |
WO2004014932A1 (ja) | 2002-08-08 | 2004-02-19 | Kissei Pharmaceutical Co., Ltd. | ピラゾール誘導体、それを含有する医薬組成物、その医薬用途及びその製造中間体 |
WO2004018491A1 (ja) | 2002-08-23 | 2004-03-04 | Kissei Pharmaceutical Co., Ltd. | ピラゾール誘導体、それを含有する医薬組成物、その医薬用途及びその製造中間体 |
WO2004019958A1 (ja) | 2002-08-27 | 2004-03-11 | Kissei Pharmaceutical Co., Ltd. | ピラゾール誘導体、それを含有する医薬組成物及びその医薬用途 |
WO2004050122A1 (ja) | 2002-12-04 | 2004-06-17 | Kissei Pharmaceutical Co., Ltd. | 高血糖症に起因する疾患の予防又は治療剤 |
WO2005121161A1 (de) | 2004-06-11 | 2005-12-22 | Sanofi-Aventis Deutschland Gmbh | Neue fluorglykosidderivate von pyrazolen, diese verbindungen enthaltende arzneimittel und deren verwendung |
WO2007136116A2 (en) | 2006-05-19 | 2007-11-29 | Taisho Pharmaceutical Co., Ltd. | C-phenyl glycitol compound for the treatment of diabetes |
JP2009107997A (ja) * | 2007-10-31 | 2009-05-21 | Taisho Pharmaceutical Co Ltd | (1s)−1,5−アンヒドロ−1−[5−(4−エトキシベンジル)−2−メトキシ−4−メチルフェニル]−1−チオ−d−グルシトールの結晶形とその製造方法 |
WO2010095768A1 (en) * | 2009-02-23 | 2010-08-26 | Taisho Pharmaceutical Co., Ltd. | 4 -isopropylphenyl glucitol compounds as sgltl inhibitors |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA200501094B (en) * | 2002-08-08 | 2006-10-25 | Kissei Pharmaceutical | Pyrazole derivative, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof |
-
2011
- 2011-08-19 WO PCT/JP2011/068736 patent/WO2012023598A1/ja active Application Filing
- 2011-08-19 JP JP2012529619A patent/JP5656092B2/ja not_active Expired - Fee Related
- 2011-08-19 TW TW100129749A patent/TW201219414A/zh unknown
- 2011-08-19 US US13/816,647 patent/US8822674B2/en not_active Expired - Fee Related
- 2011-08-19 CN CN201180040334.6A patent/CN103168035B/zh not_active Expired - Fee Related
- 2011-08-19 AU AU2011291709A patent/AU2011291709B2/en not_active Ceased
- 2011-08-19 CA CA2807755A patent/CA2807755A1/en not_active Abandoned
- 2011-08-19 KR KR1020137002375A patent/KR20130097711A/ko not_active Application Discontinuation
- 2011-08-19 SG SG2013012067A patent/SG187893A1/en unknown
- 2011-08-19 EP EP11818238.5A patent/EP2607359A4/en not_active Withdrawn
- 2011-08-19 RU RU2013112368/04A patent/RU2013112368A/ru not_active Application Discontinuation
-
2013
- 2013-02-07 ZA ZA2013/01034A patent/ZA201301034B/en unknown
- 2013-09-06 HK HK13110387.5A patent/HK1183025A1/zh not_active IP Right Cessation
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002098893A1 (en) | 2001-05-30 | 2002-12-12 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivative, medicinal composition containing the same, medicinal use thereof, and intermediate therefor |
WO2004014932A1 (ja) | 2002-08-08 | 2004-02-19 | Kissei Pharmaceutical Co., Ltd. | ピラゾール誘導体、それを含有する医薬組成物、その医薬用途及びその製造中間体 |
WO2004018491A1 (ja) | 2002-08-23 | 2004-03-04 | Kissei Pharmaceutical Co., Ltd. | ピラゾール誘導体、それを含有する医薬組成物、その医薬用途及びその製造中間体 |
WO2004019958A1 (ja) | 2002-08-27 | 2004-03-11 | Kissei Pharmaceutical Co., Ltd. | ピラゾール誘導体、それを含有する医薬組成物及びその医薬用途 |
WO2004050122A1 (ja) | 2002-12-04 | 2004-06-17 | Kissei Pharmaceutical Co., Ltd. | 高血糖症に起因する疾患の予防又は治療剤 |
WO2005121161A1 (de) | 2004-06-11 | 2005-12-22 | Sanofi-Aventis Deutschland Gmbh | Neue fluorglykosidderivate von pyrazolen, diese verbindungen enthaltende arzneimittel und deren verwendung |
WO2007136116A2 (en) | 2006-05-19 | 2007-11-29 | Taisho Pharmaceutical Co., Ltd. | C-phenyl glycitol compound for the treatment of diabetes |
JP2009537509A (ja) * | 2006-05-19 | 2009-10-29 | 大正製薬株式会社 | C−フェニルグリシト−ル化合物 |
JP2009107997A (ja) * | 2007-10-31 | 2009-05-21 | Taisho Pharmaceutical Co Ltd | (1s)−1,5−アンヒドロ−1−[5−(4−エトキシベンジル)−2−メトキシ−4−メチルフェニル]−1−チオ−d−グルシトールの結晶形とその製造方法 |
WO2010095768A1 (en) * | 2009-02-23 | 2010-08-26 | Taisho Pharmaceutical Co., Ltd. | 4 -isopropylphenyl glucitol compounds as sgltl inhibitors |
Non-Patent Citations (8)
Title |
---|
E. M. WRIGHT, AM. J. PHYSIOL. RENAL. PHYSIOL., vol. 280, 2001, pages F10 |
FOLIA PHARMACOL. JPN., vol. 113, 1999, pages 19 |
G. TOGGENBURGER ET AL., BIOCHIM. BIOPHYS. ACTA, vol. 688, 1982, pages 557 |
J. ORG. CHEM., vol. 65, 2000, pages 8402 |
J.-L. CHIASSON ET AL., LANCENT, vol. 359, pages 2072,2002 |
M TOMINAGA ET AL., DIABETES CARE, vol. 22, 1999, pages 920 |
PAN XR ET AL., DIABETES CARE, vol. 20, 1997, pages 537 |
See also references of EP2607359A4 |
Cited By (8)
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WO2014119787A1 (ja) | 2013-02-04 | 2014-08-07 | 大正製薬株式会社 | 便秘症の予防又は治療薬 |
CN104955481A (zh) * | 2013-02-04 | 2015-09-30 | 大正制药株式会社 | 便秘症的预防或治疗药 |
KR20150112949A (ko) | 2013-02-04 | 2015-10-07 | 다이쇼 세이야꾸 가부시끼가이샤 | 변비증의 예방 또는 치료약 |
US10022389B2 (en) | 2013-02-04 | 2018-07-17 | Taisho Pharmaceutical Co., Ltd. | Prophylactic or therapeutic drug for constipation |
KR102078433B1 (ko) | 2013-02-04 | 2020-02-17 | 다이쇼 세이야꾸 가부시끼가이샤 | 변비증의 예방 또는 치료약 |
WO2017221886A1 (ja) * | 2016-06-20 | 2017-12-28 | 大正製薬株式会社 | 腸内環境改善剤 |
JP2020176914A (ja) * | 2019-04-18 | 2020-10-29 | 株式会社島津製作所 | 培地処理システム及び培地処理方法 |
JP7156154B2 (ja) | 2019-04-18 | 2022-10-19 | 株式会社島津製作所 | 培地処理システム及び培地処理方法 |
Also Published As
Publication number | Publication date |
---|---|
ZA201301034B (en) | 2014-04-30 |
HK1183025A1 (zh) | 2013-12-13 |
CN103168035A (zh) | 2013-06-19 |
US8822674B2 (en) | 2014-09-02 |
EP2607359A4 (en) | 2014-01-15 |
EP2607359A1 (en) | 2013-06-26 |
SG187893A1 (en) | 2013-03-28 |
US20130144050A1 (en) | 2013-06-06 |
AU2011291709A1 (en) | 2013-03-07 |
CN103168035B (zh) | 2016-01-20 |
TW201219414A (en) | 2012-05-16 |
KR20130097711A (ko) | 2013-09-03 |
CA2807755A1 (en) | 2012-02-23 |
AU2011291709B2 (en) | 2014-03-27 |
JP5656092B2 (ja) | 2015-01-21 |
JPWO2012023598A1 (ja) | 2013-10-28 |
RU2013112368A (ru) | 2014-09-27 |
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