JPWO2009128421A1 - ピラゾール誘導体の1/2フマル酸塩 - Google Patents
ピラゾール誘導体の1/2フマル酸塩 Download PDFInfo
- Publication number
- JPWO2009128421A1 JPWO2009128421A1 JP2010508201A JP2010508201A JPWO2009128421A1 JP WO2009128421 A1 JPWO2009128421 A1 JP WO2009128421A1 JP 2010508201 A JP2010508201 A JP 2010508201A JP 2010508201 A JP2010508201 A JP 2010508201A JP WO2009128421 A1 JPWO2009128421 A1 JP WO2009128421A1
- Authority
- JP
- Japan
- Prior art keywords
- compound
- fumarate dihydrate
- storage stability
- fumarate
- present
- 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.)
- Granted
Links
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title description 12
- 150000003217 pyrazoles Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 32
- 201000010099 disease Diseases 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 239000008280 blood Substances 0.000 claims description 8
- 210000004369 blood Anatomy 0.000 claims description 8
- 201000001421 hyperglycemia Diseases 0.000 claims description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- 238000001228 spectrum Methods 0.000 claims description 7
- 238000004922 13C solid-state nuclear magnetic resonance spectroscopy Methods 0.000 claims description 6
- 229930182830 galactose Natural products 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- NWLPAIVRIWBEIT-SEPHDYHBSA-N (e)-but-2-enedioic acid;dihydrate Chemical compound O.O.OC(=O)\C=C\C(O)=O NWLPAIVRIWBEIT-SEPHDYHBSA-N 0.000 abstract description 34
- 238000003860 storage Methods 0.000 abstract description 22
- 238000000034 method Methods 0.000 abstract description 8
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 6
- 229940088679 drug related substance Drugs 0.000 abstract description 6
- LREHMKLEOJAVMQ-TXKDOCKMSA-N 2,2-dimethyl-3-[3-[3-methyl-4-[[5-propan-2-yl-3-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-1h-pyrazol-4-yl]methyl]phenoxy]propylamino]propanamide Chemical compound C=1C=C(OCCCNCC(C)(C)C(N)=O)C=C(C)C=1CC1=C(C(C)C)NN=C1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O LREHMKLEOJAVMQ-TXKDOCKMSA-N 0.000 abstract description 3
- -1 3- {4- [3- (β-D-glucopyranosyloxy) -5-isopropyl-1H-pyrazol-4-ylmethyl] -3-methylphenoxy} propylamino Chemical group 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 239000013078 crystal Substances 0.000 description 11
- 229940079593 drug Drugs 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 239000012046 mixed solvent Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- 229940100389 Sulfonylurea Drugs 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000001530 fumaric acid Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 208000002249 Diabetes Complications Diseases 0.000 description 3
- 206010012655 Diabetic complications Diseases 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 208000002705 Glucose Intolerance Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 208000008589 Obesity Diseases 0.000 description 3
- 230000005856 abnormality Effects 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 201000009104 prediabetes syndrome Diseases 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- MJOQOTRVEGLXRH-XVDCZHRMSA-N (E)-but-2-enedioic acid 2,2-dimethyl-3-[3-[3-methyl-4-[[5-propan-2-yl-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-1H-pyrazol-4-yl]methyl]phenoxy]propylamino]propanamide dihydrate Chemical compound O.O.OC(=O)\C=C\C(O)=O.C=1C=C(OCCCNCC(C)(C)C(N)=O)C=C(C)C=1CC1=C(C(C)C)NN=C1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O MJOQOTRVEGLXRH-XVDCZHRMSA-N 0.000 description 2
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 101000716688 Homo sapiens Sodium/glucose cotransporter 1 Proteins 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 2
- 125000002351 beta-D-glucopyranosyloxy group Chemical group 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- QEVLNUAVAONTEW-UZYHXJQGSA-L calcium;(2s)-4-[(3as,7ar)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-2-benzyl-4-oxobutanoate;dihydrate Chemical compound O.O.[Ca+2].C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1.C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1 QEVLNUAVAONTEW-UZYHXJQGSA-L 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000004455 differential thermal analysis Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960000346 gliclazide Drugs 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 102000052194 human SLC5A1 Human genes 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 229960003365 mitiglinide Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- CAQZTSCRGMRSHX-TYYBGVCCSA-N (e)-but-2-enedioic acid;ethanol Chemical compound CCO.OC(=O)\C=C\C(O)=O CAQZTSCRGMRSHX-TYYBGVCCSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 208000027472 Galactosemias Diseases 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- HNSCCNJWTJUGNQ-UHFFFAOYSA-N Glyclopyramide Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)NC(=O)NN1CCCC1 HNSCCNJWTJUGNQ-UHFFFAOYSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960001466 acetohexamide Drugs 0.000 description 1
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 229960003362 carbutamide Drugs 0.000 description 1
- VDTNNGKXZGSZIP-UHFFFAOYSA-N carbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 VDTNNGKXZGSZIP-UHFFFAOYSA-N 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 238000005384 cross polarization magic-angle spinning Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- IEPRKVQEAMIZSS-AATRIKPKSA-N diethyl fumarate Chemical compound CCOC(=O)\C=C\C(=O)OCC IEPRKVQEAMIZSS-AATRIKPKSA-N 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 239000003085 diluting agent Substances 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
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- OYJXTOVLKZDGFK-UHFFFAOYSA-N ethanol;2-propan-2-yloxypropane Chemical compound CCO.CC(C)OC(C)C OYJXTOVLKZDGFK-UHFFFAOYSA-N 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960001764 glibornuride Drugs 0.000 description 1
- RMTYNAPTNBJHQI-LLDVTBCESA-N glibornuride Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)N[C@H]1[C@H](C2(C)C)CC[C@@]2(C)[C@H]1O RMTYNAPTNBJHQI-LLDVTBCESA-N 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 229950002888 glyclopyramide Drugs 0.000 description 1
- 229950005514 glycyclamide Drugs 0.000 description 1
- RIGBPMDIGYBTBJ-UHFFFAOYSA-N glycyclamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 RIGBPMDIGYBTBJ-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- RHMQNXNXUZLEIY-UHFFFAOYSA-N methanol;2-propan-2-yloxypropane Chemical compound OC.CC(C)OC(C)C RHMQNXNXUZLEIY-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229950008557 phenbutamide Drugs 0.000 description 1
- AFOGBLYPWJJVAL-UHFFFAOYSA-N phenbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=CC=C1 AFOGBLYPWJJVAL-UHFFFAOYSA-N 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 229940043274 prophylactic drug Drugs 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Obesity (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
本発明は、高い保存安定性を有し、医薬品原体としての使用に適する前記化合物(B)の別異な形態を提供することを課題とする。
(1)前記化学構造式(A)で表される化合物;
(2)結晶性である、前記(1)記載の化合物;
(3)粉末X線回析図において、回折角(2θ(°))として7.6±0.1、10.8±0.1、13.0±0.1、13.3±0.1、22.9±0.1及び27.2±0.1に特徴的なピークを有することを特徴とする、前記(2)記載の化合物;
(4)示差熱チャートにおいて、76℃付近及び129℃付近に吸熱ピークを有することを特徴とする、前記(2)記載の化合物;
(5)13C固体NMRスペクトルチャートにおいて、化学シフト値(δ(ppm))として132.8±0.2,102.3±0.2,76.9±0.2,26.9±0.2に特徴的なピークを有することを特徴とする、前記(2)記載の化合物;
(6)前記(1)〜(5)のいずれかに記載の化合物を有効成分として含有する医薬組成物;
(7)高血糖症に起因する疾患又は血中ガラクトース値の上昇に起因する疾患の予防又は治療用である前記(6)記載の医薬組成物;
(8)前記(1)〜(5)のいずれかに記載の化合物とスルフォニルウレア薬及びグリニド系薬のいずれかとを組み合わせてなる医薬;
(9)前記(1)〜(5)のいずれかに記載の化合物とグリクラジド及びミチグリニドカルシウム水和物のいずれかとを組み合わせてなる前記(8)記載の医薬;
(10)高血糖症に起因する疾患の予防又は治療用である前記(8)又は(9)記載の医薬;等に関するものである。
すなわち、例えば、特許文献1に記載の方法又はそれに準拠した方法に従い製造できる、前記化合物(B)に対して、1/2当量のフマル酸を適当な良溶媒中で混合し、加熱溶解後、必要に応じて適宜貧溶媒を加え、放冷又は水冷下、或いは室温付近にて析出する1/2フマル酸塩を得ることができる。このとき1/2フマル酸塩は使用する溶媒との溶媒和物の結晶として得られ(例えば、エタノールを用いた場合にはエタノール和物の結晶が得られる)、その溶媒和結晶を加湿保存することにより、1/2フマル酸塩二水和物の結晶を製造することができる。
3−(3−{4−〔3−(β−D−グルコピラノシルオキシ)−5−イソプロピル−1H−ピラゾール−4−イルメチル〕−3−メチルフェノキシ}プロピルアミノ)−2,2−ジメチルプロピオンアミド・1/2フマル酸塩二水和物
3−(3−{4−〔3−(β−D−グルコピラノシルオキシ)−5−イソプロピル−1H−ピラゾール−4−イルメチル〕−3−メチルフェノキシ}プロピルアミノ)−2,2−ジメチルプロピオンアミド(17g)をエタノール(150mL)に40℃で加熱溶解し、1/2当量のフマル酸(1.75g)及びエタノール(105mL)を添加し、70℃加熱下攪拌した。室温まで冷却後、2時間攪拌した。析出物をろ取し、70℃で12時間減圧乾燥することにより、1/2フマル酸塩エタノール和物の結晶(18.5g)を得た。
1/2フマル酸塩エタノール和物の結晶(6.4g)をエタノール(64mL)及び水(3.2mL)の混合溶媒に、60℃加熱下溶解した。不溶物をろ去し、ろ液を室温下15時間攪拌した。析出した結晶をろ取し、50℃で減圧乾燥した。得られた結晶を25℃/60%相対湿度下に2日間静置し、更に40℃/75%相対湿度下に7日間静置し、1/2フマル酸塩二水和物の結晶(5.3g)を得た。
1H−NMR(DMSO−d6)(δ(ppm)):1.00-1.10 (12H, m), 1.88 (2H, t, J=6.5Hz),2.26 (3H, s), 2.64 (2H, s), 2.70-2.80 (3H, m), 3.10-3.30 (4H, m), 3.40-3.60(3H, m), 3.62 (1H, d, J=11.0Hz), 3.95 (2H, t, J=6.0Hz), 4.40-4.60 (1H, br), 5.18 (1H, d, J=7.5Hz), 6.47 (1H, s), 6.61 (1H, d,J=7.5Hz), 6.70 (1H, s), 6.82 (1H, d, J=8.5Hz), 6.89 (1H, s), 7.50 (1H, s),11.00-12.00 (1H, br)
吸熱ピーク:75.9℃、129.4℃
赤外吸収ピークの特徴的な波数(cm-1):3205、1675、1576、1490、1363、1061
13C固体NMRの化学シフト値(δ(ppm)):178.9,132.8,102.3,99.5,77.7,76.9,76.1,41.7,40.9,26.9,25.6,24.9,23.4,21.9,21.2,20.0
3−(3−{4−〔3−(β−D−グルコピラノシルオキシ)−5−イソプロピル−1H−ピラゾール−4−イルメチル〕−3−メチルフェノキシ}プロピルアミノ)−2,2−ジメチルプロピオンアミド・3/4フマル酸塩二水和物
3−(3−{4−〔3−(β−D−グルコピラノシルオキシ)−5−イソプロピル−1H−ピラゾール−4−イルメチル〕−3−メチルフェノキシ}プロピルアミノ)−2,2−ジメチルプロピオンアミド(1.00g)と1当量のフマル酸(0.21g)をエタノール(15mL)に懸濁し、5分間加熱還流して溶解した。加熱下、トルエン(7.5mL)を加え、室温まで冷却し、一晩撹拌した。析出物をろ取し、エタノール及びトルエン(2:1)の混合溶媒で洗浄後、減圧下乾燥し、3/4フマル酸塩二水和物の結晶(1.17g)を得た。
1H−NMR(DMSO−d6)(δ(ppm)):1.04-1.10 (12H, m), 1.87-1.94 (2H, m), 2.26(3H, s), 2.69 (2H, s), 2.72-2.75 (1H, m), 2.79 (2H, t, J=5.6Hz), 3.08-3.21 (4H,m), 3.40-3.55 (3H, m), 3.62 (1H, d, J=10.4Hz), 3.95 (2H, t, J=6.4Hz), 4.40-4.50(1H, br), 5.18 (1H, d, J=8.0Hz), 6.50 (1.5H, s), 6.62(1H, d, J=8.4Hz), 6.70 (1H, s), 6.82 (1H, d, J=8.4Hz), 6.95 (1H, s), 7.50 (1H,s), 11.25-11.75 (1H, br)
保存安定性試験(潮解性)
実施例1の1/2フマル酸塩二水和物、比較例1の3/4フマル酸塩二水和物及び前記化合物(B)をそれぞれ40℃/75%相対湿度下において保存し、潮解性の有無を調べた。
本条件下において、比較例1の3/4フマル酸塩二水和物及び前記化合物(B)は試験開始初期より潮解性が認められたのに対し、実施例1の1/2フマル酸塩二水和物は試験開始から2ヶ月間潮解性が認められず、優れた保存安定性を示した。
保存安定性試験(純度)
実施例1の1/2フマル酸塩二水和物及び前記化合物(B)をそれぞれ40℃/75%相対湿度下及び60℃開放下において保存し、2ヶ月間の保存安定性を調べた。保存安定性に関しては、被験化合物の開始時と2ヶ月後の純度をHPLCにより測定し、比較した。HPLCによる測定条件は下記の通りである。
測定条件
検出器:紫外可視吸光光度計、波長:225nm、
カラム:Phenomenex社製LUNA C18(2),5μm,4.6x250mm,細孔径100×10-10m
カラム温度:25℃付近一定温度
試料濃度:1mg/mL
注入量:10μL
流量:1.2mL/min
移動相A:リン酸でpH7.8に調整した10mMリン酸水素二カリウム水溶液
移動相B:アセトニトリル
濃度勾配:
0分:移動相B=22%
30分:移動相B=22%
50分:移動相B=70%
60分:移動相B=70%
面積測定範囲:分析開始から50分までとした。なお、フマル酸のピーク(保持時間2分)、不純物であるフマル酸ジエチルのピーク(保持時間44分付近)及びブランク由来のピークの面積を計算から除外した。
Claims (7)
- 結晶性である、請求項1記載の化合物。
- 粉末X線回析図において、回折角(2θ(°))として7.6±0.1、10.8±0.1、13.0±0.1、13.3±0.1、22.9±0.1及び27.2±0.1に特徴的なピークを有することを特徴とする、請求項2記載の化合物。
- 示差熱チャートにおいて、76℃付近及び129℃付近に吸熱ピークを有することを特徴とする、請求項2記載の化合物。
- 13C固体NMRスペクトルチャートにおいて、化学シフト値(δ(ppm))として132.8±0.2,102.3±0.2,76.9±0.2,26.9±0.2に特徴的なピークを有することを特徴とする、請求項2記載の化合物。
- 請求項1〜5のいずれかに記載の化合物を有効成分として含有する医薬組成物。
- 高血糖症に起因する疾患又は血中ガラクトース値の上昇に起因する疾患の予防又は治療用である請求項6記載の医薬組成物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010508201A JP5467040B2 (ja) | 2008-04-16 | 2009-04-13 | ピラゾール誘導体の1/2フマル酸塩 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008106582 | 2008-04-16 | ||
JP2008106582 | 2008-04-16 | ||
PCT/JP2009/057439 WO2009128421A1 (ja) | 2008-04-16 | 2009-04-13 | ピラゾール誘導体の1/2フマル酸塩 |
JP2010508201A JP5467040B2 (ja) | 2008-04-16 | 2009-04-13 | ピラゾール誘導体の1/2フマル酸塩 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPWO2009128421A1 true JPWO2009128421A1 (ja) | 2011-08-04 |
JP5467040B2 JP5467040B2 (ja) | 2014-04-09 |
Family
ID=41199112
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010508201A Active JP5467040B2 (ja) | 2008-04-16 | 2009-04-13 | ピラゾール誘導体の1/2フマル酸塩 |
Country Status (7)
Country | Link |
---|---|
US (1) | US8354382B2 (ja) |
EP (1) | EP2275430B1 (ja) |
JP (1) | JP5467040B2 (ja) |
CN (1) | CN102007138B (ja) |
CA (1) | CA2725230C (ja) |
ES (1) | ES2385185T3 (ja) |
WO (1) | WO2009128421A1 (ja) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
EP2760862B1 (en) | 2011-09-27 | 2015-10-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
CN104284665B (zh) * | 2012-05-07 | 2016-11-16 | 橘生药品工业株式会社 | 吡唑衍生物及其医药用途 |
ES2694110T3 (es) | 2013-02-04 | 2018-12-18 | Taisho Pharmaceutical Co., Ltd. | Fármaco profiláctico o terapéutico para el estreñimiento |
CA3094118A1 (en) | 2018-03-28 | 2019-10-03 | Avolynt | Method for treating post-prandial hypoglycemia |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1507437A (zh) | 1999-11-12 | 2004-06-23 | 具有5-羟色胺5-ht1a活性的支链金刚烷基及降金刚烷基芳基-与芳烷基-哌嗪 | |
CA2420847C (en) * | 2000-09-01 | 2008-02-05 | Chugai Seiyaku Kabushiki Kaisha | Process for producing erythromycin derivative |
CN100413878C (zh) * | 2002-08-23 | 2008-08-27 | 橘生药品工业株式会社 | 吡唑衍生物、含该衍生物的医药组合物、其医药用途及用于制备的中间体 |
JP2004137245A (ja) * | 2002-08-23 | 2004-05-13 | Kissei Pharmaceut 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 |
DE10356717A1 (de) * | 2003-12-02 | 2005-07-07 | Aventis Pharma Deutschland Gmbh | Verfahren zur Herstellung von (3-Oxo-2,3-dihydro-1H-isoindol-1-yl)-acetylguanidin-Derivaten |
US7531569B2 (en) * | 2003-12-02 | 2009-05-12 | Sanofi-Aventis Deutschland Gmbh | Process for preparing (3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetylguanidine derivatives |
US7803276B2 (en) | 2003-12-05 | 2010-09-28 | Exxonmobil Research And Engineering Company | Regeneration of sulfuric acid |
UY30082A1 (es) | 2006-01-11 | 2007-08-31 | Boehringer Ingelheim Int | Forma cristalina de 1-(1-metiletil)-4`-((2-fluoro-4-metoxifenil)metil)-5`- metil-1h-pirazol-3`-o-b-d-glucopiranosido, un metodo para su preparacion y el uso de la misma para preparar medicamentos |
EP2228378B1 (en) * | 2007-12-27 | 2015-09-09 | Kissei Pharmaceutical Co., Ltd. | Monosebacate of pyrazole derivative |
-
2009
- 2009-04-13 CA CA2725230A patent/CA2725230C/en active Active
- 2009-04-13 EP EP09733364A patent/EP2275430B1/en active Active
- 2009-04-13 JP JP2010508201A patent/JP5467040B2/ja active Active
- 2009-04-13 CN CN200980113752.6A patent/CN102007138B/zh active Active
- 2009-04-13 WO PCT/JP2009/057439 patent/WO2009128421A1/ja active Application Filing
- 2009-04-13 ES ES09733364T patent/ES2385185T3/es active Active
- 2009-04-13 US US12/988,273 patent/US8354382B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
CA2725230A1 (en) | 2009-10-22 |
ES2385185T3 (es) | 2012-07-19 |
CA2725230C (en) | 2016-05-17 |
US20110034679A1 (en) | 2011-02-10 |
EP2275430A4 (en) | 2011-04-06 |
US8354382B2 (en) | 2013-01-15 |
CN102007138B (zh) | 2014-05-21 |
EP2275430B1 (en) | 2012-05-16 |
WO2009128421A1 (ja) | 2009-10-22 |
CN102007138A (zh) | 2011-04-06 |
JP5467040B2 (ja) | 2014-04-09 |
EP2275430A1 (en) | 2011-01-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5467040B2 (ja) | ピラゾール誘導体の1/2フマル酸塩 | |
JP5144683B2 (ja) | ピラゾール誘導体のモノセバシン酸塩 | |
JP6727419B2 (ja) | ナトリウム−グルコース共輸送体阻害薬の新規な結晶形及びその製造方法並びに用途 | |
WO2007007628A1 (ja) | アズレン系化合物のコリン塩結晶 | |
BR112019012340A2 (pt) | sais cristalinos e polimorfos de um antagonista p2x3 | |
CN106008277A (zh) | 一种新型二甲双胍盐酸盐及其制备方法 | |
JP6294665B2 (ja) | スピロケタール誘導体の結晶 | |
JPWO2012147832A1 (ja) | フェニルピロール誘導体の結晶 | |
US11155571B2 (en) | Salt of pyranose-substituted heterocyclic compound, preparation method therefor and use thereof | |
WO2022009815A1 (ja) | オクタヒドロチエノキノリン化合物のコハク酸塩及びその結晶 | |
JP2005179272A (ja) | カルボキサミド誘導体のマロン酸塩結晶 | |
TW200302830A (en) | Anhydrate/hydrate of an erythromycin derivative and processes for preparing said anhydrate/hydrate |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20120404 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20131001 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20131128 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20140121 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20140127 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 Ref document number: 5467040 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |