WO2012109996A1 - 一种芳基糖苷类化合物及其制备方法和应用 - Google Patents
一种芳基糖苷类化合物及其制备方法和应用 Download PDFInfo
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- WO2012109996A1 WO2012109996A1 PCT/CN2012/071243 CN2012071243W WO2012109996A1 WO 2012109996 A1 WO2012109996 A1 WO 2012109996A1 CN 2012071243 W CN2012071243 W CN 2012071243W WO 2012109996 A1 WO2012109996 A1 WO 2012109996A1
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- -1 Aryl glycoside compound Chemical class 0.000 title claims abstract description 75
- 229930182470 glycoside Natural products 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims description 21
- 238000000034 method Methods 0.000 claims abstract description 93
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 230000003287 optical effect Effects 0.000 claims abstract description 18
- 229940002612 prodrug Drugs 0.000 claims abstract description 15
- 239000000651 prodrug Substances 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 13
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 355
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 234
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 186
- 238000006243 chemical reaction Methods 0.000 claims description 176
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 132
- 239000002904 solvent Substances 0.000 claims description 132
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 111
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 76
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 75
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 75
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 64
- 239000000203 mixture Substances 0.000 claims description 61
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 56
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 49
- 239000011734 sodium Substances 0.000 claims description 46
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 239000002585 base Substances 0.000 claims description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 36
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- 230000009471 action Effects 0.000 claims description 30
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 27
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 27
- 230000035484 reaction time Effects 0.000 claims description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- 239000003054 catalyst Substances 0.000 claims description 21
- 125000005842 heteroatom Chemical group 0.000 claims description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 20
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 229910052763 palladium Inorganic materials 0.000 claims description 17
- 238000006482 condensation reaction Methods 0.000 claims description 16
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 16
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 16
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 239000012046 mixed solvent Substances 0.000 claims description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 14
- 229910052760 oxygen Chemical group 0.000 claims description 14
- 239000001301 oxygen Chemical group 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 229910000077 silane Inorganic materials 0.000 claims description 14
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 150000002900 organolithium compounds Chemical class 0.000 claims description 11
- 125000002947 alkylene group Chemical group 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 10
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- 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 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 238000005906 dihydroxylation reaction Methods 0.000 claims description 8
- 239000011261 inert gas Substances 0.000 claims description 8
- 235000011056 potassium acetate Nutrition 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
- 239000003472 antidiabetic agent Substances 0.000 claims description 7
- HRQGCQVOJVTVLU-UHFFFAOYSA-N bis(chloromethyl) ether Chemical compound ClCOCCl HRQGCQVOJVTVLU-UHFFFAOYSA-N 0.000 claims description 7
- 238000005859 coupling reaction Methods 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 238000006640 acetylation reaction Methods 0.000 claims description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 6
- 238000007069 methylation reaction Methods 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 238000006722 reduction reaction Methods 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 claims description 6
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 6
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 claims description 5
- 208000002249 Diabetes Complications Diseases 0.000 claims description 5
- 206010012655 Diabetic complications Diseases 0.000 claims description 5
- 125000003158 alcohol group Chemical group 0.000 claims description 5
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 5
- 229940127003 anti-diabetic drug Drugs 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 239000008280 blood Substances 0.000 claims description 5
- 210000004369 blood Anatomy 0.000 claims description 5
- 150000001721 carbon Chemical group 0.000 claims description 5
- 229940125782 compound 2 Drugs 0.000 claims description 5
- 230000001419 dependent effect Effects 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Substances CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 claims description 4
- 108091052347 Glucose transporter family Proteins 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 4
- 125000002393 azetidinyl group Chemical group 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 4
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 229910015900 BF3 Inorganic materials 0.000 claims description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 3
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
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- 239000003524 antilipemic agent Substances 0.000 claims description 3
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 3
- 230000003111 delayed effect Effects 0.000 claims description 3
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- 150000004665 fatty acids Chemical class 0.000 claims description 3
- 201000001421 hyperglycemia Diseases 0.000 claims description 3
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- 201000008980 hyperinsulinism Diseases 0.000 claims description 3
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- 235000020824 obesity Nutrition 0.000 claims description 3
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- 230000006340 racemization Effects 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
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- 229910052725 zinc Inorganic materials 0.000 claims description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
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Definitions
- the present invention particularly relates to an aryl glycoside compound, a pharmaceutically acceptable salt thereof, an optical isomer thereof or a prodrug thereof, a process for the preparation thereof and use thereof, and a pharmaceutical composition containing the same.
- SGLTs Sodium-glucose co-transporters
- Kidney SGLT reabsorbs glucose from the kidney filtrate to prevent blood sugar from being lost from the urine.
- SGLT2 transports kidneys to reabsorb 98% of glucose, while SGLT1 accounts for only 2% of the rest.
- Inhibition of SGLT2 activity specifically inhibits glucose reabsorption in the kidney and increases glucose excretion in the urine, which may normalize plasma glucose in diabetic patients. Therefore, SGLT, especially SGLT2 inhibitors, is a promising candidate for antidiabetic drugs (Handlon, A.L., Expert Opin. Ther. Patents (2005) 15(11): 1531-1540).
- Aryl glycosides as SGLT2 inhibitors are also known from the following patent applications, WO 01/27128, WO 02/083066 WO 03/099836 US 2003/0114390, WO 04/063209, WO 2005/012326, US 2005/0209166 US 2006/0122126 WO 2006/011502 US 2007/0293690 WO 2008/034859, WO 2008/122014, and WO 2009/026537. Summary of the invention
- the technical problem to be solved by the present invention is to provide a novel aryl glycoside derivative or an isomer thereof, a racemate, a pharmaceutically acceptable salt, and a use thereof which are very effective for inhibiting SGLT, particularly SGLT2. And pharmaceutical compositions containing the same.
- the invention also provides methods of preparing the compounds of the invention.
- the present invention relates to an aryl glycoside compound of the formula I or hydrazine, a pharmaceutically acceptable salt thereof, an optical isomer thereof or a prodrug thereof;
- X is 0, S, SO, S0 2 , CO, CONR 6 , NHCO, NHS0 2 or a single bond;
- L is C r C 6 alkylene, (C r C 6 alkylene) -(C 3 -C 1Q cycloalkylene), or (C r C 6 alkylene) -(C 3 -C 10 a cycloalkyl)-(dC 6 alkylene); wherein the carbon atom on the cycloalkylene group may also be heteroatoms 0, N or
- M is a 4-membered heterocycloalkyl; when M is azetidinyl and the nitrogen atom in the azetidinyl group is bonded to L, XL is not 0 (;CH 2 ) m CH(;OR 6f H 2 , wherein m is 1-3, and R 6f is hydrogen, alkyl or alkylcarbonyl;
- RR 2 and R 3 are independently hydrogen, OH, -OR 7 , alkyl, -SR 51 or halogen, or two of R ⁇ R 2 and R 3 may form 5, 6 or together with the carbon to which they are attached. a 7-membered carbocyclic ring or a heterocyclic ring containing from 1 to 4 heteroatoms of N, 0, S, SO and/or S0 2 ;
- R 3a , R 4 and R 5 are independently hydrogen, 0H, -0R 5a , -0 aryl, -0CH 2 aryl, alkyl, cycloalkyl, halogen, -CN, -C0 2 R 5b , -C0 2 H, C0R 6b , -CH(0H)R 6c , -CH(OR 5h )R 6d , -CONR 6a R 6e , -NHC0R 5c , -NHS0 2 R 5d , -NHS0 2 aryl, aryl, -SR 5e , -S0R 5f , -S0 2 R 5g , -S0 2 aryl, or 5, 6 or 7 which may contain 1-4 heteroatoms of N, 0, S, SO and/or S0 2 on the ring a heterocyclic ring; or R 4 and R 5 together with the carbon to which they are attached form a 5, 6 or 7 membere
- R 7 , R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5h and R 51 are independently alkyl (e.g., ethyl);
- R 6 R 6a R 6b R 6c R M and R 6e are independently hydrogen, alkyl, aryl, alkaryl or cycloalkyl, or R 6a and R 6e together with the nitrogen to which they are attached may form on the ring a 5, 6 or 7 membered heterocyclic ring containing from 1 to 4 heteroatoms which are N, 0, S, SO and/or S0 2 ;
- A is 0, S, 1, 1-cyclopropylene, CHF, CF 2 or (CH 2 ) n , wherein n is 1-3.
- substitution position of the group A in the compound I is preferably as follows:
- substitution position of the group X is preferably the alignment of A
- substitution position of the group A in the oxime is preferably as follows:
- the substitution position of the group X in the compound I, ruthenium, osmium or iridium is preferably the para position of ruthenium (
- ⁇ , RR 2 , R 3 , R 4 , R 5 , X, L and A are defined as described above;
- Y is carbon or oxygen
- G is carbon, oxygen, nitrogen, S, or SO.
- R 8 is absent; Y and G are not carbon at the same time; when G is nitrogen, R 8 is H, Ci ⁇ C 3 alkyl, a carbonyl group bonded to a C3 alkyl group, a carbonyl group (such as a tert-butoxycarbonyl group) bonded to a C Ce alkoxy group, or a halogen (such as fluorine, chlorine, bromine or iodine) substituted C 6 ⁇ a C 1Q aryl group, a heterocyclic heteroalkyl group in which the hetero atom is an oxygen atom or S0 2 linked to a C alkyl group ;
- R 9 and R 1Q are independently C6 alkyl, halogen (such as fluorine, chlorine, bromine or iodine), hydroxy, cycloalkyl, C ⁇ Ce alkoxy, ⁇ alkylcarbonyloxy, amino, C ⁇ Cs haloalkyl (preferably monofluoromethyl or difluoromethyl), d-C 6 alkylamino or C ⁇ Cs alkyl-carbonylamino.
- halogen such as fluorine, chlorine, bromine or iodine
- the compound ⁇ is preferably as follows:
- G is carbon, oxygen, nitrogen, S, or SO.
- R 8 is absent; when G is nitrogen,
- R 9 and R 1Q are independently C ⁇ Ce alkyl, halogen (such as fluorine, chlorine, bromine or iodine), hydroxy, cycloalkyl, 6 alkoxy, C ⁇ Cs alkylcarbonyloxy, amino, C3 haloalkyl , - ⁇ alkylamino or C ⁇ Cs alkyl-carbonylamino.
- the compound ⁇ is preferably the following structure IIAa or II
- RR 2 , R 3 , R 4 , R 5 , X, L, A, R 8 and R 9 are as defined above;
- G is oxygen, nitrogen, S, or SO; * represents racemization, or R or S absolute configuration;
- the compound I is more preferably any of the following compounds:
- the * carbon in the compounds 3 and 4 indicates that the absolute configurations of the carbons in the two compounds are mutually enantiomeric, and the compounds 3 and 4 are optical isomers of the compound 2.
- the compound ⁇ is preferably any of the following compounds:
- the present invention further relates to a method for preparing the compound I or hydrazine, which is any one of the following three methods: 1.
- the compound 1 and R'OTs or ROMs are subjected to a nucleophilic substitution reaction to obtain a compound I;
- La 1 will carry out the reaction of dehydrating the acetyl group of the compound la' to obtain the compound I;
- R'-OTs is M and R'.OMs is M, and the definitions of each group and letter are as described above.
- the method and conditions of the nucleophilic substitution reaction may be the conventional methods and conditions for the reaction of such a nucleophilic substitution reaction in the art, and the present invention particularly preferably has the following methods and conditions: in a solvent, in a base Under the action, the compound la and R'OTs or ROMs can be subjected to a nucleophilic substitution reaction.
- the solvent is preferably a polar solvent such as dimethylformamide or acetone, preferably dimethylformamide.
- the volumetric mass of the solvent and the compound la is preferably from 20 to 100 mL/g.
- the base is preferably one or more of potassium carbonate, sodium carbonate and cesium carbonate, preferably cesium carbonate.
- the amount of the base to be used is preferably from 1 to 3 times, more preferably from 1.5 to 2.5 times, the molar amount of the compound la.
- the R'OTs or ROMs are preferably used in an amount of from 0.8 to 1.6 times, more preferably from 1 to 1.4 times, the molar amount of the compound la.
- the temperature of the reaction is preferably from 20 to 180 ° C, more preferably from 60 to 130 ° C.
- the reaction time is preferably such that the reaction is completed, usually from 2 to 15 hours.
- the method and conditions for the reaction of removing the hydroxy group of the hydroxy group may be the conventional methods and conditions for such a reaction in the art, and the following methods and conditions are particularly preferred in the present invention: in a solvent, in a base such as hydrogen
- a solvent in a base such as hydrogen
- the reaction of the compound la' with the acetyl group of the hydroxyl group may be carried out by using lithium oxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide.
- the solvent is preferably tetrahydrofuran, a mixed solvent of methanol and water, or a mixed solvent of methanol and water, preferably a mixed solvent of tetrahydrofuran, methanol and water.
- the volume of the solvent and the compound la' is preferably 50 to 200 mL/g.
- the base is preferably used in an amount of from 4 to 30 times, more preferably from 10 to 25 times, the mole of the compound la'.
- the temperature of the reaction is preferably from -20 to 100 ° C, more preferably from 0 to 50 ° C.
- the reaction time is preferably such that the reaction is completed, usually 0.5 to 2 hours.
- the method and conditions of the nucleophilic substitution reaction may be conventional methods and conditions for the reaction of such a nucleophilic substitution reaction in the art, and the present invention particularly preferably has the following methods and conditions: in a solvent, in a base Under the action, the compound I'a and the R'OTs or the ROMs are subjected to a nucleophilic substitution reaction, wherein the solvent is preferably a polar solvent; and the volume of the solvent and the compound I'a is better.
- the base is preferably one or more of potassium carbonate, sodium carbonate and cesium carbonate, preferably cesium carbonate;
- the amount of the base is preferably the compound I'a 1 to 3 times the molar amount, more preferably 1.5 to 2.5 times;
- the amount of the R'OTs or ROMs is preferably 0.8 to 1.6 times the molar amount of the compound I'a, more preferably 1 to 1. 1.4 times;
- the temperature of the reaction is preferably 20 to 180 ° C, more preferably 60 to 130 ° C; the reaction time is preferably to detect the reaction is complete;
- the method and conditions for the reaction of removing the benzyl protecting group of the hydroxy group may be the conventional methods and conditions for the deprotection group reaction in the art, and the following methods and conditions are particularly preferred in the present invention: under hydrogen conditions, solvent in the zinc halides such as ZnBr 2 or ZnCl 2, ZnBr 2 preferably under the action of the compound is reacted I'b removal of hydroxyl benzyl group under palladium catalyst, can; wherein said solvent than Preferably, it is methanol, ethanol or ethyl acetate, preferably ethyl acetate; the palladium catalyst may be Pd/C or Pd(OH) 2 /C, preferably Pd(OH) 2 /C; solvent and compound I'b
- the volumetric mass is preferably from 20 to 200 mL/g; the amount of the zinc halide is preferably from 0.5% to 5%, more preferably from 1% to 2%, based on the molar amount of the
- the compound la' can be produced by any of the following methods:
- each group and letter are as defined above, and A is most preferably CH 2 , and M' is an alkali metal such as potassium or sodium, preferably potassium.
- the method and conditions for the ether-forming reaction may be conventional methods and conditions for such reactions in the art, and the present invention particularly preferably has the following methods and conditions: under nitrogen protection, in a solvent, in an even Nitrodiyl dipiperidine
- the compound lb' and the ROH are subjected to an ether reaction under the action of (ADDP) and tri-n-butylphosphine.
- the solvent is preferably one or more of tetrahydrofuran, dichloromethane and toluene, preferably tetrahydrofuran.
- the volume of the solvent and the compound lb' is preferably from 20 to 200 mL/g.
- the ROH is preferably used in an amount of from 0.8 to 8 times, more preferably from 2 to 5 times, the mole of the compound lb'.
- the azodiyldipiperidine is preferably used in an amount of from 1 to 10 times, more preferably from 4 to 6 times, the mole of the compound lb'.
- the amount of the tri-n-butylphosphine is preferably from 1 to 10 times, more preferably from 4 to 6 times the molar amount of the compound lb'.
- the temperature of the reaction is preferably -20 to 80 ° C, more preferably 0 to 50 ° C.
- the reaction time is preferably such that the reaction is completed, usually from 2 to 15 hours.
- the method and conditions of the coupling reaction may be conventional methods and conditions for such a coupling reaction in the art, and the following methods and conditions are particularly preferred in the present invention: in a solvent, under the protection of an inert gas,
- the compound Ibb and lb" may be subjected to a coupling reaction under the action of a base and a palladium catalyst, wherein the inert gas may be argon gas and/or nitrogen gas.
- the solvent is preferably tetrahydrofuran or toluene.
- the volume of tetrahydrofuran and water is better. It is 50:1 to 1:1, preferably 10:1.
- the volume of the solvent and the compound lb" is preferably from 20 to 100 mL/g.
- the base is preferably one or more of potassium carbonate, cesium carbonate, sodium carbonate and potassium phosphate, preferably cesium carbonate.
- the amount of the base is preferably from 1 to 10 times, more preferably from 3 to 5 times the molar amount of the compound lb".
- the palladium catalyst is preferably a catalyst commonly used in such a coupling reaction, such as palladium acetate. Tetrakis(triphenylphosphine) palladium and [1,1 '-double
- the amount of the catalyst is preferably 0.005 to 0.5 times, more preferably 0.01 to 0.10 times the molar amount of the compound lb".
- the molar ratio of the reactant Ibb to lb" is preferably 0.5 to 2, more preferably It is 0.9 to 1.5.
- the temperature of the reaction is preferably from 20 to 120 V, more preferably from 70 to 90 °C.
- the reaction time is preferably such that the reaction is completed, usually from 2 to 20 hours.
- the compound I'a can be obtained by the following method: Deprotection of the compound I'b
- the method and conditions for the desiliconization protecting group reaction can be the conventional methods and conditions for such reactions in the art, and the following methods and conditions are particularly preferred in the present invention: in the solvent, the action of tetrabutylammonium fluoride
- the silicon protecting group of the phenolic hydroxyl group is removed, wherein the solvent is preferably tetrahydrofuran; the solvent and the compound I'b preferably have a volumetric mass of 5 to 50 mL/g;
- the amount of the tetrabutylammonium fluoride is preferably from 1 to 5 times, more preferably from 1 to 2 times the molar amount of the compound I'b;
- the temperature of the reaction is preferably from -10 to 50 V, More preferably, it is 0 to 30 ° C; the reaction time is preferably used to detect completion of the reaction.
- the compound lb' can be obtained by the following method: removing the compound Ic' from a hydroxyl group
- the method and conditions for the reaction of removing the hydroxy protecting group of the hydroxy group may be the conventional methods and conditions for the reaction of the acetyl protecting group of the selective dephenolic hydroxyl group in the art, and the following methods are particularly preferred in the present invention.
- the solvent In the solvent, the compound Ic' can be selectively reacted with an acetyl protecting group of a phenolic hydroxyl group by the action of ammonium acetate (AcONH 4 ).
- the solvent is preferably one or more of tetrahydrofuran, methanol and water, and a mixed solvent of methanol and water is preferred.
- the volumetric mass of the solvent and the compound Ic' is preferably from 5 to 50 mL/g.
- the amount of the acetylammonium used is preferably from 5 to 50 times, more preferably from 8 to 15 times, the mole of the compound Ic'.
- the temperature of the reaction is preferably from 0 to 150 ° C, more preferably from 20 to 80 ° C.
- the reaction time is preferably such that the reaction is completed, usually 5 to 20 hours.
- the compound lb" can be obtained by the following method: Compound Ic" and M'HF 2 (such as potassium dihydrogen fluoride) are carried out as
- the method and conditions of the reaction can be conventional methods and conditions for such reactions in the field, Particularly preferred are the following methods and conditions:
- the solvent is preferably one or more of acetonitrile, methanol and water, preferably.
- the volume of the solvent and the compound Ic" is preferably from 3 to 30 mL/g.
- the amount of the M ⁇ F 2 is preferably from 1 to 5 times, more preferably from 2 to 3 times the molar amount of the compound Ic".
- the temperature of the reaction is preferably from 0 to 40 ° C, more preferably
- the reaction time is preferably 10 to 30 ° C. The reaction time is preferably such that the reaction is completed, usually 1 to 5 hours.
- the compound I'b can be obtained by the following method: the compound I'c and the silane are subjected to a reduction reaction;
- the method and conditions of the reduction reaction can be conventional methods and conditions for such reactions in the art, and the following methods and conditions are particularly preferred in the present invention: in a solvent, in silane and trimethylsilyl trifluoromethanesulfonic acid Under the action of the salt, the reduction reaction is carried out, and the phenolic hydroxyl group is also protected by the silicon reagent; wherein the solvent is preferably one or more of dichloromethane, acetonitrile, toluene, tetrahydrofuran and diethyl ether.
- dichloromethane the volume of the solvent and the compound I'c is preferably from 20 to 100 mL/g; the silane is preferably triethylsilyl or triisopropylsilane, preferably triisopropylsilane.
- the amount of the silane is preferably from 1 to 5 times, more preferably from 1 to 2 times the molar amount of the compound I'c; and the amount of the TMSOTf is preferably the molar amount of the compound I'c. 0.5 to 2 times, more preferably 0.9 to 1.2 times;
- the temperature of the reaction is preferably -100 to 10 ° C, more preferably -80 to 20 ° C; Preferably, the reaction is detected to be complete.
- the compound Ic' can be obtained by the following method: The compound Id' is subjected to acetylation of a hydroxyl group.
- the method and conditions for the acetylation reaction of the hydroxyl group can be the conventional methods and conditions for such reactions in the art, and the present invention particularly preferably has the following methods and conditions:
- the solvent is preferably one or more of dichloromethane, tetrahydrofuran, hydrazine, hydrazine-dimethylformamide and pyridine, preferably dichloromethane.
- the base in the basic condition is preferably a mixture of 4-dimethylaminopyridine and another organic base, and the "other organic base” is preferably triethylamine or diisopropylethyl.
- the "other organic base” is preferably triethylamine or diisopropylethyl.
- the volumetric mass of the solvent and the compound Id' is preferably from 10 to 100 mL/g.
- the amount of the acetic anhydride to be used is preferably from 4 to 20 times, more preferably from 8 to 15 times the molar amount of the compound Id'.
- the other organic base is preferably used in an amount of from 5 to 20 times, more preferably from 8 to 15 times, the mole of the compound Id'.
- the amount of 4-dimethylaminopyridine is preferably 0.01 to 1 times, more preferably 0.05 to 0.2 times the molar amount of the compound Id'.
- the temperature of the reaction is preferably from 0 to 100 V, more preferably from 20 to 50 V.
- the reaction time is preferably such that the reaction is completed, usually 0.5 to 2 hours.
- the compound Ic" can be obtained by the following method: the compound Id" and the boronic acid pinacol ester are as
- the method and conditions of the reaction can be the conventional methods and conditions for such reactions in the art, and the following methods and conditions are particularly preferred in the present invention: in a solvent, under the protection of an inert gas, in the action of a weak base and a palladium catalyst Next, the compound Id" and the boronic acid pinacol ester are reacted, wherein the inert gas may be nitrogen or argon.
- the solvent is preferably dimethyl sulfoxide, N, N-.
- One or more of dimethylformamide, 1,4-dioxane, and toluene preferably dimethyl sulfoxide.
- the volume of the solvent and the compound Id" is preferably from 10 to 100 mL/g.
- the weak base is preferably one or more of triethylamine, sodium acetate and/or potassium acetate, preferably potassium acetate.
- the amount of the weak base is preferably from 1 to 5 times, more preferably from 1 to 3 times the molar amount of the compound Id".
- the amount of the diboronic acid pinacol ester is preferably the compound Id"
- the molar amount is 1 to 2 times, more preferably 0.9 to 1.5 times.
- the palladium catalyst is preferably a catalyst commonly used in such reactions, such as bistriphenylphosphine palladium dichloride and [1,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride.
- the amount of the catalyst is preferably 0.005 to 0.5 times, more preferably 0.01 to 0.20 times the molar amount of the compound Id".
- the temperature of the reaction is preferably 50 to 150 ° C, more preferably 80 to
- the reaction time is preferably 120 ° C to detect the completion of the reaction, generally 5 to 20 hours.
- the compound I'c can be obtained by subjecting the compounds I'd and I'e to a condensation reaction
- the method and the conditions of the condensation reaction can be the conventional methods and conditions for such reactions in the art, and the present invention particularly preferably has the following methods and conditions: in the solvent, the compound I'd is reacted with NaH, and then in the organic a condensation reaction with I'e under the action of a lithium compound; wherein the solvent is preferably one or more of diethyl ether, dichloromethane, toluene, n-hexane and tetrahydrofuran, preferably tetrahydrofuran, or a mixture of tetrahydrofuran and toluene; the volume of the solvent and the compound I'd is preferably 2 to 20 mL/g; and the amount of the NaH is preferably 0.9 to 2 times the molar amount of the compound I'd.
- the solvent is preferably one or more of diethyl ether, dichloromethane, toluene, n-hexane and tetrahydrofuran, preferably
- the organolithium compound is n-butyllithium, sec-butyllithium or t-butyllithium; and the organolithium compound is preferably used in the amount of the compound I'd.
- the molar amount is 0.9 to 2 times, more preferably 1 to 1.3 times; and the amount of the compound I'e is preferably 0.9 to 1.5 times the molar amount of the compound I'd, more preferably 1 to 1.2.
- the temperature of the I'd and NaH reaction is preferably -10 to 10 V, more preferably 0 to 10 ° C; the temperature of the condensation reaction is preferably from 0 to -100 ° C, more preferably from -10 to - 80 ° C; The time is preferably to detect the completion of the reaction.
- the preparation of the compound Id can be referred to J Am. C/iem c., 2009, 2786-2787; Angew. Chem. Int. Ed., 2010, 49, 3524-3527 and WO2008/0021032. Prepared by the method described on pages 81-83. Preparation of compound I'd can be found in 'oorg. Med. Chem., 2011, 19, 5468-5479. Preparation of compound I'e, reference J Org Chem., 1967, 32(8), 2531-2534.
- the compound Id' can be obtained by the following method: Deamination of the compound Ie' to the methoxy group
- the method and conditions for the demethoxylation reaction can be conventional methods and conditions for such reactions in the art, and the following methods and conditions are particularly preferred in the present invention: in a solvent, in silane and trifluoride Under the action of boron, the reaction of removing the methoxy group can be carried out.
- the solvent is preferably dichloromethane, acetonitrile, toluene, tetrahydrofuran
- methane and diethyl ether are preferably dichloromethane or acetonitrile.
- the volume of the solvent and the compound Ie' is preferably from 10 to 100 mL/g.
- the silane is preferably triethylsilane or triisopropylsilane; the silane is preferably used in an amount of from 1 to 5 times, more preferably from 2 to 3 times, the mole of the compound Ie'.
- the boron trifluoride is preferably used in an amount of from 0.5 to 5 times, more preferably from 1 to 2 times, the mole of the compound Ie'.
- the temperature of the reaction is preferably from -50 to 50, more preferably from -15 to 10 °C.
- the reaction time is preferably such that the reaction is completed, usually from 2 to 6 hours.
- the compound Ie' can be obtained by the following method: After the compound If' and f are subjected to a condensation reaction, the obtained substance and a methanol solution of methanesulfonic acid are subjected to methylation reaction to remove the hydroxyl group of trimethylsilane. Base reaction and dehydroxylation
- the condensation reaction, the methylation reaction, the dehydroxylation of the trimethylsilyl group and the dehydroxylation of the methoxymethyl group can be carried out in the manner of conditions and conditions for such reactions in the art.
- the following methods and conditions are particularly preferred: in the solvent, under the action of nitrogen, the compound If' and f are subjected to a condensation reaction under the action of an organolithium compound, and the obtained substance and the methanol solution of methanesulfonic acid are methylated.
- the reaction can be carried out by dehydrating the trimethylsilyl group of the hydroxyl group and removing the methoxymethyl group of the hydroxyl group.
- the solvent is preferably one or more of diethyl ether, dichloromethane, toluene, n-hexane and tetrahydrofuran, preferably tetrahydrofuran, or a mixture of tetrahydrofuran and toluene.
- the volume of the solvent and the compound If' is preferably 5 to 50 mL/g.
- the organolithium compound is preferably n-butyllithium, sec-butyllithium or t-butyllithium; the organolithium compound is preferably used in an amount of from 0.9 to 2 times the molar amount of the compound If'. The best is 1 to 1.3 times.
- the compound f is preferably used in an amount of from 0.9 to 2 times, more preferably from 1 to 1.3 times, the molar amount of the compound If'.
- the amount of the methanesulfonic acid is preferably from 2 to 20 times, more preferably from 8 to 12 times, the mole of the compound If'.
- the temperature of the condensation reaction is preferably from 0 to - 100 ° C, more preferably from -10 to - 80 °C.
- the temperature of the methylation reaction and the dehydroxylation of the trimethylsilyl group is preferably from 0 to 100 V, more preferably from -30 to 80. C.
- the time of the three reactions described above is preferably such that the reaction is detected to be complete.
- the compound if' can be obtained by the following method: nucleophilic substitution of the compound Ig' and chloromethyl ether Counter
- the method and conditions of the nucleophilic substitution reaction can be the conventional methods and conditions for such reactions in the art, and the present invention particularly preferably has the following methods and conditions:
- the solvent under the action of a base, the compound ig'
- the nucleophilic substitution reaction with chloromethyl ether is sufficient.
- the solvent is preferably one or more of N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, and acetonitrile, preferably N, N-dimethylformamide.
- the volume-mass ratio of the solvent to the compound Ig' is preferably from 10 to 50 mL/g.
- the base is preferably sodium hydride or diisopropylethylamine, preferably NaH.
- the amount of the base to be used is preferably from 0.9 to 2 times, more preferably from 1 to 1.5 times, the mole of the compound Ig'.
- the amount of the chloromethyl ether to be used is preferably from 0.9 to 2 times, more preferably from 1 to 1.5 times, the mole of the compound Ig'.
- the temperature of the reaction is preferably from 0 to 70 ° C, more preferably from 10 to 40 ° C.
- the reaction time is preferably such that the reaction is completed, usually from 1 to 5 hours.
- the preparation of the compound Ig' can be prepared by referring to the patent WO2009/026537.
- the compounds of the present invention can be obtained by a variety of methods well known in the art, using known starting materials, such as chemical synthesis or methods of extraction from plants. These methods are all included in the present invention.
- the starting materials used to prepare the compounds of the present invention or intermediates thereof are known in the art or are commercially available unless otherwise stated or provided.
- each of the preferred conditions in the preparation method can be arbitrarily combined to obtain various preferred examples of the present invention.
- the compounds of the present invention can be prepared by the following reaction schemes and description. First, the preparation of intermediates
- each group is the same as described above.
- Example 2 is as follows:
- the compound Ig"-6 can be prepared by reference to J Org. Chem., 1984, 49(22), 4226-4237; T. A, 2001, (4), 585-596.
- the compound If '-6 can be referred to Prepared by J. Med. Chem., 2005, 48(19), 5980-5988. 2. Preparation of final product (Scheme 4 ⁇ 5) Process 4
- R'OH is M.
- ADDP azodicarbonyl dipiperidine is the abbreviation of ADDP azodicarbonyl dipiperidine of each group and the letters are as previously defined in the process c 6
- the present invention further relates to an intermediate compound for preparing the above aryl glycoside compound I as shown in any of the following structures:
- the invention further relates to the use of the above aryl glycoside compound I, a pharmaceutically acceptable salt thereof, an optical isomer thereof or a prodrug thereof for the preparation of a sodium-dependent glucose transporter (preferably SGLT2) inhibitor.
- a sodium-dependent glucose transporter preferably SGLT2
- the present invention relates to the above arylglycoside compound I, a pharmaceutically acceptable salt thereof, an optical isomer thereof or a prodrug thereof for use in the treatment or delay of development or onset of the following diseases or for increasing high-density fat
- a protein at a level selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, fatty acids in the blood or Elevated levels of glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications, or atherosclerosis or hypertension.
- the diabetes is preferably type 2 diabetes.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising an effective amount of an aryl glycoside compound of the formula I, a pharmaceutically acceptable salt thereof, an optical isomer thereof or a prodrug thereof and A pharmaceutically acceptable carrier or excipient.
- the pharmaceutical composition can be used for the preparation of a medicament for treating or delaying the development or onset of a disease or for increasing the level of high-density lipoprotein, wherein the disease is selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, and diabetes.
- Kidney disease delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol in the blood, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications Or atherosclerosis or high blood pressure.
- the composition may further comprise: a non-sodium-dependent glucose transporter inhibitor anti-diabetic drug, a diabetic complication drug, an anti-obesity drug, an antihypertensive drug, an anti-platelet drug, Anti-atherosclerotic drugs and/or hypolipidemic drugs.
- the antidiabetic agent is selected from one or more of the following: metformin, glibenclamide, glimepiride, glipizide, gliclazide, Glipyride, pioglitazone, koji Glitazone, rosiglitazone, Acarbose, miglitol, chlorosulfonate, nateglinide, repaglinide, insulin, AC2993, AJ7677, AR-H039242, GI-262570, Isaglitazone, JTT-501, KADI 129, K P297 , LY315902, cis-2344, NVP-DPP-728A R-119702 or YM-440.
- Alkyl as used herein (including when used alone and in other groups) is meant to include from 1 to 20 a branched and straight-chain saturated aliphatic hydrocarbon group of carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl , t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 4, 4 - dimethyl pentyl, 2,2,4-trimethylpentyl, undecyl An alkyl group, a dodecyl group, and various isomers thereof and the like; and the above alkyl group comprising any one of the following 1-4 substituents: halogen (preferably F, Br,
- C xl -C yl fluorenyl group (xl and yl are integers), such as “ ⁇ 3 ⁇ 4 alkyl”, defined in the present invention, in addition to the carbon number range and the “alkyl group” in this paragraph
- the definitions are the same except that the carbon number has a different definition range.
- alkylene (including when used alone or in another group) is meant to include a branched and straight chain subsaturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 10 carbons. Atom, more preferably 1 to 8 carbon atoms, such as methylene, ethylene, propylene, isopropylidene, n-butylene, tert-butyl, isobutylene, pentylene, hexylene , heptylene, octylene, fluorenylene, fluorenylene, arylene (4,4-dimethylpentyl), sub (2,2,4-trimethylpentyl), undecylene , dodecylene group, and various isomers thereof and the like; and the above alkylene group containing any one of the following 1-4 substituents: halogen (preferably F, Br, CI or 1), alkyl group, Alkoxy, aryl, aryloxy,
- cycloalkyl includes a cyclic hydrocarbon group containing 1-3 rings which is saturated or partially unsaturated (containing 1 or 2 double bonds), Including monocycloalkyl, bicycloalkyl and tricycloalkyl, which contain 3-20 ring-forming carbons, preferably 3-10 carbons, for example: cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecane and cyclododecyl, cyclohexenyl; cycloalkyl may be substituted by any of the following 1-4 substituents: halogen, alkyl, alkoxy , hydroxy, aryl, aryloxy, aralkyl, cycloalkyl, alkylamino, acylamino, oxy, acyl, arylcarbonylamino, amino, nitro
- cycloalkylene (including when used alone or in another group) comprises a cyclic hydrocarbon group containing 1-3 rings, saturated or partially unsaturated (containing 1 or 2 double bonds), It comprises a monomonocycloalkyl group, a bibicycloalkyl group and a tritricycloalkyl group, which comprises 3-20 ring-forming carbons, preferably 3-10 carbons, for example: cyclopropylene, cyclopentylene, Cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclodecane and cyclopentylene, cyclohexylene; cycloalkylene can be any of the following 1-4 Substituent substitution: halogen, alkyl, alkoxy, alkylcarbonyloxy, alkoxycarbonyl, hydroxy, aryl, aryloxy, aralkyl, cycloalkyl, alkylamino, acyl,
- alkoxy denotes a cyclic or acyclic alkyl group having the number of carbon atoms attached through an oxygen bridge.
- alkoxy includes the definitions of the above alkyl and cycloalkyl.
- alkenyl refers to a straight, branched or cyclic non-aromatic hydrocarbon radical containing the specified number of carbon atoms and at least one carbon to carbon double bond. Preferably there is one carbon-carbon double bond and up to four non-aromatic carbon-carbon double bonds may be present.
- C 2 -C 1 () alkenyl means an alkenyl group having 2 to 10 carbon atoms.
- the "C 2 -C 6 alkenyl group” means an alkenyl group having 2 to 6 carbon atoms, and includes a vinyl group, a propenyl group, a butenyl group, a 2-methylbutenyl group, and a cyclohexenyl group.
- the linear, branched or cyclic moiety of the alkenyl group may contain a double bond and, if indicated to be a substituted alkenyl group, may be substituted.
- block group refers to a straight chain, branched or cyclic hydrocarbon group containing the specified number of carbon atoms and at least one carbon to carbon triple bond. There may be up to three carbon-carbon triple bonds.
- C2-C10 block group means a block group having 2 to 10 carbon atoms.
- C 2 -C 6 block group means a block group having 2 to 6 carbon atoms, and includes an ethyl group, a propyl group, a butyl group, a 3-methylbutyl group, and the like.
- aryl refers to any stable monocyclic or bicyclic carbon ring which may be up to 7 atoms in each ring, at least one of which is an aromatic ring.
- aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl (acena phthyl). It will be understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the linkage is carried out through an aromatic ring.
- aryl group comprising any one of the following 1-4 substituents: halogen (F, Br, CI or 1), alkyl, alkoxy, aryl, aryloxy, aryl substituted aryl or diaryl Alkyl, aralkyl, aralkoxy, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkoxy, optionally substituted amino, hydroxy, hydroxyalkyl , acyl, aldehyde, heteroaryl, heteroaryloxy, heterocycloalkyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, Aryloxyaryl, alkylamino, amido, arylcarbonylamino, nitro, nitrile, fluorenyl, haloalkyl, trihaloalkyl, al
- alkylthio denotes a cyclic or acyclic alkyl group having the number of carbon atoms attached through a sulfur bridge.
- alkylthio embraces the definitions of the above alkyl and cycloalkyl groups.
- halogen means fluoro, chloro, bromo, iodo or quinone.
- haloalkyl denotes an alkyl group substituted at any position of the halogen.
- haloalkyl embraces the definitions of the above halo and alkyl.
- haloalkoxy denotes an alkoxy group substituted at any position of the halogen.
- haloalkoxy includes the definitions of the above halo and alkoxy.
- aryloxy denotes an aryl group having the number of carbon atoms attached through an oxygen bridge. Thus, “aryloxy” embraces the definition of the above aryl group.
- arylhetero or “heteroaryl” as used herein denotes a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is an aromatic ring and contains from 1 to 4 selected from 0, Heteroatoms of N, and S.
- Heteroaryl groups within the scope of this definition include, but are not limited to: acridinyl, oxazolyl, porphyrin, quinoxalinyl, pyrazolyl, fluorenyl, benzotriazolyl, furyl, thienyl , benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, fluorenyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, Tetrahydroquinoline.
- heteroaryl is also understood to include any nitrogen-containing heteroaryl N-oxide derivative.
- heteroaryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or does not contain a hetero atom, it is understood that the linkage is carried out by an aromatic ring or by a hetero atom containing a ring, respectively.
- heterocycle or “heterocyclyl” as used herein denotes a 5-10 membered aromatic or non-aromatic heterocyclic ring containing from 1 to 4 heteroatoms selected from 0, N and S, and includes a bicyclic group.
- heterocyclyl includes the above heteroaryl as well as its dihydro or tetrahydro analog.
- heterocyclic group examples include, but are not limited to, the following: benzimidazolyl, benzofuranyl, benzofurazyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxanthate Azolyl, carbazolyl, porphyrinyl, porphyrinyl, furyl, imidazolyl, indanyl, fluorenyl, oxazolyl, isobenzofuranyl, isoindolyl, isoquinoline Base, isothiazolyl, isoxazolyl, naphthylpyridyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxocyclobutyl, pyranyl, pyrazinyl, pyrazolyl, Pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyri
- heterocycloalkyl refers to a 5-, 6- or 7-membered saturation containing 1-2 heteroatoms such as nitrogen, oxygen and/or sulfur. Or partially unsaturated rings.
- the heterocycloalkyl group may contain from 1 to 4 substituents such as alkyl, halo, oxo and/or any of the alkyl substituents listed above.
- any heterocycloalkyl ring may be fused to a cycloalkyl, aryl, heteroaryl or heterocycloalkyl ring.
- the heterocycloalkyl substituent may be bonded via a carbon atom or a hetero atom thereto and other groups.
- 4-membered heterocycloalkyl refers to 1-2 heteroatoms (N, 0 or S, which may be S when the heteroatom is S, SO or S0 2) a 4-membered ring, e.g.
- the above heterocycloalkyl groups may contain from 1 to 4 substituents such as alkyl, halo, oxo and/or any of the alkyl substituents listed above.
- the 4-membered heterocycloalkyl substituent may be bonded to other groups via a carbon atom or a hetero atom therein.
- pharmaceutical composition means a mixture of one or more of the aryl glycoside compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as pharmaceutically acceptable Carrier and excipients.
- the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
- the above pharmaceutical compositions may or may not contain another anti-diabetic drug and/or antihyperlipidemic drug, or other type of therapeutic agent.
- the positive progress of the present invention is that the aryl glycoside compound of the present invention has a very good inhibitory activity against SGLT2 and is a highly promising anti-diabetic drug.
- Example 1 4-(5-Bromo-2-chloro-benzyl)-phenol Dissolving 4-bromo-I-chloro-2-(4-ethoxy-benzyl)-benzene (see, for example, Journal of Medicinal Chemistry, 2008 51, 1 145-1 149) (8.47 g, 0.026 mol) A solution of 250 mL of dichloromethane was cooled to -78 ° C, and then 8 mL of a 4 M solution of boron tribromide in dichloromethane was slowly added dropwise to the solution, and stirring was continued at -78 ° C for 30 minutes after the addition. The cooling device was removed and allowed to warm to room temperature for 1 hour.
- Example 3 1-Chloro-4-(1-methoxy-D-glucopyranose-1-yl)-2-(4-hydroxybenzyl)-benzene 4-Bromo-1-chloro-2-(4-(methoxymethoxy)benzyl)-benzene (1.17 g, 3.44 mmol) in 12 mL of anhydrous tetrahydrofuran / toluene (2:1) Cool down to -78 °C. 1.5 mL of a 2.5 M solution of n-butyllithium in n-hexane was slowly added dropwise to the cooled solution; after the addition, stirring was continued at -78 °C for 30 minutes.
- Example 16 2-oxetanium methyl 4-methylbenzenesulfonate A solution of commercially available 2-oxetanemethanol (212 mg, 2.41 mmol) in 10 mL dichloromethane was cooled to 0. Add 0.54 g (4.82 mmol) of 1,4 -diazabicyclo[2,2,2]octane (DABCO), then slowly add 528 mg (2.77 mmol) of p-toluenesulfonyl chloride and stir at 0 °C. 10 minutes. The reaction mixture was then filtered and washed with dichloromethane. The solvent was evaporated under reduced pressure and the obtained residue (410 mg)
- DABCO 1,4 -diazabicyclo[2,2,2]octane
- Example 17 3-Methyl-3-oxo 4-methylbenzenesulfonate
- a solution of commercially available 3-methyl-3-oxetanemethanol (507 mg, 4.97 mmol) in 15 mL dichloromethane was cooled to 0.
- Add 1.12 g (9.94 mmol) of 1,4 -diazabicyclo[2,2,2]octane (DABCO) then slowly add 1.09 g (5.72 mmol) of p-toluenesulfonyl chloride and stir at 0 °C. 15 minutes.
- the reaction mixture was then filtered and washed with dichloromethane.
- the solvent was evaporated under reduced pressure, and the obtained residue (m.
- Example 18 2-(3-oxa-methylbenzenesulfonate Cool 2-(3-oxetane)ethanol (refer to, for example, Journal of American Chemical Society, 2009, 131, 2786-2787) (193 mg, 1.89 mmol) in 15 mL of dichloromethane to 0 °C . Add 847 mg (7.56 mmol) of 1,4-diazabicyclo[2,2,2]octane (DABCO), then slowly add 1.43 g (7.56 mmol) of p-toluenesulfonyl chloride and stir at 0 °C. 15 minutes. The reaction mixture was then filtered and washed with dichloromethane. The solvent was evaporated under reduced pressure.
- DABCO 1,4-diazabicyclo[2,2,2]octane
- the solvent was evaporated under reduced pressure, and the obtained residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
- the compound Ie"-23 (8.41 g, 21.24 mmol) was dissolved in dimethylformamide (150 mL), cooled in ice water, and sodium hydrogen (60%, 2.97 g, 74.33 mmol) was slowly added. The mixture was stirred at 0 ° C for 1.5 hours until TLC showed the disappearance of the starting material. To the reaction mixture, iced water was added slowly, ethyl acetate was extracted, and the combined organic phases were dried over anhydrous sodium sulfate.
- a cDNA clone of human SGLT1/SGLT2 was purchased from GenerScript. After obtaining the sequence information, the pcDNA5 vector was constructed by a conventional molecular biological method, and then the expression plasmid was introduced into Flp-in CHO cells by Lipofetamin 200 lipofection. The transfected cells were subjected to hygromycin resistance screening, and single cell clones were screened by gradient dilution. The uptake of 14 C-AMG in Flp-in CHO cells stably expressing SGLT1/SGLT2 was evaluated after obtaining single cell clones.
- the cells were plated at 3 ⁇ 10 4 per well, and the cells in the plate were cultured overnight to allow for absorption test. After at least 12 hours of cell seeding, wash the cells with 150 ⁇ l/well of the absorption solution KRH-NMG (120 mM NMG, 4.7 mM KCl, 1.2 mM MgCl 2 , 2.2 mM CaCl 2 , 10 mM HEPES, pH 7.4 with HC1). once. The wells were blotted and a [ 14C ]-AMG solution containing 2.5 ⁇ /ml of Buffer KRH-Na+ was added to Buffer KRH-Na + and KRH-NMG cleaned wells at 45 ⁇ L/well.
- KRH-NMG 120 mM NMG, 4.7 mM KCl, 1.2 mM MgCl 2 , 2.2 mM CaCl 2 , 10 mM HEPES, pH 7.4 with HC1.
- Table 1 shows the compound chosen, on human SGLT2 and human SGLT IC 5 to 1. Value:
- the arylglycoside compounds of the present invention are excellent SGLT2 inhibitors both in vitro and in vivo, and are a promising drug for the treatment or prevention of diabetes.
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WO2015158206A1 (zh) * | 2014-04-14 | 2015-10-22 | 上海迪诺医药科技有限公司 | C-芳基糖苷衍生物、其药物组合物、制备方法及应用 |
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JP2016504340A (ja) * | 2012-12-31 | 2016-02-12 | チャイナ ゲートウェイ ファーマシューティカル ディベロプメント カンパニー リミテッド | ブドウ糖誘導体とプロリンの複合物、結晶体、その製造方法及び使用 |
US9738603B2 (en) | 2012-12-31 | 2017-08-22 | Shanghai Yingli Pharmaceutical Co., Ltd. | Complex of glucose derivative and proline, crystal, preparation method and use |
WO2015158206A1 (zh) * | 2014-04-14 | 2015-10-22 | 上海迪诺医药科技有限公司 | C-芳基糖苷衍生物、其药物组合物、制备方法及应用 |
US9914724B2 (en) | 2014-04-14 | 2018-03-13 | Shanghai De Novo Pharmatech Co., Ltd. | C-aryl glycosid derivatives, pharmaceutical composition, preparation process and uses thereof |
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CN103965176A (zh) | 2014-08-06 |
EP2676965B1 (en) | 2017-10-04 |
EP2676965A1 (en) | 2013-12-25 |
US20130324464A1 (en) | 2013-12-05 |
US8980829B2 (en) | 2015-03-17 |
JP2014505709A (ja) | 2014-03-06 |
CN102643256B (zh) | 2014-12-24 |
CN102643256A (zh) | 2012-08-22 |
EP2676965A4 (en) | 2014-07-30 |
JP6105489B2 (ja) | 2017-03-29 |
CN103965176B (zh) | 2016-03-16 |
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