CN102675378A - 一类含环丙烷结构的c-葡萄糖苷衍生物、其制备方法和用途 - Google Patents
一类含环丙烷结构的c-葡萄糖苷衍生物、其制备方法和用途 Download PDFInfo
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- CN102675378A CN102675378A CN2011100564388A CN201110056438A CN102675378A CN 102675378 A CN102675378 A CN 102675378A CN 2011100564388 A CN2011100564388 A CN 2011100564388A CN 201110056438 A CN201110056438 A CN 201110056438A CN 102675378 A CN102675378 A CN 102675378A
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- Prior art keywords
- compound
- alkyl
- injection
- cyclopropyl
- sodium
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title description 7
- 229930182478 glucoside Natural products 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 12
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 5
- VKVJIWVUYNTBEZ-UHFFFAOYSA-N 1,3-bis(3,5-dichlorophenyl)urea Chemical compound ClC1=CC(Cl)=CC(NC(=O)NC=2C=C(Cl)C=C(Cl)C=2)=C1 VKVJIWVUYNTBEZ-UHFFFAOYSA-N 0.000 claims abstract description 3
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 3
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 40
- 238000002347 injection Methods 0.000 claims description 11
- 239000007924 injection Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000000651 prodrug Chemical class 0.000 claims description 6
- 229940002612 prodrug Drugs 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 238000001802 infusion Methods 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 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 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 7
- 239000011734 sodium Substances 0.000 abstract description 7
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- 239000003112 inhibitor Substances 0.000 abstract description 6
- 230000001419 dependent effect Effects 0.000 abstract description 2
- 101710193897 Galactose transporter Proteins 0.000 abstract 4
- 101710103223 Galactose-proton symporter Proteins 0.000 abstract 4
- 125000000217 alkyl group Chemical group 0.000 abstract 4
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 abstract 1
- 108091052347 Glucose transporter family Proteins 0.000 abstract 1
- 108010081348 HRT1 protein Hairy Proteins 0.000 abstract 1
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 15
- -1 methyl grignard reagent Chemical class 0.000 description 15
- 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 13
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- 239000008187 granular material Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 6
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
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- 239000002274 desiccant Substances 0.000 description 4
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 4
- 239000012153 distilled water Substances 0.000 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 description 4
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- OEURLNJEQCLGPS-UHFFFAOYSA-N (5-bromo-2-chlorophenyl)-(4-ethoxyphenyl)methanone Chemical compound C1=CC(OCC)=CC=C1C(=O)C1=CC(Br)=CC=C1Cl OEURLNJEQCLGPS-UHFFFAOYSA-N 0.000 description 3
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
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- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D309/06—Radicals substituted by oxygen atoms
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Abstract
本发明涉及与糖尿病相关的药物领域。具体而言，本发明涉及一类含环己烷结构的C-葡萄糖苷类2型钠半乳糖转运子(SGLT2)抑制剂、其制备方法、及含有它们的药物组合物以及它们在制备糖尿病药物中的应用。其中，R1选自H，F，Cl，Br，I，OR3，SR4，OCF3，CF3，CHF2，CH2F，C1-C3的烷基，含3-5个碳原子的环烷基，其中R3和R4独立选自C1-C3的烷基；R2选自C1-C3的烷基、环丙基和OR5，其中R5选自C1-C3的烷基和环丙基。
Description
技术领域
本发明涉及与糖尿病相关的药物领域。具体而言，本发明涉及对糖尿病有治疗作用的含环丙烷结构的C-葡萄糖苷类2型钠葡萄糖共转运子(SGLT2)抑制剂及其制备方法，以及含有它们的药物组合物。
背景技术
全球糖尿病患者目前大约有1.7亿左右，其中约绝大多数为II型(即非胰岛素依赖型)糖尿病患者。目前在临床使用的抗糖尿病药物主要有二甲双胍类、磺酰脲类、胰岛素类、噻唑烷二酮类、α-葡糖苷酶抑制剂类和二肽基肽酶-IV抑制剂类药物，这些药物具有良好的治疗效果，但长期治疗存在安全性问题，如：肝毒性、低血糖、体重增加等诸多问题。
2型钠葡萄糖共转运子(SGLT2)是近年来发现的治疗糖尿病的新靶点。SGLT2主要分布在肾脏近端小管，其作用是吸收尿中的葡萄糖，并将其返回到血液中，因此抑制SGLT2的就能够降低血液中葡萄糖浓度，这个方法从以往不同的途径降低了血糖水平。当SGLT2功能受阻时，尿液中将分泌更多的葡萄糖，这将有助于糖尿病患者保持正确的血糖水平。由于SGLT2抑制剂不介入葡萄糖代谢，它可以作为血糖控制主流方法的补充手段。
中国专利CN200610093189.9公开了下列结构的化合物作为SGLT2抑制剂：
其中，A为O，S，NH，(CH2)n，n＝0-3。
中国专利CN200380110040.1公开了下列结构的化合物作为SGLT2抑制剂：
其中，A为共价键，O，S，NH，(CH2)n，n＝1-3。
中国专利CN200480006761.2公开了下列结构的化合物作为SGLT2抑制剂：
其中，X为共价键或低级亚烷基。
WO2005/012326公开了下列结构的化合物作为SGLT2抑制剂：
本发明公开了一类含环丙烷结构的C-葡萄糖苷类衍生物作为新型的SGLT2抑制剂，这些抑制剂可以用于制备治疗糖尿病，特别是非胰岛素依赖型糖尿病的药物。
发明内容
本发明的一个目的是克服现有技术的缺点和不足，提供一种具有良好活性，具有通式I的化合物及其药学上可以接受的盐和前药酯。
本发明的另一个目的是提供制备具有通式I的化合物及其药学上可以接受的盐和前药酯的方法。
本发明的再一个目的是提供含有通式I的化合物及其药学上可以接受的盐和前药酯作为有效成分，以及一种或多种药学上可接受的载体、赋形剂或稀释剂的药用组合物，及其在治疗糖尿病方面的应用。
现结合本发明的目的对本发明内容进行具体描述。
本发明具有通式I的化合物具有下述结构式：
其中，
R1选自H，F，Cl，Br，I，OR3，SR4，OCF3，CF3，CHF2，CH2F，C1-C3的烷基，含3-5个碳原子的环烷基，其中R3和R4独立选自C1-C3的烷基；
R2选自C1-C3的烷基、环丙基和OR5，其中R5选自C1-C3的烷基和环丙基。
优选以下通式I化合物，
其中，
R1选自H，F，Cl，OR3，OCF3，CF3，Me，环丙基，其中R3的定义如上所述；
R2选自C1-C3的烷基和OR5，其中R5选自C1-C3的烷基。
更优选以下具有通式I的化合物，
本发明所述通式I化合物可以通过以下步骤合成：
化合物II在碱存在下用三甲基硅基化试剂进行处理，得到化合物III，所用的碱如N-甲基吗啉、三乙胺、吡啶、4-二甲氨基吡啶等，三甲基硅基化试剂如三甲基氯硅烷等。
化合物IV使用酰氯化试剂，如氯化亚砜或草酰氯，转化为对应的酰氯V。化合物V在三氯化铝催化下与化合物PhR2发生付克酰基化反应，得到化合物VI。化合物VI用甲基格氏试剂MeMgX(X＝Cl、Br、I)处理，得到化合物VII。化合物VII用酸，如甲磺酸、硫酸、三氟甲磺酸等，处理发生脱水反应得到化合物VIII。化合物VIII在催化剂作用存在下用二碘甲烷处理，得到化合物IX，催化剂如Et2Zn、Zn-Cu等。化合物IX用烷基锂试剂，如正丁基锂，处理，得到化合物X，化合物X不加分离在反应体系中直接与化合物III反应，得到化合物XI。化合物XI在酸，如甲磺酸、三氟甲磺酸、对甲苯磺酸等，催化下用甲醇处理，得到化合物XII。化合物XII在路易斯酸如BF3·Et2O、BF3·MeCN或者三氟乙酸等存在下用还原剂如三乙基硅烷、三异丙基硅烷等还原得到化合物XIII。化合物XIII用在碱如无水醋酸钠、吡啶、4-二甲氨基吡啶等存在下用醋酸酐、乙酰氯等试剂乙酰化得到XIV。化合物XIV用柱层析或者重结晶等方法处理，得到化合物XV。化合物XV用碱，如甲醇钠、NaOH、KOH等处理，脱掉乙酰基得到化合物I。
本发明所述式I化合物的药学上可接受的前药酯，包括分子中的任意一个或多个羟基与乙酰基、特戊酰基、各种磷酰基、氨基甲酰基、烷氧甲酰基等形成的酯。
本发明所述式I化合物，可以与一种或多种药学上可接受的载体、赋形剂或稀释剂共同制成药物组合物。该药物组合物可以制成固体口服制剂、液体口服制剂、注射剂等剂型。所述固体及液体口服制剂包括：片剂、分散片、糖衣剂、颗粒剂、干粉剂、胶囊剂和溶液剂。所述的注射剂包括：小针、大输液、冻干粉针等。
本发明的组合物，所述的药学或食品学上可接受辅料选自：填充剂、崩解剂、润滑剂、助流剂、泡腾剂、矫味剂、防腐剂、包衣材料、或其它赋形剂。
本发明的组合物，所述的药学或食品学上可接受辅料。填充剂为填充剂包括乳糖、蔗糖、糊精、淀粉、预胶化淀粉、甘露醇、山梨醇、磷酸氢钙、硫酸钙、碳酸钙、微晶纤维素的一种或几种的组合物；所述的粘合剂包括蔗糖、淀粉、聚维酮、羧甲基纤维素钠、羟丙甲纤维素、羟丙纤维素、甲基纤维素、聚乙二醇、药用乙醇、水的一种或几种的组合物；所述的崩解剂包括淀粉、交联聚微酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲纤维素钠、泡腾崩解剂的一种或几种的组合物。
本发明所述通式I化合物具有SGLT2酶的抑制作用，可作为有效成分用于制备糖尿病方面的治疗药物。本发明所述通式I化合物的活性是通过体内降糖模型验证的。
本发明的通式I化合物在相当宽的剂量范围内是有效的。例如每天服用的剂量约在1mg-1000mg/人范围内，分为一次或数次给药。实际服用本发明通式I化合物的剂量可由医生根据有关的情况来决定。这些情况包括：被治疗者的身体状态、给药途径、年龄、体重、对药物的个体反应，症状的严重程度等。
具体实施方式
下面结合实施例对本发明作进一步的说明。需要说明的是，下述实施例仅是用于说明，而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1
1-{4-氯-3-[1-(4-乙氧基苯基)环丙烷-1-基]苯基}-1-脱氧-β-D-吡喃葡萄糖
A.(5-溴-2-氯苯基)(4-乙氧基苯基)甲酮
一只100mL的干燥圆底烧瓶中加入4.71g(20mmol)5-溴-2-氯苯甲酸、20mL干燥的二氯甲烷、3.81g(30mmol)重蒸的草酰氯和一滴DMF，所得白色混浊混合物在室温下搅拌过夜，直到体系不再有气体冒出且变为一澄清的溶液。在旋转蒸发仪上蒸出过量的草酰氯和溶剂，所得残余物用15mL干燥的二氯甲烷溶解，再加入2.44g(20mmol)苯乙醚，冰水浴冷却下搅拌，分批加入4.00g(30mmol)无水三氯化铝。加完后，所得混合物在室温下搅拌过夜。
反应混合物小心倾倒到200mL冰水中，搅拌，用50mL×3的二氯甲烷萃取。合并萃取相，用饱和食盐水洗涤，无水硫酸钠干燥。抽滤除去干燥剂后，滤液在旋转蒸发仪上蒸去溶剂，得到一残余物，柱层析纯化，得到(5-溴-2-氯苯基)(4-乙氧基苯基)甲酮纯品。无色晶体，熔点69-70℃，ESI-MS，m/z＝339([M+H]+)，341([M+H]+).
B.1-(5-溴-2-氯苯基)-1-(4-乙氧基苯基)乙醇
一只干燥的100mL的圆底烧瓶中加入5.88g(17.3mmol)上述制备的(5-溴-2-氯苯基)(4-乙氧基苯基)甲酮和60mL干燥的THF，用氮气吹扫后用橡胶软塞密封。烧瓶置于-10℃的冰盐浴中冷却，电磁搅拌，用注射器往烧瓶中逐滴加入8mL(24mmol)3M的甲基氯化镁的THF溶液。滴加完毕后，所得混合物在该温度下继续搅拌半小时。
反应混合物小心倾倒到300mL冰水中，加入200mL二氯甲烷，搅拌，所得两相混合物经过一层硅藻土抽滤。从滤液中分出有机相，水相再用50mL二氯甲烷萃取一次。合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。抽滤除去干燥剂后，滤液在旋转蒸发仪上蒸去溶剂，得到一残余物，柱层析纯化，得到1-(5-溴-2-氯苯基)-1-(4-乙氧基苯基)乙醇的纯品。无色油状物，1H NMR(DMSO-d6，400MHz)，δ8.14(d，1H，J＝2.4Hz)，7.47(dd，1H，J＝2.4Hz and 8.4Hz)，7.23(d，1H，J＝8.4Hz)，7.12(d，2H，J＝8.8Hz)，6.80(d，2H，J＝8.8Hz)，5.80(s，1H)，3.97(q，2H，J＝6.9Hz)，1.88(s，3H)，1.29(t，3H，J＝7.0Hz)。
C.1-(5-溴-2-氯苯基)-1-(4-乙氧基苯基)乙烯
一只100mL的圆底烧瓶中加入5.33g(15mmol)上述制备的1-(5-溴-2-氯苯基)-1-(4-乙氧基苯基)乙醇和15mL二氯甲烷，所得混合物在室温下搅拌，而后加入0.96g(10mmol)甲磺酸。所得混合物在室温下搅拌过夜。
反应混合物倾倒到200mL饱和食盐水中，用50mL×3的二氯甲烷萃取。合并萃取相，饱和食盐水洗涤，无水硫酸钠干燥。抽滤除去干燥剂后，滤液在旋转蒸发仪上蒸去溶剂，得到一残余物，柱层析纯化，得到1-(5-溴-2-氯苯基)-1-(4-乙氧基苯基)乙烯的纯品。ESI-MS，m/z＝337([M+H]+)，339([M+H]+).
D.1-(5-溴-2-氯苯基)-1-(4-乙氧基苯基)环丙烷
一只250mL的干燥的圆底烧瓶中加入干燥的磁子、10mL干燥的THF和5mL干燥的DME，用氮气吹扫后，用橡胶软塞封口后在-20℃的冷浴中冷却，开动电磁搅拌。用注射器往其中加入24mL(24mmol)1.0M的Et2Zn的正己烷溶液，而后用注射器往烧瓶中逐滴加入12.86g(48mmol)二碘甲烷溶于10mL干燥的THF制成的溶液。滴加完毕后，继续搅拌2小时，而后通过注射器慢慢滴加4.05g(12mmol)上述制备的1-(5-溴-2-氯苯基)-1-(4-乙氧基苯基)乙烯溶于5mL干燥的THF制成的溶液。滴加完毕后所得混合物在室温下搅拌过夜，而后再在氮气气氛下回流1小时。
反应混合物冷却后，小心倾倒到300mL冰水中，加入200mL二氯甲烷，搅拌，所得两相混合物经过一层硅藻土抽滤。从滤液中分出有机相，水相再用50mL二氯甲烷萃取一次。合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。抽滤除去干燥剂后，滤液在旋转蒸发仪上蒸去溶剂，得到一残余物，柱层析纯化，得到1-(5-溴-2-氯苯基)-1-(4-乙氧基苯基)环丙烷的纯品。ESI-MS，m/z＝351([M+H]+)，353([M+H]+).
E.2，3，4，6-四-O-三甲基硅基葡萄糖酸内酯
一只250mL的圆底烧瓶中加入1.78g(10mmol)葡萄糖酸内酯、8.09g(80mmol)N-甲基吗啉和干燥四氢呋喃20mL，体系在冰水浴冷却下电磁搅拌，慢慢滴加6.52g(60mmol)的三甲基氯硅烷溶解到10mL干燥THF中得到的溶液。滴加完毕后，体系在室温下搅拌过夜，用100mL甲苯稀释，冰水冷却下往其中慢慢滴加10mL水，而后把所得混合物转移到分液漏斗中，依次用100mL饱和磷酸二氢钠溶液和饱和食盐水洗涤，无水硫酸钠干燥，在旋转蒸发仪上蒸干，得到一无色油状物，为2，3，4，6-四-O-三甲基硅基葡萄糖酸内酯，在真空油泵上室温下干燥两小时，备用。无色油状物，4.68g。
F.1-{4-氯-3-[1-(4-乙氧基苯基)环丙烷-1-基]苯基}-1-脱氧-β-D-吡喃葡萄糖
一只100mL的圆底烧瓶中加入上述制备的2.99g(8.5mmol)1-(5-溴-2-氯苯基)-1-(4-乙氧基苯基)环丙烷，10mL干燥的四氢呋喃和一个磁子，而后以薄橡胶塞封口，置于丙酮-干冰体系中冷却到-78℃。搅拌下，用注射器往此反应容器中慢慢加入5.6mL(9mmol；1.6M)n-BuLi的正己烷溶液，加完后体系在-78℃下再搅拌一小时，而后用注射器再往该反应容器中慢慢加入上述制备的2，3，4，6-四-O-三甲基硅基葡萄糖酸内酯溶解到10mL干燥甲苯中形成的溶液。加完后，体系再搅拌一小时，而后用注射器加入1.92g(20mmol)的甲磺酸溶解到10mL无水甲醇中形成的溶液，而后体系慢慢升温到室温，室温下搅拌过夜。反应混合物倾倒到饱和食盐水中，用100mL二氯甲烷分两次萃取，合并萃取液体用饱和食盐水洗涤一次，无水硫酸钠干燥，在旋转蒸发仪上蒸干，得到一无色油状物，即为1-{4-氯-3-[1-(4-乙氧基苯基)环丙烷-1-基]苯基}-α/β-D-甲基吡喃葡萄糖苷，油状物，ESI-MS，m/z＝465([M+H]+)。
上述得到的1-{4-氯-3-[1-(4-乙氧基苯基)环丙烷-1-基]苯基}-α/β-D-甲基吡喃葡萄糖苷油状物溶解到3mL干燥二氯甲烷中，冰水浴冷却下搅拌，先后加入三乙基硅烷2mL和三氟化硼乙醚1mL。所得反应体系在室温下搅拌过夜，小心倾倒到100mL冰水中，以饱和碳酸氢钠溶液调节到pH＝8，用100mL二氯甲烷分两次萃取，合并萃取液体用饱和食盐水洗涤一次，无水硫酸钠干燥，在旋转蒸发仪上蒸干，得到一无色油状物，即为1-{4-氯-3-[1-(4-乙氧基苯基)环丙烷-1-基]苯基}-1-脱氧-α/β-D-吡喃葡萄糖，油状物，ESI-MS，m/z＝435([M+H]+)。
上述得到的1-{4-氯-3-[1-(4-乙氧基苯基)环丙烷-1-基]苯基}-1-脱氧-α/β-D-吡喃葡萄糖无色油状物溶解到20mL醋酸酐中，加入0.5g无水醋酸钠，电磁搅拌升温回流1小时。冷却后，体系倾倒到100mL水中，室温下搅拌过夜，用100mL二氯甲烷分两次萃取，合并萃取液体用饱和食盐水洗涤一次，无水硫酸钠干燥，在旋转蒸发仪上蒸干，得到类白色固体，经过硅胶柱层析纯化得到一无色晶体，2，3，4，6-四-O-乙酰基-1-1-{4-氯-3-[1-(4-乙氧基苯基)环丙烷-1-基]苯基}-1-脱氧-β-D-吡喃葡萄糖，ESI-MS，m/z＝603([M+H]+)。
上述2，3，4，6-四-O-乙酰基-1-1-{4-氯-3-[1-(4-乙氧基苯基)环丙烷-1-基]苯基}-1-脱氧-β-D-吡喃葡萄糖溶解到含有0.11g(2mmol)甲醇钠的10mL无水甲醇中，室温下搅拌5小时，而后加入1g干燥的强酸性阳离子交换树脂，室温下搅拌过夜。过滤除去树脂，所得滤液在旋转蒸发仪上蒸干，得到一白色固体，即为1-{4-氯-3-[1-(4-乙氧基苯基)环丙烷-1-基]苯基}-1-脱氧-β-D-吡喃葡萄糖，白色固体，ESI-MS，m/z＝435([M+H]+)。
实施例2-13
可以理解的是，使用实施例1的方法和流程，改变R1、R2可以得到下表所列的化合物。
实施例14
将活性成分、预胶化淀粉和微晶纤维素过筛，充分混合，加入聚乙烯吡咯烷酮溶液，混合，制软材，过筛，制湿颗粒，于50-60℃干燥，将羧甲基淀粉钠盐，硬脂酸镁和滑石粉预先过筛，然后加入到上述的颗粒中压片。
实施例15
将活性成分、预胶化淀粉和微晶纤维素过筛，充分混合，加入聚乙烯吡咯烷酮溶液，混合，制软材，过筛，制湿颗粒，于50-60℃干燥，将羧甲基淀粉钠盐，硬脂酸镁和滑石粉预先过筛，然后加入到上述的颗粒中压片。
实施例16
将活性成分、预胶化淀粉和微晶纤维素过筛，充分混合，加入聚乙烯吡咯烷酮溶液，混合，制软材，过筛，制湿颗粒，于50-60℃干燥，将硬脂酸镁和滑石粉预先过筛，然后加入到上述的颗粒中，装胶囊，即得。
实施例17
将活性成分、预胶化淀粉和微晶纤维素过筛，充分混合，加入聚乙烯吡咯烷酮溶液，混合，制软材，过筛，制湿颗粒，于50-60℃干燥，将硬脂酸镁和滑石粉预先过筛，然后加入到上述的颗粒中，装胶囊，即得。
实施例18
在蒸馏水中，先加入蒸馏水和柠檬酸，搅拌溶解和后，再加入样品，微热使溶解，调pH值为4.0-5.0，加0.2克活性碳，室温下搅拌20分钟，过滤，滤液，中控测定溶液浓度，按每安瓶5毫升分装，高温灭菌30分钟，即得注射液。
实施例19
在蒸馏水中，先加入蒸馏水和柠檬酸，搅拌溶解和后，再加入样品，微热使溶解，调pH值为4.0-5.0，加0.2克活性碳，室温下搅拌20分钟，过滤，滤液，中控测定溶液浓度，按每安瓶5毫升分装，高温灭菌30分钟，即得注射液。
实施例20
制备工艺：取注射用水80mL，加主药、甘露醇、乳糖、泊洛沙姆搅拌使溶解后，加1mol/L的枸橼酸调节PH至7.0-9.0，补加水至100mL。加入0.5g活性炭，在30℃下搅拌20分钟，脱炭，采用微孔滤膜过滤除菌，滤液按每支1mL进行分装，预冻2小时后，冷冻下减压干燥12小时，至样品温度到室温后，再干燥5小时，制得白色疏松块状物，封口即得。
实施例21
制备工艺：将主药与辅料分别过100目筛，充分混合，然后称取处方量辅料与主药充分混合。再加入粘合剂制软材，14目筛制粒，55℃干燥，12目筛整粒，测定袋重包装。
实施例22
样品以1％羧甲基纤维素钠配制成10mg/mL浓度的混悬液，给药容量为0.2mL/20g体重，相当于20mg/kg剂量。
健康ICR小鼠，雌雄各半，体重20-24g，符合一级标准。动物禁食16小时，药后2h腹腔注射2g/kg的葡萄糖盐水溶液(Dapagliflozin药后1.5h注射葡萄糖)，于造模后0.5h、1h、2h、3h和4h定时取用毛细管自小鼠球后静脉丛取血，离心分离血清，用葡萄糖氧化酶法测定各时间点血清葡萄糖含量。以时间为横坐标以血糖值为纵坐标绘图，计算曲线下面积(AUC)。各化合物的降血糖活性以血糖抑制率来计算，抑制率(％)＝[AUC(模型)-AUC(化合物I或dapagliflozin)]/[AUC(模型)-AUC(空白)]×100％。结果见下面的表格：
以上结果表明，各化合物均能显著降低葡萄糖引起的小鼠血糖耐受量。
Claims (7)
1.具有通式I结构的化合物及其药学上可以接受的盐和前药酯：
其中，
R1选自H，F，Cl，Br，I，OR3，SR4，OCF3，CF3，CHF2，CH2F，C1-C3的烷基，含3-5个碳原子的环烷基，其中R3和R4独立选自C1-C3的烷基；
R2选自C1-C3的烷基、环丙基和OR5，其中R5选自C1-C3的烷基和环丙基。
2.权利要求1所定义的具有通式I的化合物及其药学上可以接受的盐和前药酯：
其中，
R1选自H，F，Cl，OR3，OCF3，CF3，Me，环丙基，其中R3的定义如上所述；
R2选自C1-C3的烷基和OR5，其中R5选自C1-C3的烷基。
3.权利要求2所定义的通式I化合物，选自下列化合物：
4.权利要求1-3所定义的通式I化合物及其药学上可以接受的盐和前药酯在制备治疗糖尿病药物方面的应用。
5.一种药物组合物，含有权利要求1-3之一的通式I化合物及其药学上可以接受的盐和前药酯，以及适当的载体或赋形剂。
6.权利要求5所述的药物组合物，其中，所述的组合物为固体口服制剂、液体口服制剂或注射剂。
7.根据权利要求6所述固体及液体口服制剂包括：片剂、胶囊、颗粒剂、口服溶液剂，所述注射剂制剂包括注射用水针、注射用冻干粉针、大输液、小输液。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100564388A CN102675378A (zh) | 2011-03-09 | 2011-03-09 | 一类含环丙烷结构的c-葡萄糖苷衍生物、其制备方法和用途 |
| PCT/CN2012/072053 WO2012119550A1 (zh) | 2011-03-09 | 2012-03-07 | 含环丙烷结构的c-葡萄糖苷衍生物及其制备方法、药物组合物和用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102827122A (zh) * | 2011-06-17 | 2012-12-19 | 山东亨利医药科技有限责任公司 | 糖苷衍生物 |
| CN110054657A (zh) * | 2018-01-18 | 2019-07-26 | 亚宝药业集团股份有限公司 | 吡喃葡萄糖取代的吡唑化合物及其制备方法 |
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| CA2889699C (en) | 2013-09-27 | 2017-06-06 | Sunshine Lake Pharma Co., Ltd. | Glucopyranosyl derivatives and their uses in medicine |
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| CN102827122A (zh) * | 2011-06-17 | 2012-12-19 | 山东亨利医药科技有限责任公司 | 糖苷衍生物 |
| CN102827122B (zh) * | 2011-06-17 | 2015-01-14 | 山东轩竹医药科技有限公司 | 糖苷衍生物 |
| CN110054657A (zh) * | 2018-01-18 | 2019-07-26 | 亚宝药业集团股份有限公司 | 吡喃葡萄糖取代的吡唑化合物及其制备方法 |
| CN110054657B (zh) * | 2018-01-18 | 2021-06-29 | 亚宝药业集团股份有限公司 | 吡喃葡萄糖取代的吡唑化合物及其制备方法 |
| US11377465B2 (en) | 2018-01-18 | 2022-07-05 | Yabao Pharmaceutical Group Co., Ltd. | Pyranoglucose-substituted pyrazole compound, preparation method thereof and application thereof |
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| WO2012119550A1 (zh) | 2012-09-13 |
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