CN110551088B - 氘修饰的苄基-4-氯苯基的c-糖苷衍生物 - Google Patents
氘修饰的苄基-4-氯苯基的c-糖苷衍生物 Download PDFInfo
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- CN110551088B CN110551088B CN201910460511.4A CN201910460511A CN110551088B CN 110551088 B CN110551088 B CN 110551088B CN 201910460511 A CN201910460511 A CN 201910460511A CN 110551088 B CN110551088 B CN 110551088B
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Classifications
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/235—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring
- C07C43/247—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/18—All rings being cycloaliphatic the ring system containing six carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明属于医药技术领域，具体涉及氘修饰的苄基‑4‑氯苯基的C‑糖苷衍生物或其药学上可接受的盐，制备这些化合物的方法，含有这些化合物的药物制剂和药物组合物，以及氘修饰的苄基‑4‑氯苯基的C‑糖苷衍生物或其药学上可接受的盐作为钠‑葡萄糖协同转运蛋白(SGLT)抑制剂在制备治疗和/或预防各种糖尿病(包括胰岛素依赖型的糖尿病和非胰岛素依赖型糖尿病)或各种糖尿病相关疾病(包括胰岛素抗性疾病和肥胖)的药物中的应用。
Description
技术领域
本发明属于医药技术领域，具体涉及氘修饰的苄基-4-氯苯基的C-糖苷衍生物或其药用可接受的盐，制备这些化合物的方法，含有这些化合物的药物制剂和药物组合物，以及本发明氘修饰的苄基-4-氯苯基的C-糖苷衍生物或其药用可接受的盐作为钠-葡萄糖协同转运蛋白(SGLT)抑制剂在制备用于治疗和/或预防各种糖尿病(包括胰岛素依赖型的糖尿病和非胰岛素依赖型糖尿病)或各种糖尿病相关疾病(包括胰岛素抗性疾病和肥胖)的药物中的应用。
背景技术
全世界大约有1亿人患有II型糖尿病，其特征在于因过量肝葡萄糖产生和外周胰岛素抗性所致的高血糖。高血糖被认为是形成糖尿病并发症的主要危险因素，并且可能与晚期II型糖尿病的胰岛素分泌受损直接相关。因此可以预计胰岛素的正常化可以改善II型糖尿病患者的血糖。目前已有的糖尿病药物大多数为促胰岛素分泌药或胰岛素增敏剂，如磺酰脲类、格列奈类、噻唑烷二酮类、和二甲双胍等，具有潜在的副作用，如易引起体重增加、低血糖、乳酸酸中毒等，因此，亟需开发作用机制新颖、安全、有效的抗糖尿病药物。
在肾脏，葡萄糖可以自由地从肾小球滤过(约180g/天)，但几乎在近曲小管主动转运而重吸收。其中两个钠-葡萄糖转运体对葡萄糖的重吸收发挥了重要作用，即SGLT-1和SGLT-2，而SGLT-2的作用尤为突出。SGLT-2是仅在近端小管的S1段特异表达的跨膜蛋白，其最主要的生理作用之一是吸收流过肾小管血液中的糖份，占重吸收作用的90％，SGLT-2以钠－葡萄糖1：1的比率进行转运，SGLT-2抑制剂能抑制血糖在肾小管的吸收，使糖份从尿中大量排出。而SGLT-1主要在远曲小管表达，占重吸收作用的10％，SGLT-1以钠－葡萄糖2：1的比率转运。另外在肠道和其他组织中也发现了SGLT-1。这些转运体通过Na+/ATP酶泵发挥作用，并且通过葡萄糖转运体2(GLUT2)转移回血液中。这表明最有可能发展成药物作用靶点的是SGLT-2转运体，一方面是它对葡萄糖的绝对重吸收作用，另一方面是它仅表达于肾脏。在对家族型肾病尿糖的研究，也证实了该途径的可行性。家族性肾病尿糖主要表现为不定量的尿糖(约10-120g/天)，但患者一般状况良好，没有发现对健康不利的长期负面影响。这种良性尿糖主要是由于SGLT-2转运体基因突变所致，这表明选择性地对SGLT-2的药理抑制除了诱导糖尿外不会产生不良后果。已有证据表明SGLT-2抑制剂的一个重要的临床优势是不易引起低血糖症。而抑制SGLT-1会引起糖-半乳糖吸收不良综合征，可导致脱水，且已有证据表明SGLT-1抑制剂将延缓碳水化合物的吸收，会引起个体难以耐受的胃肠道症状，而选择高的SGLT-2抑制剂不会阻断SGLT-1在肠道转运吸收葡萄糖的作用，因此不易引起胃肠道症状。另外，SGLT-1同样高度表达于人体心肌组织，对其阻断后将可能会引起心脏功能新或器质性病变。因此，开发对SGLT-2具有高选择性的化合物对研究治疗糖尿病的药物具有重要意义。
虽然现有技术中已知多个SGLT-2抑制剂，但开发具有良好性质的且副作用小的SGLT-2抑制剂仍具有挑战性，因此，本领域仍需要开发对SGLT-2具有高选择性且具有更好的药效学或药代动力学的化合物。
发明内容
本发明的技术方案如下：
技术方案1：通式(I)所示的化合物或其药学上可接受的盐：
其中，
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29分别独立地选自氢或氘，且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29至少有一个为氘原子。
技术方案2：如技术方案1所述的化合物或其药学上可接受的盐：
其中，
R5、R6、R7、R23、R24、R25、R26、R27、R28、R29分别独立地选自氢；
R1、R2、R3、R4、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22分别独立地选自氢或氘，且R1、R2、R3、R4至少有一个为氘原子。
技术方案3：如技术方案1或2所述的化合物或其药学上可接受的盐，具有式(II)所示的结构：
技术方案4：如技术方案3所述的化合物或其药学上可接受的盐，
其中，
R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22分别独立地选自氢；
R1、R2、R3、R4分别独立地选自氢或氘，且R1、R2、R3、R4至少有一个为氘原子。
技术方案5：如技术方案4所述的化合物或其药学上可接受的盐，
其中，
R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22分别独立地选自氢；
R1、R2、R3、R4分别独立地选自氢或氘，且R1、R2、R3、R4至少有两个为氘原子。
技术方案5-1：如技术方案5所述的化合物或其药学上可接受的盐，
其中，
R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22分别独立地选自氢；
R1、R2、R3、R4分别独立地选自氢或氘，且R1、R2、R3、R4至少有三个为氘原子。
技术方案6：如技术方案5或5-1所述的化合物或其药学上可接受的盐，
其中，
R1、R2、R3、R4分别独立地选自氘；
R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22分别独立地选自氢。
技术方案7：如技术方案6所述化合物的制备方法，包括如下步骤：
将式(II-1)所示的化合物与
反应得到式(II-2)化合物，将式(II-2)化合物在氮气保护下反应生成式(II)化合物，其中，X选自氟、氯、溴或碘，G代表羟基保护基，选自三甲基硅烷基、三乙基硅烷基、苄基、对甲氧基苄基、对硝基苄基、特戊酰基、烯丙基、甲氧甲基、苄氧甲基或三甲基硅烷基乙基，优选地，所述的G选自三甲基硅烷基，
技术方案8：中间体化合物，选自，
技术方案9：中间体化合物，选自，
其中，X选自氟、氯、溴或碘。
技术方案10：如技术方案3所述的化合物或其药学上可接受的盐，其中，
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R14、R15、R16、R17、R18、R19、R20、R21、R22分别独立地选自氢；
R12、R13分别独立地选自氢或氘，且R12、R13至少有一个为氘原子。
技术方案11：如技术方案10所述的化合物或其药学上可接受的盐，
其中，
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R14、R15、R16、R17、R18、R19、R20、R21、R22分别独立地选自氢；
R12、R13分别独立地选自氘原子。
技术方案12：如技术方案3所述的化合物或其药学上可接受的盐，
其中，
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13分别独立地选自氢；
R14、R15、R16、R17、R18、R19、R20、R21、R22选自氢或氘，且R14、R15、R16、R17、R18、R19、R20、R21、R22至少有一个为氘原子。
技术方案13：如技术方案12所述的化合物，其选自以下化合物：
| 编号 | R<sup>14</sup> | R<sup>15</sup> | R<sup>16</sup> | R<sup>17</sup> | R<sup>18</sup> | R<sup>19</sup> | R<sup>20</sup> | R<sup>21</sup> | R<sup>22</sup> |
| 4-1 | H | D | H | D | H | H | H | H | H |
| 4-2 | D | D | H | D | H | D | H | H | H |
| 4-3 | D | D | H | D | D | D | D | H | H |
| 4-4 | D | D | D | D | D | D | D | D | H |
| 4-5 | D | D | D | D | D | D | D | D | D |
| 4-6 | D | H | H | H | H | D | H | H | H |
| 4-7 | H | H | D | H | H | H | H | D | H |
| 4-8 | H | H | H | H | D | H | D | H | H |
| 4-9 | H | H | H | H | H | H | H | H | D |
| 4-10 | H | D | D | D | H | H | H | D | H |
| 4-11 | H | D | H | D | D | H | D | H | H |
| 4-12 | H | D | H | D | H | H | H | H | D |
技术方案14：如技术方案3所述的化合物或其药学上可接受的盐，
其中，
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11分别独立地选自氢；
R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22分别独立地选自氢或氘，且R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22至少有一个为氘原子。
技术方案15：如技术方案14所述的化合物，其选自以下化合物：
| 编号 | R<sup>12</sup> | R<sup>13</sup> | R<sup>14</sup> | R<sup>15</sup> | R<sup>16</sup> | R<sup>17</sup> | R<sup>18</sup> | R<sup>19</sup> | R<sup>20</sup> | R<sup>21</sup> | R<sup>22</sup> |
| 5-1 | D | D | H | D | H | D | H | H | H | H | H |
| 5-2 | D | D | H | H | H | H | H | H | H | H | D |
| 5-3 | D | D | D | H | H | H | H | D | H | H | H |
| 5-4 | D | D | H | H | D | H | H | H | H | D | H |
| 5-5 | D | D | H | H | H | H | D | H | D | H | H |
技术方案16：下述化合物或其药学上可接受的盐，所述化合物选自，
本发明中，
所述的“药学上可接受的盐”包括碱金属盐，如钠盐、钾盐、锂盐等；碱土金属盐，如钙盐、镁盐等；其他金属盐，如铝盐、铁盐、锌盐、铜盐、镍盐、钴盐等；无机碱盐，如铵盐；有机碱盐，如叔辛基胺盐、二苄基胺盐、吗啉盐、葡糖胺盐、苯基甘氨酸烷基酯盐、乙二胺盐、N-甲基葡糖胺盐、胍盐、二乙胺盐、三乙胺盐、二环己基胺盐、N,N'-二苄基乙二胺盐、氯普鲁卡因盐、普鲁卡因盐、二乙醇胺盐、N-苄基-苯乙基胺盐、哌嗪盐、四甲基胺盐、三(羟甲基)胺基甲烷盐等；氢卤酸盐，如氢氟酸盐、盐酸盐、氢溴酸盐、氢碘酸盐等；无机酸盐，如硝酸盐、高氯酸盐、硫酸盐、磷酸盐等；低级烷磺酸盐，如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐等；芳基磺酸盐，如苯磺酸盐、对苯磺酸盐等；有机酸盐，如醋酸盐、苹果酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、草酸盐、马来酸盐等；氨基酸盐，如甘氨酸盐、三甲基甘氨酸盐、精氨酸盐、鸟氨酸盐、谷氨酸盐、天冬氨酸盐等。
本发明还要求保护包括本发明的化合物或其药学上可接受的盐与一种或多种药用载体和/或稀释剂的药物组合物，可以制成药学上可接受的任一剂型。以口服、肠胃外、直肠或经肺给药等方式施用于需要其的患者。用于口服给药时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配制注射剂时，可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。用于直肠给药时，可制成栓剂等。用于经肺给药时，可制成吸入剂或喷雾剂等。每一单位制剂中含有生理有效量的式(Ⅰ)所示的化合物0.005g至10g，可以为0.005g、0.01g、0.05g、0.1g、0.125g、0.2g、0.25g、0.3g、0.4g、0.5g、0.6g、0.75g、1g、1.25g、1.5g、1.75g、2g、2.5g、3g、4g、5g、10g等。
本发明进一步要求保护本发明的化合物或其药学上可接受的盐与其它药用活性成分的药物组合物，所述其它药用活性成分可以为一种或多种降糖药物，所述的降糖药物选自降糖药物选自磷酸西格列汀、维格列汀、沙格列汀、苯甲酸阿格列汀、利格列汀、替格列汀、吉米格列汀、二甲双胍、苯乙双胍、依西那肽或利拉鲁肽等。
本发明还要求保护包括本发明的化合物或其药学上可接受的盐在制备治疗和/或预防各种糖尿病或各种糖尿病相关疾病的药物中的应用。所述糖尿病包括胰岛素依赖型的糖尿病(I型糖尿病)和非胰岛素依赖型糖尿病(II型糖尿病)，所述糖尿病相关疾病包括胰岛素抗性疾病和肥胖等。
本发明进一步要求保护治疗和/或预防各种糖尿病(包括胰岛素依赖型的糖尿病和非胰岛素依赖型糖尿病)或各种糖尿病相关疾病(包括胰岛素抗性疾病和肥胖)的方法，该方法包括给需要其的包括人在内的哺乳动物施用有效剂量的本发明的化合物或其药学上可接受的盐。
本发明化合物具有以下特点：
(1)本发明化合物对SGLT-2具有高度的选择性，能被安全的用于治疗和/或预防各种哺乳动物(包括人类)的糖尿病以及由糖尿病所引起的各种疾病。
(2)本发明化合物对SGLT-2具有高效的抑制作用和显著的降血糖作用，起效快、毒副作用小、安全性高。
(3)本发明化合物具有良好的药代动力学性质。
(4)本发明化合物显示较好的理化性质，纯度高，稳定性好，质量易控，适合进行大规模工业生产。
具体实施方式
实施例1(2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-二环[3.1.0]己烷-3-基)氧基)苄基-2,3,5,6-d4)-4-氯苯基)-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇的制备(化合物1-1)
(1)苯甲醚-2,3,4,5,6-d5的制备
将苯酚-d6(5.0g,0.05mmol)加入到60mL四氢呋喃中，降温至0℃，加入NaH(60％,2.4g,0.06mol)，后升温至25℃搅拌1.0小时，降温至0℃，加入碘甲烷后升温至25℃反应4.0小时，降温至0℃，加入1mL水淬灭反应，浓缩，加入饱和碳酸氢钠水溶液和乙酸乙酯各150mL，分层得有机相，无水硫酸钠干燥，过滤，滤液浓缩得产物5.2g，产率91.9％。
(2)5-溴-2-氯苯甲酰氯的制备
将5-溴-2-氯苯甲酸(10.3g,43.7mmol)加入到DCM(100mL)的中，降温至0℃，加入DMF(0.2mL)缓慢滴加草酰氯(16.6g,0.13mol)，滴毕，升温至25℃反应3.0小时，反应液澄清，转移至恒压滴液漏斗中用于下一步反应。
(3)(5-溴-2-氯苯基)(4-甲氧基苯基-2,3,5,6-d4)甲酮的制备
将三氯化铝(6.12g，45.9mmol)加入到100mL二氯甲烷中降温至-5℃，加入苯甲醚-2,3,4,5,6-D5(5.2g,45.9mmol)，搅拌0.5小时后，将上一步二氯甲烷溶液滴加到该反应液中，滴毕，-5℃下反应3.0小时，反应结束后倒入2mol/L的盐酸(30mL)，分液得二氯甲烷相，有机相经饱和碳酸氢钠水溶液洗，氯化钠水溶液洗，无水硫酸钠干燥，过滤，滤液浓缩，硅胶柱层析(PE/EA＝50:1)得产物8.6g，两步产率59.7％。
(4)1-(5-溴-2-氯苄基)-4-甲氧基苯-2,3,5,6-d4的制备
将(5-溴-2-氯苯基)(4-甲氧基苯基-2,3,5,6-d4)甲酮(8.6g,26.1mmol)加入到50mL二氯甲烷和100mL乙腈混合溶剂中，加入三乙基硅烷(6.07g,52.2mmol)。氮气保护下降温至0℃，滴加三氟化硼***(7.41g,52.2mmol)，滴毕，升温至25℃反应2.0小时。反应结束后加入二氯甲烷(200mL)和饱和碳酸氢钠水溶液(100mL)，搅拌0.5小时，分层得有机相，有机相用饱和碳酸氢钠水溶液洗涤两次，饱和氯化钠水溶液洗一次，无水硫酸钠干燥，过滤，滤液浓缩，加入乙醇(100mL)，25℃搅拌0.5小时后冰浴至0℃搅拌0.5小时，析出大量固体，过滤，滤饼干燥得产物8.0g，产率97.1％。
(5)4-(5-溴-2-氯苄基)苯-2,3,5,6-d4醇的制备
将1-(5-溴-2-氯苄基)-4-甲氧基苯-2,3,5,6-d4(8.0g,25.3mmol)溶于100mL二氯甲烷中，降温至-78℃，缓慢滴加1M三溴化硼的二氯甲烷溶液(50.6mL,50.6mmol)，滴加完毕后升温至25℃反应2.0小时，反应结束后冰水浴下缓慢滴加2mL水淬灭反应后再补加30mL水，分层得有机相，有机相用饱和氯化钠水溶液洗涤一次，无水硫酸钠干燥，过滤，滤液浓缩得产物7.1g，产率93.0％。
(6)(1R,3s,5S)-3-(4-(5-溴-2-氯苄基)苯氧基-2,3,5,6-d4)双环[3.1.0]己烷的制备
将4-(5-溴-2-氯苄基)苯-2,3,5,6-d4醇(7.1g,23.5mmol)和(1R,3r,5S)-二环[3.1.0]己-3-基甲磺酸酯(8.3g,47.1mmol)加入到100mL NMP中，搅拌下加入碳酸铯(15.3g,47.0mmol)和苄基三乙基氯化铵(182mg,0.80mmol)，升温至50℃反应18小时，加入水(200mL)，冷却至0℃，抽滤，滤饼水洗，干燥得产物8.1g，产率：90.3％。
(7)(3R,4S,5S,6R)-2-(3-(4-(((1R,3s,5S)-二环[3.1.0]己烷-3-基)氧基)苄基-2,3,5,6-d4)-4-氯苯基)-6-(羟甲基)-2-甲氧基四氢-2H-吡喃-3,4,5-三醇的制备
氮气保护下，将(1R,3s,5S)-3-(4-(5-溴-2-氯苄基)苯氧基-2,3,5,6-d4)双环[3.1.0]己烷(3.8g,10.0mmol)加入到甲苯(60mL)和四氢呋喃(60mL)混合溶剂中，降温至-78℃，滴加正丁基锂(2.4M,5.4mL,13.0mmol)，加完后-78℃反应2.0小时，将其抽取到(3R,4S,5R,6R)-3,4,5-三((三甲基甲硅烷基)氧基)-6-(((三甲基甲硅烷基)氧基)甲基)四氢-2H-吡喃-2-酮(6.06g,13.0mmol)的甲苯(60mL)中，于-78℃反应1.0小时，加入甲基磺酸(5.76g,60.0mmol)的甲醇(90mL)溶液中，-78℃反应1.0小时后升温至25℃反应24小时，加入饱和碳酸氢钠水溶液(50mL)淬灭，二氯甲烷(100mL)萃取，有机相经饱和氯化钠水溶液洗涤后，无水硫酸钠干燥，过滤，滤液旋干得产物4.1g，产率：82.8％。
(8)(2S,3R,4R,5S,6R)-2-(3-(4-(((1R,3s,5S)-二环[3.1.0]己烷-3-基)氧基)苄基-2,3,5,6-d4)-4-氯苯基)-6-(羟甲基)四氢-2H-吡喃-3,4,5-三醇的制备
氮气保护下，将(3R,4S,5S,6R)-2-(3-(4-(((1R,3s,5S)-二环[3.1.0]己烷-3-基)氧基)苄基-2,3,5,6-d4)-4-氯苯基)-6-(羟甲基)-2-甲氧基四氢-2H-吡喃-3,4,5-三醇(2.3g,4.65mmol)，溶于二氯甲烷(50mL)中，降温至-78℃，滴加三乙基硅烷(2.05g,17.63mmol)和三氟化硼***(2.04g,14.4mmol)，滴毕缓慢升温至20℃反应1.0小时，反应结束后滴入饱和碳酸氢钠水溶液(100mL)，加入二氯甲烷(100mL)萃取，分层得有机相，有机相饱和氯化钠水洗，水洗，无水硫酸钠干燥，硅胶柱层析(PE:EA＝1:3后DCM/MeOH＝15:1)得产物1.4g，产率64.8％。分子式：C25H25ClD4O6分子量：465.0
1H-NMR(400MHz,MeOD)δ:7.34-7.27-(m,3H),4.46-4.42(m,1H),4.11-4.07(m,1H),4.03-4.01(m,2H),3.90-3.87(m,1H),3.72-3.68(m,1H),3.46-3.39(m,3H),3.30-3.27(m,1H),2.35-2.30(m,2H),1.88-1.82(m,2H),1.38-1.31(m,2H),0.45-0.43(m,1H),0.12-0.09(m,1H)。
参考实施例1-1的制备方法，采用合适的原料及中间体，制备得到以下化合物。
实验例1本发明化合物的体外药理活性
体外评价实验
本发明的体外评价方法是把人的SGLT1或SGLT2序列转染到中华仓鼠卵巢细胞上稳定表达，通过抑制细胞对【14C】-标记-R-甲基-D-吡喃葡萄糖苷(AMG)的钠依赖性的吸收，测得半抑制浓度IC50。
供试品：本发明化合物，自制，其化学名称和结构式如前文所述。
细胞：源自高表达Human-SGLT1蛋白(hSGLT1,Gene bank:NM_000343)的CHO细胞试剂：
NaCl(Fluka,Cat#71383)
CaCl2(Sigma,Cat#5080)
KCl(Sigma,Cat#P9333)
MgCl2(Sigma,Cat#M1028)
NaOH(Aldrich,Cat#221465)
Hepes(Invitrogen,Cat#15630130)
Ultima Gold Cocktail闪烁液(Perkin Elmer,Cat#6013329)
[14C]-Methylα-D-glucopyranoside(PerkinElmer,Cat#NEC659250UC)
仪器与耗材：
96孔细胞培养板(Greiner,Cat#655098)
闪烁管(Perkin Elmer,Cat#6000192)
液体闪烁计数仪(PerkinElmer,Tricarb)
Human-SGLT1转运试验的方法与步骤：
将Human-SGLT1细胞以8×104/孔加入Cytostar-T 96孔细胞板中，37℃，5％CO2培养过夜。次日，使用DMSO稀释样品，所有样品起始浓度为10mM(终浓度为100μM)，10个点5倍连续梯度稀释。用实验缓冲液(10mM Hepes,1.2mM MgCl2,4.7mM KCl,2.2mM CaCl2,120mMNaCl)将[14C]Methylα-D-glucopyranoside稀释到3μM。从培养箱中取出细胞板，用实验缓冲液润洗细胞一次。根据96孔板布局，每孔加入49μL的实验缓冲液，加入1μL不同浓度的化合物溶液；高信号对照孔(High control)加入1μL DMSO，低信号对照孔(Low control)加入1μL的Dapaglifozin，终浓度为100μM。加入50μL 3μM[14C]同位素至96孔板。37℃孵育2小时。孵育结束后，用闪烁计数法用MicroBeta Trilux检测[14C]-AMG的放射性，计算半抑制浓度IC50。Human-SGLT2转运试验的方法与步骤：将Human-SGLT2细胞以6×104/孔加入96孔细胞板中，37℃，5％CO2培养过夜。次日，使用DMSO稀释样品，参照样品Dapaglifozin起始浓度为100μM(终浓度为1μM)，10个点5倍连续梯度稀释；化合物1-1起始浓度为2mM(终浓度为20μM)，10个点5倍连续梯度稀释。用实验缓冲液(10mM Hepes,1.2mM MgCl2,4.7mM KCl,2.2mMCaCl2,120mM NaCl)将[14C]Methylα-glucopyranoside稀释到6μM。从培养箱中取出细胞板，用实验缓冲液润洗细胞一次。根据96孔板布局，每孔加入49μL的实验缓冲液，加入1μL不同浓度的化合物溶液；高信号对照孔(High control)加入1μL DMSO，低信号对照孔(Lowcontrol)加入1μL Dapaglifozin，终浓度为1μM。加入50μL 6μM[14C]同位素至96孔板。37℃孵育1小时。孵育结束后，将孔内液体吸出，用预冷的终止缓冲液(10mM Hepes,1.2mMMgCl2,4.7mM KCl,2.2mM CaCl2,120mM NaCl，1μM Dapaglifozin)润洗细胞3遍。用10％的NaOH溶液裂解细胞。将细胞裂解液吸到闪烁管内，再加入2mL闪烁液，用Tricarb读数。
实验结果和结论：
表1本发明化合物的抑制作用评价结果如下：
由此可知，本发明化合物对SGLT2有较好的抑制作用和较好的选择性。
实验例2本发明化合物的正常鼠尿糖实验
试验方法：
取24只SPF级雄性Sprague-Dawley大鼠，6～8周龄，按体重随机分组，每组8只，分别口服给药3mg/kg化合物1-1，空白对照组口服给予等体积溶媒(0.1％SDS+0.5％MC)，给药后放置于大鼠代谢笼内，分别收集给药后0-5h和5-24h的尿液，记录尿液体积并检测尿糖浓度，并按如下公式计算尿糖含量。
计算方式：
尿糖含量UGE(mg/只)＝尿糖浓度(mmol/L)×尿体积(L)×180
数据以均值±标准误差表示，采用Student-t test对数据进行统计学分析，p<0.05即为具有统计学差异。
试验结果：
表2.化合物1-1单次给药后对SD大鼠尿液内葡萄糖浓度的影响
注：*p<0.05,***p<0.001与空白对照组相比。
表3.化合物1-1单次给药对正常SD大鼠尿体积的影响
注：*p<0.05,与空白对照组相比。
表4.化合物1-1单次给药后对各时间段SD大鼠尿糖含量的影响
注：*p<0.05,***p<0.001,与空白对照组相比。
试验结论：
本发明化合物表现出较好的降糖作用。具有更好的药代动力学性质，更好的降糖作用，可以降低副作用，增加药物稳定性，增强疗效，延长半衰期。
Claims (5)
1.一种化合物或其药学上可接受的盐，所述化合物选自：
2.如权利要求1所述化合物的制备方法，包括如下步骤：
将式(II-1)所示的化合物与
反应得到式(II-2)化合物，将式(II-2)化合物
在氮气保护下反应生成权利要求1所述化合物，其中，
X选自氟、氯、溴或碘，
G代表羟基保护基，选自三甲基硅烷基、三乙基硅烷基、苄基、对甲氧基苄基、对硝基苄基、特戊酰基、烯丙基、甲氧甲基、苄氧甲基或三甲基硅烷基乙基，
3.如权利要求2所述的制备方法，所述的G选自三甲基硅烷基。
4.含有权利要求1所述的化合物或其药学上可接受的盐的药物组合物，任选地，所述药物组合物还包含一种或多种药学上可接受的载体。
5.权利要求1所述的化合物或其药学上可接受的盐作为钠-葡萄糖协同转运蛋白抑制剂在制备治疗和/或预防糖尿病或糖尿病相关疾病的药物中的应用；
所述糖尿病选自胰岛素依赖型的糖尿病和非胰岛素依赖型糖尿病，所述糖尿病相关疾病选自胰岛素抗性疾病和肥胖。
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Effective date of registration: 20200924 Address after: 135000 No. 666, Kangmei Avenue, Meihekou City, Tonghua City, Jilin Province Applicant after: Jilin Huisheng biopharmaceutical Co.,Ltd. Applicant after: Beijing huizhiheng Biotechnology Co.,Ltd. Address before: Room 510, building 2, No. 88, Kechuang 6th Street, Beijing Economic and Technological Development Zone, Daxing District, Beijing Applicant before: Xuanzhu (Beijing) Pharmaceutical Technology Co.,Ltd. |
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Address after: 100025 1703, 14th floor, No.97 Sili, Balizhuang, Chaoyang District, Beijing Applicant after: Beijing huizhiheng Biotechnology Co.,Ltd. Applicant after: Jilin Huisheng biopharmaceutical Co.,Ltd. Address before: NO.666 Kangmei Avenue, Meihekou City, Tonghua City, Jilin Province Applicant before: Jilin Huisheng biopharmaceutical Co.,Ltd. Applicant before: Beijing huizhiheng Biotechnology Co.,Ltd. |
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Address after: 100025 1703, 14th floor, No.97 Sili, Balizhuang, Chaoyang District, Beijing Patentee after: Beijing huizhiheng Biotechnology Co.,Ltd. Patentee after: Jilin Huisheng Biopharmaceutical Co.,Ltd. Address before: 100025 1703, 14th floor, No.97 Sili, Balizhuang, Chaoyang District, Beijing Patentee before: Beijing huizhiheng Biotechnology Co.,Ltd. Patentee before: Jilin Huisheng biopharmaceutical Co.,Ltd. |
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Denomination of invention: Deuterium modified C-glycoside derivatives of benzyl-4-chlorophenyl Effective date of registration: 20231013 Granted publication date: 20221021 Pledgee: Jilin Bank Co.,Ltd. Tonghua Meihekou Branch Pledgor: Jilin Huisheng Biopharmaceutical Co.,Ltd. Registration number: Y2023220000102 |