CN115557876A - 一种用于治疗消化性溃疡的3-芳环基磺酰基-1-n-杂吡咯衍生物、其制备方法和用途 - Google Patents
一种用于治疗消化性溃疡的3-芳环基磺酰基-1-n-杂吡咯衍生物、其制备方法和用途 Download PDFInfo
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- CN115557876A CN115557876A CN202211318457.8A CN202211318457A CN115557876A CN 115557876 A CN115557876 A CN 115557876A CN 202211318457 A CN202211318457 A CN 202211318457A CN 115557876 A CN115557876 A CN 115557876A
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- 208000011906 peptic ulcer disease Diseases 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims description 7
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- 238000002360 preparation method Methods 0.000 claims abstract description 28
- 208000025865 Ulcer Diseases 0.000 claims abstract description 26
- 231100000397 ulcer Toxicity 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 22
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- 201000005917 gastric ulcer Diseases 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims description 24
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- 125000003118 aryl group Chemical group 0.000 claims description 8
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- 229910052736 halogen Inorganic materials 0.000 claims description 3
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- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 description 9
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- 229950003825 vonoprazan Drugs 0.000 description 5
- ROGSHYHKHPCCJW-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-n-methylmethanamine Chemical compound OC(=O)\C=C\C(O)=O.C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F ROGSHYHKHPCCJW-WLHGVMLRSA-N 0.000 description 4
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- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
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- 229920006395 saturated elastomer Polymers 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
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- 229910052794 bromium Inorganic materials 0.000 description 1
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- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- WHIDHHUCCTYJKA-UHFFFAOYSA-N isoquinoline-5-sulfonyl chloride Chemical compound N1=CC=C2C(S(=O)(=O)Cl)=CC=CC2=C1 WHIDHHUCCTYJKA-UHFFFAOYSA-N 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- OPECTNGATDYLSS-UHFFFAOYSA-N naphthalene-2-sulfonyl chloride Chemical compound C1=CC=CC2=CC(S(=O)(=O)Cl)=CC=C21 OPECTNGATDYLSS-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 239000002244 precipitate Substances 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明属于医药技术领域,具体涉及一种用于治疗消化性溃疡的3‑芳环基磺酰基‑1‑N‑杂吡咯衍生物、其制备方法和用途。本发明提供的3‑芳环基磺酰基‑1‑N‑杂吡咯衍生物的结构如式I所示。实验表明,本发明提供的化合物对胃溃疡具有优异的抑制效果,可以用来制备预防和/或治疗溃疡(特别是胃溃疡)的药物,应用前景广阔。
Description
技术领域
本发明属于医药技术领域,具体涉及一种用于治疗消化性溃疡的3-芳环基磺酰基-1-N-杂吡咯衍生物、其制备方法和用途。
背景技术
消化性溃疡主要指发生于胃和十二指肠的慢性溃疡,是一多发病、常见病。溃疡的形成有各种因素,其中酸性胃液对黏膜的消化作用是溃疡形成的基本因素,因此得名。
消化性溃疡的治疗药物主要包括药物治疗和手术治疗,药物治疗方法主要可采用抗氧剂、四联药物和粘膜保护剂等。其中,抗氧剂包括H2受体阻断剂;四联药物适合幽门螺杆菌感染者,特别是2种抗生素、质子泵抑制剂联合治疗;粘膜保护剂具有保护伤口、促进愈合的作用。此外,为了提供更多的临床用药选择,本领域仍然在开发新的消化性溃疡治疗药物。例如,中国发明专利“CN102743330B药物组合物”公开了可用于治疗消化性溃疡的药物组合物,其包括多种新的化学药物。
然而,由于患者的个体差异以及对药物的耐受性不同等因素,目前对于消化性溃疡开发新的治疗药物能够为消化性溃疡的治疗提供更多临床用药选择,仍然很有意义。
发明内容
针对现有技术的问题,本发明提供一种用于治疗消化性溃疡的3-芳环基磺酰基-1-N-杂吡咯衍生物、其制备方法和用途,目的在于为消化性溃疡的治疗提供治疗效果优异的新药物,为消化性溃疡的临床治疗提供更多的用药选择。
式I所示化合物、或其立体异构体、或其同位素替代形式、或其药学上可接受的盐,式I所示化合物的结构式为:
其中,R选自C6-C10芳基、6-10元杂芳基,所述C6-C10芳基或6-10元杂芳基可进一步被R1和R2取代;
所述R1选自氰基、至少一个氟原子取代的C1-C4烷氧基、至少一个氟原子取代的C1-C4烷基、至少一个氟原子取代的C1-C4烷磺酰基或C1-C4烷基;
所述R2选自H或卤素;
或者,R1和R2相连形成6-10元杂环或C6-C10芳基。
优选的,所述R选自苯基或9-10元杂芳基,所述苯基或9-10元杂芳基可进一步被R1和R2取代。
优选的,所述R1选自氰基、-OCF3、-CF3或CF3SO2-。
优选的,所述R2选自H或F。
优选的,R1和R2相连形成6元杂环或苯基。
优选的,所述化合物的结构式如式II所示:
其中,R1选自氰基、-CF3;R2选自H;
或者,R1和R2相连形成6元杂环或苯基。
优选的,所述化合物选自如下结构:
本发明还提供上述化合物的制备方法,采用如下合成路线:
其中,R如权利要求1-7任一项所述;
具体包括如下步骤:
(a)化合物A与磺酰氯在拔氢剂下发生缩合反应,生成中间体K;
(b)中间体K与甲基发生还原胺化反应,得式I化合物。
优选的,步骤(a)中。化合物A与磺酰氯摩尔比为1:(0.8-1.5),优选1:0.9;所述拔氢剂为氢化钠、叔丁醇钠、叔丁醇钾,优选NaH;所述反应温度为0-5℃,反应时间0.5-1.5h;所述溶剂为有机溶剂,优选DMF。
本发明还提供一种用于预防和/或治疗溃疡的药物组合物,它是以上述化合物、或其立体异构体、或其同位素替代形式、或其药学上可接受的盐作为活性成分,加上药学上可接受的辅料或辅助性成分制得的制剂。
本发明还提供上述化合物、或其立体异构体、或其同位素替代形式、或其药学上可接受的盐在制备预防和/或治疗溃疡的药物中的用途。
优选的,所述溃疡为消化性溃疡。
优选的,所述溃疡为消化性溃疡为胃溃疡。
优选的,所述胃溃疡为胃酸分泌过多引发的胃溃疡。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca-Cb烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,“C1-C4烷基”是指包含1-4个碳原子的烷基。
“烷基”是指具有指定数目的成员原子的饱和烃链。例如,C1-C6烷基是指具有1至6个成员原子,例如1至4个成员原子的烷基基团。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团可任选地被一个或多个如本文所定义的取代基取代。烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基。烷基基团也可以是其他基团的一部分,所述其他基团为例如C1-C6烷氧基。
“卤素”为氟、氯、溴或碘。
“杂环”、“杂环烷基”指包含至少一个杂原子的饱和环或非芳香性的不饱和环;其中杂原子指氮原子、氧原子、硫原子;
“杂芳基”指包含至少一个杂原子的芳香性不饱和环基;其中杂原子指氮原子、氧原子、硫原子;
“Ra和Rb相连形成杂环”指Ra和Rb中分别至少有一个原子通过化学键连接,使得通式结构中Ra和Rb共同连接的原子或原子链作为环结构的一部分骨架与Ra和Rb共同构成杂环。
“立体异构体”包括对映异构体和非对映异构体。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常
在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
在某些实施方式中,本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用,用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物,则可将这些化合物同时、分别或有序地对受试对象进行给药。
本发明提供了一类新的能够治疗溃疡类疾病的化合物。动物实验表明,这类化合物对溃疡类疾病具有很好的治疗效果,能够有效抑制大鼠胃溃疡,溃疡抑制率达38.0%~43.8%,特别是化合物1、化合物4、化合物6和化合物7,其对大鼠胃溃疡的抑制率高达42.1%、43.8%、41.0%和40.3%,抑制效果显著优于阳性对照药物TAK-438(38.1%)。
可见,本发明提供的化合物对胃溃疡具有优异的抑制效果,可以用来制备预防和/或治疗溃疡(特别是胃溃疡)的药物,应用前景广阔。
本发明的制备方法简单,条件温和,成本低廉,容易工业化生产。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
以下实施例和实验例中所用的试剂和材料中,未特别说明的均为市售品。
实施例1化合物1的制备
合成路线为:
具体的制备方法包括:
向反应瓶中加入化合物A 0.50g(2.66mmol),THF 5.0mL,氩气置换,降温至0℃~5℃,分批加入60%NaH 0.17g(4.15mmol),0℃~5℃反应半约0.5h,分批加入3-氰基苯磺酰氯0.50g(2.50mmol),保温反0.5h后,升至室温反应1h,加入DCM 20.0mL稀释,用氯化铵水溶液调PH至6以淬灭NaH,再用碳酸氢钠水溶液调PH至7~8,分液,水相用二氯甲烷20.0mL萃取3次,合并有机相,水30.0mL洗1次,无水硫酸钠干燥,浓缩得粗品1.15g。过柱(EA:PE=1:7)除去原点杂质得化合物B 0.90g,收率91.6%。LCMS m/z=355.0[M+H]+。
取化合物B 0.45g(1.27mmol),DCM 10.0mL搅拌溶解,氩气置换,降温至2.6℃,加入30%甲胺甲醇溶液0.26g(2.55mmol),保温0℃~5℃反应约5分钟加入乙酸,分批加入硼氢化钠0.98g(2.59mmol)。反应45分钟,加入DCM20.0mL稀释反应液,氯化铵水溶液调PH至6,淬灭硼氢化钠,碳酸氢钠水溶液调PH至7~8,分液,水相用DCM 20.0mL萃取3次,合并有机相,水30.0mL洗1次,有机相干燥、过滤、浓缩得粗品0.32g,将其溶于EA5.0mL,用HCl/EA调PH至2~3,析出固体,过滤,50℃真空干燥的化合物1的盐酸盐0.084g,收率16.6%,LCMS m/z=370.1[M+H]+,1H-NMR(DMSO-d6):δ9.01(s,2H),8.22-8.24(m,1H),7.81-7.83(m,2H),7.75-7.79(m,2H),7.52-7.58(m,1H),7.21-7.25(m,2H),7.05-7.10(m,1H),6.55(d,J=1.8Hz,1H),3.98(s,2H),2.51(s,3H)。
实施例2化合物2的制备
合成路线为:
具体的制备方法包括:
向反应瓶中加入化合物A 0.40g(2.11mmol),THF 4.0mL,氩气置换,降温至0℃~5℃,分批加入60%NaH 0.12g(3.06mmol),反应0.5h,加入3-(三氟甲氧基)苯-1-磺酰氯0.50g(1.92mmol),反应0.5h,再升至室温反应1小时,加入DCM约20.0mL稀释,氯化铵水溶液调PH至6淬灭NaH,碳酸氢钠水溶液调PH至7~8,分液,DCM20.0mL萃取水相2次,合并有机相,水30.0ml洗1次,无水硫酸钠干燥,过滤,浓缩得化合物C粗品0.83g过柱纯化(EA:PE=1:5)得纯品0.41g,收率51.7%,LCMS m/z=414.0[M+H]+。
取化合物C 0.20g溶于DCM2.0mL,氩气置换,降温至0℃~5℃,依次加入30%甲胺甲醇溶液0.085g(0.82mmol),乙酸0.058g(0.97mmol),硼氢化钠0.031g(0.82mmol),反应约1.5h,加入DCM5.0mL稀释,氯化铵水溶液调PH至5~6,碳酸氢钠水溶液调PH至7~8,水相用DCM 10.0mL萃取2次,合并有机相,水10mL洗1次,合并有机相,无水硫酸钠干燥,过滤,浓缩干加入0.5mL EA溶清,用HCl/EA调PH至2~3,析出白色固体,过滤,50℃真空干燥得化合物2的盐酸盐0.066g,收率29.6%,LCMS m/z=429.1LC-MS m/z=414.0[M+H]+。1H-NMR(DMSO-d6):δ9.30(s,2H),7.85(d,J=1.7Hz,1H),7.74-7.81(m,2H),7.57-7.60(m,1H),7.50-7.54(m,1H),7.30(s,1H),7.18-7.24(m,2H),7.04-7.08(m,1H),6.60(d,J=1.8Hz,1H),3.98(s,2H),2.48(s,3H)。
实施例3化合物3的制备
合成路线为:
具体的制备方法包括:
向反应瓶中加入化合物A 0.14g(0.76mmol),THF 3.0mL,氩气置换,降温至0℃~5℃,加入60%NaH 0.045g(1.13mmol),反应0.5h,加入2,1,3-苯并二唑-4-磺酰氯0.15g(0.068mmol),0℃反应0.5h,室温再反应1h,加入20.0mL DCM稀释,氯化铵水溶液调PH至5~6,碳酸氢钠水溶液调PH至7~8,分液,有机相用水20.0mL洗1次,无水硫酸钠干燥,过滤浓缩干过柱纯化(洗脱剂为DCM),得化合物D 0.040g,收率14.3%,LC-MS m/z=372.0[M+H]+。
取化合物D0.04g(0.11mmol),DCM2.0mL,30%甲胺甲醇溶液0.017g(0.16mmol),于反应瓶中室温搅拌约15分钟,依次加入乙酸0.013g(0.22mmol),硼氢化钠0.006g(0.16mmol),继续反应1h,加入10.0mL DCM稀释,饱和碳酸氢钠水溶液调PH至7~8,分液,有机相饱和食盐水5.0mL洗1次,无水硫酸钠干燥,过滤,浓缩干,加入乙酸乙酯1.0mL溶解,用HCl/EA调PH至2~3析出固体,过滤,干燥得0.02g化合物3的盐酸盐。收率43.0%,LCMS m/z=387.1[M+H]+。1H-NMR(DMSO-d6):δ9.41(s,2H),8.12-8.18(m,2H),7.72-7.78(m,1H),7.50-7.53(m,1H),7.20-7.24(m,2H),7.03-7.08(m,1H),6.59(d,J=1.8Hz,1H),3.98(s,2H),2.48(s,3H)。
实施例4化合物4的制备
合成路线为:
具体的制备方法包括:
向反应瓶中加入化合物A0.22g(1.19mmol),THF5.0mL,氩气置换,降温至0℃~5℃,加入60%NaH 0.064g(1.61mmol),反应约0.5h,加入2,3-二氢-1,4-苯并二氧-6-磺酰氯0.28g(1.19mmol),反应0.5h,升至室温继续反应1h,加入乙酸乙酯20.0mL稀释反应液,氯化铵水溶液调PH至5~6,水10mL洗1次,无水硫酸干燥有机相,过滤,浓缩得化合物E粗品0.55g,过(DCM)得化合物E 0.40g,收率97.7%,LCMS m/z=388.1[M+H]+。
向反应瓶中依次加入化合物E 0.40g(1.04mmol),30%甲胺甲醇溶液0.16g(1.56mmol),乙酸0.13g(2.09mmol),硼氢化钠0.059g(1.57mmol),DCM9.0mL,室温反应1h,加入DCM 20.0mL稀释饱和碳酸氢钠水溶液调PH至7~8,饱和食盐水10.0mL洗1次,无水硫酸钠干燥,过滤,浓缩得棕色油状液体,用EA5.0mL溶解,用HCl/EA调PH至2~3,析出固体,过滤,50℃真空干燥得化合物4的盐酸盐140mg,收率26.8%,LCMS m/z=403.1[M+H]+。1H-NMR(DMSO-d6):δ8.89(s,2H),7.72(d,J=1.8Hz,1H),7.49-7.55(m,1H),7.20-7.25(m,2H),7.06-7.10(m,1H),6.99(d,J=8.6Hz,1H),6.91-6.94(m,1H),6.84(d,J=2.3Hz,1H),6.47(d,J=1.8Hz,1H),4.32-4.34(m,2H),4.27-4.28(m,2H),3.98(s,2H),2.52(s,3H)。
实施例5化合物5的制备
合成路线为:
具体的制备方法包括:
向反应瓶中加入化合物A0.074g(0.35mmol),THF 2.5mL,氩气置换,降温至0℃~5℃,加入60%NaH 0.021g(0.53mmol),反应1h,,加入氯化铵水溶液调PH至6,EA20.0mL萃取2次,饱和食盐水10mL洗1次,无水硫酸钠,干燥,过滤,浓缩干,过柱纯化(EA:PE=4:1)得化合物F 0.06g,收率40.6%,LC-MS m/z=378.0[M+H]+。
取化合物F 0.06g(0.16mmol),DCM 2.5mL,30%甲胺甲醇溶液0.025g(0.24mmol)于反应瓶中室温搅拌,约0.5h后,依次加入乙酸0.019g(0.32mmol),硼氢化钠0.009g(0.24mmol),反应1.5h,加入DCM 10.0mL稀释,碳酸氢钠水溶液调PH至7~8,分液,有机相用饱和食盐水10.0mL洗,无水硫酸钠干燥,过滤,浓缩干,用EA2.0mL溶解,用HCl/EA调PH至2~3,析出固体,过滤,真空干燥的化合物5的盐酸盐0.017g,收率25.1%,LCMS m/z=394.1[M+H]+。1H-NMR(DMSO-d6):9.10(s,1H),8.90(s,2H),7.78(s,1H),7.49-7.55(m,1H),7.20-7.25(m,2H),7.06-7.10(m,1H),6.87-6.91(m,1H),6.52(d,J=1.8Hz,1H),3.99(s,2H),2.47(s,3H),1.83(s,3H)。
实施例6化合物6的制备
合成路线为:
具体的制备方法包括:
向反应瓶中加入化合物A0.50g(2.64mmol),THF 5.0mL,氩气置换,降温至0℃~5℃,分批加入60%NaH 0.16g(3.96mmol),反应约0.5h,加入3-三氟甲基苯磺酰氯0.71g(2.91mmol),反应约1h,加入DCM 10.0mL稀释,氯化铵水溶液调PH至5~6,再用碳酸氢钠水溶液调PH至7~8,分液,水相用DCM10.0mL萃取2次,水20.0mL洗1次,合并有机相,无水硫酸钠干燥,过滤,浓缩,过柱纯化(DCM)得化合物G 0.81g,收率:77.1%,LC-MS m/z=398.0[M+H]+。
取化合物G 0.40g(1.01mmol),DCM 10.0mL于反应瓶中,氩气置换,降温至0℃~5℃,依次加入30%甲胺甲醇溶液0.16g(1.51mmol),乙酸0.12g(2.01mmol),硼氢化钠0.057g(1.51mmol),约反应3h,加DCM20.0mL稀释,用碳酸氢钠水溶液调PH至7~8,分液,水相用DCM10.0mL萃取2次,无水硫酸钠干燥,过滤,浓缩干,用2.0mL EA溶解,用HCl/EA调PH至2~3,析出固体,过滤,50℃真空干燥得化合物6的盐酸盐0.28g,收率61.7%,LC-MS m/z=413.1[M+H]+,1HNMR(DMSO-d6):δ9.47(s,2H),8.15(d,J=7.5Hz,1H),7.83-7.91(m,3H),7.52-7.57(m,2H),7.19-7.23(m,2H),7.04-7.09(m,1H),6.58(d,J=1.8Hz,1H),3.99(s,2H),2.49(s,3H)。
实施例7化合物7的制备
合成路线为:
具体的制备方法包括:
向反应瓶中加入化合物A0.38g(2.00mmol),THF 4.0mL,氩气置换,降温至-7.8℃,加入NaH 0.12g(2.98mmol),保温-10℃~0℃反应0.5h,加入2-萘磺酰氯0.45g(2.00mmol),反应约0.5h,加入DCM 25.0mL稀释,用氯化铵水溶液调PH至6,再用碳酸氢钠水溶液调至7~8,分液,水相用DCM10.0mL萃取2次,合并有机相,水20mL洗1次,无水硫酸钠干燥,过滤,浓缩,过柱纯化(EA:PE=1:5)得化合物H 0.64g,收率84.0%,LC-MS m/z=380.1[M+H]+。
取化合物H 0.64g(1.69mmol),DCM 10.0mL于反应瓶中,氩气置换,降温至-3.3℃,依次加入30%甲胺甲醇溶液0.26g(2.54mmol),乙酸0.21g(3.47mmol),硼氢化钠0.098mg(2.59mmol),反应0.5h,用碳酸氢钠水溶液调PH至7~8,分液,水相用DCM10.0mL萃取2次,合并有机相无水硫酸钠干燥,过滤,浓缩干,过柱纯化(DCM:MeOH=20:1~1:1),并将纯品盐酸盐,得化合物7的盐酸盐0.06g,收率8.2%,LC-MS m/z=395.1[M+H]+,1HNMR(DMSO-d6):δ9.46(s,2H),8.04-8.11(m,4H),7.88(d,J=1.7Hz,1H),7.75-7.79(m,1H),7.68-7.72(m,1H),7.47-7.53(m,2H),7.14-7.18(m,2H),6.98-7.02(m,1H),6.56(d,J=1.7Hz,1H),3.97(s,2H),2.46(s,3H)。
实施例8化合物8的制备
合成路线为:
具体的制备方法包括:
向反应瓶中加入化合物A0.29g(1.53mmol),THF 5.0mL,氩气置换,降温至0℃~5℃,分批加入60%NaH 0.092g(2.30mmol),反应0.5h,加入3-(三氟甲基磺酰基)-4-氟苯磺酰氯0.50g(1.53mmol)反应0.5h,加入DCM20.0mL稀释,用碳酸氢钠水溶液调PH至7~8,分液,水相用DCM 10.0mL萃取2次,合并有机相,水20mL洗1次,无水硫酸钠干燥,过滤,浓缩,过柱纯化(EA:PE=1:3),得化合物I 0.51g,收率69.2%,LC-MS m/z=480.0[M+H]+。
取化合物I 0.50g(1.04mmol),DCM10.0mL于反应瓶中,氩气置换,降温至0℃~5℃,加入30%甲胺甲醇溶液0.16g(1.56mmol),搅拌15分钟,依次加入乙酸0.13g(2.09mmol),硼氢化钠0.059g(1.56mmol),反应0.5h,加入DCM 10.0mL稀释,用碳酸氢钠水溶液调PH至7~8,水相用DCM10.0mL萃取2次,合并有机相,用水10.0mL洗1次,无水硫酸钠干燥,过滤,浓缩干,用10.0mL EA溶解,用HCl/EA调PH至2~3,析出固体,过滤,50℃真空干燥得化合物8的盐酸盐0.17g,收率32.6%,LC-MSm/z=495.0[M+H]+,1H-NMR(DMSO-d6):δ9.45(s,2H),8.12-8.23(m,2H),7.87-7.92(m,1H),7.52-7.57(m,2H),7.19-7.23(m,2H),7.04-7.09(m,1H),6.58(d,J=1.8Hz,1H),3.99(s,2H),2.49(s,3H)。
实施例9化合物9的制备
合成路线为:
具体的制备方法包括:
向反应瓶中加入化合物A0.36g(1.91mmol),四氢呋喃4.0mL,氩气置换,降温至3℃,加入60%NaH(0.19g,4.81mmol),反应约20分钟,加入异喹啉-5磺酰氯盐酸盐0.51g(1.91mmol),0℃~5℃反应1.5h,加入DCM 20.0mL稀释,加入氯化铵水溶液调PH至5~6,再用碳酸氢钠水溶液调PH至7~8,分液,水相用DCM 10.0mL萃取2次,合并有机相,用水20.0mL洗1次,无水硫酸钠干燥,过滤,浓缩干,过柱纯化(EA:PE=1:1),得化合物J 0.35g,收率48.35%,LCMS m/z=381.1[M+H]+。
取化合物J 0.35g(0.93mmol),DCM 10.0mL于反应瓶中,氩气置换,降温至-2.5℃,依次加入30%甲胺甲醇溶液0.15g(1.40mmol),乙酸0.11g(1.84mmol),硼氢化钠0.055g(1.45mmol),-5℃~0℃反应2h.加入氯化铵水溶液调PH至5~6,再用碳酸氢钠水溶液调PH至7~8,分液,水相用DCM10.0mL萃取2次,合并有机相,用水20.0mL洗1次,无水硫酸钠干燥,过滤,浓缩干,过柱纯化(DCM:MeOH=20:1~3:1),并将纯品溶解于DCM:MeOH=20:1的混合溶液2.0mL,用HCl/EA调PH至2~3,析出固体,过滤,40℃真空干燥得化合物9的盐酸盐0.094g,收率23.5%,LC-MS m/z=396.1[M+H]+,1H-NMR(DMSO-d6):δ9.75(s,1H),9.56(s,2H),8.73(d,J=6.4Hz,1H),8.65(d,J=8.0Hz,1H),8.22(d,J=6.4Hz,1H),8.12(d,J=1.8Hz,1H),7.69-7.79(m,2H),7.42-7.47(m,1H),6.99-7.11(m,2H),6.87-6.91(m,1H),6.52(d,J=1.8Hz,1H),3.99(s,2H),2.47(s,3H)。
下面通过实验对本发明的技术方案作进一步的说明。
实验例1本发明化合物的抗溃疡活性
(1)实验方法
取健康雄性SD大鼠90只,体重300g。禁食12h后,灌胃乙酸。胃溃疡模型建模成功后,将大鼠分为模型对照组、给药组1~7、阳性对照组,每组10只。给药组1~7组分别口服灌胃本发明制得的化合物1~7,剂量为12mg/(kg.d),连续灌胃14天。阳性对照组灌胃相同剂量的TAK-438(沃诺拉赞),模型对照组灌胃相同剂量的生理盐水。测定各组大鼠溃疡抑制率,计算平均值。
溃疡抑制率计算公式为:
溃疡抑制率=(模型对照组溃疡面积均值-给药组溃疡面积均值)/模型对照组溃疡面积均值×100%
(2)实验结果
表1胃溃疡抑制率结果
化合物 | 溃疡抑制率 |
TAK-438 | 38.1% |
化合物1 | 42.1% |
化合物2 | 41.3% |
化合物3 | 38.8% |
化合物4 | 43.8% |
化合物5 | 39.7% |
化合物6 | 41.0% |
化合物7 | 40.3% |
化合物8 | 39.2% |
化合物9 | 38.0% |
根据各组解剖结果可知,大鼠胃溃疡模型建模成功。从表1各组大鼠的溃疡抑制率结果可知,本发明制得的化合物都能够有效抑制大鼠胃溃疡,溃疡抑制率达38.0%~43.8%,特别是化合物1、化合物4、化合物6和化合物7,其对大鼠胃溃疡的抑制率高达42.1%、43.8%、41.0%和40.3%,抑制效果显著优于阳性对照药物TAK-438(38.1%)。
实验表明,本发明提供的化合物能够有效抑制胃溃疡,可以用来制备预防和/或治疗胃酸分泌过多引发的胃溃疡的药物。
综上,本发明提供了一种3-芳环基磺酰基-1-N-杂吡咯衍生物及其制备方法和用途。实验结果表明,本发明提供的化合物对胃溃疡具有优异的抑制效果,可以用来制备预防和/或治疗溃疡(特别是胃溃疡)的药物,应用前景广阔。
Claims (10)
5.按照权利要求4所述的制备方法,其特征在于:步骤(a)中。化合物A与磺酰氯摩尔比为1:(0.8-1.5);所述拔氢剂为氢化钠、叔丁醇钠、叔丁醇钾;所述反应温度为0-5℃,反应时间0.5-1.5h;所述溶剂为有机溶剂。
6.一种用于预防和/或治疗溃疡的药物组合物,其特征在于:它是以权利要求1-7任一项所述的化合物、或其立体异构体、或其同位素替代形式、或其药学上可接受的盐作为活性成分,加上药学上可接受的辅料或辅助性成分制得的制剂。
7.权利要求1-3任一项所述的化合物、或其立体异构体、或其同位素替代形式、或其药学上可接受的盐在制备预防和/或治疗溃疡的药物中的用途。
8.按照权利要求7所述的用途,其特征在于:所述溃疡为消化性溃疡。
9.按照权利要求8所述的用途,其特征在于:所述溃疡为消化性溃疡为胃溃疡。
10.按照权利要求9所述的用途,其特征在于:所述胃溃疡为胃酸分泌过多引发的胃溃疡。
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CN117126093A (zh) * | 2023-10-24 | 2023-11-28 | 潍坊医学院 | 伏诺拉生中间体的制备方法 |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014019442A1 (zh) * | 2012-08-03 | 2014-02-06 | 上海恒瑞医药有限公司 | 苯并呋喃类衍生物、其制备方法及其在医药上的应用 |
CN105330647A (zh) * | 2014-08-14 | 2016-02-17 | 江苏柯菲平医药股份有限公司 | 吡咯磺酰类衍生物、其制备方法及其在医药上的应用 |
CN105985278A (zh) * | 2015-01-27 | 2016-10-05 | 江苏柯菲平医药股份有限公司 | 吡咯磺酰类衍生物、其制备方法及其在医药上的应用 |
CN106905216A (zh) * | 2017-04-19 | 2017-06-30 | 刘德鹏 | 一种质子泵抑制剂药物化合物及其制备方法 |
CN106928117A (zh) * | 2017-02-21 | 2017-07-07 | 武汉大学 | 一种氘代芳香类有机化合物的制备方法 |
WO2018059455A1 (zh) * | 2016-09-29 | 2018-04-05 | 江苏吉贝尔药业股份有限公司 | 1-[(吡啶-3-基-磺酰基)-1h-吡咯-3-基]甲胺衍生物及其药物组合物和用途 |
CN109498811A (zh) * | 2017-09-15 | 2019-03-22 | 江苏吉贝尔药业股份有限公司 | 一种含钾离子竞争性酸阻滞剂和非甾体抗炎药的复方制剂 |
CN111943932A (zh) * | 2020-08-06 | 2020-11-17 | 四川国康药业有限公司 | 一种可以治疗消化性溃疡的3-吡啶磺酰-1-n-杂吡咯衍生物及其制备方法和用途 |
CN112830920A (zh) * | 2019-11-25 | 2021-05-25 | 杭州华东医药集团新药研究院有限公司 | 一种杂环衍生物、其药物组合物及用途 |
KR20220097863A (ko) * | 2021-11-19 | 2022-07-08 | 하나제약 주식회사 | 피롤 유도체 또는 이의 약학적 또는 식품학적으로 허용 가능한 염, 및 이를 유효성분으로 포함하는 위장 질환의 예방, 개선 또는 치료용 조성물 |
CN115232106A (zh) * | 2022-07-29 | 2022-10-25 | 南京唯创远医药科技有限公司 | 一种富马酸伏诺拉生杂质的制备方法 |
CN116239606A (zh) * | 2021-07-09 | 2023-06-09 | 天地恒一制药股份有限公司 | 一种吡咯磺酰类衍生物、及其制备方法与应用 |
-
2022
- 2022-10-26 CN CN202211318457.8A patent/CN115557876A/zh active Pending
Patent Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014019442A1 (zh) * | 2012-08-03 | 2014-02-06 | 上海恒瑞医药有限公司 | 苯并呋喃类衍生物、其制备方法及其在医药上的应用 |
CN104039776A (zh) * | 2012-08-03 | 2014-09-10 | 上海恒瑞医药有限公司 | 苯并呋喃类衍生物、其制备方法及其在医药上的应用 |
CN105330647A (zh) * | 2014-08-14 | 2016-02-17 | 江苏柯菲平医药股份有限公司 | 吡咯磺酰类衍生物、其制备方法及其在医药上的应用 |
CN105985278A (zh) * | 2015-01-27 | 2016-10-05 | 江苏柯菲平医药股份有限公司 | 吡咯磺酰类衍生物、其制备方法及其在医药上的应用 |
WO2018059455A1 (zh) * | 2016-09-29 | 2018-04-05 | 江苏吉贝尔药业股份有限公司 | 1-[(吡啶-3-基-磺酰基)-1h-吡咯-3-基]甲胺衍生物及其药物组合物和用途 |
CN109843869A (zh) * | 2016-09-29 | 2019-06-04 | 江苏吉贝尔药业股份有限公司 | 1-[(吡啶-3-基-磺酰基)-1h-吡咯-3-基]甲胺衍生物及其药物组合物和用途 |
CN106928117A (zh) * | 2017-02-21 | 2017-07-07 | 武汉大学 | 一种氘代芳香类有机化合物的制备方法 |
CN106905216A (zh) * | 2017-04-19 | 2017-06-30 | 刘德鹏 | 一种质子泵抑制剂药物化合物及其制备方法 |
CN109498811A (zh) * | 2017-09-15 | 2019-03-22 | 江苏吉贝尔药业股份有限公司 | 一种含钾离子竞争性酸阻滞剂和非甾体抗炎药的复方制剂 |
CN112830920A (zh) * | 2019-11-25 | 2021-05-25 | 杭州华东医药集团新药研究院有限公司 | 一种杂环衍生物、其药物组合物及用途 |
CN111943932A (zh) * | 2020-08-06 | 2020-11-17 | 四川国康药业有限公司 | 一种可以治疗消化性溃疡的3-吡啶磺酰-1-n-杂吡咯衍生物及其制备方法和用途 |
CN116239606A (zh) * | 2021-07-09 | 2023-06-09 | 天地恒一制药股份有限公司 | 一种吡咯磺酰类衍生物、及其制备方法与应用 |
KR20220097863A (ko) * | 2021-11-19 | 2022-07-08 | 하나제약 주식회사 | 피롤 유도체 또는 이의 약학적 또는 식품학적으로 허용 가능한 염, 및 이를 유효성분으로 포함하는 위장 질환의 예방, 개선 또는 치료용 조성물 |
CN115232106A (zh) * | 2022-07-29 | 2022-10-25 | 南京唯创远医药科技有限公司 | 一种富马酸伏诺拉生杂质的制备方法 |
Non-Patent Citations (1)
Title |
---|
NISHIDA, HARUYUKI,等: "Identification of a novel fluoropyrrole derivative as a potassium-competitive acid blocker with long duration of action", 《BIOORGANIC & MEDICINAL CHEMISTRY》, vol. 25, no. 13, pages 3298 - 3314, XP085037276, DOI: 10.1016/j.bmc.2017.04.014 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117126093A (zh) * | 2023-10-24 | 2023-11-28 | 潍坊医学院 | 伏诺拉生中间体的制备方法 |
CN117126093B (zh) * | 2023-10-24 | 2023-12-29 | 潍坊医学院 | 伏诺拉生中间体的制备方法 |
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