CN112300170B - 吡咯并吡唑类衍生物、其制备方法及其在医药上的应用 - Google Patents
吡咯并吡唑类衍生物、其制备方法及其在医药上的应用 Download PDFInfo
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- CN112300170B CN112300170B CN201910683538.XA CN201910683538A CN112300170B CN 112300170 B CN112300170 B CN 112300170B CN 201910683538 A CN201910683538 A CN 201910683538A CN 112300170 B CN112300170 B CN 112300170B
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
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- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
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- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
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- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
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- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
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- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- IBUNCTVDGYIKAP-UHFFFAOYSA-N tert-butyl 4,6-dihydro-1h-pyrrolo[3,4-c]pyrazole-5-carboxylate Chemical compound C1=NNC2=C1CN(C(=O)OC(C)(C)C)C2 IBUNCTVDGYIKAP-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Abstract
本发明涉及吡咯并吡唑类衍生物、其制备方法及其在医药上的应用。具体的说，本发明涉及一类通式(I)所示的新的吡咯并吡唑类衍生物、其制备方法以及其本身或含有此类衍生物的药物组合物作为治疗剂，特别是作为胃酸分泌抑制剂和钾离子竞争性酸阻滞剂(P‑CABs)在生物医药中的用途。其中通式(I)中的各取代基(R1、R2、R3)和基团(X、n)与说明书中的定义相同。
Description
技术领域
本发明涉及一类新的吡咯并吡唑类衍生物、其制备方法以及其本身或含有此类衍生物的药物组合物作为治疗剂特别是作为胃酸分泌抑制剂和钾离子竞争性酸阻滞剂(P-CABs)的用途。
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。虽然有地区差异，但消化性溃疡发病率通常占总人口的10％～20％，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，抑制胃酸分泌逐渐成为治疗消化性溃疡类疾病的首选方法。
自1988年第一个质子泵抑制剂(Proton Pump Inhibitors，PPIs)奥美拉唑上市以来，至今全球已有数个PPIs产品上市，包括兰索拉唑、泮托拉唑、雷贝拉唑和艾司奥美拉唑等。PPIs已经成为治疗胃酸相关性疾病包括消化性溃疡、反流性食管炎和卓-艾综合征等疾病的首选药物。质子泵(Proton Pump)实质为H+/K+-腺苷三磷酸酶(H+/K+-ATPase)，它特异性的将质子(H+)泵入胃腔从而形成胃内的强酸性。质子泵抑制剂可以抑制质子泵的活性从而调节质子泵介导的胃酸分泌。
钾离子竞争性酸阻滞剂(Potassium-Competitive Acid Blockers，P-CABs)是一类新型的胃酸阻滞剂，它通过可逆的、与钾离子(K+)竞争性的结合H+/K+-ATPase从而起到抑制H+/K+-ATPase酶活性的作用。与PPIs相比较，P-CABs具有亲脂性、弱碱性以及在酸性(低pH)条件下稳定等特点。同时，P-CABs具有起效迅速以及比较容易达到抑酸效果等优势。
第一款P-CABs新药沃诺拉赞于2014年在日本上市，用于治疗胃酸相关疾病如消化性溃疡。一系列的钾离子竞争性酸阻滞剂结构也已经被公开。但仍然需要开发结构类型多样性的具有更好成药性的新化合物。
发明内容
针对上述问题，本发明的目的在于提供新的结构类型且具有优异的效果和作用的用于治疗胃酸相关疾病如消化性溃疡的化合物。
一方面，本发明提供一种通式(I)所示的化合物或其药学上可接受的盐，
其中：
R1选自氢原子、卤素或烷基；
R2选自氢原子、卤素、羟基或烷基；
n＝1或2；
R3与碳原子或X相连；
当R3与碳原子相连时，X选自CH2、O或NRa，其中Ra选自氢原子或烷基，R3选自氢原子、羟基、烷基或NRbRc，其中Rb和Rc各自独立选自C1～3烷基、或者Rb和Rc互相连接并且跟它们相连的N形成四元、五元、六元或七元杂环；
当R3与X相连时，X选自CH、O或N，R3不存在或选自氢原子、烷基或NRbRc，其中Rb和Rc各自独立选自C1～3烷基、或者Rb和Rc互相连接并且跟它们相连的N形成四元、五元、六元或七元杂环。
优选地，R1为氟原子；
R2为氢原子；
n＝1或2；
R3与X相连，X选自CH、O或N，R3不存在或选自氢原子、甲基、哌啶基。
优选地，所述化合物选自：
4-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)吗啉；
3-(2-氟苯基)-5-甲基-2-(3-(哌啶-1-基)苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑；
3-(2-氟苯基)-5-甲基-2-(3-(吡咯烷-1-基)苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑；
3-(2-氟苯基)-5-甲基-2-(3-(4-甲基哌嗪-1-基)苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑；
2-(3-([1,4'-联哌啶]-1'-基)苄基)-3-(2-氟苯基)-5-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑。
第二方面，本发明提供一种药物组合物，包括通式(I)所示的化合物或其药学上可接受的盐以及药学上可接受的载体、赋形剂或稀释剂。
第三方面，本发明提供通式(I)所示的化合物或其药学上可接受的盐或上述药物组合物在制备胃酸分泌抑制剂中的用途。
第四方面，本发明提供通式(I)所示的化合物或其药学上可接受的盐或上述药物组合物在制备H+/K+-腺苷三磷酸酶(H+/K+-ATPase)抑制剂中的用途。
第五方面，本发明提供通式(I)所示的化合物或其药学上可接受的盐或上述药物组合物在制备钾离子竞争性酸阻滞剂(P-CABs)中的用途。
第六方面，本发明提供通式(I)所示的化合物或其药学上可接受的盐或上述药物组合物在制备药物中的用途，所述药物用于治疗和/或预防消化性溃疡、卓-艾综合征、胃炎、糜烂性食管炎、反流性食管炎、症状性胃食管反流疾病、巴雷特食管炎、功能性消化不良、幽门螺旋杆菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡或手术后应激导致的胃酸过多或溃疡；或者抑制消化性溃疡、急性应激性溃疡、出血性胃炎或侵入性应激造成的上消化道出血。
具体实施方式
以下通过下述实施方式进一步说明本发明，应理解，下述实施方式仅用于说明本发明，而非限制本发明。
除非有相反陈述，下列用在说明书和权利要求中的术语具有下述含义。
术语“烷基”指饱和的脂族烃基团，包括1至10个碳原子的直链或支链基团。优选含有1至5个碳原子的烷基。更优选含有1至3个碳原子的烷基，例如甲基，乙基，正丙基，异丙基。
各种含碳氢结构部分的碳原子含量由该部分的标有最小和最大碳原子数目的前缀表示，即前缀Ci～j表示该部分的碳原子数为整数“i”至整数“j”(包括i和j)。因此，例如，C1～3烷基是指1至3个碳原子的烷基(包括1和3)。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“杂环”指具有至少一个饱和或不饱和的环，构成环的原子除碳原子外，还至少含有一个杂原子，例如氮、氧、硫原子，优选至少含有一个氮原子。杂环的实例包括非芳族杂环(或称脂杂环)，诸如吗啉、哌啶、吡咯烷；以及杂芳环(或称芳杂环)，诸如呋喃、苯并呋喃、噻吩、苯并噻吩、吡咯、吡啶、嘧啶、吡嗪、喹啉、异喹啉、酞嗪、苯并-1,2,5-噻二唑、苯并噻唑、吲哚、苯并三唑、苯并二氧戊环、苯并二噁唑、咔唑及喹唑啉。
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的异构体，例如互变异构体、对映异构体、非对映异构体、及其混合物形式。
术语“本发明化合物”指通式(I)所示的化合物。该术语还包括通式(I)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
术语“药学上可接受的载体”表示能用于制备药物组合物的载体，它们一般是安全的、无毒性的，不是生物上或其他方面不期待的，且包括能被动物和人类药学上接受的载体。在说明书和权利要求书中使用的“药学上可接受的载体”包括一种或一种以上的这类载体。
术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含有”中。
术语“预防”例如是指在可能暴露或预先处置于疾病但尚未经历或显示疾病症状的哺乳动物中使疾病临床症状不发展。
术语“治疗”可指抑制疾病，例如阻止或降低疾病或其临床症状的发展，或者缓解疾病，例如使疾病或其临床症状退化。
通式(I)化合物
本发明一些实施方式中，R1选自氢原子、卤素或烷基。更优选实施方式中，R1为氟原子。R1的取代位点优选为2位。
本发明一些实施方式中，R2选自氢原子、卤素、羟基或烷基。更优选实施方式中，R2为氢原子。
本发明一些实施方式中，n＝1或2。
本发明一些实施方式中，R3连接于X以外的碳原子上。该情况下，R3可选自氢原子、羟基、烷基或NRbRc，其中Rb和Rc选自C1～3烷基，Rb和Rc可以互相连接并且跟他们相连的N形成四元、五元、六元或七元杂环。X可选自CH2、O或NRa，其中Ra选自氢原子或烷基。
本发明一些实施方式中，R3连接于X上。该情况下，X可选自CH、O、N。R3可不存在或选自氢原子、羟基、烷基或NRbRc，其中Rb和Rc选自C1～3烷基，Rb和Rc可以互相连接并且跟他们相连的N形成四元、五元、六元或七元杂环。X可选自CH2、O或NRa，其中Ra选自氢原子或烷基。
优选实施方式中，R3连接于X上，X选自CH、O、N，R3不存在或选自氢原子、甲基、哌啶基。
更优选实施方式中，
选自如下基团：
本发明一些实施方式中，通式(I)化合物选自表1中所示的化合物。
表1
通式(I)化合物的制备方法
本发明一些实施方式中，通式(I)化合物的制备可采用如下通用合成路线：
其中，n、X、R1、R2、R3的定义如上所述。
P1基可为本领域公知的氨基保护基，例如可选自苄基、对甲氧基苯基甲基、邻硝基苯基甲基等可被取代的C7-11芳烷基；乙酰基、三氟乙酰基等可被取代的C1-6烷羰基；苯甲酰基等可被取代的C6-10芳羰基；甲氧羰基、乙氧羰基、Boc基(叔丁氧羰基)、Cbz基(苄氧羰基)、Fmoc基(芴甲氧羰基)、Teoc基(三甲基甲硅烷基乙氧羰基)等可被取代的C1-6烷氧羰基；Alloc基(烯丙氧羰基)等烯氧羰基；甲磺酰基等烷基磺酰基；对甲苯磺酰基等可被取代的C6-10芳基磺酰基。
X1基可为本领域公知的离去基团，例如可选自氟原子、氯原子、溴原子、碘原子等卤素原子。
X2基可选自氯原子、溴原子、碘原子等卤素原子。
X3基可选自氯原子、溴原子、碘原子等卤素原子。
步骤(a)中，用式I-1化合物和式I-2化合物反应，得到式I-3化合物。
式I-1化合物和式I-2化合物的摩尔比可为1：(0.5～3.0)。反应溶剂可为乙腈、丙酮、四氢呋喃、二氧六环、N，N-二甲基甲酰胺等。步骤(a)的反应可在碱存在下进行。所述碱可选自：碳酸铯、碳酸钾、碳酸钠、氢氧化钾、氢氧化钠等。式I-1化合物与碱的摩尔比可为1：(1.0～6.0)。步骤(a)的反应温度可以由本领域技术人员适当设定，例如可为0～100℃。
步骤(b)中，用式I-3化合物和式I-4化合物反应，得到式I-5化合物。
式I-3化合物和式I-4化合物的摩尔比可为1：(0.5～3.0)。反应溶剂可为N，N-二甲基乙酰胺、N，N-二甲基甲酰胺、甲苯、乙腈等。步骤(b)可在钯催化剂存在下进行。所述钯催化剂可选自：氯化烯丙基钯(II)二聚物、三(二亚苄基丙酮)二钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、氯化钯等。另外，步骤(b)的反应可在碱存在下进行。所述碱可选自：乙酸钾、乙酸钠、磷酸钾、磷酸二氢钾、双三甲基硅基胺基钾、双三甲基硅基胺基钠等。式I-3化合物与碱的摩尔比可为1：(0.5～3.0)。步骤(b)的反应温度可以由本领域技术人员适当设定，例如可为40～150℃。
步骤(c)中，脱除P1保护基。反应条件可采用本领域常用的脱除氨基保护基的反应条件。例如，P1为Boc时，可以用质子酸(例如三氟乙酸)或路易斯酸进行处理。
步骤(d)中，对式I-6化合物进行氨基甲基化反应，得到式I-7化合物。该步骤可采用本领域公知的氨基甲基化反应条件。一些实施方式中，将式I-6化合物与甲醛搅拌一段时间生成席夫碱，然后加入还原剂例如醋酸硼氢化钠反应一段时间，得到式I-7化合物。
步骤(e)中，将式I-7化合物与式I-8化合物反应，得到通式(I)化合物。
式I-7化合物与式I-8化合物的摩尔比可为1：(0.5～5.0)。反应溶剂可为二氧六环、四氢呋喃、甲苯、N，N-二甲基甲酰胺等。步骤(e)可在钯催化剂存在下进行。所述钯催化剂可选自：三(二亚苄基丙酮)二钯(Pd2(dba)3)、氯化烯丙基钯(II)二聚物、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、氯化钯等。另外，步骤(e)的反应中还可以加入膦配体，例如2-二环己基磷-2',4',6'-三异丙基联苯(X-phos)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xant-phos)、1,1'-联萘-2,2'-双二苯膦(BINAP)、三环己基膦等。步骤(e)的反应可在碱存在下进行。所述碱可选自：叔丁醇钠、碳酸铯、碳酸钠、碳酸氢钠、磷酸钾等。式I-7化合物与碱的摩尔比可为1：(0.5～5.0)。步骤(e)的反应温度可以由本领域技术人员适当设定，例如可为40～150℃。
通式(I)化合物的应用
通式(I)化合物可作为胃酸分泌抑制剂。
通式(I)化合物可作为H+/K+-腺苷三磷酸酶(H+/K+-ATPase)抑制剂。
通式(I)化合物可作为钾离子竞争性酸阻滞剂(P-CABs)。
通式(I)化合物可用于治疗和/或预防消化性溃疡、卓-艾综合征、胃炎、糜烂性食管炎、反流性食管炎、症状性胃食管反流疾病、巴雷特食管炎、功能性消化不良、幽门螺旋杆菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡或手术后应激导致的胃酸过多或溃疡；或者抑制消化性溃疡、急性应激性溃疡、出血性胃炎或侵入性应激造成的上消化道出血。上述消化性溃疡包括但不限于胃溃疡、十二指肠溃疡或吻合口溃疡。症状性胃食管反流疾病包括但不限于非糜烂性的反流性疾病或无食管炎的胃食管反流疾病。
药物组合物
本发明的药物组合物包含有效量的通式(I)所示的化合物或其互变异构体、对映异构体、非对映异构体、及其混合物形式、及其可药用的盐、及其药学上可接受的载体或赋形剂或稀释剂。
“有效量”意指本发明化合物：(i)治疗特定疾病、病症或障碍，(ii)减弱、改善或消除特定疾病、病症或障碍的一或多种症状，或(iii)预防或延迟本文所述特定疾病、病症或障碍的一或多种症状发作的量。
药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
本发明的另一方面涉及一种抑制胃酸分泌的方法，该方法包括给予需要治疗的患者有效剂量的通式(I)所示的化合物或其互变异构体、对映异构体、非对映异构体、及其混合物形式、及其可药用的盐或其药物组合物。
本发明的另一方面涉及一种抑制H+/K+-腺苷三磷酸酶(H+/K+-ATPase)的方法，该方法包括给予需要治疗的患者有效剂量的通式(I)所示的化合物或其互变异构体、对映异构体、非对映异构体、及其混合物形式、及其可药用的盐或其药物组合物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的，化合物的纯度是通过液相高压色谱仪(HPLC)测定的。NMR的测定是用Bruker AVANCE-400核磁共振仪，溶剂为氘代二甲基亚砜(DMSO-d6)或氘代甲醇(MeOH-d4)，内标为四甲基硅烷(TMS)，化学位移以ppm为单位。MS的测定使用安捷伦6120质谱仪。HPLC使用安捷伦1200DAD高压液相色谱仪测定。
实施例1：4-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)吗啉
第一步：2-(3-氯苄基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯
将2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1a(2.8g，13.5mmol)溶于乙腈(50mL)中，加入3-氯苄溴(3.3g，16.2mmol)及碳酸铯(32.5g，47mmol)，氮气换气3次，置于80℃油浴中反应3小时。将反应液过滤，滤液浓缩。残留物通过柱层析分离(石油醚：乙酸乙酯＝2：1)进行纯化，得到2-(3-氯苄基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1b(4.1g，黄色油状物)，产率91％。MS m/z(ESI)：334.1[M+H]。
第二步：2-(3-氯苄基)-3-(2-氟苯基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯
依次在茄形瓶中加入2-(3-氯苄基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1b(4.6g，13.7mmol)、乙酸钾(8g，82.2mmol)、氯化烯丙基钯(II)二聚物(499mg，1.37mmol)、N，N-二甲基乙酰胺(50mL)及邻氟碘苯(6.1g，27.4mmol)。油泵换气(氩气)四次后放入提前升温到100℃的油浴中反应3小时。反应恢复至室温后，把反应液直接倒入水(80mL)中，用乙酸乙酯(40mL x 3)萃取。有机相用盐水(40mL x 2)洗，然后用无水硫酸钠干燥、过滤及浓缩。粗品经柱层析(石油醚/乙酸乙酯＝3/l)分离得到2-(3-氯苄基)-3-(2-氟苯基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1c(1.21g，黄色油状物)，产率：20.6％。MS m/z(ESI)：428.3[M+H]。
第三步：2-(3-氯苄基)-3-(2-氟苯基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑
将三氟乙酸(0.5mL)加入到2-(3-氯苄基)-3-(2-氟苯基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1c(729mg，1.45mmol)的二氯甲烷(1.5mL)溶液中，室温反应1小时。反应结束后，直接浓缩得到粗品2-(3-氯苄基)-3-(2-氟苯基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1d(581mg，棕色油状)，产率：100％。MS m/z(ESI)：328[M+1]
第四步：2-(3-氯苄基)-3-(2-氟苯基)-5-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑
将甲醛水溶液(37％，1.2g，14.5mmol)加入到2-(3-氯苄基)-3-(2-氟苯基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1d(581mg，1.45mmol)的二氯甲烷/甲醇(6mL，2/1)溶液中，室温搅拌半小时。将醋酸硼氢化钠(1.8g，8.7mmol)缓慢加入反应液中，再室温反应过夜。反应液浓缩后用二氯甲烷(10mL)溶解稀释，再依次用氨水/水(10mL x 2，1/5)、饱和食盐水(10mL)洗涤，有机相用无水硫酸钠干燥、浓缩。取50mg粗品用高压液相色谱制备(乙腈/水(含0.05％三氟乙酸)得到2-(3-氯苄基)-3-(2-氟苯基)-5-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(三氟乙酸盐，盐系数＝1.3，20.1mg，黄色油状物)，产率：24.5％。MS m/z(ESI)：341[M+1]。1H NMR(400MHz,CDCl3)δ7.38(dt,J＝9.5,3.7Hz,1H),7.17(d,J＝16.1Hz,1H),7.09(dd,J＝22.2,12.7Hz,2H),6.99-6.77(m,2H),5.15(s,2H),4.82(d,J＝15.1Hz,2H),4.03(dd,J＝28.1,12.0Hz,2H),3.04(s,4H)。
第五步：4-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)吗啉
将化合物2-(3-氯苄基)-3-(2-氟苯基)-5-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(50mg，0.15mmol)溶于1,4-二氧六环(3mL)溶液中，依次加入吗啡啉(26mg，0.29mmol)、三(二亚苄基丙酮)二钯(14mg，0.015mmol)、2-二环己基磷-2',4',6'-三异丙基联苯(14mg，0.029mmol)、叔丁醇钠(42mg，0.44mmol)，氩气气氛中于100℃反应过夜。反应液降至室温后倒入水(10mL)中，用乙酸乙酯(30mL×3)萃取。有机相合并后用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥、过滤并浓缩。残留物经HPLC制备(乙腈/水(含0.05％NH3)梯度冲洗)得化合物4-(3-((3-(2-氟苯基)-5-甲基-5,6-二氢吡咯并[3,4-c]吡唑-2(4H)-基)甲基)苯基)吗啉1(16mg，黄色油状物)，产率：25.5％。MS m/z(ESI)：393.3[M+1]。1H NMR(400MHz,CDCl3)δ7.33-7.27(m,1H),7.15(m,1H),7.10-7.04(m,3H),6.68(dd,1H),6.49(s,1H),6.43(d,1H),5.12(s,2H),3.77(s,2H),3.74(t,4H),3.66(s,2H),2.98(t,4H),2.56(s,3H)。
实施例2：3-(2-氟苯基)-5-甲基-2-(3-(哌啶-1-基)苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑
将化合物2-(3-氯苄基)-3-(2-氟苯基)-5-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(100mg，0.29mmol)溶于N，N-二甲基甲酰胺(3mL)溶液中，依次加入哌啶(74mg，0.87mmol)、三(二亚苄基丙酮)二钯(27mg，0.029mmol)、2-二环己基磷-2',4',6'-三异丙基联苯(28mg，0.058mmol)、碳酸铯(189mg，0.58mmol)，在氩气气氛中于110℃反应过夜。反应液降至室温后倒入水(10mL)中，用乙酸乙酯(20mL×3)萃取。有机相合并后用饱和食盐水(15mL×2)洗涤，无水硫酸钠干燥、过滤并浓缩。残留物用高HPLC制备(乙腈/水(含0.05％三氟乙酸)梯度冲洗)得化合物3-(2-氟苯基)-5-甲基-2-(3-(哌啶-1-基)苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑2(三氟乙酸盐，盐系数＝3.70，含盐分子量：812.39，13mg，淡红色油状物)，产率：11.5％。MS m/z(ESI)：391.2[M+1]。1H NMR(400MHz,CDCl3)δ7.47-7.34(m,3H),7.30(s,1H),7.26-7.21(m,2H),7.19-7.15(m,2H),5.30(d,2H),4.91(s,2H),4.27-4.12(d,2H),3.43(s,4H),3.17(s,3H),2.07(t,4H),1.73(s,2H)。
实施例3：3-(2-氟苯基)-5-甲基-2-(3-(吡咯烷-1-基)苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑
依次在茄形瓶中加入2-(3-氯苄基)-3-(2-氟苯基)-5-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(0.15g，0.44mmol)、叔丁醇钠(0.12g，1.3mmol)、Pd2(dba)3(40mg，0.044mmol)、1,4-二氧六环(5mL)、X-phos(41mg，0.088mmol)、吡咯烷(0.62g，0.88mmol)。油泵换气(氩气)四次后放入提前升温到100℃的油浴中反应16小时。反应恢复至室温后，把反应液直接倒入水(40mL)中，用乙酸乙酯(20mL x 3)萃取。有机相用盐水(20mLx 2)洗，然后用无水硫酸钠干燥、过滤、浓缩。将有机层浓缩后用高压液相色谱制备(乙腈/水(含0.05％三氟乙酸)得到3-(2-氟苯基)-5-甲基-2-(3-(吡咯烷-1-基)苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑3(三氟乙酸盐，盐系数＝2.4，26.0mg，黄棕色油状物)，产率：3.5％。MS m/z(ESI)：377.2[M+1]。1H NMR(400MHz,CDCl3)δ7.38(dt,J＝7.3,3.7Hz,1H),7.22–7.06(m,4H),6.77(d,J＝7.1Hz,1H),6.59(d,J＝7.5Hz,1H),6.54(s,1H),5.19(s,2H),4.84(d,J＝13.5Hz,2H),4.04(dd,J＝31.6,12.2Hz,2H),3.32(s,4H),3.06(s,3H),2.02(t,J＝6.4Hz,4H)。
实施例4：3-(2-氟苯基)-5-甲基-2-(3-(4-甲基哌嗪-1-基)苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑
依次在茄形瓶中加入2-(3-氯苄基)-3-(2-氟苯基)-5-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(150mg，0.44mmol)、叔丁醇钠(0.13g，1.32mmol)、Pd2(dba)3(40mg，0.044mmol)，X-phos(41mg，0.088mmol)，1,4-二氧六环(5mL)，N-甲基哌嗪(0.88g，0.88mmol)。油泵换气(氩气)四次后放入提前升温到100℃的油浴中反应16小时。反应恢复至室温后，把反应液直接倒入水(40mL)中，用乙酸乙酯(20mL x 3)萃取。有机相用盐水(20mL x 2)洗，然后用无水硫酸钠干燥、过滤、浓缩。将有机层浓缩后用高压液相色谱制备(乙腈/水(含0.05％三氟乙酸)得到3-(2-氟苯基)-5-甲基-2-(3-(4-甲基哌嗪-1-基)苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑4(三氟乙酸盐，盐系数＝3.1，79.9mg，黑色油状物)，产率：23.9％。MS m/z(ESI)：406.5[M+1]。1H NMR(400MHz,CDCl3)δ7.37(d,J＝5.8Hz,1H),7.20–7.01(m,4H),6.72(d,J＝8.0Hz,1H),6.53(d,J＝7.3Hz,1H),6.42(s,1H),5.15(s,2H),4.80(s,2H),4.01(s,2H),3.49(dd,J＝23.9,11.5Hz,4H),3.07(d,J＝13.5Hz,2H),3.04(d,J＝13.5Hz,3H),2.94(d,J＝10.5Hz,2H),2.76(s,3H)。
实施例5：2-(3-([1,4'-联哌啶]-1'-基)苄基)-3-(2-氟苯基)-5-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑
将化合物2-(3-氯苄基)-3-(2-氟苯基)-5-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(100mg，0.29mmol)溶于N，N-二甲基甲酰胺(3mL)溶液中，依次加入4-哌啶基哌啶(168mg，0.87mmol)、三(二亚苄基丙酮)二钯(27mg，0.029mmol)、2-二环己基磷-2',4',6'-三异丙基联苯(28mg，0.058mmol)、碳酸铯(189mg，0.58mmol)，氩气气氛中于110℃反应过夜。反应液降至室温后倒入水(10mL)中，用乙酸乙酯(20mL×3)萃取。有机相合并后用饱和食盐水(15mL×2)洗涤，无水硫酸钠干燥、过滤并浓缩。残留物用HPLC制备(乙腈/水(含0.05％三氟乙酸)梯度冲洗)得化合物2-(3-([1,4'-联哌啶]-1'-基)苄基)-3-(2-氟苯基)-5-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑5(三氟乙酸盐，17mg，棕色固体)，产率：12.4％。MS m/z(ESI)：474.4[M+1]。1H NMR(400MHz,MeOD)δ7.52(m,1H),7.39(m,1H),7.27(m,2H),7.12(t,1H),6.90(m,1H),6.65(s,1H),6.51(d,1H),5.29(s,2H),3.70(d,2H),3.52(d,2H),3.29(s,2H),3.15-3.10(m,4H),3.00(t,2H),2.77(t,2H),2.15(d,2H),1.96(d,2H),1.89-1.49(m,8H)。
测试例：化合物对H+/K+ATPase酶活性抑制的测定
下面的实验是用来测定本发明化合物对H+/K+ATPase酶活性的抑制作用。
1.实验材料
Plate reader:SpectraMax M5(MD)
孔雀石绿(Sigma Aldrich,213020-25G)
钼酸铵(Sigma Aldrich,277908-20G)
ATP(Sigma Aldrich,A1852-1VL)。
2.缓冲液配制
酶工作液：对酶进行滴定，用缓冲液1将酶稀释，反应时，取5μl稀释液至50μl的反应体系中
ATP溶液：100mM的ATP用无K+buffer稀释至5mM，取5μl稀释液至50μl的反应体系中，即ATP的终浓度为500μM
MLG显色液：将0.12％的MLG、7.5％钼酸铵、11％的Tween-20按100：25：2的体积混匀，检测时每孔加入15μl
缓冲液1:50mM Tris-HCl pH 6.5,5mM氯化镁(magnesium chloride),10μM缬氨霉素(valinomycin)
缓冲液2:50mM Tris-HCl pH 6.5,5mM氯化镁(magnesium chloride),10μM缬氨霉素(valinomycin),20mM KCl
匀浆缓冲液：10mmol/L Tris-HCl,pH 6.8，0.25M蔗糖(sucrose),1mmol/LEDTA7.5％Ficoll分层液：匀浆缓冲液+7.5％(W/W)
400(聚蔗糖400)。
3.实验步骤
3.1.H+/K+ATP酶提取
(1)分离出兔胃组织，自来水冲洗血迹，食物残留；
(2)利用预冷的NaCl溶液彻底清洗胃底部位，去除表面粘液；
(3)将剥离的粘膜，装于样品袋或50ml离心管，迅速冻于液氮罐中；
(4)取出组织，用手术剪刀剪碎，加入预冷的匀浆缓冲液(4ml/g组织)，于组织匀浆机中匀浆2-10min；
(5)匀浆后，如果有较大的组织颗粒，可离心(600g,10min)去除，然后将上清移至干净的离心管中，20000g离心30min后，然后将上清移至干净的离心管中，进一步离心，100000g离心90min，收集沉淀；
(6)利用匀浆缓冲液重悬沉淀，吹散均匀，等比例加入7.5％Ficoll分层液，100000g离心90min，收集沉淀；
(7)匀浆缓冲液重悬沉淀，吹散均匀，用Bradford测蛋白浓度。分管冻存于-80℃备用。
3.2.H+/K+ATP酶活性实验
(1)每个实验孔中加入35μl反应缓冲液，再加入35μl的缓冲液1
(2)全酶和缓冲液孔中，加入5μl含10％DMSO的缓冲液1
(3)化合物孔中，加入5μl 10X化合物工作液混匀
(4)缓冲液孔中加入5μl的缓冲液1
(5)其余孔中，加入5μl 10X酶工作液混匀于37℃孵育30min
(6)向所有实验孔中加入5μl 10XATP工作液，并混匀于37℃孵育20min
(7)向所有实验孔中加入15μl MLG显色液，并混匀于室温孵5-30min
(8)M5仪器检测620nm的读数。
4.数据分析
抑制率用以下公式计算：
抑制率(IC50)＝【OD(样品孔)-OD(含氯化钾的全酶孔)】/【(OD(含氯化钾的全酶孔)-(OD(不含氯化钾的全酶孔)】×100％
5.实验结果
各实施例化合物的抑制率(IC50)在表2中示出
表2
| 化合物编号 | IC<sub>50</sub>(μM) |
| 实施例1 | 0.4105 |
| 实施例2 | 0.4312 |
| 实施例3 | 1.861 |
| 实施例4 | 0.5803 |
| 实施例5 | 2.579 |
从表2可以看出，本发明化合物具有优异的H+/K+ATPase酶抑制活性，可用于制备胃酸分泌抑制剂。
Claims (6)
1.一种通式(I)所示的化合物或其药学上可接受的盐，
其中：
R1选自氢原子、Cl、Br、I或C1～5烷基；
R2选自卤素、羟基或C1～5烷基；
n＝1或2；
R3与碳原子或X相连；
当R3与碳原子相连时，X选自CH2，R3选自NRbRc，其中Rb和Rc互相连接并且跟它们相连的N形成六元杂环；
当R3与X相连时，X选自N，R3选自C1～C5烷基。
2.一种药物组合物，包括权利要求1所述的化合物或其药学上可接受的盐以及药学上可接受的载体、赋形剂或稀释剂。
3.权利要求1所述的化合物或其药学上可接受的盐在制备胃酸分泌抑制剂中的用途。
4.权利要求1所述的化合物或其药学上可接受的盐在制备H+/K+-腺苷三磷酸酶抑制剂中的用途。
5.权利要求1所述的化合物或其药学上可接受的盐在制备钾离子竞争性酸阻滞剂中的用途。
6.权利要求1所述的化合物或其药学上可接受的盐在制备药物中的用途，所述药物用于治疗和/或预防消化性溃疡、卓-艾综合征、胃炎、糜烂性食管炎、反流性食管炎、症状性胃食管反流疾病、巴雷特食管炎、功能性消化不良、幽门螺旋杆菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡或手术后应激导致的胃酸过多或溃疡；或者抑制消化性溃疡、急性应激性溃疡、出血性胃炎或侵入性应激造成的上消化道出血。
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| CN110117284A (zh) * | 2018-02-06 | 2019-08-13 | 江苏奥赛康药业有限公司 | 含氮杂环类化合物及其制备方法和用途 |
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| WO2021017067A1 (zh) | 2021-02-04 |
| US20220281877A1 (en) | 2022-09-08 |
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