CN112300168B - 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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- CN112300168B CN112300168B CN201910682799.XA CN201910682799A CN112300168B CN 112300168 B CN112300168 B CN 112300168B CN 201910682799 A CN201910682799 A CN 201910682799A CN 112300168 B CN112300168 B CN 112300168B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- GZTPJDLYPMPRDF-UHFFFAOYSA-N pyrrolo[3,2-c]pyrazole Chemical class N1=NC2=CC=NC2=C1 GZTPJDLYPMPRDF-UHFFFAOYSA-N 0.000 title abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 12
- 230000027119 gastric acid secretion Effects 0.000 claims abstract description 9
- 239000003112 inhibitor Substances 0.000 claims abstract description 9
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 7
- 229910001414 potassium ion Inorganic materials 0.000 claims abstract description 7
- 230000002860 competitive effect Effects 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 107
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 22
- 208000008469 Peptic Ulcer Diseases 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 208000011906 peptic ulcer disease Diseases 0.000 claims description 11
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 208000025865 Ulcer Diseases 0.000 claims description 9
- 231100000397 ulcer Toxicity 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
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- 238000011282 treatment Methods 0.000 claims description 6
- 201000008629 Zollinger-Ellison syndrome Diseases 0.000 claims description 4
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- 201000000052 gastrinoma Diseases 0.000 claims description 4
- 208000000689 peptic esophagitis Diseases 0.000 claims description 4
- 208000023665 Barrett oesophagus Diseases 0.000 claims description 3
- 206010063655 Erosive oesophagitis Diseases 0.000 claims description 3
- 208000007882 Gastritis Diseases 0.000 claims description 3
- 206010017866 Gastritis haemorrhagic Diseases 0.000 claims description 3
- 206010020601 Hyperchlorhydria Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
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- 206010046274 Upper gastrointestinal haemorrhage Diseases 0.000 claims description 3
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- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 208000017215 gastric mucosa-associated lymphoid tissue lymphoma Diseases 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
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- 229910052794 bromium Inorganic materials 0.000 claims description 2
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- 229940037467 helicobacter pylori Drugs 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- 229920006217 cellulose acetate butyrate Polymers 0.000 abstract 1
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- 238000006243 chemical reaction Methods 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 12
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- 239000000243 solution Substances 0.000 description 10
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- 102000004190 Enzymes Human genes 0.000 description 8
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 8
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- 239000011541 reaction mixture Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
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- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 6
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 5
- XEPKCIGMNNYZMK-UHFFFAOYSA-N 3-(2-fluorophenyl)-5-methyl-2-[(3-nitrophenyl)methyl]-4,6-dihydropyrrolo[3,4-c]pyrazole Chemical compound CN1CC2=C(N(N=C2C1)CC3=CC(=CC=C3)[N+](=O)[O-])C4=CC=CC=C4F XEPKCIGMNNYZMK-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 4
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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)和基团(X、Y、Z、U、V)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：
X为NRa，其中Ra选自氢原子或烷基；
Y、Z、U和V各自独立选自N、NH、CRb或C(＝O)，并且Y、Z、U和V有且只有一个或两个同时含有N，其中Rb选自氢原子、卤素、羟基、烷基、烷氧基、NRcRd、五元或六元饱和杂环，其中Rc和Rd各自独立选自氢原子或C1～3烷基；
R1选自氢原子、卤素或烷基；
R2选自氢原子、卤素、羟基或烷基。
优选地，X为NRa，其中Ra选自氢原子或C1～3烷基；
Y、Z、U和V各自独立选自N、NH、CRb或C(＝O)，并且Y、Z、U和V有且只有一个或两个同时含有N，其中Rb选自氢原子、卤素、羟基、烷基、C1～3烷氧基、NRcRd、六元饱和杂环，其中Rc和Rd中一者为氢，另一者选自氢原子或C1～3烷基；
R1选自氢原子或氟原子；
R2选自氢原子、氟原子或羟基。
优选地，X为NH；
Y、Z、U和V各自独立选自N、NH、CRb或C(＝O)，并且Y、Z、U和V有且只有一个或两个同时含有N，其中Rb选自氢原子、氯原子、羟基、甲基、甲氧基、NHCH3或吗啉；
R1为氟原子；
R2为氢原子。
优选地，所述化合物选自：
2-氯-N-(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)-6-甲氧基吡啶-3-胺；
2-氯-N-(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)-6-甲基吡啶-3-胺；
2-氯-N-(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)嘧啶-4-胺；
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)氨基)嘧啶-2-(1H)-酮；
N4-(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)-N2-甲基嘧啶-2,4-二胺；
N-(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)-2-吗啉代嘧啶-4-胺；
6-氯-N-(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)吡嗪-2-胺。
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“烷基”指-O-烷基，其中所述烷基如本文所定义。
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。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。优选实施方式中，R1选自氢原子或氟原子。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。优选实施方式中，R2选自氢原子、氟原子或羟基。更优选实施方式中，R2为氢原子。
本发明一些实施方式中，X为NRa，其中Ra选自氢原子或烷基。优选实施方式中，X为NRa，其中Ra选自氢原子或C1～3烷基。更优选实施方式中，X为NH。
本发明一些实施方式中，Y、Z、U和V各自独立选自N、NH、CRb或C(＝O)，并且Y、Z、U和V有且只有一个或两个同时含有N，其中Rb选自氢原子、卤素、羟基、烷基、烷氧基、NRcRd、五元或六元饱和杂环，其中Rc和Rd各自独立选自氢原子或C1～3烷基。
优选实施方式中，Y、Z、U和V各自独立选自N、NH、CRb或C(＝O)，并且Y、Z、U和V有且只有一个或两个同时含有N，其中Rb选自氢原子、卤素、羟基、烷基、C1～3烷氧基、NRcRd、六元饱和杂环，其中Rc和Rd中一者为氢，另一者选自氢原子或C1～3烷基。
更优选实施方式中，Y、Z、U和V各自独立选自N、NH、CRb或C(＝O)，并且Y、Z、U和V有且只有一个或两个同时含有N，其中Rb选自氢原子、氯原子、羟基、甲基、甲氧基、NHCH3或吗啉。
进一步优选实施方式中，
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)化合物为下述式(Ia)化合物或式(Ib)化合物，制备可采用如下通用合成路线：
其中，X、Y、Z、U、V、R1、R2、Ra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。
X4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。
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化合物中的硝基还原为氨基，得到式I-8化合物。该步骤可采用本领域公知的将硝基还原为氨基的反应条件。一些实施方式中，将式I-7化合物在Raney-Ni催化剂存在下与水合肼反应，得到式I-8化合物。
步骤(f)中，用式I-8化合物和式I-9化合物反应，得到式Ia化合物。
式I-8化合物与式I-9化合物的摩尔比可为1：(0.5～3.0)。一些实施方式中，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。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。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)、1,1'-联萘-2,2'-双二苯膦(BINAP)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xant-phos)、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-8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℃。
一些实施方式中，可将式I-8化合物中的氨基变成碘原子(例如将式I-8化合物与亚硝酸钠和碘化钾反应)，再与式I-9化合物(其中X3为氨基)反应，得到式Ia化合物。
一些实施方式中，步骤(e)可在酸性条件下进行。
步骤(g)中，式Ia化合物与式I-10化合物反应，得到式Ib化合物。
式Ia化合物和式I-10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Ia化合物与碱的摩尔比可为1：(1.0～6.0)。步骤(g)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℃。
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1：2-氯-N-(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)-6-甲氧基吡啶-3-胺
第一步：2-(3-硝基苄基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯
化合物2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1a(1g，4.78mmol)溶于乙腈(50mL)中，加入3-硝基溴苄(1.23g，5.74mmol)，碳酸铯(4.67g，14.345mmol)，在氩气气氛中于80℃反应过夜。反应液直接过滤，浓缩，残余物通过柱层析分离(石油醚/乙酸乙酯＝4/1)得到粗品化合物2-(3-硝基苄基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1b(1.1g，黄色油状物)，产率：66.8％。MS m/z(ESI)：345.2[M+1]。
第二步：3-(2-氟苯基)-2-(3-硝基苄基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯
化合物2-(3-硝基苄基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1b(1g，2.91mmol)，醋酸钾(1.71g，17.46mmol)，氯化烯丙基钯(II)二聚物(106mg，0.291mmol)，邻氟碘苯(1.292g，5.82mmol)，DMA(30mL)依次加入反应器中，在氩气气氛中于100℃反应3小时。将反应液倒入水(80mL)中，用乙酸乙酯(30mL×3)萃取。有机相用饱和氯化钠水溶液(50mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩，残余物经柱层析分离(石油醚/乙酸乙酯＝2/1)得到化合物3-(2-氟苯基)-2-(3-硝基苄基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1c(300mg，黄色油状物)，产率：23.5％。
第三步：3-(2-氟苯基)-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑
化合物3-(2-氟苯基)-2-(3-硝基苄基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯1c(300mg，0.685mmol)溶于二氯甲烷(9mL)，加入三氟乙酸(3mL)，室温反应2小时。将反应液浓缩得到化合物3-(2-氟苯基)-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1d(220mg，棕色液体)，产率：94.5％。MS m/z(ESI)：339.2[M+1]。
第四步：3-(2-氟苯基)-5-甲基-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑
化合物3-(2-氟苯基)-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1d(220mg，0.65mmol)溶于二氯甲烷/甲醇(2/1，24mL)溶液中，加入甲醛水溶液(37％，460mg，5.68mmol)，室温搅拌1小时，然后加入醋酸硼氢化钠(1.2g，5.68mmol)，再室温反应2小时。反应液浓缩后经HPLC制备(乙腈/水(含0.05％NH3)梯度冲洗)得到化合物3-(2-氟苯基)-5-甲基-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(160mg，黄色油状液体)，产率：71.0％。MS m/z(ESI):353.3[M+1]。1H NMR(400MHz,CDCl3)δ8.00(d,J＝7.9Hz,1H),7.81(s,1H),7.33(dt,J＝7.7,5.2Hz,2H),7.27(d,J＝7.6Hz,1H),7.19-7.03(m,3H),5.23(s,2H),3.73(d,J＝39.1Hz,4H),2.57(s,3H)。
第五步：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)苯胺
将化合物3-(2-氟苯基)-5-甲基-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(120mg，0.34mmol)溶解于溶剂甲醇(15mL)中，加入Raney-Ni催化剂(1.0mL)。反应液加热到40℃，滴加水合肼(50％，1.0mL，10mmol)。滴加完毕后，加热搅拌2小时。将反应液过滤，滤液浓缩得到化合物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)苯胺1f(80mg，灰白色固体)。MS m/z(ESI)：323.2[M+H]。1H NMR(400MHz,CDCl3)δ7.36(s,1H),7.18(m,2H),7.01(m,1H),6.52(m,1H),6.46–6.10(m,2H),5.15(s,2H),3.80(d,J＝42.7Hz,4H),3.53(s,2H),2.64(s,3H)。
第六步：2-氯-N-(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)-6-甲氧基吡啶-3-胺
依次在反应瓶中加入化合物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)苯胺1f(100mg，1.31mmol)、碳酸铯(0.41g，1.24mmol)、三(二亚苄基丙酮)二钯(28mg，0.031mmol)、2-二环己基磷-2，4，6-三异丙基联苯(29.5mg，0.062mmol)、N，N-二甲基甲酰胺(10mL)、2-氯-3-碘-6-甲氧基吡啶(0.18g，0.62mmol)，在氩气气氛中于110℃反应16小时。反应液恢复至室温后倒入水(40mL)中，用乙酸乙酯(20mL×3)萃取。有机相用盐水(20mL×2)洗，无水硫酸钠干燥、过滤、浓缩。残留物用HPLC制备(乙腈/水(含0.05％三氟乙酸)得到化合物2-氯-N-(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)-6-甲氧基吡啶-3-胺1(三氟乙酸盐，盐系数＝2，17.2mg，黑棕色油状物)，产率：3.3％。MS m/z(ESI)：464.1[M+1]。1H NMR(400MHz,CDCl3)δ7.47-7.33(m,2H),7.20-7.06(m,4H),6.75(dd,J＝8.0,1.6Hz,1H),6.57(d,J＝8.6Hz,1H),6.55-6.42(m,2H),5.15(d,J＝7.2Hz,2H),4.90(s,2H),3.98(dd,J＝27.8,11.1Hz,2H),3.85(s,3H),3.05(s,3H)。
实施例2：2-氯-N-(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)-6-甲基吡啶-3-胺
第一步：3-(2-氟苯基)-2-(3-碘苄基)-5-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑
将化合物3-(2-氟苯基)-5-甲基-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(350mg，1.09mmol)溶于浓硫酸/水(11mL，10/1)溶液中，加入溶于水(1mL)的亚硝酸钠(90mg，1.30mmol)，在0℃反应1h后，加入溶于水(1mL)的碘化钾(325mg，1.96mmol)，于15℃以下反应2h。反应液恢复至室温后倒入水(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、过滤并浓缩得化合物3-(2-氟苯基)-2-(3-碘苄基)-5-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑2a(300mg，浅黄色油状物)，产率：63.5％。MS m/z(ESI)：434.3[M+1]。1H NMR(400MHz,CDCl3)δ7.61(d,1H),7.52-7.46(m,1H),7.40(s,1H),7.25-7.20(m,3H),7.05-6.99(m,2H),5.21(s,2H),4.97(t,2H),4.12-4.01(m,2H),3.13(s,3H)。
第二步：2-氯-N-(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)-6-甲基吡啶-3-胺
依次在反应瓶中加入化合物3-(2-氟苯基)-2-(3-碘苄基)-5-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑2a(300mg，0.69mmol)、2-氯-6-甲基吡啶-3-胺(200mg，1.39mmol)、碳酸铯(900mg，2.76mmol)、三(二亚苄基丙酮)二钯(63mg，0.07mmol)、2-二环己基磷-2，4，6-三异丙基联苯(69mg，0.14mmol)、N，N-二甲基甲酰胺(20mL)，氩气气氛中于110℃反应过夜。反应液冷却至室温后倒入水(100mL)中，用乙酸乙酯(50mL×3)萃取。有机相合并后用饱和食盐水(50mL×2)洗涤，用无水硫酸钠干燥、过滤并浓缩。残留物用HPLC制备(乙腈/水(含0.05％NH3)梯度冲洗)得到化合物2-氯-N-(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)-6-甲基吡啶-3-胺2(35mg，黄色粉末)，产率：10.6％。MS m/z(ESI)：478.3[M+1]。1H NMR(400MHz,CDCl3)δ7.36(d,J＝8.0Hz,1H),7.30(d,J＝8.2Hz,1H),7.18-7.07(m,4H),6.90(t,J＝6.6Hz,2H),6.67(s,1H),6.61(d,J＝7.6Hz,1H),5.87(s,1H),5.15(s,2H),4.08(d,J＝33.0Hz,4H),2.80(s,3H),2.40(s,3H),2.10(s,1H)。
实施例3：2-氯-N-(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)嘧啶-4-胺
将化合物3-(2-氟苯基)-5-甲基-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(320mg，1.0mmol)、水(5mL)、盐酸(1滴)、2,4-二氯嘧啶(179mg，1.2mmol)混合，室温反应48小时。反应结束后冻干，取50mg用HPLC制备(乙腈/水(含0.05％三氟乙酸)得到粗品，粗品用TLC制备板(二氯甲烷/甲醇＝10/1)纯化得到化合物2-氯-N-(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)嘧啶-4-胺3(5mg，黄色油状物)，产率：1.2％。MS m/z(ESI)：435.1[M+1]。1H NMR(400MHz,CDCl3)δ8.01(d,J＝5.8Hz,1H),7.48(s,1H),7.33(d,J＝4.8Hz,2H),7.17(dd,J＝9.7,6.7Hz,2H),7.14-7.04(m,2H),6.78(d,J＝7.6Hz,1H),6.67(s,1H),6.50(d,J＝5.8Hz,1H),5.19(s,2H),3.92(d,J＝33.4Hz,4H),2.69(s,3H)。
实施例4：4-((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)氨基)嘧啶-2-(1H)-酮
在反应瓶中加入化合物2-氯-N-(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)嘧啶-4-胺3(100mg，0.23mmol)和甲酸(1ml)，65℃反应6小时，反应结束后，用乙酸乙酯(10mL×3)萃取。有机相用盐水(10mL×2)洗，无水硫酸钠干燥、过滤、浓缩。残留物用HPLC制备(乙腈/水(含0.05％三氟乙酸)得到化合物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)氨基)嘧啶-2-(1H)-酮4(三氟乙酸盐，盐系数＝4，3mg，黄色油状物)，产率：3.1％。MS m/z(ESI)：417.1[M+1]。1HNMR(400MHz,MeOD)δ7.48(d,J＝7.1Hz,3H),7.40(s,1H),7.23(dd,J＝23.9,10.3Hz,4H),6.76(s,1H),5.97(d,J＝7.1Hz,1H),5.37(s,2H),4.47(d,J＝31.9Hz,4H),3.11(s,3H)。
实施例5：N4-(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)-N2-甲基嘧啶-2,4-二胺
将化合物2-氯-N-(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)嘧啶-4-胺3(100mg，0.23mmol)与甲胺醇溶液(2ml)混合，100℃反应过夜，反应结束后，反应液用乙酸乙酯(10mL×3)萃取。有机相用盐水(10mL×2)洗，无水硫酸钠干燥、过滤、浓缩。残留物用HPLC制备(乙腈/水(含0.05％三氟乙酸)得到化合物N4-(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)-N2-甲基嘧啶-2,4-二胺5(三氟乙酸盐，盐系数＝1.6，5mg，黄色油状物)，产率：5.1％。MS m/z(ESI)：430.2[M+1]。1H NMR(400MHz,CDCl3)δ7.67(s,1H),7.45(s,1H),7.39-7.30(m,1H),7.19-7.06(m,4H),6.79(d,J＝7.5Hz,1H),6.63(s,1H),6.00(d,J＝6.3Hz,1H),5.23(s,2H),4.10(d,J＝32.6Hz,4H),2.96-2.77(m,6H)。
实施例6：N-(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)-2-吗啉代嘧啶-4-胺
将化合物2-氯-N-(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)嘧啶-4-胺3(100mg，0.23mmol)于封管内，加入DIEA(1mL)、叔丁醇(1mL)，吗啡啉(3mL)，加热100℃反应过夜，反应结束后，用乙酸乙酯(10mLx3)萃取。有机相用盐水(10mLx2)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N-(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)-2-吗啉代嘧啶-4-胺6(5mg，黄色油状物)，产率：4.4％。MS m/z(ESI)：486.2[M+1]。1H NMR(400MHz,CDCl3)δ7.88(d,J＝5.7Hz,1H),7.43(d,J＝7.9Hz,1H),7.37–7.28(m,1H),7.20–7.05(m,4H),7.01(s,1H),6.75(s,1H),6.65(d,J＝7.6Hz,1H),5.98(d,J＝5.7Hz,1H),5.18(s,2H),4.08(d,J＝32.9Hz,4H),3.67(s,8H),2.79(s,3H)。
实施例7：6-氯-N-(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)吡嗪-2-胺
依次在反应瓶中加入化合物3-(2-氟苯基)-5-甲基-2-(3-硝基苄基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1e(100mg，0.31mmol)、叔丁醇钠(0.041g，0.43mmol)、三(二亚苄基丙酮)二钯(2.8mg，0.0031mmol)、BINAP(7.7mg，0.012mmol)、1,4-二氧六环(2mL)、2，6-二氯吡嗪(0.055g，0.37mmol)，在氩气气氛中于90℃反应16小时。反应液恢复至室温后倒入水(40mL)中，用乙酸乙酯(20mL×3)萃取。有机相用盐水(20mL×2)洗，无水硫酸钠干燥、过滤、浓缩。残留物用HPLC制备(乙腈/水(含0.05％三氟乙酸)得到粗品，粗品用TLC制备板(二氯甲烷/甲醇＝10/1)纯化得到化合物6-氯-N-(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)吡嗪-2-胺7(6mg，黄棕色固体)，产率：4.5％。MS m/z(ESI)：435.1[M+1]。1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.86(s,1H),7.41(d,J＝7.9Hz,1H),7.32(d,J＝7.0Hz,1H),7.18-7.12(m,2H),7.13-7.05(m,2H),6.78(s,1H),6.69(d,J＝7.5Hz,1H),5.18(s,2H),3.88(d,J＝35.3Hz,4H),2.66(s,3H)。
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/L EDTA
7.5％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 | 0.4154 |
| 实施例2 | 0.6688 |
| 实施例3 | 0.9658 |
| 实施例4 | 0.7293 |
| 实施例5 | 0.2789 |
| 实施例6 | 2.847 |
| 实施例7 | 0.3254 |
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：
X为NRa，其中Ra选自氢原子或C1～5烷基；
Y、Z、U和V各自独立选自N、NH、CRb，并且Y、Z、U和V有且只有一个或两个同时含有N，Y、Z、U和V组成的六元环中的虚线部分为单键或双键，其中Rb选自氢原子、卤素、羟基、C1～5烷基、C1～5烷氧基、NRcRd、五元或六元饱和杂环，其中Rc和Rd各自独立选自氢原子或C1～3烷基；
R1选自氢原子、Cl、Br、I或C1～5烷基；
R2选自氢原子、卤素、羟基或C1～5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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| EP1905774A1 (en) * | 2003-09-17 | 2008-04-02 | Janssen Pharmaceutica, N.V. | Fused heterocyclic compounds as serotonin receptor modulators |
| 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 |
| CN105367550A (zh) * | 2014-08-11 | 2016-03-02 | 江苏柯菲平医药股份有限公司 | 四氢环戊二烯并[c]吡咯类衍生物、其制备方法及其在医药上的应用 |
| CN105492423A (zh) * | 2013-08-29 | 2016-04-13 | 株式会社大熊制药 | 四氢环戊并吡咯衍生物及用于制备其的方法 |
| 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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| EP1905774A1 (en) * | 2003-09-17 | 2008-04-02 | Janssen Pharmaceutica, N.V. | Fused heterocyclic compounds as serotonin receptor modulators |
| CN105492423A (zh) * | 2013-08-29 | 2016-04-13 | 株式会社大熊制药 | 四氢环戊并吡咯衍生物及用于制备其的方法 |
| CN105367550A (zh) * | 2014-08-11 | 2016-03-02 | 江苏柯菲平医药股份有限公司 | 四氢环戊二烯并[c]吡咯类衍生物、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 |
| 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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