WO2022127774A1 - 吡啶衍生物及其在医药上的应用 - Google Patents

吡啶衍生物及其在医药上的应用 Download PDF

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WO2022127774A1
WO2022127774A1 PCT/CN2021/137836 CN2021137836W WO2022127774A1 WO 2022127774 A1 WO2022127774 A1 WO 2022127774A1 CN 2021137836 W CN2021137836 W CN 2021137836W WO 2022127774 A1 WO2022127774 A1 WO 2022127774A1
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compound
pharmaceutically acceptable
present application
acceptable salt
stereoisomer
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PCT/CN2021/137836
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French (fr)
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张靖
周锡兵
魏用刚
孙毅
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成都百裕制药股份有限公司
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Priority to CN202180084209.9A priority Critical patent/CN116670137A/zh
Publication of WO2022127774A1 publication Critical patent/WO2022127774A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention relates to pyridine derivatives and their application in medicine.
  • IBD Inflammatory bowel disease
  • TNF monotherapy The common treatment method for moderate to severe inflammatory bowel disease is TNF monotherapy.
  • Antibiotics are not only expensive, they also need to be injected intravenously or subcutaneously, and there is a risk of infection.
  • Lanthionine C-like protein 2 (LANCL2) is a signaling pathway protein expressed in immune cells, gastrointestinal tract, neurons, testis and pancreas.
  • LANCL2 Activation of the LANCL2 pathway reduces the pro-inflammatory factors TNF- ⁇ , INF- ⁇ , IL-6 and MCP1 and increases the anti-inflammatory activity of regulatory T regulatory cells, thus LANCL2 agonists have the potential to treat inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • One or more embodiments of the present application provide a compound or a stereoisomer or pharmaceutically acceptable salt thereof, the compound is selected from:
  • One or more embodiments of the present application provide use of a compound of the present application or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application in the preparation of inflammatory bowel disease.
  • One or more embodiments of the present application provide the use of a compound of the present application, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, in the preparation of a LANCL2 agonist.
  • One or more embodiments of the present application provide a compound of the present application, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, for use in medicine.
  • One or more embodiments of the present application provide a compound of the present application, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, for use in the treatment of inflammatory bowel disease.
  • One or more embodiments of the present application provide a compound of the present application, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, for use as a LANCL2 agonist.
  • One or more embodiments of the present application provide methods of treating inflammatory bowel disease, comprising administering to a subject in need thereof a compound of the present application, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • One or more embodiments of the present application provide methods of activating LANCL2, comprising administering to a subject in need thereof a compound of the present application, or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application .
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotopic conditions, and the carbons involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12C, 13C and 14C, and hydrogen isotopes include protium (H), deuterium (D, also known as heavy Hydrogen), tritium (T, also known as super heavy hydrogen), oxygen isotopes include 16O, 17O and 18O, sulfur isotopes include 32S, 33S, 34S and 36S, nitrogen isotopes include 14N and 15N, and fluorine isotopes include 17F and 19F , the isotopes of chlorine include 35Cl and 37Cl, and the isotopes of bromine include 79Br and 81Br.
  • carbon isotopes include 12C, 13C and
  • “Pharmaceutical composition” refers to a mixture of one or more of the compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable Accepted carriers, excipients and/or one or more other therapeutic agents.
  • Carrier refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binding agents agent and disintegrant.
  • Steps refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • “Pharmaceutically acceptable salt” or “a pharmaceutically acceptable salt thereof” means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with a non-toxic inorganic base or Organic bases, said free bases are salts obtained by reacting with non-toxic inorganic or organic acids.
  • heterocyclyl optionally substituted with an alkyl group means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group happening.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm.
  • 6-(1H-benzimidazol-2-yl)picolinic acid 1a (purchased from Chengdu Esther Chemical Technology Co., Ltd., 1 g, 4.18 mmol) was dissolved in 4 mL of N,N-dimethylformamide, under 0 Stir at °C for 10min, then add N,N-diisopropylethylamine (650g, 5.02mmol), continue to stir at 0°C for 10min, then add 1-hydroxybenzotriazole (850mg, 6.28mmol), 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.28 mmol), continue to stir at 0 °C for 10 min, and then add 1,3-adamantanediamine 1b (purchased from Axon) Kang Bio, 350 mg, 2.09 mmol), gradually heated to 80 °C and stirred for 4 h.
  • 1,3-adamantanediamine 1b (purchased
  • Biacore S200 was used to detect the affinity (K D value) of compounds and LANCL2, and the specific method was as follows.
  • the LANCL2 protein was immobilized on a CM5 sensor chip, and MOPS (10 mM MOPS, 150 mM NaCl, 5% DMSO and 0.05% Tween 20, pH 6.5) was used as the running buffer, and the compounds to be tested were diluted to 0.024 ⁇ M, 0.049 ⁇ M, 0.098 ⁇ M, 0.19 ⁇ M, 0.39 ⁇ M, 0.78 ⁇ M, 1.56 ⁇ M, 3.12 ⁇ M, 6.25 ⁇ M, 12.5 ⁇ M and 25 ⁇ M, injection flow rate 30 ⁇ L/min, contact time 90 s, dissociation time 900 s.
  • Table 1 The results are shown in Table 1.
  • the compound of the present invention has a good binding effect with LANCL2 protein.
  • ND means not detected.
  • mice SPF healthy female C57BL/6J mice, weighing 17-20 g, with a total of 80 mice (purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.). Animals were kept in special breeding cages for mice, the temperature was 20 ⁇ 2°C, the humidity was 40-70%, the light and dark were alternated for 12 hours, and the animals were fed with regular maintenance feed and free drinking water.
  • mice were randomly divided into groups, 10 mice in each group, and the grouping and administration conditions were shown in Table 3. Animals in the model group and the administration group drank 3% DSS aqueous solution freely, and continuously drank it until the ulcerative colitis model was successfully established.
  • the reference substance (the compound of Example 2 of the WO2016064445 patent, purchased from MCE Company) and the compound of the present invention were continuously administered at any time, and the normal group and the model group were administered with equal volume of vehicle.
  • the condition of the animals was observed and recorded every day, and the DAI score was calculated; at the end of the experiment, the animals were dissected, and the weight and length of the colon and the weight of the spleen were detected.
  • the experimental results are shown in Table 3.

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Abstract

公开了吡啶衍生物及其在医药上的应用。所述吡啶衍生物与LANCL2蛋白具有良好的结合作用，对于溃疡性结肠炎具有显著的药效。

Description

吡啶衍生物及其在医药上的应用 技术领域
本发明涉及吡啶衍生物及其在医药上的应用。
背景技术
炎症性肠病(IBD)是一种普遍存在的自身免疫疾病，针对该疾病当前的治疗效果不令人满意，而且还存在严重的副作用，针对中重度炎症性肠病普遍的治疗方法为TNF单抗，此类药物不仅价格昂贵，还需要通过静脉注射或皮下注射，同时还存在感染风险。羊毛硫氨酸C样蛋白2(LANCL2)是一种表达在免疫细胞、胃肠道、神经元、睾丸和胰腺的信号通路蛋白。激活LANCL2途径可减少促炎性因子TNF-α、INF-γ、IL-6和MCP1，增加调节性T调节细胞的抗炎活性，因此LANCL2激动剂具有治疗炎症性肠病(IBD)的潜力。
发明内容
本申请的一个或多个实施方式提供了化合物或者其立体异构体或药学上可接受的盐，所述的化合物选自：
Figure PCTCN2021137836-appb-000001
本申请的一个或多个实施方式提供了药物组合物，所述药物组合物包括：
(1)本申请的化合物，或者其立体异构体或药学上可接受的盐；
(2)任选的一种或者多种其他活性成分；以及
(3)药学上可接受的载体和/或赋形剂。
本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体或药学上可接受的盐、或者本申请的药物组合物在制备炎症性肠病中的用途。
本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体或药学上可接受的盐、或者本申请的药物组合物在制备LANCL2激动剂中的用途。
本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体或药学上可接受的盐、或者本申请的药物组合物，其用于药物。
本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体或药学上可接受的盐、或者本申请的药物组合物，其用于治疗炎症性肠病。
本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体或药学上可接受的盐、或者本申请的药物组合物，其用作LANCL2激动剂。
本申请的一个或多个实施方式提供了治疗炎症性肠病的方法，其包括向有此需要的对象给予本申请的化合物或者其立体异构体或药学上可接受的盐、或者本申请的药物组合物。
本申请的一个或多个实施方式提供了激活LANCL2的方法，其包括向有此需要的对象给予本申请的化合物或者其立体异构体或药学上可接受的盐、或者本申请的药物组合物。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。
具体实施方式
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
实施例1
N,N'-((1s,3s,5s,7s)-金刚烷-1,3-二基)双(6-(1H-苯并[d]咪唑-2-基)吡啶啉酰胺)(化合物1)
N,N'-((1s,3s,5s,7s)-adamantane-1,3-diyl)bis(6-(1H-benzo[d]imidazol-2-yl)picolinamide)
Figure PCTCN2021137836-appb-000002
将6-(1H-苯并咪唑-2-基)吡啶甲酸1a(购自成都爱斯特化学技术有限公司，1g，4.18mmol)溶于4mL N，N-二甲基甲酰胺中，在0℃下搅拌10min，再加入N，N-二异丙基乙胺(650g，5.02mmol)，继续0℃下搅拌10min，再加入1-羟基苯并三唑(850mg，6.28mmol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.2g，6.28mmol)，继续0℃下搅拌10min，再加入1,3-金刚烷二胺1b(购自艾康生物，350mg，2.09mmol)，逐渐升温至80℃搅拌反应4h。将反应液冷却至室温，向反应体系中加入10mL水，乙酸乙酯(30mL×3)萃取，合并有机相，20mL饱和食盐水洗涤，有机相用硫酸钠干燥、旋干，残留物使用硅胶柱色谱(二氯甲烷/甲醇(v/v)＝10/1)分离提纯，得到化合物1，白色固体(400mg，32％产率，98％纯度)。
1H NMR(400MHz,DMSO-d6)δ＝13.33(s,2H),8.47-8.51(m,4H),8.13-8.20(m,4H),7.76(d,2H),7.69(d,2H),7.33-7.24(m,4H),2.71(s,2H),2.21-2.37(m,10H),1.74(s,2H)。
LC-MS m/z(ESI)＝609.30[M+1]。
实施例2
(2,6-二氮杂螺[3.3]庚烷-2,6-二基)双(((6-(1H-苯并[d]咪唑-2-基]吡啶-2-基)甲酮)(化合物2)
(2,6-diazaspiro[3.3]heptane-2,6-diyl)bis((6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)methanone)
Figure PCTCN2021137836-appb-000003
Figure PCTCN2021137836-appb-000004
将6-(1H-苯并咪唑-2-基)吡啶甲酸1a(购自成都爱斯特化学技术有限公司，1g，4.18mmol)溶于4mL N,N-二甲基甲酰胺中，在0℃下搅拌10min，再加入N,N-二异丙基乙胺(650mg，5.02mmol),继续0℃下搅拌10min，再加入1-羟基苯并三唑(850mg，6.28mmol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.2g，6.28mmol)，继续0℃下搅拌10min，再加入2,6-二氮杂螺[3.3]庚烷2a(205mg，2.09mmol)后，逐渐升温至80℃反应4h。将反应液冷却至室温，向反应体系中加入10mL水，乙酸乙酯(30mL×3)萃取，合并有机相，20mL饱和食盐水洗涤，无水硫酸钠干燥有机相，浓缩有机相，柱层析纯化(二氯甲烷/甲醇(v/v)＝20/1)，得化合物2，黄色固体800mg，产率73％。
1H NMR(400MHz,DMSO-d6)δ12.65(s,2H),8.45(d,2H),8.04(m,4H),7.72(d,4H),7.27(d,4H),5.08(m,4H),4.42(m,4H)。
LC-MS m/z(ESI)＝541.2[M+1]。
实施例3
(R)-4-((1Z,3E)-5-(4-(6-(1H-苯并[d]咪唑-2-基)吡啶酰)哌嗪-1-基)-2-甲基-5-氧代戊基-1,3-二烯-1-基)-4-羟基-3,5,5-三甲基环己-2-烯-1-酮(化合物3)
(R)-4-((1Z,3E)-5-(4-(6-(1H-benzo[d]imidazol-2-yl)picolinoyl)piperazin-1-yl)-2-methyl-5-oxopenta-1,3-dien-1-yl)-4-hydroxy-3,5,5-trimethylcyclohex-2-en-1-one
Figure PCTCN2021137836-appb-000005
按照化合物1的合成方法，将1a(购自成都爱斯特化学技术有限公司，1.2g)与3a(180mg)反应制备得到3b，再将3b(1.12g)与3c(购自华捷明生物科技，1.32g)按化合物1的合成方法分离得到1.1g白色固体化合物3，产率39.7％。
1H NMR(400MHz,DMSO-d 6)δ12.90(s,1H),8.39(dd,1H),8.13(t,1H),7.73(d,1H),7.68(d,1H),7.57(t,1H),7.25(dt,2H),7.00(d,1H),6.13-5.98(m,2H),5.81(s,1H),5.18(d,1H), 3.71-3.59(m,4H),3.60-3.41(m,4H),2.14-2.07(m,2H),1.96-1.88(m,3H),1.81(d,3H),0.99-0.88(m,6H)。
LC-MS m/z(ESI)＝554.66[M+1]。
实施例4
[4,4'-联哌啶]-1,1'-二酰基双((6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)甲酮)(化合物4)
[4,4'-bipiperidine]-1,1'-diylbis((6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)methanone)
Figure PCTCN2021137836-appb-000006
按照化合物1的合成方法，将1a(购自成都爱斯特化学技术有限公司，760mg)与4a(268mg)反应制备分离得到360mg淡黄色固体化合物4，产率37％。
1H NMR(400MHz,DMSO-d6)δ12.96(s,2H),8.36(ddd,2H),8.09(td,2H),7.71(s,2H),7.61-7.53(m,4H),7.23(s,5H),4.60(s,2H),3.58(d,2H),3.08(t,2H),2.77(t,2H),2.07(s,4H),1.92-1.76(m,2H),1.62(t,2H),1.44(s,2H),1.23(s,4H)。
LC-MS m/z(ESI)＝612.72[M+1]。
实施例5
((3as,6as)-四氢吡咯并[3,4-c]吡咯-2,5(1H,3H)-二基)双((6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)甲酮)(化合物5)
((3as,6as)-tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-diyl)bis((6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)methanone)
Figure PCTCN2021137836-appb-000007
按照化合物1的合成方法，将1a(购自成都爱斯特化学技术有限公司，3.8g)与5a(购自华捷明生物科技，900mg)反应制备分离得到400mg淡黄色化合物5，产率9.0％。
1H NMR(400MHz,DMSO-d 6)δ12.93(s,1H),12.88(s,1H),8.42(dd,1H),8.36(dd,1H),8.14(t,1H),8.08(t,1H),7.80(d,2H),7.74(d,1H),7.69(d,1H),7.61(d,1H),7.53(d,1H),7.33–7.16(m,4H),4.18(dd,1H),4.05(dd,1H),3.93(dd,1H),3.84(dd,1H),3.67(td,2H),3.51(td,2H),3.12–3.00(m,2H)。
LC-MS m/z(ESI)＝554.60[M+1]。
生物评价
1.与LANCL2结合亲和力常数(K D)的测定
使用Biacore S200进行化合物与LANCL2亲和力(K D值)检测，具体方法如下。将LANCL2蛋白固定于CM5传感器芯片，以MOPS(10mM MOPS，150mM NaCl，5％DMSO和0.05％Tween 20，pH 6.5)为运行缓冲液，将待测化合物稀释为0.024μM、0.049μM、0.098μM、0.19μM、0.39μM、0.78μM、1.56μM、3.12μM、6.25μM、12.5μM和25μM，进样流速30μL/min，接触时间90s，解离时间900s。结果如表1所示。
表1本发明化合物与LANCL2蛋白结合亲和力常数(K D)
实施例编号 K D/μM
化合物1 7.3μM
结论：本发明化合物与LANCL2蛋白具有良好的结合作用。
2.大鼠药代动力学(PK)
180-220g健康成年雄性SD大鼠(购买自成都达硕实验动物有限公司)，过夜禁食，给药后4h统一进食。灌胃口服80mg/kg(溶媒为0.5％MC溶液)本发明化合物，分别于0h、0.5h、2h、8h、24h采集血浆、结肠内容物及结肠组织，采用LC-MS/MS法测定样品内药物浓度，绘制血药浓度-时间曲线，采用WinNonlin 6.3软件计算主要药代动力学参数。结果如表2所示。
表2大鼠药代动力学实验结果
Figure PCTCN2021137836-appb-000008
注：ND表示未检测到。
结论：大鼠药代动力学实验结果显示，24h内检测到本发明化合物主要分布在结肠内容物中，血液中无分布，具有良好的肠道靶向性。
3.DSS诱导小鼠溃疡性结肠炎药效
实验动物为SPF健康雌性C57BL/6J小鼠，体重17-20g，共80只(购买自北京维通利华实验动物技术有限公司)。动物饲养于小鼠专用饲养笼内，温度20±2℃，湿度40-70％，12h明暗交替，常规普通维持饲料喂养，自由饮水。
将小鼠随机分组，每组10只，分组及给药情况如表3所示。模型组和给药组动物自由饮水3％DSS水溶液，连续饮用至溃疡性结肠炎模型建立成功，撤掉DSS水溶液，后续正常饮水。随时连续给与对照品(WO2016064445专利实施例2化合物，购买自MCE公司) 与本发明化合物，正常组和模型组给予等体积溶媒。每天观察记录动物的情况，并计算DAI评分；试验结束时解剖动物，进行结肠重量和长度、脾脏重量检测。实验结果如表3所示。
表3 DSS诱导小鼠溃疡性结肠炎药效
组别 给药时间/(天) DAI评分
正常组 10 0.6
模型组 10 4.2
对照品50mg/kg 10 2.8
化合物1 10mg/kg 10 2.8
化合物1 50mg/kg 10 1.2
结论：实验结果表明，本发明化合物给药剂量仅为对照品剂量1/5时即达到相同的疗效，而同为50mg/kg剂量时，药效更为显著。
本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。

Claims (4)

  1. 化合物或者其立体异构体或药学上可接受的盐，所述的化合物选自：
    Figure PCTCN2021137836-appb-100001
  2. 药物组合物，所述药物组合物包括：
    (1)权利要求1所述的化合物，或者其立体异构体或药学上可接受的盐；
    (2)任选的一种或者多种其他活性成分；以及
    (3)药学上可接受的载体和/或赋形剂。
  3. 权利要求1所述的化合物或者其立体异构体或药学上可接受的盐、或者权利要求2所述的药物组合物在制备炎症性肠病中的用途。
  4. 权利要求1所述的化合物或者其立体异构体或药学上可接受的盐、或者权利要求2所述的药物组合物在制备LANCL2激动剂中的用途。
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