WO2024255920A1 - 噻吩-2-羧酸衍生物、其制备方法及医药用途 - Google Patents

噻吩-2-羧酸衍生物、其制备方法及医药用途 Download PDF

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WO2024255920A1
WO2024255920A1 PCT/CN2024/107199 CN2024107199W WO2024255920A1 WO 2024255920 A1 WO2024255920 A1 WO 2024255920A1 CN 2024107199 W CN2024107199 W CN 2024107199W WO 2024255920 A1 WO2024255920 A1 WO 2024255920A1
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alkyl
carboxylic acid
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thiophene
pharmaceutically acceptable
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江程
胡庆华
王雨杭
周梦泽
王平平
高蕊
李欣玥
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a compound, a preparation method and an application thereof, and in particular to a thiophene-2-carboxylic acid derivative, a preparation method and a medical application thereof.
  • adenosine-5'-triphosphate ATP
  • UDP uridine-5'-triphosphate
  • P1 and P2Y receptors P2X receptors and P2Y receptors
  • P2YRs belong to the family of G protein-coupled receptors (GPCRs) and consist of P2Y1-like receptors (P2Y 1,2,4,6,11 ) and P2Y12-like (P2Y 12,13,14 ).
  • GPCRs G protein-coupled receptors
  • the P2Y receptor family of G protein-coupled receptors reported to date includes 8 subtypes (P2Y 1, 2, 4 , 6, 11, 12, 13, 14), which are widely distributed in various cells and tissues, and the homology between the subtypes is relatively low, so different subtypes have high selectivity for ligands.
  • P2Y 1, 2, 4, and 6 receptors bind to G q and activate the PLC pathway; P2Y 12, 13, and 14 receptors bind to Gi to inhibit the activity of adenylate cyclase; P2Y 4 receptors couple to two G proteins, G q /G i ; and P2Y 11 couples to two G proteins, G q /G s .
  • P2Y receptors mediate a series of biological effects such as immune regulation, platelet aggregation, and smooth muscle cell proliferation.
  • the P2Y14 receptor is activated by at least four naturally occurring UDP sugars, particularly UDP glucose (UDPG).
  • UDP glucose UDP glucose
  • the P2Y14 receptor has been found to be widely expressed in a range of human tissues, including the brain, heart, adipose tissue, placenta, intestine, and hematopoietic stem cells.
  • the P2Y14 receptor inhibits adenylate cyclase (AC) by activating the Gi protein coupled to it, reducing the production of intracellular 3',5' cyclic adenosine monophosphate (cAMP) and the corresponding biological effects.
  • AC adenylate cyclase
  • the P2Y14 receptor has been shown to be a potential target for innate immune inflammatory diseases such as diabetes, cystic fibrosis, renal sterile inflammation, acute gouty arthritis, and allergic diseases.
  • the P2Y14 receptor promotes the recruitment and chemotaxis of neutrophils and macrophages, releasing proinflammatory cytokines, chemokines, and mast cell mediators.
  • P2Y14 receptors may be a potential therapeutic target for innate immune system diseases.
  • the purpose of the present invention is to provide a class of novel thiophene-2-carboxylic acid derivatives and pharmaceutically acceptable salts thereof having P2Y14 receptor antagonism. Another purpose of the present invention is to provide a method for preparing the above thiophene-2-carboxylic acid derivatives. Another purpose of the present invention is to provide a use of the above thiophene-2-carboxylic acid derivatives in the treatment of inflammatory diseases.
  • R1 is selected from CnH2n - COOR5 , CnH2n - CONHR5 , CnH2n -CN and tetrazole , wherein n is selected from 0, 1 and 2;
  • R2 is selected from H or halogen
  • R3 is selected from C5-10 membered monocyclic aryl, C5-14 membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O or S, C3-10 membered cycloalkyl or C3-10 membered heterocycloalkyl; the C5-10 membered monocyclic aryl, C5-14 membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O or S, C3-10 membered cycloalkyl or C3-10 membered heterocycloalkyl are independently optionally substituted by 1 to 5 substituents selected from the following: C1-6 alkyl, halogen, cyano, halogenated C1-4 alkyl, OH, C1-6 alkoxy, dimethylamino;
  • X is selected from O, S, NH;
  • R4 is selected from:
  • Ring is a C 5-7 membered monocyclic aromatic group, or a C 5-7 membered monocyclic heteroaromatic group containing 1 to 4 heteroatoms selected from N, O or S;
  • R 5 is H, C 2-6 alkyl, C 0-3 OOCCH 3 , C 0-3 OCNMe 2 , C 0-3 NMe 2 , wherein the C 2-6 alkyl is unsubstituted or substituted by 1 to 6 substituents selected from the following: F, OH, C 1-3 alkoxy, C 3-6 cycloalkyl, aryl;
  • R 11 is selected from the following substituents: H, NO 2 , CN, OH, NH 2 , F, Cl, Br, I, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 0-6 heteroalkyl-NR 7 R 8 , C 0-6 heteroalkyl-COR 8 , C 0-6 heteroalkyl-CO 2 R 8 , C 0-6 heteroalkyl-CONR 7 R 8 , C 0-6 heteroalkyl-SO 3 R 8 , C 0-6 heteroalkyl-SO 2 NR 7 R 8 , or in R 11 , two adjacent substituents form a 3-8 membered saturated or unsaturated ring containing carbon atoms and optionally containing 1-3 heteroatoms selected from N, O or S;
  • R7 is H
  • R 8 is selected from H, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 heteroalkyl-C 3-10 cycloalkyl, C 1-10 heteroalkyl-C 3-10 heterocycloalkyl, C 1-10 heteroalkyl-(5-membered heteroaryl), wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl and heteroaryl of the C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-10 heteroalkyl-C 3-10 cycloalkyl, C 1-10 heteroalkyl-C 3-10 heterocycloalkyl, C 1-10 heteroalkyl-(5-membered heteroaryl) are unsubstituted or independently substituted with 1-7 substituents selected from the following: OR 9 , C 1-6 alkyl, CO 2 R 9 , CONR 9 R 10 , NR 9 COR 9 , C
  • R 1 is selected from CH 2 COOR 5 , COOR 5 or CONHR 5 ;
  • R2 is selected from H, F, Cl, Br;
  • R3 is selected from C5-6 membered monocyclic aryl, C5-6 membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O or S, C5-6 membered cycloalkyl or C5-6 membered heterocycloalkyl; the C5-6 membered monocyclic aryl, C5-6 membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O or S, C5-6 membered cycloalkyl or C5-6 membered heterocycloalkyl are independently optionally substituted by 1 to 5 substituents selected from the following: C1-6 alkyl, halogen, cyano, halogenated C1-4 alkyl, OH, C1-6 alkoxy, dimethylamino.
  • R2 is selected from H or F
  • R3 is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, imidazolyl; the phenyl, pyridyl, pyrazinyl, pyrimidinyl, imidazolyl are independently optionally substituted by 1 to 5 substituents selected from the following: C1-6 alkyl, halogen, cyano, halogenated C1-4 alkyl, OH, C1-6 alkoxy, dimethylamino; X is selected from O, S, NH;
  • R4 is selected from:
  • Ring is phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, furanyl, thiazolyl, isothiazole, imidazolyl, pyrazolyl;
  • R 5 is H, C 2 H 5 , C 2-3 alkyl- C 3-6 cycloalkyl, C 2-3 alkyl-aryl, C 2-3 OOCCH 3 , C 2-3 OCNMe 2 , C 2-3 NMe 2 ;
  • R7 is H
  • R 8 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, CH 2 CONH 2 , CH 2 COMe 2 , CH 2 CH 2 OH, CH 2 CH 2 Me, (CH2) 3 OH, ( CH 3 ) 3 OMe, (CH 2 ) 4 OH, (CH 2 ) 4 OMe, (CH 2 ) 5 OH, (CH 2 ) 2 COOH, (CH 2 ) 3 COOH, (CH 2 ) 4 COOH, (CH 2 ) 5 COOH, (CH 2 ) 2 CH(CH 3 )COOH, C(CH 2 OH) 3 , C(CH 2 OH) 2 CH 3 , CH 2 CH(CH 3 )OH, (CH 2 ) 2 CF 3 , (CH 2 ) 3 CF 3 , (CH 2 ) 4 CF 3 ,
  • R 11 is selected from H, NO 2 , CN, OH, NH 2 , F, Cl, Br, I, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, COR 8 , CONR 7 R 8 , CO 2 R 8 , SO 2 NR 7 R 8 , SO 3 R 8 .
  • R 4 is selected from:
  • Ring is phenyl, pyrimidinyl, pyridazinyl, isothiazolyl;
  • R 11 is selected from H, NO 2 , CN, OH, NH 2 , F, Cl, Br, I, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, CONR 7 R 8 , CO 2 R 8 , SO 2 NR 7 R 8 , SO 3 R 8 ;
  • R7 is H
  • R8 is selected from H, C1-6 alkyl, C3-6 cycloalkyl, CH2CONH2 , CH2COMe2 , CH2CH2OH , CH2CH2Me , ( CH2 )3OH, (CH3) 3OMe , ( CH2 ) 4OH , ( CH2 )4OMe, ( CH2 )2COOH , (CH2)3COOH, ( CH2 ) 4COOH, ( CH2 ) 2CH ( CH3 )COOH , C ( CH2OH ) 3 , C ( CH2OH ) 2CH3 , CH2CH ( CH3 ) OH,
  • the compound of general formula (I) is preferably selected from the following compounds:
  • the method for preparing the thiophene-2-carboxylic acid derivative and its enantiomers, diastereomers, tautomers, N-oxides, solvates, physiologically hydrolyzable esters, preparations and pharmaceutically acceptable salts comprises the following steps:
  • Compound D is a compound of formula (I), wherein R 1 , R 2 , R 3 , R 4 and X are the same as above.
  • a pharmaceutical composition comprising the compound of general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipients refer to various conventional excipients required when preparing different dosage forms, such as diluents, adhesives, disintegrants, glidants, lubricants, flavoring agents, inclusion materials, adsorbents, etc., which are prepared into any commonly used oral preparations by conventional preparation methods, such as granules, powders, tablets, capsules, pills, oral liquids, decoctions, and pellets.
  • the present invention has the following advantages: the present invention discloses a type of P2Y 14 receptor Thiophene-2-carboxylic acid derivatives and pharmaceutically acceptable salts thereof having inhibitory effects on the body are provided. Pharmacological experiments have confirmed that the compounds have significant inhibitory effects on P2Y14 receptors and can be used as drugs for treating inflammatory diseases.
  • Figure 5 is the IL-1 ⁇ level in the supernatant of THP-I cell culture medium, wherein the data are mean ⁇ standard deviation, and variance analysis was performed using one-way anova ( #### represents P ⁇ 0.0001 compared with the normal group, * represents P ⁇ 0.05 compared with the model control group, # represents P ⁇ 0.01 compared with the model control group, *** represents P ⁇ 0.001 compared with the model control group, * *** represents P ⁇ 0.0001 compared with the model control group);
  • Figure 6 shows the gene expression levels of various inflammatory factors in the peritoneal fluid of mice, wherein the data are mean ⁇ standard deviation, and variance analysis was performed using one-way anova ( #### represents P ⁇ 0.0001 compared with the normal group, * represents P ⁇ 0.05 compared with the model control group, # represents P ⁇ 0.01 compared with the model control group, *** represents P ⁇ 0.001 compared with the model control group, * *** represents P ⁇ 0.0001 compared with the model control group);
  • Figure 7 is the gene expression level of each inflammatory factor in the peritoneal fluid of mice, wherein the data are mean ⁇ standard deviation, and variance analysis was performed using one-way anova ( #### represents P ⁇ 0.0001 compared with the normal group, * represents P ⁇ 0.05 compared with the model control group, # represents P ⁇ 0.01 compared with the model control group, *** represents P ⁇ 0.001 compared with the model control group, * *** represents P ⁇ 0.0001 compared with the model control group);
  • Figure 8 shows the gene expression levels of various inflammatory factors in the peritoneal fluid of mice, where the data are mean ⁇ standard deviation, and variance analysis was performed using one-way anova ( #### represents P ⁇ 0.0001 compared with the normal group, * represents P ⁇ 0.05 compared with the model control group, # represents P ⁇ 0.01 compared with the model control group, *** represents P ⁇ 0.001 compared with the model control group, * *** represents P ⁇ 0.0001 compared with the model control group).
  • the product obtained in the previous step was dissolved in a mixed solvent of 4 ml of anhydrous tetrahydrofuran, and triethylamine (0.98 g, 0.97 mmol) and 4-methylbenzoyl chloride (0.97 g, 0.63 mmol) were slowly added dropwise at 0°C. After the addition was completed, the mixture was moved to room temperature and stirred for 4 hours. After the reaction was complete, water was added and extracted with ethyl acetate (3 times). The organic phases were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4.
  • Step 2 Ethyl 5-((6-methylpyridin-3-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylate (4)
  • Step 3 5-((6-methylpyridin-3-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylic acid (5)
  • the product obtained in the previous step was dissolved in a mixed solvent of 4 ml of anhydrous tetrahydrofuran, and triethylamine (0.99 g, 0.99 mmol) and 4-methylbenzoyl chloride (0.98 g, 0.64 mmol) were slowly added dropwise at 0°C. After the addition was completed, the mixture was moved to room temperature and stirred for 4 hours. After the reaction was complete, water was added and extracted with ethyl acetate (3 times). The organic phases were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4.
  • Step 3 4-(4-methylbenzamido)-5-(p-tolylamino)thiophene-2-carboxylic acid (8)
  • the product obtained in the previous step was dissolved in a mixed solvent of 4 ml of anhydrous tetrahydrofuran, and triethylamine (0.94 g, 0.93 mmol) and 4-methylbenzoyl chloride (0.94 g, 0.60 mmol) were slowly added dropwise at 0°C. After the addition was completed, the mixture was moved to room temperature and stirred for 4 hours. After the reaction was complete, water was added and extracted with ethyl acetate (3 times). The organic phases were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4.
  • Step 3 4-(4-Methylbenzamido)-5-(p-tolylthio)thiophene-2-carboxylic acid (8)
  • the product obtained in the previous step was dissolved in 4 ml of anhydrous dichloromethane, and 6-methylnicotinamide (0.10 g, 0.73 mmol), triethylamine (0.10 g, 0.97 mmol) and Carter condensation agent (PyBOP) (0.38 mg, 0.73 mmol) were added in sequence. After the addition was completed, the reaction was stirred at room temperature for 10 hours. After the reaction was complete, the insoluble matter was filtered out, and water was added to the filtrate, and ethyl acetate was extracted (3 times). The organic phases were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4.
  • HEK293 cells stably expressing P2Y14 receptor were cultured in DMEM medium (containing 10% fetal bovine serum, 100U/ml penicillin and 100 ⁇ g/ml streptomycin). Before the experiment, cells were seeded into culture plates and replaced with serum-free medium. The seeding density was 1 ⁇ 10 5 cells/well. The cells were cultured at 37°C, 95% O 2 , and 5% CO 2 humidity. IBMX was added to inhibit PDEs activity to ensure that cAMP was at a high level. AC agonist Forskolin (30 ⁇ M) was used to stimulate the production of cellular cAMP. Different concentrations of the test compound (0.01, 0.1, 1, 10, 100nm) were added in advance, and PPTN was used as a positive control.
  • Human THP-1 cells were cultured in RPMI-1640 medium (containing 10% fetal bovine serum, 100U/ml penicillin and 100 ⁇ g/ml streptomycin), inoculated into culture plates before the experiment, with an inoculation density of 1 ⁇ 10 5 cells/well, and cultured at 37°C, 95% O 2 , 5% CO 2 humidity. Before the experiment, 100ng/ml PMA was added to each well and incubated for 24h to induce THP-1 cells to differentiate into macrophages.
  • RPMI-1640 medium containing 10% fetal bovine serum, 100U/ml penicillin and 100 ⁇ g/ml streptomycin
  • Test compound 5 (2.5, 5, 10 ⁇ M) and PPTN (5 ⁇ M) were added to the culture medium in advance for intervention, and LPS with a final concentration of 100ng/ml was added to the cells 1h later, and ATP with a final concentration of 5mM was added 3h later.
  • LPS with a final concentration of 100ng/ml was added to the cells 1h later
  • ATP with a final concentration of 5mM was added 3h later.
  • the following indicators were measured 1h later:
  • the level of IL-1 ⁇ in the supernatant of the cell culture medium was detected by ELISA kit (Shenzhen Xinbosheng). The results are shown in Figure 5.
  • LPS caused a significant increase in the level of IL-1 ⁇ in the supernatant of the THP-1 cell culture medium, indicating that the model was successfully established; different doses of the test compound were able to downregulate the level of IL-1 ⁇ in the supernatant of the cell culture medium to varying degrees, and there were significant differences compared with the model control group; PPTN also showed the expected effect, indicating that the experimental results were true and reliable.
  • mice Male clean-grade ICR mice were fed with free water and food, and were illuminated for 12 hours a day at an ambient temperature of 25 ⁇ 2°C.
  • the animals were divided into several groups: normal control group, model control group, and drug-treated group (test compound and dexamethasone).
  • the acute peritonitis model was induced by a single intraperitoneal injection of LSP, while the normal control group was injected with an equal amount of saline into the joint cavity.
  • Each drug-treated group was given the test compound 5 (5, 10, 20 mg/kg) and dexamethasone (10 mg/kg) by intra-articular injection. 6 hours after injection, 8 mL of PBS was injected to collect the peritoneal fluid. The levels of various inflammatory factors in the collected fluid were detected.
  • LPS caused a significant increase in the gene expression level of inflammatory factors in the mouse peritoneal fluid, which improved the success of modeling; different doses of test compounds were able to downregulate the gene expression level of inflammatory factors to different degrees, and compared with the model control group, they all showed significant differences; dexamethasone also showed the expected effect, indicating that the experimental results are true and credible.

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Abstract

提供了噻吩-2-羧酸衍生物、其制备方法及医药用途，如通式(I)所示的噻吩-2-羧酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐。提供了一类对P2Y 14受体有抑制作用的噻吩-2-羧酸衍生物及其可药用盐，该类化合物通过药理学实验证实，其对P2Y 14受体具有显著的抑制作用，尤其可以作为治疗炎症疾病药物。

Description

噻吩-2-羧酸衍生物、其制备方法及医药用途 技术领域
本发明涉及化合物及其制法和用途，具体涉及噻吩-2-羧酸衍生物、其制备方法及医药用途。
背景技术
当身体受到压力或损伤时，各种重要的细胞内分子，如腺苷-5'-三磷酸(ATP)和尿苷-5'-三磷酸(UTP)，会被特定的组织或器官释放到细胞外液中。这些核苷酸具有通过与细胞表面受体结合来调节先天和适应性免疫反应的能力，被结合的受体被鉴定为嘌呤能受体，主要分为腺苷(P1)和核苷酸(P2)受体。P2家族进一步被分为两个亚家族，P2X受体和P2Y受体(P2YRs)。P2YRs属于G蛋白偶联受体(GPCRs)家族，由P2Y1样受体(P2Y1,2,4,6,11)和P2Y12样(P2Y12,13,14)组成。已经报道的G蛋白偶联受体的P2Y受体家族包含8种亚型(P2Y1、2、4、6、11、12、13、14)，广泛分布于各种细胞和组织中，而且各亚型之间同源性比较低，因此不同的亚型对配体具有很高的选择性。其中P2Y1、2、4、6受体结合Gq并激活PLC途径；P2Y12、13、14受体结合Gi抑制腺苷酸环化酶的活性；P2Y4受体偶联Gq/Gi两种G蛋白；P2Y11偶联Gq/Gs两种G蛋白。P2Y受体介导免疫调节、血小板聚集、平滑肌细胞增殖等一系列生物学效应。
P2Y14受体被至少四种自然存在的UDP糖，特别是UDP葡萄糖(UDPG)激活。P2Y14受体已被发现在一系列人类组织中广泛表达，包括大脑、心脏、脂肪组织、胎盘、肠道和造血干细胞。P2Y14受体通过激活与其偶联的Gi蛋白，抑制腺苷酸环化酶(AC)，减少细胞内3',5'环磷酸腺苷(cAMP)的产生及相应的生物学效应。
P2Y14受体已被证明是先天免疫炎症性疾病的潜在靶点，如糖尿病、囊性纤维化、肾无菌性炎症、急性痛风性关节炎和过敏性疾病。P2Y14受体可促进中性粒细胞和巨噬细胞的招募和趋化，释放促炎细胞因子、趋化因子和肥大细胞介质。在COVID-19引起的重症病例中，很大一部分严重病程是由系统性炎症引起的，称为“细胞因子风暴”。基于P2Y14受体对中性粒细胞的作用和COVID-19致重症患者中发现的高水平UDPG，一种通过P2Y14受体拮抗剂防止中性粒细胞趋化失控的机制被提出，以避免细胞因子风暴和全身炎症，从而降低患者死亡率。此外，P2Y14受体基因被敲除可抑制巨噬细胞的募集和组织炎症，减轻高脂肪饮食诱导的胰岛素抵抗。另一项研究表明，糖原代谢也会增加巨噬细胞中UDPG的水平和P2Y14受体的数量，阻断这一糖原代谢途径可有效抑制脂多糖(LPS)诱导的急性腹膜炎。综上所述，P2Y14受体可能是先天性免疫系统疾病的潜在治疗靶点。
目前对P2Y14受体拮抗剂的研究仅仅报道了4种结构类型的化合物(嘧啶并哌啶类、2-萘酸类、3-取代苯甲酸类和吡唑-3-羧酸类)，但还都在临床前研究阶段。其中活性和选择性最高的为2-萘酸类，然而目前报道的2-萘酸类结构的拮抗剂存在溶解性差、口服生物利用度低、合成纯化难度大等缺陷，给进一步讨论构效关系及生物学评价带来了较大的困难。因此寻找新结构类型的P2Y14受体拮抗剂，改善2-萘酸类拮抗剂存在的成药性差等问题，成为发现活性强、选择性好的P2Y14受体拮抗剂的新策略。
发明内容
发明目的：本发明的目的在于提供一类结构新颖的且具有P2Y14受体拮抗作用的噻吩-2-羧酸衍生物及其可药用盐。本发明的另一个目的是提供一种上述噻吩-2-羧酸衍生物的制备方法。本发明还有一个目的是提供一种上述噻吩-2-羧酸衍生物在治疗炎症性疾病方面的应用。
技术方案：本发明所述的通式(I)所示的噻吩-2-羧酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐：
R1选自CnH2n-COOR5、CnH2n-CONHR5、CnH2n-CN及四氮唑，其中n选自0、1及2；
R2选自H或卤素；
R3选自C5-10元单环芳基、含有1～4个选自N、O或S杂原子的C5-14元单环杂芳基、C3-10元环烷基或C3-10元杂环烷基；所述C5-10元单环芳基、含有1～4个选自N、O或S杂原子的C5-14元单环杂芳基、C3-10元环烷基或C3-10元杂环烷基独立地任选地被1至5个选自下列的取代基取代：C1-6烷基、卤素、氰基、卤代C1-4烷基、OH、C1-6烷氧基、二甲氨基；
X选自O、S、NH；
R4选自：
其中，Ring为C5-7元单环芳基、含有1～4个选自N、O或S杂原子的C5-7元单环杂芳基；
R5为Η、C2-6烷基、C0-3OOCCH3、C0-3OCNMe2、C0-3NMe2，其中，C2-6烷基未被取代或被1至6个选自下列的取代基取代：F、OH、Cl-3烷氧基、C3-6环烷基、芳基；
其中，R11选自如下取代基：H、NO2、CN、OH、NH2、F、Cl、Br、I、C1-6烷基、卤代-C1-6烷基、C1-6烷氧基、卤代-C1-6烷氧基、C0-6杂烷基-NR7R8、C0-6杂烷基-COR8、C0-6杂烷基-CO2R8、C0-6杂烷基-CONR7R8、C0-6杂烷基-SO3R8、C0-6杂烷基-SO2NR7R8，或R11中，两个毗邻的取代基形成含有碳原子及任选地含有1-3个选自N、O或S的杂原子的3-8元饱和或不饱和环；
R7为H；
R8选自H、Cl-10烷基、C3-10环烷基、C3-10杂环烷基、Cl-10杂烷基-C3-10环烷基，Cl-10杂烷基-C3-10杂环烷基、Cl-10杂烷基-(5元杂芳基)，其中，所述Cl-10烷基、C3-10环烷基、C3-10杂环烷基、Cl-10杂烷基-C3-10环烷基，Cl-10杂烷基-C3-10杂环烷基、Cl-10杂烷基-(5元杂芳基)的烷基、亚烷基、环烷基、杂环烷基及杂芳基未被取代或独立地被1-7个选自下列的取代基取代：OR9、C1-6烷基、CO2R9、CONR9R10、NR9COR9、C3-10杂环烷基；R9选自H、C1-6烷基，其中，C1-6烷基未被取代或被1-6个选自下列的取代基取 代：F、O-C1-3烷基。
所述的噻吩-2-羧酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐，R1选自CH2COOR5、COOR5或CONHR5；
R2选自H、F、Cl、Br；
R3选自C5-6元单环芳基、含有1～4个选自N、O或S杂原子的C5-6元单环杂芳基、C5-6元环烷基或C5-6元杂环烷基；所述C5-6元单环芳基、含有1～4个选自N、O或S杂原子的C5-6元单环杂芳基、C5-6元环烷基或C5-6元杂环烷基独立地任选地被1至5个选自下列的取代基取代：C1-6烷基、卤素、氰基、卤代C1-4烷基、OH、C1-6烷氧基、二甲氨基。
所述的噻吩-2-羧酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐，R1选自COOR5；
R2选自H或F；
R3选自苯基、吡啶基、吡嗪基、嘧啶基、咪唑基；所述苯基、吡啶基、吡嗪基、嘧啶基、咪唑基独立地任选地被1至5个选自下列的取代基取代：C1-6烷基、卤素、氰基、卤代C1-4烷基、OH、C1-6烷氧基、二甲氨基；X选自O、S、NH；
R4选自：
Ring为苯基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡咯基、噻吩基、呋喃基、噻唑基、异噻唑、咪唑基、吡唑基；
R5为Η、C2H5、C2-3烷基-C3-6环烷基、C2-3烷基-芳基、C2-3OOCCH3、C2-3OCNMe2、C2-3NMe2；
R7为H；
R8选自H、C1-6烷基、C3-6环烷基、CH2CONH2、CH2COMe2、CH2CH2OH、CH2CH2Me、(CH2)3OH、(CH3)3OMe、(CH2)4OH、(CH2)4OMe、(CH2)5OH、(CH2)2COOH、(CH2)3COOH、(CH2)4COOH、(CH2)5COOH、(CH2)2CH(CH3)COOH、C(CH2OH)3、C(CH2OH)2CH3、CH2CH(CH3)OH、(CH2)2CF3、(CH2)3CF3、(CH2)4CF3、
R11选自H、NO2、CN、OH、NH2、F、Cl、Br、I、C1-6烷基、卤代-C1-6烷基、C1-6烷氧基、卤代-C1-6烷氧基、COR8、CONR7R8、CO2R8、SO2NR7R8、SO3R8。
所述的噻吩-2-羧酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐，R4选自：
Ring为苯基、嘧啶基、哒嗪基、异噻唑基；
R11选自H、NO2、CN、OH、NH2、F、Cl、Br、I、C1-6烷基、卤代-C1-6烷基、C1-6烷氧基、卤代-C1-6烷氧基、CONR7R8、CO2R8、SO2NR7R8、SO3R8；
R7为H；
R8选自H、C1-6烷基、C3-6环烷基、CH2CONH2、CH2COMe2、CH2CH2OH、CH2CH2Me、(CH2)3OH、(CH3)3OMe、(CH2)4OH、(CH2)4OMe、(CH2)2COOH、(CH2)3COOH、(CH2)4COOH、(CH2)2CH(CH3)COOH、C(CH2OH)3、C(CH2OH)2CH3、CH2CH(CH3)OH、
所述的噻吩-2-羧酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐，通式(I)化合物优选自如下化合物：
所述的噻吩-2-羧酸衍生物及其对映异构体、非对映异构体、互变异构体、N-氧化物、溶剂合物、生理可水解酯、制剂及药学上可接受的盐的制备方法，包括如下步骤：
(1)通式化合物A进行硝化反应制得通式B化合物；
(2)通式化合物B与不同酚类衍生物进行取代反应制得通式化合物C；
(3)通式化合物C先经硝基还原，再与不同羧酸或磺酸衍生物进行缩合反应，或不同的烃基衍生物进行取代反应、最后经脱保护基反应制得通式化合物D；
化合物D即通式(I)化合物，R1、R2、R3、R4及X同上述。
药物组合物，其中含有所述的通式(I)化合物或其药学上可接受的盐及药学上可接受的辅料。
所述的通式(I)化合物或其药学上可接受的盐、或所述的药物组合物在制备P2Y14受体拮抗剂药物中的用途。
所述的通式(I)化合物或其药学上可接受的盐或所述的药物组合物在制备治疗炎症疾病药物中的用途。
所述的用途，所述药物添加药学上可接受的辅料制成不同剂型。
所述药学上可接受的辅料，是指制备不同剂型时加入所需的各种常规辅料，例如稀释剂、黏合剂、崩解剂、助流剂、润滑剂、矫味剂、包合材料、吸附材料等以常规的制剂方法制备成任何一种常用的口服制剂，例如可以是颗粒剂、散剂、片剂、胶囊剂、丸剂、口服液、汤剂、滴丸剂等。
有益效果：本发明与现有技术相比，具有如下优点：本发明公开了一类对P2Y14受 体有抑制作用的噻吩-2-羧酸衍生物及其可药用盐，该类化合物通过药理学实验证实，其对P2Y14受体具有显著的抑制作用，尤其可以作为治疗炎症疾病药物。
附图说明
图1是THP-I细胞UDPG/P2Y14受体信号通路下游蛋白相对表达，其中，数据是平均值土标准差(n＝4)，用one-way anova进行方差分析(####代表与正常组比较P<0.0001，*代表与模型对照组比较P<0.05，#代表与模型对照组比较P<0.01，***代表与模型对照组比较P<0.001，****代表与模型对照组比较P<0.0001)；
图2是THP-I细胞UDPG/P2Y14受体信号通路下游蛋白相对表达，其中，数据是平均值土标准差(n＝4)，用one-way anova进行方差分析(####代表与正常组比较P<0.0001，*代表与模型对照组比较P<0.05，#代表与模型对照组比较P<0.01，***代表与模型对照组比较P<0.001，****代表与模型对照组比较P<0.0001)；
图3是THP-I细胞UDPG/P2Y14受体信号通路下游蛋白相对表达，其中，数据是平均值土标准差(n＝4)，用one-way anova进行方差分析(####代表与正常组比较P<0.0001，*代表与模型对照组比较P<0.05，#代表与模型对照组比较P<0.01，***代表与模型对照组比较P<0.001，****代表与模型对照组比较P<0.0001)；
图4是THP-I细胞UDPG/P2Y14受体信号通路下游蛋白相对表达，其中，数据是平均值土标准差(n＝4)，用one-way anova进行方差分析(####代表与正常组比较P<0.0001，*代表与模型对照组比较P<0.05，#代表与模型对照组比较P<0.01，***代表与模型对照组比较P<0.001，****代表与模型对照组比较P<0.0001)；
图5是THP-I细胞培养基上清液中IL-1β水平，其中，数据是平均值土标准差，用one-way anova进行方差分析(####代表与正常组比较P<0.0001，*代表与模型对照组比较P<0.05，#代表与模型对照组比较P<0.01，***代表与模型对照组比较P<0.001，****代表与模型对照组比较P<0.0001)；
图6是小鼠腹腔液中各炎性因子的基因表达水平，其中，数据平均值土标准差，用one-way anova进行方差分析(####代表与正常组比较P<0.0001，*代表与模型对照组比较P<0.05，#代表与模型对照组比较P<0.01，***代表与模型对照组比较P<0.001，****代表与模型对照组比较P<0.0001)；
图7是小鼠腹腔液中各炎性因子的基因表达水平，其中，数据平均值土标准差，用one-way anova进行方差分析(####代表与正常组比较P<0.0001，*代表与模型对照组比较P<0.05，#代表与模型对照组比较P<0.01，***代表与模型对照组比较P<0.001，****代表与模型对照组比较P<0.0001)；
图8是小鼠腹腔液中各炎性因子的基因表达水平，其中，数据平均值土标准差，用one-way anova进行方差分析(####代表与正常组比较P<0.0001，*代表与模型对照组比较P<0.05，#代表与模型对照组比较P<0.01，***代表与模型对照组比较P<0.001，****代表与模型对照组比较P<0.0001)。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中，以下所述的实施例是为了更好的阐述本发明，并不是用来限制本发明的范围。
实施例1和实施例2
步骤一：5-溴-4-硝基噻吩-2-甲酸乙酯(1a)
将5-溴噻吩-2-甲酸乙酯(5.00g,21.27mmol)分批滴加到冷却到-20℃的发烟硝酸，控制温度不高于-20℃。加完在此温度下反应两个小时，TLC监测反应完全。将反应液加至冰水中，用乙酸乙酯萃取(3次)。合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥。硅胶柱层析纯化(石油醚/乙酸乙酯＝50:1)，得到淡黄色固体2.15g，产率36.09％。1H NMR(300MHz,Chloroform-d)δ8.15(s,1H),4.38(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H)。
步骤二：5-(4-氟苯氧基)-4-硝基噻吩-2-甲酸乙酯(1b)
将5-溴-4-硝基噻吩-2-甲酸乙酯(0.20g,0.71mmol)溶于N,N-二甲基甲酰胺(4mL)中，加入K2CO3(0.20g,1.43mmol)和4-氟苯酚(0.12g,1.07mmol)，室温下搅拌混合物4h。反应完全后，加水，乙酸乙酯萃取(3次)。合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥。硅胶柱层析纯化(石油醚/乙酸乙酯＝20:1)，得到淡黄色固体0.21g，产率94.48％。1H NMR(300MHz,Chloroform-d)δ(ppm)8.13(s,1H),7.31(dt,J＝6.7,2.1Hz,2H),7.26–7.16(m,2H),4.34(q,J＝7.1Hz,2H),1.36(t,J＝7.1Hz,3H)。
步骤三：5-(4-氟苯氧基)-4-(4-甲基苯甲酰氨基)噻吩-2-甲酸乙酯(1)
将5-(4-氟苯氧基)-4-硝基噻吩-2-甲酸乙酯(0.15g,0.48mmol)溶于乙醇/水(10/1)(5ml)混合溶剂中，加入NH4Cl(0.26g,4.82mmol),0℃条件下缓慢加入铁粉(0.27g,4.82mmol),加入完毕后，继续搅拌30min，85℃回流加热4h。反应完全后，使用硅藻土过滤，减压除去溶剂得黄色油状物。
将上一步得到的产物溶于4ml无水四氢呋喃的混合溶剂中，0℃条件下缓慢滴加三乙胺(0.98g,0.97mmol)和4-甲基苯甲酰氯(0.97g,0.63mmol)，加入完毕后，移至室温搅拌4h。反应完全后，加水，乙酸乙酯萃取(3次)。合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥。硅胶柱层析纯化(石油醚/乙酸乙酯＝8:1)，得到淡黄色固体0.14g，产率73.46％。1H NMR(300MHz,Chloroform-d)δ8.53(s,1H),7.85(s,1H),7.75(d,J＝8.0Hz,2H),7.33(s,3H),7.23–7.08(m,4H),4.37(q,J＝7.1Hz,2H),2.46(s,3H),1.40(t,J＝7.1Hz,3H)。
步骤四：5-(4-氟苯氧基)-4-(4-甲基苯甲酰氨基)噻吩-2-甲酸(2)
将5-(4-氟苯氧基)-4-(4-甲基苯甲酰氨基)噻吩-2-甲酸乙酯(100mg,0.253mmol)溶于甲醇/四氢呋喃(1/1)(2ml)混合溶剂中，加入4mol/L的LiOH溶液(1mL)，加毕，室温搅拌反应5h。反应完全后，加入1N的HCl调至溶液pH＝2，继续搅拌30min，过滤，得到白色固体86mg，产率为92.57％。1H NMR(300MHz,DMSO-d6)δ10.10(s,1H),7.81(s,1H),7.77(d,J＝8.1Hz,2H),7.29(d,J＝7.9Hz,2H),7.27–7.21(m,4H),2.36(s,3H)。
实施例3
如实施例1及实施例2方法类似地制备下列化合物：




实施例4和实施例5
步骤一：5-((6-甲基吡啶-3-基)氧基)-4-硝基噻吩-2-甲酸乙酯(4b)
将5-溴-4-硝基噻吩-2-甲酸乙酯(0.20g,0.71mmol)溶于N,N-二甲基甲酰胺(4mL)中，加入K2CO3(0.20g,1.43mmol)和3-羟基-6-甲基吡啶(0.12g,1.07mmol)，室温下搅拌混合物4h。反应完全后，加水，乙酸乙酯萃取(3次)。合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥。硅胶柱层析纯化(石油醚/乙酸乙酯＝20:1)，得到淡黄色固体0.21g，产率94.48％。1H NMR(300MHz,DMSO-d6)δ8.65(d,J＝2.9Hz,1H),8.07(s,1H),7.92(dd,J＝8.6,3.0Hz,1H),7.47(d,J＝8.6Hz,1H),4.27(q,J＝7.1Hz,2H),2.55(s,3H),1.25(t,J＝7.1Hz,3H)。
步骤二：5-((6-甲基吡啶-3-基)氧基)-4-(4-甲基苯甲酰氨基)噻吩-2-甲酸乙酯(4)
将5-((6-甲基吡啶-3-基)氧基)-4-硝基噻吩-2-甲酸乙酯(0.15g,0.49mmol)溶于乙醇/水(10/1)(5ml)混合溶剂中，加入NH4Cl(0.26g,4.87mmol),0℃条件下缓慢加入铁粉(0.27g,4.87mmol),加入完毕后，继续搅拌30min，85℃回流加热4h。反应完全后，使用硅藻土过滤，减压除去溶剂得黄色油状物。
将上一步得到的产物溶于4ml无水四氢呋喃的混合溶剂中，0℃条件下缓慢滴加三乙胺(0.98g,0.97mmol)和4-甲基苯甲酰氯(0.98g,0.63mmol)，加入完毕后，移至室温搅拌 4h。反应完全后，加水，乙酸乙酯萃取(3次)。合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥。硅胶柱层析纯化(石油醚/乙酸乙酯＝8:1)，得到淡黄色固体0.13g，产率67.4％。1H NMR(300MHz,DMSO-d6)δ10.16(s,1H),8.38(d,J＝3.0Hz,1H),7.92(s,1H),7.76(d,J＝7.9Hz,2H),7.53(dd,J＝8.6,3.0Hz,1H),7.29(dd,J＝8.4,2.3Hz,3H),4.27(q,J＝7.1Hz,2H),2.45(s,3H),2.36(s,3H),1.28(t,J＝7.1Hz,3H)。
步骤三：5-((6-甲基吡啶-3-基)氧基)-4-(4-甲基苯甲酰氨基)噻吩-2-甲酸(5)
将5-(4-氟苯氧基)-4-(4-甲基苯甲酰氨基)噻吩-2-甲酸乙酯(100.00mg,0.253mmol)溶于甲醇/四氢呋喃(1/1)(2ml)混合溶剂中，加入4mol/L的LiOH溶液(1mL)，加毕，室温搅拌反应5h。反应完全后，加入1N的HCl调至溶液pH＝5～7，继续搅拌30min，过滤，得到白色固体75.5mg，产率为77.75％。1H NMR(300MHz,DMSO-d6)δ10.13(s,1H),8.37(d,J＝3.0Hz,1H),7.85(s,1H),7.76(d,J＝7.8Hz,2H),7.51(dd,J＝8.6,3.0Hz,1H),7.28(d,J＝8.1Hz,3H),2.43(s,3H),2.35(s,3H)。
实施例6
如实施例4及实施例5方法类似地制备下列化合物：

实施例7和实施例8
步骤一：4-硝基-5-(对甲苯氨基)噻吩-2-甲酸乙酯(7b)
将5-溴-4-硝基噻吩-2-甲酸乙酯(0.15g,0.53mmol)溶于甲苯(3mL)中，加入醋酸钯(3.61mg,0.016mmol)、BINAP(13.34mg,0.021mmol)和碳酸铯(0.244g,0.750mmol)，氩气保护，加入至115℃，5min之后加入4-甲基苯胺(0.069g,0.643mmol)，反应4h。反应完全后，减压除去有机溶剂，硅胶柱层析纯化(石油醚/乙酸乙酯＝15:1)，得到淡黄色固体0.92g，产率56.09％。1H NMR(300MHz,DMSO-d6)δ10.76(s,1H),7.88(s,1H),7.43–7.37(m,2H),7.31(d,J＝8.4Hz,2H),4.21(q,J＝7.1Hz,2H),2.35(s,3H),1.23(t,J＝7.1Hz,3H)。
步骤二：4-(4-甲基苯甲酰氨基)-5-(对甲苯氨基)噻吩-2-甲酸乙酯(7)
将4-硝基-5-(对甲苯氨基)噻吩-2-甲酸乙酯(0.15g,0.49mmol)溶于乙醇/水(10/1)(5ml)混合溶剂中，加入NH4Cl(0.26g,4.90mmol),0℃条件下缓慢加入铁粉(0.27g,4.90mmol),加入完毕后，继续搅拌30min，85℃回流加热4h。反应完全后，使用硅藻土过滤，减压除去溶剂得黄色油状物。
将上一步得到的产物溶于4ml无水四氢呋喃的混合溶剂中，0℃条件下缓慢滴加三乙胺(0.99g,0.99mmol)和4-甲基苯甲酰氯(0.98g,0.64mmol)，加入完毕后，移至室温搅拌4h。反应完全后，加水，乙酸乙酯萃取(3次)。合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥。硅胶柱层析纯化(石油醚/乙酸乙酯＝8:1)，得到淡黄色固体0.12g，产率62.0％。1H NMR(300MHz,DMSO-d6)δ9.82(s,1H),8.69(s,1H),7.87(d,J＝8.1Hz,2H),7.79(s,1H),7.32(d,J＝8.0Hz,2H),7.13(s,4H),4.23(q,J＝7.1Hz,2H),2.38(s,3H),2.25(s,3H),1.27(t,J＝7.1Hz,4H)。
步骤三：4-(4-甲基苯甲酰氨基)-5-(对甲苯氨基)噻吩-2-甲酸(8)
将4-(4-甲基苯甲酰氨基)-5-(对甲苯氨基)噻吩-2-甲酸乙酯(100.00mg,0.253mmol)溶于甲醇/四氢呋喃(1/1)(2ml)混合溶剂中，加入4mol/L的LiOH溶液(1mL)，加毕，室温搅拌反应5h。反应完全后，加入1N的HCl调至溶液pH＝5～7，继续搅拌30min，过滤，得到白色固体45.5mg，产率为49.0％。1H NMR(300MHz,DMSO-d6)δ11.90(s,1H),10.28(s,1H),7.78(d,J＝7.4Hz,2H),7.53(d,J＝8.2Hz,2H),7.39(d,J＝7.5Hz,2H),7.11(d,J＝8.2Hz,2H),2.40(s,3H),2.25(s,3H)。
实施例9
如实施例7及实施例8方法类似地制备下列化合物：
实施例10和实施例11
步骤一：4-硝基-5-(对甲苯硫基)噻吩-2-甲酸乙酯(7b)
将5-溴-4-硝基噻吩-2-甲酸乙酯(0.20g,0.71mmol)溶于N,N-二甲基甲酰胺(4mL)中，加入K2CO3(0.20g,1.43mmol)和4-甲基硫酚(0.13g,1.07mmol)，室温下搅拌混合物4h。 反应完全后，加水，乙酸乙酯萃取(3次)。合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥。硅胶柱层析纯化(石油醚/乙酸乙酯＝20:1)，得到黄色固体0.16g，产率73.2％。1H NMR(300MHz,DMSO-d6)δ8.10(s,1H),7.74–7.64(m,2H),7.51–7.42(m,2H),4.24(q,J＝7.2Hz,2H),2.43(s,3H),1.23(t,J＝7.1Hz,3H)。
步骤二：4-(4-甲基苯甲酰氨基)-5-(对甲苯硫基)噻吩-2-甲酸乙酯(7)
将4-硝基-5-(对甲苯硫基)噻吩-2-甲酸乙酯(0.15g,0.46mmol)溶于乙醇/水(10/1)(5ml)混合溶剂中，加入NH4Cl(0.25g,4.64mmol),0℃条件下缓慢加入铁粉(0.26g,4.64mmol),加入完毕后，继续搅拌30min，85℃回流加热4h。反应完全后，使用硅藻土过滤，减压除去溶剂得黄色油状物。
将上一步得到的产物溶于4ml无水四氢呋喃的混合溶剂中，0℃条件下缓慢滴加三乙胺(0.94g,0.93mmol)和4-甲基苯甲酰氯(0.94g,0.60mmol)，加入完毕后，移至室温搅拌4h。反应完全后，加水，乙酸乙酯萃取(3次)。合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥。硅胶柱层析纯化(石油醚/乙酸乙酯＝8:1)，得到淡黄色固体0.11g，产率57.6％。1H NMR(300MHz,DMSO-d6)δ10.14(s,1H),7.99(s,1H),7.82(d,J＝8.3Hz,2H),7.33(d,J＝7.8Hz,2H),7.27(d,J＝8.3Hz,2H),7.19(d,J＝8.4Hz,2H),4.27(q,J＝7.2Hz,2H),2.38(s,3H),2.27(s,3H),1.27(t,J＝7.1Hz,3H)。
步骤三：4-(4-甲基苯甲酰氨基)-5-(对甲苯硫基)噻吩-2-甲酸(8)
将4-(4-甲基苯甲酰氨基)-5-(对甲苯氨基)噻吩-2-甲酸乙酯(100.00mg,0.253mmol)溶于甲醇/四氢呋喃(1/1)(2ml)混合溶剂中，加入4mol/L的LiOH溶液(1mL)，加毕，室温搅拌反应5h。反应完全后，加入1N的HCl调至溶液pH＝4，继续搅拌30min，过滤，得到白色固体88.7mg，产率为95.0％。1H NMR(300MHz,DMSO-d6)δ10.10(s,1H),7.92(s,1H),7.83(d,J＝8.2Hz,2H),7.31(d,J＝8.2Hz,2H),7.23(d,J＝8.2Hz,2H),7.16(d,J＝8.4Hz,2H),2.36(s,3H),2.25(s,3H)。
实施例12
如实施例10及实施例11方法类似地制备下列化合物：

实施例13和实施例14
步骤一：5-((6-甲基吡啶-3-基)氧基)-4-(苯甲酰氨基)噻吩-2-甲酸乙酯(13)
将5-((6-甲基吡啶-3-基)氧基)-4-硝基噻吩-2-甲酸乙酯(0.15g,0.49mmol)溶于乙醇/水(10/1)(5ml)混合溶剂中，加入NH4Cl(0.26g,4.87mmol),0℃条件下缓慢加入铁粉(0.27g,4.87mmol),加入完毕后，继续搅拌30min，85℃回流加热4h。反应完全后，使用硅藻土过滤，减压除去溶剂得黄色油状物。
将上一步得到的产物溶于4ml无水四氢呋喃的溶剂中，0℃条件下缓慢滴加三乙胺(0.98g,0.97mmol)和苯甲酰氯(0.85g,0.63mmol)，加入完毕后，移至室温搅拌4h。反应完全后，加水，乙酸乙酯萃取(3次)。合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥。硅胶柱层析纯化(石油醚/乙酸乙酯＝8:1)，得到淡黄色固体0.11g，产率57.6％。1H NMR(300MHz,DMSO-d6)δ10.36(s,1H),8.55(d,J＝2.9Hz,1H),7.95(s,1H),7.83(m,3H),7.63–7.44(m,4H),4.29(q,J＝7.1Hz,2H),2.53(s,3H),1.28(t,J＝7.1Hz,3H)。
步骤二：5-((6-甲基吡啶-3-基)氧基)-4-(苯甲酰氨基)噻吩-2-甲酸(14)
将5-((6-甲基吡啶-3-基)氧基)-4-(苯甲酰氨基)噻吩-2-甲酸乙酯(100.00mg,0.262mmol)溶于甲醇/四氢呋喃(1/1)(2ml)混合溶剂中，加入4mol/L的LiOH溶液(1mL)，加毕，室温搅拌反应5h。反应完全后，加入1N的HCl调至溶液pH＝4，继续搅拌30min，过滤，得到白色固体83.5mg，产率为90.1％。1H NMR(300MHz,DMSO-d6)δ10.27(s,1H),8.38(d,J＝3.1Hz,1H),7.84(dd,J＝9.6,2.6Hz,3H),7.62–7.50(m,2H),7.50–7.41(m,2H),7.28(d,J＝8.6Hz,1H),2.43(s,3H)。
实施例15
如实施例13及实施例14方法类似地制备下列化合物：


实施例13和实施例14
步骤一：4-(6-甲基烟酰胺基)-5-((6-甲基吡啶-3-基)氧基)噻吩-2-甲酸乙酯(16)
将5-((6-甲基吡啶-3-基)氧基)-4-硝基噻吩-2-甲酸乙酯(0.15g,0.49mmol)溶于乙醇/水(10/1)(5ml)混合溶剂中，加入NH4Cl(0.26g,4.87mmol),0℃条件下缓慢加入铁粉(0.27g,4.87mmol),加入完毕后，继续搅拌30min，85℃回流加热4h。反应完全后，使用硅藻土过滤，减压除去溶剂得黄色油状物。
将上一步得到的产物溶于4ml无水二氯甲烷的溶剂中，依次加入6-甲基烟酰胺(0.10g,0.73mmol)，三乙胺(0.10g,0.97mmol)和卡特缩合剂(PyBOP)(0.38mg,0.73mmol)，加入完毕后，室温搅拌反应10h。反应完全后，过滤除去不溶物，滤液加入水，乙酸乙酯萃取(3次)，合并有机相，用饱和食盐水洗涤，无水Na2SO4干燥。硅胶柱层析纯化(石油醚/乙酸乙酯＝2:1)，得到白色固体0.09g,产率43.6％。1H NMR(300MHz,DMSO-d6)δ10.43(s,1H),8.87(d,J＝3.0Hz,1H),8.40(d,J＝2.9Hz,1H),8.09(dd,J＝8.1,2.4Hz,1H),7.96(s,1H),7.56(dd,J＝8.5,3.0Hz,1H),7.39(d,J＝8.1Hz,1H),7.31(d,J＝8.5Hz, 1H),4.28(q,J＝7.1Hz,2H),2.53(s,3H),2.45(s,3H),1.28(t,J＝7.1Hz,3H)。
步骤二：4-(6-甲基烟酰胺基)-5-((6-甲基吡啶-3-基)氧基)噻吩-2-甲酸(17)
将4-(6-甲基烟酰胺基)-5-((6-甲基吡啶-3-基)氧基)噻吩-2-甲酸乙酯(100.00mg,0.262mmol)溶于甲醇/四氢呋喃(1/1)(2ml)混合溶剂中，加入4mol/L的LiOH溶液(1mL)，加毕，室温搅拌反应5h。反应完全后，加入1N的HCl调至溶液pH＝5～6，继续搅拌30min，过滤，得到白色固体56.0mg，产率为60.3％。1H NMR(300MHz,DMSO-d6)δ10.11(s,1H),8.54(s,1H),8.04(d,J＝3.0Hz,1H),7.76(d,J＝9.6Hz,1H),7.53(s,1H),7.19(dd,J＝8.5,3.1Hz,1H),7.03(d,J＝8.1Hz,1H),6.95(d,J＝8.5Hz,1H),2.18(s,3H),2.10(s,3H)。
实施例18
如实施例16及实施例17方法类似地制备下列化合物：
本发明中通式Ⅰ的部分化合物的药理学实验及结果如下：
实验方法：
稳转P2Y14受体的HEK293细胞株培养于DMEM培养基中(含10％胎牛血清、100U/ml青霉素和100μg/ml链霉素)，实验前接种至培养板，改用无血清培养基，接种密度为1×105个细胞/孔，细胞于37℃、95％O2、5％CO2湿度条件下培养。加入IBMX抑制PDEs活性，以保证cAMP在一个较高的水平上。采用AC激动剂Forskolin(30μM)刺激细胞cAMP的产生，预先加入不同浓度的受试化合物(0.01、0.1、1、10、100nm)，以PPTN作为阳性对照。随后加入1μM的P2Y14受体激动剂UDPG，4h后cAMP GloTM Assay试剂盒(PROMEGA Co.Ltd，美国)检测细胞内cAMP的含量。根据cAMP含量计算其抑制率值。
表1部分化合物在细胞水平对P2Y14受体的抑制率值：
受试化合物抑制LPS诱导的巨噬细胞炎性反应的药理研究实验方法
人THP-1细胞培养于RPMI-1640培养基中(含10％胎牛血清，100U/ml青霉素和100μg/ml链霉素)，实验前接种至培养板，接种密度为1×105个细胞/孔，细胞于37℃、95％ O2、5％ CO2湿度条件下培养。实验前每孔加入100ng/ml PMA孵育24h诱导THP-1细胞分化为巨噬细胞。预先向培养基中加入受试化合物5(2.5、5、10μM)和PPTN(5μM)进行干预，1h后向细胞中加入终浓度为100ng/ml的LPS，3h后再加入终浓度为5mM的ATP，1h后测定如下指标：
Western Blot法检测细胞中UDPG/P2Y14受体信号通路下游蛋白的表达，结果如图 1-4所示，LPS造成THP-1细胞的P2Y14受体下游相关蛋白表达显著升高，提示造模成功；不同剂量受试化合物能够不同程度的下调P2Y14受体下游相关蛋白表达，与模型对照组比较均体现出显著性差异；PPTN也体现出了预期的效果，表明实验结果真实可信；
按ELISA试剂盒(深圳欣博盛)方法检测细胞培养基上清液中IL-1β的水平，结果如图5所示，LPS造成THP-1细胞培养基上清液中IL-1β水平显著升高，提示造模成功；不同剂量受试化合物能够不同程度的下调细胞培养基上清液中IL-1β水平，与模型对照组比较均体现出显著性差异；PPTN也体现出了预期的效果，表明实验结果真实可信。
受试化合物在整体动物水平对急性腹膜炎的治疗作用的药理实验研究方法
雄性清洁级ICR小鼠，自由水食，每天12h照明，环境温度为25±2℃。动物分为若干组：正常对照组、模型对照组、给药组(受试化合物和地塞米松)，采用一次性腹腔注射LSP诱导急性腹膜炎模型，而正常对照组采用等量的生理盐水注射入关节腔。各给药组通过关节腔注射给予受试化合物5(5、10、20mg/kg)、地塞米松(10mg/kg)。注射后6h，注入8mLPBS收集腹膜腔液。检测收集液中各炎性因子的水平，结果如图6-8所示，LPS造成小鼠腹腔液中个炎性因子的基因表达水平显著升高，提高造模成功；不同剂量受试化合物能够与不同程度的下调个炎性因子的基因表达水平，与模型对照组比较均体现出显著性差异；地塞米松也体现了预期的效果，表明实验结果真实可信。

Claims (10)

  1. 通式(I)所示的噻吩-2-羧酸衍生物及其互变异构体及药学上可接受的盐：
    R1选自COOR5；
    R2选自H或卤素；
    R3选自苯基、吡啶基、吡嗪基、嘧啶基、咪唑基；所述苯基、吡啶基、吡嗪基、嘧啶基、咪唑基独立地任选地被1至5个选自下列的取代基取代：C1-6烷基、卤素、氰基、羧基、乙酰基、甲磺酰基、卤代C1-4烷基、卤代C1-4烷氧基、OH、C1-6烷氧基、二甲氨基；
    X选自O、S、NH；
    R4选自：
    Ring为苯基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡咯基、噻吩基、呋喃基、噻唑基、异噻唑、咪唑基、吡唑基；
    R5为Η、C2-4烷基、C2-3烷基-C3-6环烷基、C2-3OOCCH3、C2-3OCNMe2、C2-3NMe2；
    R7为H；
    R8选自H、C1-6烷基、C3-6环烷基、CH2CONH2、CH2COMe2、CH2CH2OH、CH2CH2Me、(CH2)3OH、(CH3)3OMe、(CH2)4OH、(CH2)4OMe、(CH2)5OH、(CH2)2COOH、(CH2)3COOH、(CH2)4COOH、(CH2)5COOH、(CH2)2CH(CH3)COOH、C(CH2OH)3、C(CH2OH)2CH3、CH2CH(CH3)OH、(CH2)2CF3、(CH2)3CF3、(CH2)4CF3、

    R11选自H、NO2、CN、OH、NH2、F、Cl、Br、I、C1-6烷基、卤代-C1-6烷基、C1-6烷氧基、卤代-C1-6烷氧基、COR8、CONR7R8、CO2R8、SO2NR7R8、SO3R8。
  2. 根据权利要求1所述的噻吩-2-羧酸衍生物及其互变异构体及药学上可接受的盐，其特征在于，
    R2选自H或F；
    R5为Η、C2H5、C2-3烷基-C3-6环烷基、C2-3OOCCH3、C2-3OCNMe2、C2-3NMe2。
  3. 根据权利要求1所述的噻吩-2-羧酸衍生物及其互变异构体及药学上可接受的盐，其特征在于，
    R3选自苯基、吡啶基、吡嗪基、嘧啶基、咪唑基；所述苯基、吡啶基、吡嗪基、嘧啶基、咪唑基独立地任选地被1至2个选自下列的取代基取代：C1-6烷基、卤素、氰基、卤代C1-4烷基、OH、C1-6烷氧基、二甲氨基。
  4. 根据权利要求3所述的噻吩-2-羧酸衍生物及其互变异构体及药学上可接受的盐，其特征在于，R4选自：
    Ring为苯基、嘧啶基、哒嗪基、异噻唑基；
    R11选自H、NO2、CN、OH、NH2、F、Cl、Br、I、C1-6烷基、卤代-C1-6烷基、C1-6烷氧基、卤代-C1-6烷氧基、CONR7R8、CO2R8、SO2NR7R8、SO3R8；
    R7为H；
    R8选自H、C1-6烷基、C3-6环烷基、CH2CONH2、CH2COMe2、CH2CH2OH、CH2CH2Me、(CH2)3OH、(CH3)3OMe、(CH2)4OH、(CH2)4OMe、(CH2)2COOH、(CH2)3COOH、(CH2)4COOH、(CH2)2CH(CH3)COOH、C(CH2OH)3、C(CH2OH)2CH3、CH2CH(CH3)OH、

  5. 根据权利要求1所述的噻吩-2-羧酸衍生物及其互变异构体及药学上可接受的盐，其特征在于，通式(I)化合物选自如下化合物：



  6. 一种权利要求1所述的噻吩-2-羧酸衍生物及其互变异构体及药学上可接受的盐的制备方法，其特征在于，包括如下步骤：
    (1)通式化合物A进行硝化反应制得通式B化合物；
    (2)通式化合物B与不同酚类衍生物进行取代反应制得通式化合物C；
    (3)通式化合物C先经硝基还原，再与不同羧酸或磺酸衍生物进行缩合反应，或不同的烃基衍生物进行取代反应、最后经脱保护基反应制得通式化合物D；
    化合物D即通式(I)化合物，R1、R2、R3、R4及X同权利要求1所述。
  7. 一种药物组合物，其特征在于，其中含有权利要求1所述的通式(I)化合物或其药学上可接受的盐及药学上可接受的辅料。
  8. 权利要求1所述的通式(I)化合物或其药学上可接受的盐、或权利要求7所述的药物组合物在制备P2Y14受体拮抗剂药物中的用途。
  9. 权利要求1所述的通式(I)化合物或其药学上可接受的盐或权利要求7所述的药物组合物在制备治疗炎症疾病药物中的用途。
  10. 权利要求8或9所述的用途，其特征在于，所述药物添加药学上可接受的辅料制成不同剂型。
PCT/CN2024/107199 2023-06-14 2024-07-24 噻吩-2-羧酸衍生物、其制备方法及医药用途 Ceased WO2024255920A1 (zh)

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