WO2016034103A1 - 取代的四氢噻吩并吡啶衍生物及其应用 - Google Patents

取代的四氢噻吩并吡啶衍生物及其应用 Download PDF

Info

Publication number
WO2016034103A1
WO2016034103A1 PCT/CN2015/088756 CN2015088756W WO2016034103A1 WO 2016034103 A1 WO2016034103 A1 WO 2016034103A1 CN 2015088756 W CN2015088756 W CN 2015088756W WO 2016034103 A1 WO2016034103 A1 WO 2016034103A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
carbons
clopidogrel
platelet aggregation
Prior art date
Application number
PCT/CN2015/088756
Other languages
English (en)
French (fr)
Inventor
张维威
Original Assignee
南京曼杰生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京曼杰生物科技有限公司 filed Critical 南京曼杰生物科技有限公司
Publication of WO2016034103A1 publication Critical patent/WO2016034103A1/zh

Links

Images

Classifications

    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed 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
    • A61K31/435—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
    • A61K31/445—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

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and more particularly to a novel substituted tetrahydrothienopyridine derivative, a pharmaceutically acceptable acid salt, a solvate or a hydrate thereof, a preparation method thereof, and a pharmaceutical composition And their use in the manufacture of a medicament for inhibiting platelet aggregation, preventing or treating diseases associated with thrombosis and embolism.
  • Clopidogrel is a widely used anti-platelet aggregation drug in clinical practice. In the study of its metabolic process in vivo, it was found that 85% of the prototype clopidogrel drug was hydrolyzed by the liver to an inactive clopidogrel carboxylic acid derivative; Clopidogrel, which is not metabolized into inactive metabolites, also needs to rely on the metabolic activation of P450 enzymes. Due to the difference in the expression of P450 enzymes in the liver of different individuals, the effect of clopidogrel, which is dependent on the metabolism of P450 enzymes, is clinically effective. Larger individual differences, individuals with weak P450 metabolic activity, ineffective or ineffective in taking clopidogrel, produced "clopidogrel resistance" on the scene, the incidence of cardiovascular events such as thrombosis was not reduced.
  • Prasugrel is another anti-platelet aggregation drug developed by Japan's Sankyo Pharmaceutical Co., Ltd. and Eli Lilly and Pharmaceuticals. Although there is no similar "drug resistance" compared with clopidogrel, it has a fast onset and high activity, but it has a greater risk of bleeding. .
  • anti-platelet aggregation drugs with fast onset, high activity, no drug resistance, and low risk of bleeding have become urgent clinical needs.
  • the present invention provides a novel substituted tetrahydrothienopyridine derivative as an anti-platelet aggregation drug for preventing or treating the development of thrombosis and embolism-related diseases; It has the characteristics of fast effect, strong activity, low risk of bleeding and small differences among biological individuals.
  • a second object of the present invention is to provide a process for producing the above tetrahydrothienopyridine derivative.
  • a third object of the present invention is to provide a pharmaceutical composition comprising the above tetrahydrothienopyridine derivative.
  • a fourth object of the present invention is to provide use of the above tetrahydrothienopyridine derivative or pharmaceutical composition for the preparation of a medicament for inhibiting platelet aggregation or preventing or treating a thrombosis and embolism-related disease.
  • the invention provides a substituted tetrahydrothienopyridine derivative, such as a compound of formula I, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof:
  • R 1 is a linear or branched alkyl group of 1 to 6 carbons, a cycloalkyl group of 3 to 6 carbons, or OR 3 ;
  • R 2 is Nitalsulfonyl, stearoyl, palmitoyl, lauroyl, myristoyl, oleoyl, linoleoyl, or linoleyl;
  • R 3 is a linear or branched alkyl group of 1 to 6 carbons, or a cycloalkyl group of 3 to 6 carbons;
  • R 4 is hydrogen, a linear or branched alkyl group of 1 to 6 carbons, or a cycloalkyl group of 3 to 6 carbons;
  • X is hydrogen, chlorine, fluorine, bromine, or iodine
  • n 0-6.
  • the present invention provides compounds of formula I, wherein, R 1 is cyclopropyl or methoxy, or ethoxy.
  • the invention provides a compound of formula I, wherein R 2 is
  • the invention provides a compound of formula I, wherein R 1 is cyclopropyl or methoxy, ethoxy;
  • X is chlorine or fluorine.
  • the invention provides a compound of formula I, wherein R 1 is methoxy
  • X is chlorine
  • R 2 is tauroyl, stearoyl, leucoyl, lauroyl, myristoyl, oleoyl, linoleoyl, or Flax acyl.
  • the invention provides a compound of formula I, wherein R 1 is cyclopropyl or methoxy, or ethoxy;
  • R 2 is tauroyl, stearyl, palsyl, lauroyl, myristoyl, oleoyl, linoleoyl, or linoleyl;
  • X is chlorine or fluorine.
  • the invention provides a compound of formula I, wherein R 1 is methoxy
  • R 2 is tauroyl, stearyl, palsyl, lauroyl, myristoyl, oleoyl, linoleoyl, or linoleyl;
  • X is chlorine
  • the compounds provided herein are selected from one of the following compounds, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof:
  • the derivative provided by the invention comprises an enantiomer and a racemate of a compound of formula I.
  • the derivative of the invention comprises a compound of formula I or a pharmaceutically acceptable acid salt thereof, including but not limited to a salt of a compound with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, acetic acid, maleic acid, fumaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, or succinic acid.
  • hydrochloric acid hydrobromic acid
  • sulfuric acid Nitric acid
  • citric acid tartaric acid
  • phosphoric acid lactic acid
  • acetic acid maleic acid, fumaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, or succinic acid.
  • the invention provides a compound of formula I, wherein the straight or branched alkyl group of 1 to 6 carbons is methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl, tert-butyl, pentyl, or hexyl.
  • the invention provides a compound of formula I, wherein the 3-6 carbon cycloalkyl is selected from cyclopropyl, cyclobutane, cyclopentyl, or cyclohexane. .
  • the present invention provides a process for the preparation of the above-mentioned substituted tetrahydrothienopyridine derivative of the compound of the formula I or a pharmaceutically acceptable acid salt, solvate or hydrate thereof, comprising the steps of:
  • R 1 , R 2 , X are as defined in the compound of formula I, and Z is a leaving group such as: chloro, pentafluorophenol, nitrophenol Wait.
  • the present invention provides a process for the preparation of the above-mentioned substituted tetrahydrothienopyridine derivative of the compound of formula I or a pharmaceutically acceptable acid salt, solvate or hydrate thereof, which comprises
  • the compound of II or a salt thereof is dissolved in an organic solvent, and a base is added in a batchwise manner under cooling, and then reacted with a compound of the formula III to give a compound of the formula I, and if necessary, can be further purified by a conventional method such as recrystallization, column chromatography or the like.
  • the base may be an inorganic base or an organic base, and may be selected from sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, or N,N-diisopropylethylamine.
  • a corresponding protecting group such as 9-fluorenylmethoxycarbonyl can be used, and after the ester-forming condensation reaction, a piperidine deprotection step is added.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned substituted tetrahydrothienopyridine derivative, comprising a compound of Formula I, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof, the pharmaceutical composition
  • the substance may further comprise a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition can be administered by intravenous injection, by injection into tissue, intraperitoneally, orally or intranasally.
  • the pharmaceutical composition may be in the form of a solution, a dispersion, a suspension, a powder, a capsule, a tablet, a pill, a time release capsule, a time release tablet, and a time release pill.
  • the pharmaceutical composition is administered at a dose of 5 to 5000 mg/day.
  • the present invention provides the above-mentioned substituted tetrahydrothienopyridine derivative, such as a compound of formula I, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof, for use in the preparation of an anti-platelet aggregation, prevention or treatment of thrombus and Embolism-related diseases, especially in the prevention or treatment of atherosclerotic diseases, myocardial infarction, angina pectoris, stroke, ischemic cerebral thrombosis, peripheral arterial disease, acute coronary syndrome or thrombosis after coronary intervention use.
  • the novel substituted tetrahydrothienopyridine derivative of the present invention has a remarkable inhibition of platelet aggregation, and its anti-platelet aggregation effect is even better than that of clopidogrel.
  • the compounds of the present invention are metabolized by the esterase in the blood (rather than relying on the P450 enzyme in the liver) to produce the same active metabolite as clopidogrel, avoiding the "clopidogrel resistance" phenomenon of clopidogrel.
  • Figure 2 Comparison of inhibition rate of platelet aggregation after administration of male SD rats for 5 consecutive days (20 ⁇ mol/L ADP induction).
  • the source of the compound used in the examples was: all reagents were purchased from the reagent company, starting material (2S)-2-(2-chlorophenyl)-2-(2-oxo-5,6,7,7a Methyl tetrahydrothieno[3,2-c]pyridyl)acetate was synthesized from the benzenesulfonate of methyl 2-chloromandelate and resolved by the method of Chinese Patent Application No. 201210333184.4.
  • Cyclohexyloxyacetic acid (1.58 g) was suspended in 10 ml of thionyl chloride, and reacted at 60 ° C for 2 hours, and the solvent was evaporated under reduced pressure to give cyclohexyloxyacetyl chloride; (2S)-2-(2-chlorobenzene) Methyl 2-(2-oxo-5,6,7,7a-tetrahydrothieno[3,2-c]pyridinyl)acetate (0.3 g) is dissolved in NMP (N-methylpyrrolidone) ( 10 ml), 0.3 ml of triethylamine was added, and cyclohexyloxyacetyl chloride (0.18 g) was added dropwise at 0 ° C.
  • NMP N-methylpyrrolidone
  • Propoxyacetic acid (1.18g) was suspended in 10 ml of thionyl chloride, reacted at 60 ° C for 2 hours, and the solvent was evaporated under reduced pressure to give propoxyacetyl chloride; (2S)-2-(2-chlorophenyl) Methyl 2-(2-oxo-5,6,7,7a-tetrahydrothieno[3,2-c]pyridyl)acetate (0.3 g) was dissolved in NMP (N-methylpyrrolidone) (10 ml) Add 0.3 ml of triethylamine, and add propoxyacetyl chloride (0.14 g) dropwise at 0 ° C.
  • NMP N-methylpyrrolidone
  • the mixture was heated to room temperature for 3 hours, and the reaction mixture was poured into 30 ml of water, and the aqueous phase was extracted with ethyl acetate (30 ml ⁇ 3), and the organic phase was combined and washed with saturated aqueous sodium hydrogen The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness.
  • the white solid was isolated by silica gel column chromatography to give 0.23 g of white solid.
  • test solution Take appropriate amount of clopidogrel hydrogen sulfate, add 0.5% CMC-Na solution, and grind to obtain a suspension of 0.6 mg/ml and 2.0 mg/ml.
  • a suitable amount of the compound MJ10601 and MJ10602 was obtained to prepare a suspension of 0.2 mg/ml and 0.6 mg/ml; and a suitable amount of the compound MJ10604 and MJ10611 was obtained to obtain a suspension of 0.6 mg/ml.
  • Animal SD rat, male, 250-270 g. A total of 54 were divided into 9 groups of 6 each.
  • the test solution was administered orally to the rats in a volume of 5 ml/kg, and the dose of each test substance was converted to 1-10 mg/kg.
  • the control group was given an equal volume of 0.5% CMC-Na solution.
  • RESULTS Two hours after intragastric administration, blood was taken from the femoral artery of each rat, mixed with 3.8% sodium citrate solution in an appropriate ratio, and centrifuged for 7 minutes (1000 rpm) to obtain platelet-rich plasma (PRP); Another whole blood was centrifuged at 3000 rpm for 5 minutes to obtain platelet-poor plasma (PPP). The appropriate amount of PPP was added to the PRP to make the final platelet concentration 5 ⁇ 10 9 --10 ⁇ 10 9 /L.
  • PRP platelet-rich plasma
  • PPP platelet-poor plasma
  • the appropriate amount of 5 ⁇ mA DP (adenosine diphosphate) test solution was added to the test solution, and the maximum platelet aggregation rate within 5 minutes was measured on a platelet aggregation meter, and the platelet aggregation inhibition rate was calculated accordingly.
  • Platelet aggregation inhibition rate 100% ⁇ (average platelet aggregation rate in the control group - maximum platelet aggregation rate in the test group animals) / average platelet aggregation rate in the control group, and the results are shown in Table 1.
  • clopidogrel is first metabolically activated in the body to produce 2-oxy-clopidogrel, and 2-oxy-clopidogrel is further hydrolyzed to form active metabolites.
  • the formation reaction of 2-oxy-clopidogrel is the rate-limiting step of metabolism, so the amount of 2-oxy-clopidogrel produced is the evaluation of such compound bodies. Key indicators of internal activity.
  • the present inventors examined the time course of their metabolite 2-oxy-clopidogrel by administering the compounds MJ10601, MJ10602, MJ10604, MJ10611 and clopidogrel hydrogen sulfate respectively after the rats were administered by gavage. Whether it is metabolized in the body to produce 2-oxy-clopidogrel and evaluate their production.
  • test compound can be converted to 2-oxy-clopidogrel in vivo and further metabolically activated, and the individual differences in metabolism are smaller than those in the clopidogrel group, and the specific enzyme dependence of the drug is small, resulting in clopidogrel.
  • the possibility of resistance is small; in addition, since the amount of the active metabolite precursor 2-oxy-clopidogrel produced by the test compound in vivo is significantly higher than the clopidogrel group at the same quality, it is expected to reduce the dose by administration. Reduce the adverse reactions caused by inactive metabolism under the premise of rapid onset and high efficacy.
  • the AUC of 2-oxy-clopidogrel produced by the preferred compounds of the present invention is also greater than the AUC of 2-oxy-clopidogrel produced by clopidogrel hydrogen sulfate at an equal dose, in an equal dose.
  • the platelet aggregation inhibition rate was superior to that of the clopidogrel hydrogen sulfate group.
  • test samples were intragastrically administered to normal SD rats for 5 days, and the inhibitory effects of 20 ⁇ mol ADP on platelet aggregation were compared at different time points.
  • Platelet aggregation inhibition rate 100% ⁇ (the average platelet aggregation rate of the control group - the maximum platelet aggregation rate of the test group animals) / the average platelet aggregation rate of the control group, and the results are shown in Table 3, Figure 2.
  • test results show that the compound of the present invention is administered at a dose of about 1/10 of clopidogrel, and the platelet inhibition produced is substantially the same as that of clopidogrel.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

公开了一种取代的四氢噻吩并吡啶衍生物、药学可接受的酸式盐、溶剂化物或水合物及其应用，如通式(I)所示、其中R 1、R 2和X如说明书定义。还公开了该化合物的合成方法、药物组合物及它们在制备用于抑制血小板聚集、预防或治疗血栓和栓塞相关疾病的药物中的用途。

Description

取代的四氢噻吩并吡啶衍生物及其应用 技术领域
本发明属于药物化学技术领域，更具体地说，涉及一种新型的取代的四氢噻吩并吡啶衍生物、药学可接受的酸式盐、溶剂化物或水合物，它们的制备方法、药物组合物及它们在制备用于抑制血小板聚集、预防或治疗血栓和栓塞相关疾病的药物中的用途。
背景技术
氯吡格雷是临床上广泛应用的抗血小板聚集药物，对其体内代谢过程的研究中，发现有85％的氯吡格雷原型药物经肝脏水解代谢为非活性的氯吡格雷羧酸衍生物；另外，没有代谢为非活性代谢产物的氯吡格雷还需要依赖P450酶系代谢活化，由于不同个体肝脏内P450酶系表达的差异，使得依赖P450酶系代谢起效的氯吡格雷在临床治疗效果上产生较大的个体差异，P450代谢活性弱的个体，服用氯吡格雷低效或无效，产生“氯吡格雷抵抗”现场，血栓形成等心血管事件发生率得不到降低。
普拉格雷是日本三共制药公司和美国礼来制药公司开发的另外一个抗血小板聚集药物，虽然较氯吡格雷没有类似的“药物抵抗，”起效快、活性强，但是具有更大的出血风险。
所以，起效快、活性强，没有药物抵抗，同时出血风险小的抗血小板聚集药物成为临床的迫切需求。
发明内容
本发明提供了一种新型的取代的四氢噻吩并吡啶衍生物，作为抗血小板聚集药物，预防或治疗血栓和栓塞相关疾病中的发展；这些药物具有起 效快、活性强、出血风险小及生物个体间的差异小等特点。
本发明的目的是提供一种新型的取代的四氢噻吩并吡啶衍生物,它通过血液中的酯酶(而非依靠肝脏内P450酶系)代谢产生与氯吡格雷相同的活性代谢产物。因为酯酶在人体血液中的普遍存在，避免了氯吡格雷的“氯吡格雷抵抗”现象。
本发明的第二个目的是提供上述四氢噻吩并吡啶衍生物的制备方法。
本发明的第三个目的是提供包含上述四氢噻吩并吡啶衍生物的药物组合物。
本发明的第四个目的是提供上述四氢噻吩并吡啶衍生物或药物组合物在制备用于抑制血小板聚集，或者预防或治疗血栓和栓塞相关疾病的药物中的用途。
具体地说，本发明提供了一种取代的四氢噻吩并吡啶衍生物，如通式I的化合物，或其药学上可接受的酸式盐、溶剂化物或水合物：
Figure PCTCN2015088756-appb-000001
其中：
R1为1-6个碳的直链或支链烷基、3-6个碳的环烷基、或OR3；
R2为
Figure PCTCN2015088756-appb-000002
牛磺酰基、硬脂酰基、软脂酰基、月桂酰基、豆蔻酰基、油酰基、亚油酰基、或亚麻酰基；
R3为1-6个碳的直链或支链烷基、或3-6个碳的环烷基；
R4为氢、1-6个碳的直链或支链烷基、或3-6个碳的环烷基；和
X为氢、氯、氟、溴、或碘；
n＝0-6。
在本发明的一种优选实施方案中，本发明提供的式I化合物，其中，R1 为环丙基或甲氧基、或乙氧基。
在本发明的一种优选实施方案中，本发明提供的式I化合物，其中，R2为
Figure PCTCN2015088756-appb-000003
R4为氢、1-6个碳的直链或支链烷基、或3-6个碳的环烷基；n＝0-6。
在本发明的一种优选实施方案中，本发明提供的式I化合物，其中，X为氯、或氟。
在本发明的一种优选实施方案中，本发明提供的式I化合物，其中，R1为环丙基或甲氧基、乙氧基；
R2为
Figure PCTCN2015088756-appb-000004
R4为氢、1-6个碳的直链或支链烷基、或3-6个碳的环烷基；n＝0-6；和
X为氯、或氟。
在本发明的一种更优选实施方案中，本发明提供的式I化合物，其中，R1为甲氧基；
R2为
Figure PCTCN2015088756-appb-000005
R4为氢、1-6个碳的直链或支链烷基、或3-6个碳的环烷基；n＝0-6；和
X为氯。
在本发明的一种优选实施方案中，本发明提供的式I化合物，其中，R2为牛磺酰基、硬脂酰基、软脂酰基、月桂酰基、豆蔻酰基、油酰基、亚油酰基、或亚麻酰基。
在本发明的一种优选实施方案中，本发明提供的式I化合物，其中， R1为环丙基或甲氧基、或乙氧基；
R2为牛磺酰基、硬脂酰基、软脂酰基、月桂酰基、豆蔻酰基、油酰基、亚油酰基、或亚麻酰基；和
X为氯、或氟。
在本发明的一种更优选实施方案中，本发明提供的式I化合物，其中，R1为甲氧基；
R2为牛磺酰基、硬脂酰基、软脂酰基、月桂酰基、豆蔻酰基、油酰基、亚油酰基、或亚麻酰基；和
X为氯。
在本发明的特别优选实施方案中，本发明提供的化合物选自如下化合物中的一种，或其药学上可接受的酸式盐、溶剂化物或水合物：
Figure PCTCN2015088756-appb-000006
Figure PCTCN2015088756-appb-000007
在本发明的实施方案中，本发明提供的所述衍生物包括式I化合物的对映异构体和外消旋体。
在本发明的实施方案中，本发明所述的衍生物包括式I化合物或其药学上可接受的酸式盐，包括但不限于化合物与下列酸形成的盐：盐酸、氢溴酸、硫酸、硝酸、柠檬酸、酒石酸、磷酸、乳酸、乙酸、马来酸、富马酸、苹果酸、杏仁酸、甲磺酸、苯磺酸、对甲苯磺酸、草酸、或琥珀酸。
在本发明的实施方案中，本发明提供的式I化合物，其中，所述1-6个碳的直链或支链烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、或己基。
在本发明的实施方案中，本发明提供的式I化合物，其中，所述3-6个碳的环烷基选自环丙烷基、环丁烷基、环戊烷基、或环己烷基。
第二方面，本发明提供了上述取代四氢噻吩并吡啶衍生物式I化合物或其药学上可接受酸式盐、溶剂化物或水合物的制备方法，包括下列步骤：
式II化合物与式III化合物或式IV化合物反应，得到式I化合物
Figure PCTCN2015088756-appb-000008
其中，式II化合物、式III化合物和式IV化合物中的R1、R2、X如式I化合物中所定义，Z为离去基团,如:氯、五氟酚基、硝基酚基等。
作为一种优选的实施方案，本发明提供了上述取代的四氢噻吩并吡啶衍生物式I化合物或其药学上可接受酸式盐、溶剂化物或水合物的制备方法，所述方法包括将式II化合物或其盐溶于有机溶剂中，冷却下分批加入碱，然后与式III化合物反应，得到式I化合物，如果有必要可以通过常规方法例如重结晶、柱层析等进一步纯化。这里，所述的碱可以是无机碱或有机碱，可选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、或N,N-二异丙基乙胺等。
特别的，对于本发明化合物例如MJ10605等末端含有活泼基团的化合物，可采用相应的保护基，如9-芴甲氧羰基保护，并在成酯缩合反应后，增加用哌啶脱保护步骤。
第三方面，本发明还提供包含治疗有效量的前述取代四氢噻吩并吡啶衍生物包括式I化合物、或其药学上接受的酸式盐、溶剂化物或者水合物的药物组合物，该药物组合物可以还包含可药用载体或稀释剂。该药物组合物可通过静脉注射给药、通过注射入组织给药、腹膜内给药、口服给药或鼻腔内给药。该药物组合物可具有选自溶液、分散体、悬浮液、粉末、胶囊、片剂、丸剂、延时释放胶囊、延时释放片剂和延时释放丸剂的形式。该药物组合物的给药剂量为5-5000mg/日。
第四方面，本发明提供了上述取代四氢噻吩并吡啶衍生物如式I化合物、或其药学上接受的酸式盐、溶剂化物或者水合物在制备用于抗血小板聚集、预防或治疗血栓和栓塞相关疾病，尤其是预防或治疗动脉粥样硬化疾病、心肌梗死、心绞痛、中风、缺血性脑血栓、外周动脉疾病、急性冠脉综合症或冠脉介入术后的血栓形成的药物中的用途。
与现有技术相比，本发明的新型的取代的四氢噻吩并吡啶衍生物具有显著的抑制血小板聚集作用，其抗血小板聚集作用甚至明显好于氯吡格雷。
本发明的化合物通过血液中的酯酶(而非依靠肝脏内P450酶系)代谢产生与氯吡格雷相同的活性代谢产物，避免了氯吡格雷的“氯吡格雷抵抗”现象。
此外，体内释放实验表明，本发明的新型取代四氢噻吩并吡啶衍生物可在体内有效地转化为药理活性代谢物而发挥作用，且活性代谢物的前体2-氧基-氯吡格雷浓度显著高于氯吡格雷。
附图说明
图1雄性SD大鼠(n＝3)灌胃给予2mg/kg的本发明化合物及硫酸氢氯吡格雷后2-氧基-氯吡格雷的血药浓度(ng/mL)。
图2雄性SD大鼠连续5天给药后血小板聚集抑制率比较(20μmol/L ADP诱导)。
具体实施方式
以下通过实施例来示例性说明本发明的实施方案，对于本领域的普通技术人员而言，在本发明的教导下，根据现有技术，对本发明实施方案进行的改进，仍属于本发明的保护范围内。
实施例中使用的化合物原料的来源是：所有的试剂由试剂公司购买，起始原料(2S)-2-(2-氯苯基)-2-(2-氧-5,6,7,7a-四氢噻吩并[3,2-c]吡啶基)乙酸甲酯参考中国专利申请201210333184.4的方法由2-氯扁桃酸甲酯的苯磺酸酯合成并经拆分得到。
核磁共振氢谱数据是由Bruker AV-300核磁共振波谱仪采集并处理。实施例1
环己氧基乙酸的合成
将60％的氢化钠(8.79g)混悬在四氢呋喃(500ml)中，加入环己醇(10g)，混合物在0℃下搅拌30分钟，然后加入溴乙酸(13.9g)，加完后回流反应2小时。向反应液中加入水，旋转蒸发仪去除有机溶剂，水溶液用水稀释至200ml，用甲基叔丁基醚洗涤，用1N盐酸酸化水层，用甲基叔丁基醚萃取，分离有机层，无水硫酸镁干燥，减压蒸发掉有机溶剂， 得油状物(环己氧基乙酸)(12.9g)，收率81.6％。1H-NMR(CDCl3)δ：1.18～1.47(5H,m),1.52～1.63(1H,m),1.72～1.85(2H,m),1.90～2.03(2H,m),3.36～3.47(1H,m),4.13(2H,s)。
实施例2
MJ10601的合成
Figure PCTCN2015088756-appb-000009
环己氧基乙酸(1.58g)用10ml氯化亚砜混悬，60℃反应2小时，减压蒸除溶剂，得环己氧基乙酰氯；将(2S)-2-(2-氯苯基)-2-(2-氧-5,6,7,7a-四氢噻吩并[3,2-c]吡啶基)乙酸甲酯(0.3g)溶于NMP(N-甲基吡咯烷酮)(10ml)，加入0.3ml三乙胺，在0℃下滴加环己氧基乙酰氯(0.18g)，滴加结束后，升温至室温反应3小时，将反应液倒入30ml水中，乙酸乙酯(30ml×3)萃取水相，合并有机相，用饱和碳酸氢钠水溶液洗涤，用饱和食盐水洗涤，无水硫酸钠干燥，蒸干有机相得油状物0.7g。采用硅胶柱层析分离得到白色固体0.25g，收率52.3％。MS(m/z)：478.2[M+1]+；1H-NMR(DMSO-d6)δ：1.16～1.43(5H,m),1.51～1.63(1H,m),1.72～1.86(2H,m),1.89～2.05(2H,m),2.66～2.91(m，4H),3.35～3.69(m,3H),3.71(s，3H),4.14(2H，s),4.91(s,1H),6.25(s,1H),7.21～7.68(m,4H)。
实施例3
丙氧基乙酸的合成
将60％的氢化钠(8.79g)混悬在四氢呋喃(500ml)中，加入正丙醇(6g)，混合物在0℃下搅拌30分钟，然后加入溴乙酸(13.9g)，加完后回流反应2小时。向反应液中加入水，旋转蒸发仪去除有机溶剂，水溶液用水稀释至200ml，用甲基叔丁基醚洗涤，用1N盐酸酸化水层，用甲基叔丁基醚萃取，分离有机层，无水硫酸镁干燥，减压蒸发掉有机溶剂，得 油状物(丙氧基乙酸)(10.9g)，收率92.3％。1H-NMR(CDCl3)δ：0.89(3H,t),1.51(2H,m),3.37(2H,t),4.12(2H,s)。
实施例4
MJ10602的合成
Figure PCTCN2015088756-appb-000010
丙氧基乙酸(1.18g)用10ml氯化亚砜混悬，60℃反应2小时，减压蒸除溶剂，得丙氧基乙酰氯；将(2S)-2-(2-氯苯基)-2-(2-氧-5,6,7,7a-四氢噻吩并[3,2-c]吡啶基)乙酸甲酯(0.3g)溶于NMP(N-甲基吡咯烷酮)(10ml)，加入0.3ml三乙胺，在0℃下滴加丙氧基乙酰氯(0.14g)，滴加结束后，升温至室温反应3小时，将反应液倒入30ml水中，乙酸乙酯(30ml×3)萃取水相，合并有机相，用饱和碳酸氢钠水溶液洗涤，用饱和食盐水洗涤，无水硫酸钠干燥，蒸干有机相得油状物0.8g。采用硅胶柱层析分离得到白色固体0.21g，收率47.9％。MS(m/z)：438.1[M+1]+；1H-NMR(DMSO-d6)δ：0.88(3H,t),1.51(2H,m),2.65～2.91(m，4H),3.34～3.68(m,4H),3.71(s，3H),4.13(2H,s),4.93(s,1H),6.26(s,1H),7.23～7.68(m,4H)。
实施例5
2-(四氢吡喃-4-氧基)乙酸的合成
将60％的氢化钠(8.79g)混悬在四氢呋喃(500ml)中，加入四氢吡喃-4-醇(10.2g)，混合物在0℃下搅拌30分钟，然后加入溴乙酸(13.9g)，加完后回流反应2小时。向反应液中加入水，旋转蒸发仪去除有机溶剂，水溶液用水稀释至200ml，用甲基叔丁基醚洗涤，用1N盐酸酸化水层，用甲基叔丁基醚萃取，分离有机层，无水硫酸镁干燥，减压蒸发掉有机溶剂，得油状物(2-(四氢吡喃-4-氧基)乙酸)(10.9g)，收率69.0％。1H-NMR(CDCl3)δ：1.58～1.91(4H,m),3.23(1H,m),3.41～3.65(4H,m),4.21(2H,s)。 实施例6
MJ10603的合成
Figure PCTCN2015088756-appb-000011
2-(四氢吡喃-4-氧基)乙酸(1.60g)用10ml氯化亚砜混悬，60℃反应2小时，减压蒸除溶剂，得2-(四氢吡喃-4-氧基)乙酰氯；将(2S)-2-(2-氯苯基)-2-(2-氧-5,6,7,7a-四氢噻吩并[3,2-c]吡啶基)乙酸甲酯(0.3g)溶于NMP(N-甲基吡咯烷酮)(10ml)，加入0.3ml三乙胺，在0℃下滴加2-(四氢吡喃-4-氧基)乙酰氯(0.18g)，滴加结束后，升温至室温反应3小时，将反应液倒入30ml水中，乙酸乙酯(30ml×3)萃取水相，合并有机相，用饱和碳酸氢钠水溶液洗涤，用饱和食盐水洗涤，无水硫酸钠干燥，蒸干有机相得油状物1.1g。采用硅胶柱层析分离得到白色固体0.23g，收率47.9％。MS(m/z)：480.2[M+1]+；1H-NMR(DMSO-d6)δ：1.61～1.89(m,4H)，2.66～2.91(m，4H),3.25(s,1H),3.38～3.75(m,6H),3.71(s，3H),4.21(s,2H),4.96(s,1H),6.23(s,1H),7.22～7.68(m,4H)。
实施例7
异丙基氧基乙酸的合成
将60％的氢化钠(8.79g)混悬在四氢呋喃(500ml)中，加入异丙醇(6g)，混合物在0℃下搅拌30分钟，然后加入溴乙酸(13.9g)，加完后回流反应2小时。向反应液中加入水，旋转蒸发仪去除有机溶剂，水溶液用水稀释至200ml，用甲基叔丁基醚洗涤，用1N盐酸酸化水层，用甲基叔丁基醚萃取，分离有机层，无水硫酸镁干燥，减压蒸发掉有机溶剂，得油状物异丙基氧基乙酸(10.3g)，收率87.3％。1H-NMR(CDCl3)δ：1.15(6H,d),3.21(1H,m),4.33(2H,s)。
实施例8MJ10604的合成
Figure PCTCN2015088756-appb-000012
异丙基氧基乙酸(1.18g)用10ml氯化亚砜混悬，60℃反应2小时，减压蒸除溶剂，得异丙基氧基乙酰氯；将(2S)-2-(2-氯苯基)-2-(2-氧-5,6,7,7a-四氢噻吩并[3,2-c]吡啶基)乙酸甲酯(0.3g)溶于NMP(N-甲基吡咯烷酮)(10ml)，加入0.3ml三乙胺，在0℃下滴加异丙基氧基乙酰氯(0.18g)，滴加结束后，升温至室温反应3小时，将反应液倒入30ml水中，乙酸乙酯(30ml×3)萃取水相，合并有机相，用饱和碳酸氢钠水溶液洗涤，用饱和食盐水洗涤，无水硫酸钠干燥，蒸干有机相得油状物0.9g。采用硅胶柱层析分离得到白色固体0.22g，收率49.2％。MS(m/z)：438.2[M+1]+；1H-NMR(DMSO-d6)δ：1.14(d,6H),2.63～2.91(m，4H),3.12(m,1H),3.36～3.66(m,2H),3.73(s，3H),4.37(s,2H),4.96(s,1H),6.27(s,1H),7.22～7.69(m,4H)。
实施例9
MJ10611的合成
Figure PCTCN2015088756-appb-000013
将(2S)-2-(2-氯苯基)-2-(2-氧-5,6,7,7a-四氢噻吩并[3,2-c]吡啶基)乙酸甲酯(0.3g)溶于NMP(N-甲基吡咯烷酮)(10ml)，加入0.3ml三乙胺，在0℃下滴加十六酰氯(0.4g)，滴加结束后，升温至室温反应3小时，将反应液倒入30ml水中，乙酸乙酯(30ml×3)萃取水相，合并有机相，用饱和碳酸氢钠水溶液洗涤，用饱和食盐水洗涤，无水硫酸钠干燥，蒸干有机相得油状物1.3g。采用硅胶柱层析分离得到白色固体0.45g，收率43.3％。 MS(m/z)：576.2[M+1]+；1H-NMR(DMSO-d6)δ：0.92(t,3H),1.25～1.32(m,24H),1.53(m，2H),2.53(t,2H),2.67～3.12(m,4H),3.39～3.68(m,2H),3.75(s，3H),4.96(s,1H),6.25(s,1H),7.23～7.68(m,4H)。
实施例10
MJ10601盐酸盐的制备
将化合物MJ10601(478mg)溶解于无水四氢呋喃中，搅拌下降温至0℃，通入干燥氯化氢气体，收集析出固体，得到类白色粉末(316mg)，收率61.4％。
其他盐用不同的酸在无水有机溶剂中反应制备。
实施例11抗血小板聚集试验：
供试溶液的制备：取硫酸氢氯吡格雷适量，加0.5％CMC-Na溶液，研磨，制得0.6mg/ml、2.0mg/ml的混悬液，即得。同法，取化合物MJ10601、MJ10602适量，制得0.2mg/ml、0.6mg/ml的混悬液；取化合物MJ10604、MJ10611适量，制得0.6mg/ml的混悬液，即得。
动物：SD大鼠，雄性，250-270g。共54只，分为9组，每组6只。大鼠按5ml/kg的体积灌胃给予各供试液，换算得各供试物给药剂量为1-10mg/kg。对照组给予等体积0.5％CMC-Na溶液。
方法及结果：灌胃给药后2小时，各大鼠股动脉取血，与3.8％枸橼酸钠溶液以适当比例混合，离心7分钟(1000rpm),制得富血小板血浆(PRP)；取另一份全血，同法以3000rpm离心5分钟，制得贫血小板血浆(PPP)。PRP中加入PPP适量，使最终血小板浓度为5×109--10×109/L。以5μmADP(二磷酸腺苷)试液适量为诱导剂加入测试液中，于血小板聚集仪上测定5分钟内的最大血小板聚集率，并依此计算血小板聚集抑制率。
血小板聚集抑制率＝100％×(对照组最大血小板聚集率平均值-试验组动物最大血小板聚集率)/对照组最大血小板聚集率平均值，结果见表1。
表1 对大鼠血小板聚集的抑制作用
Figure PCTCN2015088756-appb-000014
*与氯吡格雷3mg/kg组比较有极显著性差异(p<0.01)
#与氯吡格雷10mg/kg组比较有显著性差异(p<0.05)
上述试验结果显示，试验组药物疗效几乎是等剂量硫酸氯吡格雷的6倍，且这种效应在不同动物间的差异，试验用药明显较氯吡格雷小。
实施例12体内药代动力学研究
Figure PCTCN2015088756-appb-000015
研究表明，氯吡格雷在体内首先代谢活化生成2-氧基-氯吡格雷，2-氧基-氯吡格雷再进一步水解生成活性代谢物。2-氧基-氯吡格雷的生成反应是代谢的限速步骤，所以2-氧基-氯吡格雷的生成量是评价这类化合物体 内活性的关键指标。
本发明人通过考察大鼠分别灌胃给予化合物MJ10601、MJ10602、MJ10604、MJ10611及硫酸氢氯吡格雷后，它们的代谢物2-氧基-氯吡格雷的经时过程，考察化合物给药后在体内能否代谢产生2-氧基-氯吡格雷，并评价它们的生成量。
健康雄性SD大鼠15只(体重250-270g)，分为5组，每组3只，分别灌胃给予化合物MJ10601、MJ10602、MJ10604、MJ10611及硫酸氢氯吡格雷(2mg/kg)。给药后未见任何异常，提示动物对该剂量的化合物耐受。于不同时间点采集血浆样品，经有机溶剂处理后采用液相色谱-串联质谱法测定血浆中2-氧基-氯吡格雷的浓度，结果见图1。大鼠服测试化合物及硫酸氢氯吡格雷后，2-氧基-氯吡格雷的药代动力学参数按照非房室模型计算，结果见表2。
表2 雄性SD大鼠灌胃给予测试化合物及硫酸氢氯吡格雷后2-氧基-氯吡格雷的药代动力学参数
Figure PCTCN2015088756-appb-000016
Figure PCTCN2015088756-appb-000017
药代动力学研究表明，测试化合物可在体内有效地转化为药理活性代谢物而发挥作用，且灌胃给予MJ10601、MJ10602、MJ10604、MJ10611后产生活性代谢物的前体2-氧基-氯吡格雷AUC高于硫酸氢氯吡格雷组。
同时，比较各动物间主要药代动力学参数(如AUC等)的变化，试验药RSD明显小于氯吡格雷组。
以上研究表明，测试化合物在体内可转化为2-氧基-氯吡格雷并进一步代谢活化，并且代谢的个体差异性较氯吡格雷组小，药物的特殊酶依赖性较小，产生氯吡格雷抵抗的可能性较小；另外，由于测试化合物在体内产生的活性代谢物前体2-氧基-氯吡格雷的量在等质量时显著高于氯吡格雷组，有望通过减少给药剂量，在起效快、疗效高的前提下，减少非活性代谢产生的不良反应。除以上化合物外，本发明涉及的优选化合物代谢产生的2-氧基-氯吡格雷的AUC也大于等剂量下硫酸氢氯吡格雷产生的2-氧基-氯吡格雷的AUC，在等剂量条件下血小板聚集抑制率都优于硫酸氢氯吡格雷组。
实施例13多次给药后抗血小板聚集试验
本试验将供试品灌胃给予正常SD大鼠5天，比较供试品不同时间点对20μmolADP诱导血小板聚集的抑制作用。
试验用54只雄性SD大鼠，随机分为3大组，每大组18只，分别给 予19.65mg/kg硫酸氢氯吡格雷、2mg/kg MJ10611、1.52mg/kg MJ10602，连续给药5天，末次给药前禁食8～12h，第5天给药后每大组分6小组，每组3只于0.17h、2h、4h、6h、12h、24h测试20μmol/L ADP诱导血小板聚集率，测试方法见实施例11，依此计算血小板聚集抑制率。
血小板聚集抑制率＝100％×(对照组最大血小板聚集率平均值-试验组动物最大血小板聚集率)/对照组最大血小板聚集率平均值，结果见表3，图2。
表3 雄性SD大鼠连续5天给药后血小板聚集抑制作用
Figure PCTCN2015088756-appb-000018
试验结果显示，本发明的化合物以近乎氯吡格雷1/10的剂量给药，产生的血小板抑制作用与氯吡格雷基本一致。

Claims (10)

  1. 式I化合物，或其药学可接受的酸式盐，溶剂化物或水合物：
    Figure PCTCN2015088756-appb-100001
    其中：
    R1为1-6个碳的直链或支链烷基、3-6个碳的环烷基、或OR3；
    R2为
    Figure PCTCN2015088756-appb-100002
    牛磺酰基、硬脂酰基、软脂酰基、月桂酰基、豆蔻酰基、油酰基、亚油酰基、或亚麻酰基；
    R3为1-6个碳的直链或支链烷基、或3-6个碳的环烷基；
    R4为氢、1-6个碳的直链或支链烷基、或3-6个碳的环烷基；
    X为氢、氯、氟、溴、或碘；
    n＝0-6。
  2. 根据权利要求1所述化合物，其中，R1为环丙基、甲氧基、或乙氧基。
  3. 根据权利要求1所述化合物，其中，R2为
    Figure PCTCN2015088756-appb-100003
    R4为氢、1-6个碳的直链或支链烷基、或3-6个碳的环烷基；n＝0-6。
  4. 根据权利要求1所述化合物，其中，R2为牛磺酰基、硬脂酰基、软脂酰基、月桂酰基、豆蔻酰基、油酰基、亚油酰基、或亚麻酰基。
  5. 根据权利要求1所述化合物，其中，X为氯、或氟。
  6. 一种选自下列结构的化合物，或其药学可接受的酸式盐，溶剂化 物或水合物：
    Figure PCTCN2015088756-appb-100004
  7. 一种用于制备根据权利要求1-6任一项所述化合物的方法，包括下列步骤：
    式II化合物与式III化合物或式IV化合物反应，得到式I化合物
    Figure PCTCN2015088756-appb-100005
    其中，式II化合物、式III化合物和式IV化合物中的R1、R2、X如权利要求1式I化合物中所定义，Z为离去基团。
  8. 一种药物组合物，所述药物组合物包含权利要求1-6中任一项所述的化合物。
  9. 如权利要求1-6中任一项所述的化合物或如权利要求8所述的药物组合物在制备用于抑制血小板聚集，或者预防或治疗血栓和栓塞相关疾病的药物中的用途。
  10. 如权利要求9所述的用途，其中，所述制备抑制血小板聚集，或者预防或治疗血栓和栓塞相关疾病包括预防或治疗心绞痛、动脉粥样硬化疾病、心肌梗死，中风、缺血性脑血栓、外周动脉疾病、或者急性冠脉综合症或冠脉介入术后的血栓形成。
PCT/CN2015/088756 2014-09-02 2015-09-01 取代的四氢噻吩并吡啶衍生物及其应用 WO2016034103A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410444643.5 2014-09-02
CN201410444643 2014-09-02

Publications (1)

Publication Number Publication Date
WO2016034103A1 true WO2016034103A1 (zh) 2016-03-10

Family

ID=54794277

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/088756 WO2016034103A1 (zh) 2014-09-02 2015-09-01 取代的四氢噻吩并吡啶衍生物及其应用

Country Status (2)

Country Link
CN (1) CN105153192B (zh)
WO (1) WO2016034103A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107304215A (zh) * 2016-04-20 2017-10-31 陕西合成药业股份有限公司 噻吩吡啶类衍生物及其制备方法和用途
CN114286823B (zh) * 2020-08-03 2023-11-28 天地恒一制药股份有限公司 一种光学活性2-羟基四氢噻吩并吡啶类衍生物及其制备方法和用途
WO2023134682A1 (zh) * 2022-01-11 2023-07-20 天地恒一制药股份有限公司 一种光学活性2-羟基四氢噻吩并吡啶类衍生物及其制备方法和用途

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5190938A (en) * 1989-10-02 1993-03-02 Sanofi Derivatives of 2-hydroxythiophene and -furan fused with a nitrogen-containing ring and their application in therapy
CN1074446A (zh) * 1991-09-09 1993-07-21 三共株式会社 羟基吡啶衍生物
CN102120744A (zh) * 2010-02-02 2011-07-13 江苏威凯尔医药科技有限公司 光学活性2-羟基四氢噻吩并吡啶衍生物及其制备方法与在制药中的用途
CN102199163A (zh) * 2011-04-01 2011-09-28 中国药科大学 2-羟基四氢噻吩并吡啶衍生物及其制备方法与在制药中的用途
CN103068383A (zh) * 2010-08-26 2013-04-24 Ipca实验室有限公司 血栓形成或梗塞的治疗或预防方法
CN103254211A (zh) * 2012-02-17 2013-08-21 江苏威凯尔医药科技有限公司 一种制备维卡格雷及其衍生物的方法
CN103664990A (zh) * 2012-09-12 2014-03-26 江苏威凯尔医药科技有限公司 维卡格雷的制备方法
WO2015039577A1 (zh) * 2013-09-17 2015-03-26 天士力控股集团有限公司 噻吩并哌啶衍生物及其用途

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5190938A (en) * 1989-10-02 1993-03-02 Sanofi Derivatives of 2-hydroxythiophene and -furan fused with a nitrogen-containing ring and their application in therapy
CN1074446A (zh) * 1991-09-09 1993-07-21 三共株式会社 羟基吡啶衍生物
CN102120744A (zh) * 2010-02-02 2011-07-13 江苏威凯尔医药科技有限公司 光学活性2-羟基四氢噻吩并吡啶衍生物及其制备方法与在制药中的用途
CN103068383A (zh) * 2010-08-26 2013-04-24 Ipca实验室有限公司 血栓形成或梗塞的治疗或预防方法
CN102199163A (zh) * 2011-04-01 2011-09-28 中国药科大学 2-羟基四氢噻吩并吡啶衍生物及其制备方法与在制药中的用途
CN103254211A (zh) * 2012-02-17 2013-08-21 江苏威凯尔医药科技有限公司 一种制备维卡格雷及其衍生物的方法
CN103664990A (zh) * 2012-09-12 2014-03-26 江苏威凯尔医药科技有限公司 维卡格雷的制备方法
WO2015039577A1 (zh) * 2013-09-17 2015-03-26 天士力控股集团有限公司 噻吩并哌啶衍生物及其用途

Also Published As

Publication number Publication date
CN105153192A (zh) 2015-12-16
CN105153192B (zh) 2019-03-29

Similar Documents

Publication Publication Date Title
CN112424207B (zh) Nlrp3炎性小体抑制剂
CN110088105B (zh) Jak家族激酶的小分子抑制剂
JP5988381B2 (ja) 光学活性な２−ヒドロキシテトラヒドロチエノピリジン誘導体、その調製方法及び医薬の製造におけるその使用
WO2017114509A1 (zh) 醛基类化合物及其制法和用途
CN106029076A (zh) 作为bet溴域抑制剂的苯并哌嗪组合物
JP5575979B2 (ja) シアノ基を含有するチエノピリジンエステル誘導体、その調製方法、使用および組成物
CA2902436A1 (en) Salt of omecamtiv mecarbil and process for preparing salt
TW201200512A (en) A crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate
TW201729810A (zh) 嘧啶組成物、其超純組成物及鹽類、製造彼之方法、及使用彼於治療組織胺h4受體(h 4 )仲介之疾病與病情之方法
JP2018531288A6 (ja) ピリミジン組成物、超高純度組成物およびその塩、それを作成する方法、ならびにヒスタミンｈ４受容体（ｈ４）によって媒介される疾患および状態を治療するためにそれを用いる方法
WO2012136111A1 (zh) 苯丙酸化合物、其制备方法及其医药用途
WO2016034103A1 (zh) 取代的四氢噻吩并吡啶衍生物及其应用
CN112313233A (zh) Jak家族激酶的小分子抑制剂
KR102576964B1 (ko) 헤테로시클리덴 아세트아미드 유도체의 결정
KR100925900B1 (ko) 아미노산 유도체
AU2021337193A1 (en) Novel compounds for use in the treatment of diseases associated with angiotensin II
JP7478858B2 (ja) 複素環系化合物の結晶形及びその製造方法と使用
CN103228648A (zh) (s)-2-氨基-3-(4-(2-氨基-6-((r)-1-(4-氯-2-(3-甲基-1h-吡唑-1-基)苯基)-2,2,2-三氟乙氧基)嘧啶-4-基)苯基)丙酸的晶体形式
WO2018072742A1 (zh) 一种咪唑并异吲哚类衍生物的游离碱的结晶形式及其制备方法
TW200934774A (en) Arylmethylidene heterocycles as novel analgesics
JP2019529553A (ja) 結晶形
WO2017190708A1 (zh) 吡唑‐三嗪类衍生物、其制备方法、药物组合物和用途
WO2012139422A1 (zh) 新型抗血小板化合物的加成盐
JP2012524767A (ja) Ｉｋｋ−ｂセリン・スレオニンプロテインキナーゼのチオフェン阻害剤
WO2021093860A1 (zh) 取代的双三环化合物及其药物组合物和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15838519

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15838519

Country of ref document: EP

Kind code of ref document: A1