WO2016034103A1 - Dérivés de tétrahydrothiéno pyridine substitués et leur utilisation - Google Patents

Dérivés de tétrahydrothiéno pyridine substitués et leur utilisation Download PDF

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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
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compound
formula
carbons
clopidogrel
platelet aggregation
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PCT/CN2015/088756
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English (en)
Chinese (zh)
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张维威
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南京曼杰生物科技有限公司
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Publication of WO2016034103A1 publication Critical patent/WO2016034103A1/fr

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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
    • A61K31/435—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.

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  • Chemical & Material Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

L'invention concerne un dérivé tétrahydrothiéno pyridine substitué, un sel d'acide, un solvate ou un hydrate pharmaceutiquement acceptable et son utilisation tel que représenté par la formule générale (I), où R1, R2 et X sont tels que définis dans la description. L'invention concerne également un procédé de synthèse du composé, des compositions pharmaceutiques et leur utilisation dans la préparation de médicaments pour inhiber l'agrégation plaquettaire, et la prévention ou le traitement de maladies liées à la thrombose et à l'embolie.
PCT/CN2015/088756 2014-09-02 2015-09-01 Dérivés de tétrahydrothiéno pyridine substitués et leur utilisation WO2016034103A1 (fr)

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CN201410444643 2014-09-02

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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
CN116744921A (zh) * 2022-01-11 2023-09-12 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)

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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 (fr) * 2013-09-17 2015-03-26 天士力控股集团有限公司 Dérivé thiénopipéridine et son utilisation

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 (fr) * 2013-09-17 2015-03-26 天士力控股集团有限公司 Dérivé thiénopipéridine et son utilisation

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