WO2016034103A1

WO2016034103A1 - Substituted tetrahydrothieno pyridine derivatives and use thereof

Info

Publication number: WO2016034103A1
Application number: PCT/CN2015/088756
Authority: WO
Inventors: 张维威
Original assignee: 南京曼杰生物科技有限公司
Priority date: 2014-09-02
Filing date: 2015-09-01
Publication date: 2016-03-10
Also published as: CN105153192A; CN105153192B

Abstract

Disclosed are a substituted tetrahydrothieno pyridine derivative, a pharmaceutically acceptable acid salt, solvate or hydrate and a use thereof as shown by general formula (I), wherein R₁, R₂ and X are as defined in the description. Also disclosed are a method for synthesizing the compound, pharmaceutical compositions and their use in the preparation of drugs for inhibiting platelet aggregation, and preventing or treating thrombosis and embolism related diseases.

Description

Substituted tetrahydrothienopyridine derivatives and their applications

Technical field

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.

Background technique

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. .

Therefore, anti-platelet aggregation drugs with fast onset, high activity, no drug resistance, and low risk of bleeding have become urgent clinical needs.

Summary of the invention

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.

It is an object of the present invention to provide a novel substituted tetrahydrothienopyridine derivative which is metabolized by an esterase in the blood (rather than relying on a P450 enzyme in the liver) to produce the same active metabolite as clopidogrel. Because of the prevalence of esterase in human blood, the phenomenon of clopidogrel resistance to clopidogrel is avoided.

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.

In particular, the invention provides a substituted tetrahydrothienopyridine derivative, such as a compound of formula I, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof:

among them:

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.

In a preferred embodiment of the present invention, the present invention provides compounds of formula I, wherein, R ₁ is cyclopropyl or methoxy, or ethoxy.

In a preferred embodiment of the invention, the invention provides a compound of formula I, wherein R ₂ is

R ₄ is hydrogen, a linear or branched alkyl group of 1 to 6 carbons, or a cycloalkyl group of 3 to 6 carbons; n = 0 to 6.

In a preferred embodiment of the invention, there is provided a compound of formula I, wherein X is chloro, or fluoro.

In a preferred embodiment of the invention, the invention provides a compound of formula I, wherein R ₁ is cyclopropyl or methoxy, ethoxy;

R ₂ is

R ₄ is hydrogen, a straight or branched alkyl group of 1 to 6 carbons, or a cycloalkyl group of 3 to 6 carbons; n = 0 to 6;

X is chlorine or fluorine.

In a more preferred embodiment of the invention, the invention provides a compound of formula I, wherein R ₁ is methoxy;

R ₂ is

X is chlorine.

In a preferred embodiment of the invention, there is provided a compound of formula I, wherein R ₂ is tauroyl, stearoyl, leucoyl, lauroyl, myristoyl, oleoyl, linoleoyl, or Flax acyl.

In a preferred embodiment of the invention, 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.

X is chlorine.

In a particularly preferred embodiment of the invention, the compounds provided herein are selected from one of the following compounds, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof:

In an embodiment of the invention, the derivative provided by the invention comprises an enantiomer and a racemate of a compound of formula I.

In an embodiment of the invention, 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.

In an embodiment of the invention, 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.

In an embodiment of the invention, the invention provides a compound of formula I, wherein the 3-6 carbon cycloalkyl is selected from cyclopropyl, cyclobutane, cyclopentyl, or cyclohexane. .

In a second aspect, 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:

Reaction of a compound of formula II with a compound of formula III or a compound of formula IV to provide a compound of formula I

Wherein, in the compound of formula II, the compound of formula III and the compound of formula IV, 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.

As a preferred embodiment, 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. Here, 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.

In particular, for a compound of the present invention such as MJ10605, which contains a reactive group at the end, a corresponding protecting group such as 9-fluorenylmethoxycarbonyl can be used, and after the ester-forming condensation reaction, a piperidine deprotection step is added.

In a third aspect, the present invention provides 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.

In a fourth aspect, 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.

Compared with the prior art, 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.

In addition, in vivo release experiments indicate that the novel substituted tetrahydrothienopyridine derivatives of the present invention can be efficiently converted into pharmacologically active metabolites in vivo, and the precursor 2-oxy-clopidogrel concentration of active metabolites Significantly higher than clopidogrel.

DRAWINGS

Figure 1 Male SD rats (n=3) were administered a plasma concentration (ng/mL) of 2-oxy-clopidogrel after administration of 2 mg/kg of the compound of the present invention and clopidogrel hydrogen sulfate.

Figure 2 Comparison of inhibition rate of platelet aggregation after administration of male SD rats for 5 consecutive days (20 μmol/L ADP induction).

detailed description

The embodiments of the present invention are exemplified below by way of examples, and those skilled in the art, under the teachings of the present invention, according to the prior art, the improvements of the embodiments of the present invention still belong to the protection of the present invention. Within the scope.

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.

Nuclear magnetic resonance spectroscopy data was collected and processed by a Bruker AV-300 NMR spectrometer. Example 1

Synthesis of cyclohexyloxyacetic acid

60% sodium hydride (8.79 g) was suspended in tetrahydrofuran (500 ml), cyclohexanol (10 g) was added, and the mixture was stirred at 0 ° C for 30 minutes, then bromoacetic acid (13.9 g) was added, and the reaction was refluxed after the addition. 2 hours. Water was added to the reaction mixture, and the organic solvent was removed by a rotary evaporator. The aqueous solution was diluted with water to 200 ml, washed with methyl tert-butyl ether, and the aqueous layer was acidified with 1N hydrochloric acid and extracted with methyl tert-butyl ether. The residue was dried over MgSO.sub.sub. ¹ H-NMR (CDCl ₃ ) δ: 1.18 to 1.47 (5H, m), 1.52 to 1.63 (1H, m), 1.72 to 1.85 (2H, m), 1.90 to 2.03 (2H, m), 3.36 to 3.47 ( 1H, m), 4.13 (2H, s).

Example 2

Synthesis of MJ10601

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. After the completion of the dropwise addition, the mixture was heated to room temperature for 3 hours, and the reaction solution was poured into 30 ml of water, ethyl acetate. (30 ml × 3) The aqueous layer was extracted, and the organic layer was evaporated, evaporated, evaporated, evaporated The white solid was isolated by silica gel column chromatography (yield: 0.25 g). MS (m/z): 478.2 [M+1]+; ¹ H-NMR (DMSO-d6) δ: 1.16 to 1.43 (5H, m), 1.51 to 1.63 (1H, m), 1.72 to 1.86 (2H, m), 1.89 to 2.05 (2H, m), 2.66 to 2.91 (m, 4H), 3.35 to 3.69 (m, 3H), 3.71 (s, 3H), 4.14 (2H, s), 4.91 (s, 1H) , 6.25 (s, 1H), 7.21 to 7.68 (m, 4H).

Example 3

Synthesis of propoxyacetic acid

60% sodium hydride (8.79 g) was suspended in tetrahydrofuran (500 ml), n-propanol (6 g) was added, and the mixture was stirred at 0 ° C for 30 minutes, then bromoacetic acid (13.9 g) was added, and the reaction was refluxed after the addition. 2 hours. Water was added to the reaction mixture, and the organic solvent was removed by a rotary evaporator. The aqueous solution was diluted with water to 200 ml, washed with methyl tert-butyl ether, and the aqueous layer was acidified with 1N hydrochloric acid and extracted with methyl tert-butyl ether. The organic layer was evaporated to dryness crystall ¹ H-NMR (CDCl ₃ ) δ: 0.89 (3H, t), 1.51 (2H, m), 3.37 (2H, t), 4.12 (2H, s).

Example 4

Synthesis of MJ10602

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. After the dropwise addition, the mixture was warmed to room temperature for 3 hours, and the reaction solution was poured into 30 ml of water, ethyl acetate (30 ml × 3) The aqueous phase was extracted, and the organic layer was combined, evaporated, evaporated, evaporated The white solid was isolated by silica gel column chromatography to yield 0.21 g, yield 47.9%. MS (m/z): 438.1 [M+1]+; ¹ H-NMR (DMSO-d6) δ: 0.88 (3H, t), 1.51 (2H, m), 2.65 to 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 to 7.68 (m, 4H).

Example 5

Synthesis of 2-(tetrahydropyran-4-yl)acetic acid

60% sodium hydride (8.79 g) was suspended in tetrahydrofuran (500 ml), tetrahydropyran-4-ol (10.2 g) was added, and the mixture was stirred at 0 ° C for 30 minutes, then bromoacetic acid (13.9 g) was added. After the addition, the reaction was refluxed for 2 hours. Water was added to the reaction mixture, and the organic solvent was removed by a rotary evaporator. The aqueous solution was diluted with water to 200 ml, washed with methyl tert-butyl ether, and the aqueous layer was acidified with 1N hydrochloric acid and extracted with methyl tert-butyl ether. The organic layer was dried (MgSO4), evaporated, evaporated ¹ H-NMR (CDCl ₃ ) δ: 1.58 to 1.91 (4H, m), 3.23 (1H, m), 3.41 to 3.65 (4H, m), 4.21. (2H, s). Example 6

Synthesis of MJ10603

2-(Tetrahydropyran-4-yloxy)acetic acid (1.60 g) was suspended with 10 ml of thionyl chloride, reacted at 60 ° C for 2 hours, and the solvent was evaporated under reduced pressure to give 2-(tetrahydropyran-4- Oxy)acetyl chloride; (2S)-2-(2-chlorophenyl)-2-(2-oxo-5,6,7,7a-tetrahydrothieno[3,2-c]pyridinyl) Methyl acetate (0.3 g) was dissolved in NMP (N-methylpyrrolidone) (10 ml), 0.3 ml of triethylamine was added, and 2-(tetrahydropyran-4-oxy)acetyl chloride was added dropwise at 0 °C. After the completion of the dropwise addition, 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. MS (m/z): 480.2 [M+1] ⁺ ; ¹ H-NMR (DMSO-d6) δ: 1.61 to 1.89 (m, 4H), 2.66 to 2.91 (m, 4H), 3.25 (s, 1H) , 3.38 to 3.75 (m, 6H), 3.71 (s, 3H), 4.21 (s, 2H), 4.96 (s, 1H), 6.23 (s, 1H), 7.22 to 7.68 (m, 4H).

Example 7

Synthesis of isopropyloxyacetic acid

60% sodium hydride (8.79 g) was suspended in tetrahydrofuran (500 ml), isopropanol (6 g) was added, and the mixture was stirred at 0 ° C for 30 minutes, then bromoacetic acid (13.9 g) was added, and the reaction was refluxed after the addition. 2 hours. Water was added to the reaction mixture, and the organic solvent was removed by a rotary evaporator. The aqueous solution was diluted with water to 200 ml, washed with methyl tert-butyl ether, and the aqueous layer was acidified with 1N hydrochloric acid and extracted with methyl tert-butyl ether. The mixture was dried over MgSO.sub.4, and evaporated. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (6H, d), 3.21 (1H, m), 4.33 (2H, s).

Example 8 Synthesis of MJ10604

Isopropyloxyacetic acid (1.18 g) 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 isopropyloxyacetyl chloride; (2S)-2-(2- Methyl chlorophenyl)-2-(2-oxo-5,6,7,7a-tetrahydrothieno[3,2-c]pyridyl)acetate (0.3 g) is dissolved in NMP (N-methylpyrrolidone) (10 ml), 0.3 ml of triethylamine was added, and isopropyloxyacetyl chloride (0.18 g) was added dropwise at 0 ° C. After the completion of the dropwise addition, the mixture was heated to room temperature for 3 hours, and the reaction solution was poured into 30 ml of water. The organic layer was extracted with EtOAc (EtOAc m. The white solid was isolated by silica gel column chromatography (0.22 g). MS (m/z): 438.2 [M+1] ⁺ ; ¹ H-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 to 7.69 (m, 4H).

Example 9

Synthesis of MJ10611

Methyl (2S)-2-(2-chlorophenyl)-2-(2-oxo-5,6,7,7a-tetrahydrothieno[3,2-c]pyridyl)acetate (0.3 g Soluble in NMP (N-methylpyrrolidone) (10ml), add 0.3ml of triethylamine, add hexadecanoyl chloride (0.4g) at 0 ° C, after the end of the addition, warm to room temperature for 3 hours, the reaction The liquid was poured into 30 ml of water, and the aqueous layer was extracted with ethyl acetate (30 ml × 3). The organic phase was combined, washed with saturated aqueous sodium hydrogen carbonate, washed with brine, dried over anhydrous sodium sulfate g. The white solid was separated by silica gel column chromatography to yield 0.45 g (yield: 43.3%). MS (m/z): 576.2 [M+1] ⁺ ; ¹ H-NMR (DMSO-d6) δ: 0.92 (t, 3H), 1.25 to 1.32 (m, 24H), 1.53 (m, 2H), 2.53 (t, 2H), 2.67 to 3.12 (m, 4H), 3.39 to 3.68 (m, 2H), 3.75 (s, 3H), 4.96 (s, 1H), 6.25 (s, 1H), 7.23 to 7.68 (m) , 4H).

Example 10

Preparation of MJ10601 hydrochloride

The compound MJ10601 (478 mg) was dissolved in anhydrous tetrahydrofuran, and the mixture was stirred and cooled to 0° C., and then dried hydrogen chloride gas was passed, and the solid was collected to give an off-white powder (316 mg) in a yield of 61.4%.

Other salts are prepared by reacting different acids in an anhydrous organic solvent.

Example 11 Antiplatelet aggregation test:

Preparation of 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. In the same method, 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.

METHODS AND 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. The appropriate amount of 5 μmA 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.

Table 1 Inhibition of rat platelet aggregation

* There was a significant difference compared with the clopidogrel 3 mg/kg group (p<0.01)

#Compared with clopidogrel 10mg/kg group (p<0.05)

The above test results showed that the efficacy of the test group was almost six times that of the same dose of clopidogrel sulfate, and the effect was different between animals, and the test drug was significantly smaller than clopidogrel.

Example 12 in vivo pharmacokinetic study

Studies have shown that 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.

15 healthy male Sprague-Dawley rats (body weight 250-270 g) were divided into 5 groups, 3 in each group, and the compounds MJ10601, MJ10602, MJ10604, MJ10611 and clopidogrel hydrogen sulfate (2 mg/kg) were administered intragastrically. No abnormalities were observed after administration, suggesting that the animals were tolerant to the dose of the compound. Plasma samples were collected at different time points, and the concentration of 2-oxy-clopidogrel in plasma was determined by liquid chromatography-tandem mass spectrometry after treatment with an organic solvent. The results are shown in Fig. 1. After the test compound and clopidogrel hydrogen sulfate were administered to rats, the pharmacokinetic parameters of 2-oxy-clopidogrel were calculated according to the non-compartmental model. The results are shown in Table 2.

Table 2 Pharmacokinetic parameters of 2-oxy-clopidogrel after administration of test compound and clopidogrel hydrogen sulfate in male SD rats

Pharmacokinetic studies have shown that the test compound can be effectively converted into a pharmacologically active metabolite in vivo, and the precursor 2-oxy-chloropyridyl which produces active metabolites after intragastric administration of MJ10601, MJ10602, MJ10604, and MJ10611. Gray AUC was higher than the clopidogrel hydrogen sulfate group.

At the same time, the changes of main pharmacokinetic parameters (such as AUC, etc.) between animals were compared, and the RSD of the test drug was significantly smaller than that of the clopidogrel group.

The above studies indicate that the 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. In addition to the above compounds, 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.

Example 13 Antiplatelet aggregation test after multiple administrations

In this experiment, the test samples were intragastrically administered to normal SD rats for 5 days, and the inhibitory effects of 20 μmol ADP on platelet aggregation were compared at different time points.

54 male Sprague-Dawley rats were randomly divided into 3 groups, 18 in each group, respectively. 19.65mg/kg clopidogrel hydrogen sulfate, 2mg/kg MJ10611, 1.52mg/kg MJ10602, continuous administration for 5 days, fasting for 8-12 hours before the last administration, and 6 groups for each major component after the fifth day of administration. 3 groups in each group were tested for platelet aggregation rate of 20 μmol/L ADP at 0.17h, 2h, 4h, 6h, 12h, 24h. The test method is shown in Example 11, and the inhibition rate of platelet aggregation was calculated accordingly.

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.

Table 3 Inhibition of platelet aggregation after administration of male SD rats for 5 consecutive days

The 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.

Claims

a compound of formula I, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof:

among them:

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.
A compound according to claim 1 wherein R 1 is cyclopropyl, methoxy or ethoxy.
The compound according to claim 1, wherein R 2 is

R 4 is hydrogen, a linear or branched alkyl group of 1 to 6 carbons, or a cycloalkyl group of 3 to 6 carbons; n = 0 to 6.
The compound according to claim 1, wherein R 2 is tauroyl, stearyl, leusyl, lauroyl, myristoyl, oleoyl, linoleyl or linoleyl.
A compound according to claim 1 wherein X is chlorine or fluorine.
a compound selected from the following structures, or a pharmaceutically acceptable acid salt thereof, solvated Or hydrate:
A method for the preparation of a compound according to any of claims 1-6, comprising the steps of:

Reaction of a compound of formula II with a compound of formula III or a compound of formula IV to provide a compound of formula I

Wherein, R 1 , R 2 , X in the compound of the formula II, the compound of the formula III and the compound of the formula IV are as defined in the compound of the formula I according to claim 1, and Z is a leaving group.
A pharmaceutical composition comprising the compound of any one of claims 1-6.
Use of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 8 for the preparation of a medicament for inhibiting platelet aggregation or preventing or treating a thrombosis and embolism-related disease.
The use according to claim 9, wherein the preparation inhibits platelet aggregation, or prevents or treats thrombosis and embolism-related diseases including prevention or treatment of angina pectoris, atherosclerotic disease, myocardial infarction, stroke, ischemic cerebral thrombosis, Peripheral arterial disease, or thrombosis after acute coronary syndrome or coronary intervention.