WO2016034103A1 - Substituted tetrahydrothieno pyridine derivatives and use thereof - Google Patents

Substituted tetrahydrothieno pyridine derivatives and use thereof Download PDF

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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
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clopidogrel
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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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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/4523Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545Non 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic 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
    • C07D495/04Ortho-condensed systems

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 tetrahydro thienopyridine derivatives and their Applications FIELD

The present invention belongs to the technical field of pharmaceutical chemistry, and more particularly, relates to a novel substituted tetrahydro thienopyridine derivatives, pharmaceutically acceptable acid salt, solvate or hydrate thereof, processes for their preparation, pharmaceutical compositions and their use in the manufacture of a medicament for inhibiting platelet aggregation, prevention or treatment of thrombosis and embolism associated diseases.

Background technique

Clopidogrel is widely used in clinical anti-platelet aggregation drugs, their study metabolic processes in vivo and found that 85% of the carboxylic acid derivative of clopidogrel Clopidogrel active parent drug via non-metabolic liver hydrolysis; Further no metabolism of clopidogrel inactive metabolites also need to rely on P450 enzymes metabolic activation, due to differences in the expression of liver P450 enzymes in different individuals, such metabolic dependence P450 and the clinical onset of the therapeutic effect of clopidogrel have a greater individual differences, P450 metabolic activity of individual weak, inefficient or ineffective clopidogrel, have a "clopidogrel resistance" cardiovascular event rates scene, thrombosis can not be reduced.

Prasugrel is a Japanese pharmaceutical company Sankyo and Eli Lilly pharmaceutical company developing another anti-platelet drugs, although no similar clopidogrel more "drug resistance" rapid onset of strong activity, but have a greater risk of bleeding .

Therefore, the rapid onset of strong activity, no drug resistance, while a small risk of bleeding antiplatelet drugs is an urgent clinical needs.

SUMMARY

The present invention provides a novel substituted tetrahydro thienopyridine derivatives, as anti-platelet aggregation drugs, prevention or treatment of thrombosis and embolism associated diseases developed; these drugs having fast onset of action, strong activity, and a small risk of bleeding small differences between the biological characteristics of the individual.

Object of the present invention is to provide a novel substituted tetrahydro thienopyridine derivatives, which by esterases in the blood (rather than relying on P450 in the liver) metabolism of the same active metabolite of clopidogrel. Because esterase in the prevalence of human blood, to avoid the "clopidogrel resistance" phenomenon of clopidogrel.

A second object of the present invention is to provide the above-tetrahydro thieno pyridine derivatives prepared.

A third object of the present invention is to provide a pharmaceutical composition comprising the above-tetrahydro thienopyridine derivatives.

A fourth object of the present invention is to provide the above-tetrahydro thienopyridine derivative or pharmaceutical composition for inhibiting platelet aggregation in the manufacture of, a medicament or treating or preventing thrombosis and embolism associated diseases.

More specifically, the present invention provides a substituted tetrahydro thienopyridine derivatives, compounds of Formula I, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof:

Figure PCTCN2015088756-appb-000001

among them:

R 1 is 1-6 carbon straight-chain or branched-chain alkyl group, a cycloalkyl group of 3-6 carbon atoms, or OR 3;

R 2 is

Figure PCTCN2015088756-appb-000002
Bovine sulfonyl, stearoyl, palmitoyl, lauroyl, myristoyl, oleoyl, linoleoyl, or linolenoyl;

A straight-chain or branched-chain alkyl group R 3 to 6 carbons, or cycloalkyl of 3-6 carbons;

R 4 is hydrogen, 1-6 carbon straight or branched chain alkyl group, or a 3-6 carbon cycloalkyl group; and

X is hydrogen, chloro, fluoro, bromo, or iodo;

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 present invention, the present invention provides compounds of formula I, wherein, R 2 is

Figure PCTCN2015088756-appb-000003

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

In a preferred embodiment of the present invention, the present invention provides compounds of formula I, wherein, X is chlorine or fluorine.

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

R 2 is

Figure PCTCN2015088756-appb-000004

R 4 is hydrogen, a 1-6 carbon linear or branched alkyl, or cycloalkyl of 3-6 carbons; n = 0-6; and

X is chlorine or fluorine.

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

R 2 is

Figure PCTCN2015088756-appb-000005

R 4 is hydrogen, a 1-6 carbon linear or branched alkyl, or cycloalkyl of 3-6 carbons; n = 0-6; and

X is chlorine.

In a preferred embodiment of the present invention, the present invention provides compounds of formula I, wherein, R 2 is a sulfonyl group cattle, stearoyl, palmitoyl, lauroyl, myristoyl, oleoyl, linoleoyl, or linen group.

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;

R 2 is a sulfonyl group cattle, stearoyl, palmitoyl, lauroyl, myristoyl, oleoyl, linoleoyl, or linolenoyl; and

X is chlorine or fluorine.

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

R 2 is a sulfonyl group cattle, stearoyl, palmitoyl, lauroyl, myristoyl, oleoyl, linoleoyl, or linolenoyl; and

X is chlorine.

In a particularly preferred embodiment of the invention, the compounds of the present invention provides a salt selected from an acid, hydrate or solvate, pharmaceutically one compound, or a pharmaceutically acceptable:

Figure PCTCN2015088756-appb-000006

Figure PCTCN2015088756-appb-000007

In an embodiment of the present invention, the derivatives of the invention include compounds of Formula I enantiomers thereof and racemic.

In an embodiment of the present invention, the derivative of the present invention comprises a compound of formula I or a pharmaceutically acceptable acid salts, include but are not limited to salts of the compounds formed with the following acids: hydrochloric, hydrobromic, sulfuric, nitric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, acetic acid, maleic acid, fumaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, or succinic acid.

In an embodiment of the present invention, the present invention provides compounds of formula I, wherein 1-6 carbon straight-chain or branched-chain alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl group, isobutyl group, t-butyl, pentyl, or hexyl.

In an embodiment of the present invention, the present invention provides compounds of formula I, wherein the cycloalkyl of 3-6 carbon selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or .

A second aspect, the present invention provides derivatives of Formula I compounds prepared above acid substituted tetrahydrothieno pyridine or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the steps of:

A compound of formula II with a compound of Formula III or Formula IV reaction, to give a compound of formula I

Figure PCTCN2015088756-appb-000008

Wherein the compound of formula II, the compound of formula III and the compound of formula IV R 1, R 2, X as defined in compounds of formula I, Z is a leaving group, such as: chlorine, pentafluoro phenol group, group nitrophenol Wait.

As a preferred embodiment, the present invention provides the above substituted tetrahydrothiophene and preparation of acid salts, solvate or hydrate acceptable derivative of a compound of Formula I or a pharmaceutically pyridine, said method comprising the formula II or a salt thereof in an organic solvent, a base is added portionwise under cooling, followed by reaction with a compound of formulas III, to give a compound of formula I, if necessary, by a conventional method such as recrystallization, column chromatography for further purification. Here, the base may be an organic base or an inorganic base selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, or N, N- diisopropylethylamine and the like.

In particular, the compound of the present invention, e.g. MJ10605 other terminal reactive group-containing compound may be employed appropriate protecting group such as Fmoc-protected, and the ester forming condensation reaction, increasing with piperidine deprotection step.

A third aspect, the present invention also provides a therapeutically effective amount of a substituted tetrahydro thienopyridine derivatives include compounds of Formula I, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof in the pharmaceutical composition, the pharmaceutical composition It may also comprise a pharmaceutically acceptable carrier or diluent. The pharmaceutical compositions may be administered by intravenous injection intraperitoneally, orally, or through intranasal administration, administration by injection into tissue. The pharmaceutical composition may be selected from solution, dispersion, suspensions, powders, capsules, tablets, pills, delayed release capsules, time release tablets, and time release form pills. The dose of the pharmaceutical composition is 5-5000mg / day.

A fourth aspect, the present invention provides a compound of the substituted tetrahydro thienopyridine derivatives of formula I, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof for the manufacture of anti-platelet aggregation, and preventing or treating thrombosis thrombosis-related diseases, particularly the prophylaxis or treatment of thrombosis drugs atherosclerotic disease, myocardial infarction, angina, stroke, ischemic cerebral thrombosis, peripheral arterial disease, acute coronary syndrome or after percutaneous coronary intervention in the form of use.

Compared with the prior art, the novel tetrahydrothiophene substituted pyridine derivative of the present invention has significant inhibition of platelet aggregation, inhibition of platelet aggregation which is significantly better than even clopidogrel.

Metabolism same clopidogrel active metabolite of a compound of the present invention by esterases in the blood (rather than relying on P450 in the liver), clopidogrel avoid "clopidogrel resistance" phenomenon.

In addition, experiments show that the in vivo release, tetrahydrothiophene novel substituted pyridine derivative of the present invention can be efficiently converted to pharmacologically active metabolites play a role in the body, and the precursor of the active metabolite of 2-oxo - clopidogrel concentration significantly higher than clopidogrel.

BRIEF DESCRIPTION

After the 2-oxo compound of the present invention, clopidogrel bisulfate and 1 male SD rats (n = 3) oral administration of 2mg / kg of - clopidogrel plasma concentration (ng / mL).

After 5 consecutive days of FIG. 2 male SD rats comparing the rate of inhibition of platelet aggregation (20μmol / L ADP-induced).

detailed description

The following examples be illustrative embodiment of the present invention, those of ordinary skill in the art, the teachings of the present invention, according to the prior art, modifications of the embodiments of the present invention, the present invention is still protected range.

Source material compounds used in the embodiment are: All reagents were purchased from the company reagents, starting material (2S) -2- (2-chlorophenyl) -2- (2-oxo -5,6,7,7a - tetrahydrothieno [3,2-c] pyridin-yl) acetate with reference to Chinese Patent application No. 201210333184.4 synthesized by the method of 2-chloro-toluenesulfonate and methyl mandelate was obtained resolved.

Proton NMR data from the spectrometer Bruker AV-300 nuclear magnetic resonance acquisition and processing. Example 1

Synthesis cyclohexyloxy acid

60% sodium hydride (8.79 g) was suspended in tetrahydrofuran (500ml), was added cyclohexanol (10g), the mixture was stirred at 0 ℃ 30 minutes and then was added bromoacetic acid (13.9 g of), After the addition the reaction was refluxed 2 hours. Water was added to the reaction solution, the organic solvent was removed on a rotary evaporator, the aqueous solution was diluted with water to 200ml,,, and extracted with t-butyl methyl ether the aqueous layer was acidified with 1N hydrochloric acid, washed with methyl tert-butyl ether, the organic layer was separated, without over anhydrous magnesium sulfate, the organic solvent was evaporated off under reduced pressure to give an oil (cyclohexyloxy acetate) (12.9 g of), a yield of 81.6%. 1 H-NMR (CDCl 3) 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).

Example 2

The synthesis MJ10601

Figure PCTCN2015088756-appb-000009

Cyclohexyloxy acid (1.58 g of), the reaction with 10ml of thionyl chloride was suspended 60 ℃ 2 hours, the solvent was distilled off under reduced pressure to afford cyclohexyl acetyl chloride; the (2S) -2- (2- chlorophenyl yl) -2- (2-oxo -5,6,7,7a- tetrahydrothieno [3,2-c] pyridin-yl) acetate (0.3g) was dissolved in NMP (N- methylpyrrolidone) ( 10ml), was added 0.3ml of triethylamine was added dropwise cyclohexyl acetyl chloride (0.18 g of) at 0 deg.] C, after the addition, the reaction was warmed to room temperature for 3 hours, the reaction was poured into 30ml water, ethyl acetate (30ml × 3) aqueous phase was extracted organic phases were combined, washed with saturated aqueous sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness organic Xiangde oil 0.7g. By silica gel column chromatography to give a white solid 0.25g, yield 52.3%. MS (m / z): 478.2 [M + 1] +; 1 H-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).

Example 3

Propionic acid group

60% sodium hydride (8.79 g) was suspended in tetrahydrofuran (500ml), was added n-propanol (6g), the mixture was stirred at 0 ℃ 30 minutes and then was added bromoacetic acid (13.9 g of), After the addition the reaction was refluxed 2 hours. Water was added to the reaction solution, the organic solvent was removed on a rotary evaporator, the aqueous solution was diluted with water to 200ml,,, and extracted with t-butyl methyl ether the aqueous layer was acidified with 1N hydrochloric acid, washed with methyl tert-butyl ether, the organic layer was separated, without over anhydrous magnesium sulfate, the organic solvent was evaporated off under reduced pressure to give an oil (propoxy acid) (10.9 g of), a yield of 92.3%. 1 H-NMR (CDCl 3) δ: 0.89 (3H, t), 1.51 (2H, m), 3.37 (2H, t), 4.12 (2H, s).

Example 4

MJ10602 synthesis

Figure PCTCN2015088756-appb-000010

Propoxy acid (1.18 g of) was suspended with 10ml of thionyl chloride, the reaction 60 ℃ 2 hours, the solvent was distilled off under reduced pressure to give propoxy chloride; and (2S) -2- (2- chlorophenyl) 2- (2-oxo -5,6,7,7a- tetrahydrothieno [3,2-c] pyridin-yl) acetate (0.3g) was dissolved in NMP (N- methylpyrrolidone) (10ml) , was added 0.3ml of triethylamine was added dropwise propionyl chloride group (0.14 g of) at 0 deg.] C, after the addition, the reaction was warmed to room temperature for 3 hours, the reaction was poured into 30ml water, and ethyl acetate (30ml × 3) The aqueous phase was extracted, the organic phases were combined, washed with saturated aqueous sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness organic Xiangde oil 0.8g. By silica gel column chromatography to give a white solid 0.21g, 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 ~ 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).

Example 5

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

60% sodium hydride (8.79 g) was suspended in tetrahydrofuran (500ml), was added tetrahydropyran-4-ol (10.2 g of), the mixture was stirred at 0 ℃ 30 minutes and then was added bromoacetic acid (13.9 g of) Upon completion of addition the reaction was refluxed for 2 hours. Water was added to the reaction solution, the organic solvent was removed on a rotary evaporator, the aqueous solution was diluted with water to 200ml,,, and extracted with t-butyl methyl ether the aqueous layer was acidified with 1N hydrochloric acid, washed with methyl tert-butyl ether, the organic layer was separated, without over anhydrous magnesium sulfate, the organic solvent was evaporated off under reduced pressure to give an oil (2- (tetrahydropyran-4-yloxy) acetic acid) (10.9 g of), a yield of 69.0%. 1 H-NMR (CDCl 3) δ: 1.58 ~ 1.91 (4H, m), 3.23 (1H, m), 3.41 ~ 3.65 (4H, m), 4.21 (2H, s). Example 6

MJ10603 synthesis

Figure PCTCN2015088756-appb-000011

2- (tetrahydropyran-4-yloxy) acetic acid (1.60 g) was suspended with 10ml of thionyl chloride, the reaction 60 ℃ 2 hours, the solvent was distilled off under reduced pressure to give 2- (tetrahydro-4 oxy) acetyl chloride; the (2S) -2- (2-chlorophenyl) -2- (2-oxo -5,6,7,7a- tetrahydrothieno [3,2-c] pyridin-yl) acetate (0.3g) was dissolved in NMP (N- methylpyrrolidone) (10ml), was added 0.3ml of triethylamine, a solution of 2- (tetrahydropyran-4-yloxy) acetyl chloride at 0 deg.] C ( 0.18 g of), after the addition, the reaction was warmed to room temperature for 3 hours, the reaction was poured into 30ml water, and ethyl acetate (30ml × 3) aqueous phase was extracted, the organic phases were combined, washed with saturated aqueous sodium bicarbonate, with saturated washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness organic Xiangde oil 1.1g. By silica gel column chromatography to give a white solid 0.23g, yield 47.9%. MS (m / z): 480.2 [M + 1] +; 1 H-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).

Example 7

Synthesis isopropyloxy acid

60% sodium hydride (8.79 g) was suspended in tetrahydrofuran (500ml), was added isopropanol (6g), the mixture was stirred at 0 ℃ 30 minutes and then was added bromoacetic acid (13.9 g of), After the addition the reaction was refluxed 2 hours. Water was added to the reaction solution, the organic solvent was removed on a rotary evaporator, the aqueous solution was diluted with water to 200ml,,, and extracted with t-butyl methyl ether the aqueous layer was acidified with 1N hydrochloric acid, washed with methyl tert-butyl ether, the organic layer was separated, without over anhydrous magnesium sulfate, the organic solvent was evaporated off under reduced pressure to give an oil isopropyloxy acid (10.3 g of), a yield of 87.3%. 1 H-NMR (CDCl 3) δ: 1.15 (6H, d), 3.21 (1H, m), 4.33 (2H, s).

Synthesis Example embodiment 8MJ10604

Figure PCTCN2015088756-appb-000012

Isopropyloxy acid (1.18 g of) was suspended with 10ml of thionyl chloride, the reaction 60 ℃ 2 hours, the solvent was distilled off under reduced pressure to give isopropyl chloride group; and (2S) -2- (2- chlorophenyl) -2- (2-oxo -5,6,7,7a- tetrahydrothieno [3,2-c] pyridin-yl) acetate (0.3g) was dissolved in NMP (N- methylpyrrolidone ) (10ml), was added 0.3ml of triethylamine was added dropwise acetyl chloride isopropyl (0.18 g of) at 0 deg.] C, after the addition, the reaction was warmed to room temperature for 3 hours, the reaction was poured into 30ml water, ethyl acetate (30ml × 3) aqueous phase was extracted organic phases were combined, washed with saturated aqueous sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness organic Xiangde oil 0.9g. By silica gel column chromatography to give a white solid 0.22g, yield 49.2%. 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 ~ 7.69 (m, 4H).

Example 9

The synthesis MJ10611

Figure PCTCN2015088756-appb-000013

The (2S) -2- (2-chlorophenyl) -2- (2-oxo -5,6,7,7a- tetrahydrothieno [3,2-c] pyridin-yl) acetate (0.3g ) was dissolved in NMP (N- methylpyrrolidone) (10ml), was added 0.3ml of triethylamine was added dropwise in 16 chloride (0.4g) at 0 deg.] C, after the addition, the reaction was warmed to room temperature for 3 hours, the reaction 30ml of water was poured into ethyl acetate (30ml × 3) aqueous phase was extracted organic phases were combined, washed with saturated aqueous sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness organic oil Xiangde 1.3 g. By silica gel column chromatography to give a white solid 0.45g, yield 43.3%. MS (m / z): 576.2 [M + 1] +; 1 H-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).

Example 10

Hydrochloride of MJ10601

Compound MJ10601 (478mg) was dissolved in anhydrous tetrahydrofuran, cooled with stirring to 0 deg.] C, hydrogen chloride gas was passed through the drying, the precipitated solid was collected to afford an off-white powder (316 mg), yield 61.4%.

Other salts prepared by reaction of an acid with a different in an anhydrous organic solvent.

Example 11 embodiment platelet aggregation test:

Preparation of test solution: Take appropriate amount of clopidogrel hydrogen sulfate, plus 0.5% CMC-Na solution, triturated, to obtain 0.6mg / ml, 2.0mg / ml suspension, ie. The same method, a solution of compound MJ10601, MJ10602 amount, to obtain 0.2mg / ml, 0.6mg / ml suspension; of compound MJ10604, MJ10611 amount, to obtain 0.6mg / ml suspension, ie.

Animal: SD rats, male, 250-270g. 54 were divided into 9 groups of six. Rats volume of 5ml / kg, oral administration of each test solution, in terms of dose obtained for each test was of 1-10mg / kg. The control group received 0.5% CMC-Na solution of equal volume.

Methods and Results: orally 2 hours after the administration, each rat femoral artery blood, mixed with 3.8% sodium citrate solution in suitable proportions, 7 minutes centrifugation (1000 rpm for), to obtain platelet-rich plasma (the PRP); Take another whole blood, the same method to centrifugation at 3000rpm for 5 minutes to obtain platelet poor plasma (PPP). PRP, PPP was added an appropriate amount, so that the final platelet concentration of 5 × 10 9 --10 × 10 9 / L. In 5μmADP (adenosine diphosphate) as the test solution an appropriate amount of inducer added to the test solution, the maximum platelet aggregation rate was measured for 5 minutes in the aggregometer, and inhibition of platelet aggregation ratio calculated on this basis.

Platelet aggregation inhibition rate = 100% × (the maximum platelet aggregation rate in the control group Average - Test animals the maximum platelet aggregation rate) / control maximum platelet aggregation rate average results shown in Table 1.

Table 1 and the Effect on Platelet aggregation

Figure PCTCN2015088756-appb-000014

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

# Clopidogrel 10mg / There were significant differences kg group (p <0.05)

The above test results show the efficacy of the drug almost six times the test group dose of clopidogrel sulfate and the like, and this difference in effect between the different animals, the test drug significantly smaller than clopidogrel.

Kinetics of Example 12 Pharmacokinetics

Figure PCTCN2015088756-appb-000015

Studies have shown that clopidogrel first metabolic activation in vivo to produce 2-yloxy - clopidogrel, 2-oxo - clopidogrel further hydrolyzed to the active metabolite. 2-oxo - clopidogrel metabolic formation reaction rate-limiting step, the 2-oxo - clopidogrel generation amount is a key indicator compound precursor activity in such evaluation.

The present invention is by examining the rats were orally administered compound MJ10601, after MJ10602, MJ10604, MJ10611 and clopidogrel hydrogen sulfate, 2-oxo-metabolite thereof - clopidogrel process over time, after administration of the compounds investigated can vivo metabolism of 2-oxo - clopidogrel, and evaluated for their generation amount.

15 healthy male SD rats (body weight 250-270 g), divided into five groups of three, were orally administered compound MJ10601, MJ10602, MJ10604, MJ10611 and clopidogrel hydrogen sulfate (2mg / kg). It did not reveal any abnormalities after administration, suggesting that the compound tolerated dose animals. Plasma was collected at various time points samples, after treatment using an organic solvent Liquid Chromatography - Mass Spectrometry Plasma series 2-oxo - clopidogrel concentration, results shown in Figure 1. Service test compound and rat clopidogrel hydrogen sulfate, 2-oxo - clopidogrel pharmacokinetic parameters calculated by non-compartmental model (Table 2).

Table 2 Male SD rats after oral administration of test compound and clopidogrel hydrogen sulfate 2-oxo - clopidogrel pharmacokinetic parameters

Figure PCTCN2015088756-appb-000016

Figure PCTCN2015088756-appb-000017

Pharmacokinetic studies indicated that the test compound can be efficiently converted in vivo to a pharmacologically active metabolite play a role, and intragastric administration MJ10601, a precursor that generates an active metabolite of 2-oxo after MJ10602, MJ10604, MJ10611 - clopidogrel Gray AUC than clopidogrel bisulfate.

Meanwhile, inter-animal variation comparing the pharmacokinetic parameters (e.g. AUC and the like), the test drug significantly less than the RSD clopidogrel.

Studies have shown that the above test compound in vivo can be converted into 2-oxo - clopidogrel and further metabolic activation, and metabolism of the individual differences smaller than clopidogrel, drug dependence is small specific enzyme, produced clopidogrel less likelihood of resistance; in addition, since the 2-oxo test compound precursors in vivo active metabolites - clopidogrel clopidogrel significantly higher than at other quality expected by reducing the dosage, under rapid onset, high efficacy premise, reduce adverse reactions resulting inactive metabolite. In addition to the above compounds, preferred compounds of the present invention relates to metabolites produced 2-oxo - clopidogrel also greater than the AUC of 2-oxo-dose of clopidogrel hydrogen sulfate and the like generated at - clopidogrel AUC, the dose, etc. inhibition of platelet aggregation than clopidogrel hydrogen sulfate are set under the condition.

After repeated administration Example 13 embodiment platelet aggregation tests

This trial will test SD rats orally administered for 5 days comparing different time points for the test of inhibition of platelet aggregation induced 20μmolADP.

Test 54 male SD rats were randomly divided into three major groups, each group of 18 large, were administered 19.65mg / kg of clopidogrel hydrogen sulfate, 2mg / kg MJ10611,1.52mg / kg MJ10602, 5 days continuous administration before the last administration, fasted for 8 ~ 12h, 5 days after the administration of large component 6 per group, each group 3 on 0.17h, 2h, 4h, 6h, 12h, 24h test 20μmol / L ADP-induced platelet aggregation test method, see Example 11, inhibition of platelet aggregation ratio calculated on this basis.

Platelet aggregation inhibition rate = 100% × (the maximum platelet aggregation rate in the control group Average - Test animals the maximum platelet aggregation rate) / control maximum platelet aggregation rate of the average results shown in Table 3, FIG.

After 5 consecutive days Table 3 Platelet aggregation inhibitory male SD rats

Figure PCTCN2015088756-appb-000018

The test results show that the compounds of the present invention is administered in a dose of approximately 1/10 of clopidogrel, clopidogrel platelet inhibition produced substantially uniform.

Claims (10)

  1. A compound of Formula I, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof:
    Figure PCTCN2015088756-appb-100001
    among them:
    R 1 is 1-6 carbon straight-chain or branched-chain alkyl group, a cycloalkyl group of 3-6 carbon atoms, or OR 3;
    R 2 is
    Figure PCTCN2015088756-appb-100002
    Bovine sulfonyl, stearoyl, palmitoyl, lauroyl, myristoyl, oleoyl, linoleoyl, or linolenoyl;
    A straight-chain or branched-chain alkyl group R 3 to 6 carbons, or cycloalkyl of 3-6 carbons;
    R 4 is hydrogen, 1-6 carbon straight or branched chain alkyl group, or a 3-6 carbon cycloalkyl group;
    X is hydrogen, chloro, fluoro, bromo, or iodo;
    n = 0-6.
  2. The compound according to claim 1, wherein, R 1 is cyclopropyl, methoxy, or ethoxy.
  3. The compound according to claim 1, wherein, R 2 is
    Figure PCTCN2015088756-appb-100003
    R 4 is hydrogen, a 1-6 carbon linear or branched alkyl, or cycloalkyl of 3-6 carbons; n = 0-6.
  4. The compound according to claim 1, wherein, R 2 is a sulfonyl group cattle, stearoyl, palmitoyl, lauroyl, myristoyl, oleoyl, linoleoyl, or linolenoyl.
  5. The compound according to claim 1, wherein, X is chlorine or fluorine.
  6. One selected from the following structures of the compound, or a pharmaceutically acceptable acid salt, solvate or hydrate thereof:
    Figure PCTCN2015088756-appb-100004
  7. A process for preparing a compound of the method according to claims 1-6, comprising the steps of claim:
    A compound of formula II with a compound of Formula III or Formula IV reaction, to give a compound of formula I
    Figure PCTCN2015088756-appb-100005
    Wherein the compound of formula II, the compound of formula III and the compound of formula IV R 1, R 2, X compound as claimed in formula I and Z is a leaving group defined in claim.
  8. A pharmaceutical composition, said pharmaceutical composition comprising a compound of claim any one of claims 1-6.
  9. The compound claimed in any one claim or a pharmaceutical composition as claimed in claim 8 in the manufacture of a platelet aggregation inhibiting, or preventing or treating thrombosis and embolism medicament related diseases.
  10. Use according to claim 9, wherein the prepared inhibit platelet aggregation, or prevention or treatment of thrombosis and embolism associated diseases include the prophylaxis or treatment of angina pectoris, atherosclerosis disease, myocardial infarction, stroke, cerebral ischemia, peripheral arterial disease, acute coronary syndrome or coronary intervention or postoperative thrombus formation.
PCT/CN2015/088756 2014-09-02 2015-09-01 Substituted tetrahydrothieno pyridine derivatives and use thereof WO2016034103A1 (en)

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CN102199163A (en) * 2011-04-01 2011-09-28 中国药科大学 2-hydroxy tetrahydrothiophene derivative, preparation method thereof and application thereof in pharmacy
CN103068383A (en) * 2010-08-26 2013-04-24 Ipca实验室有限公司 Methods for the treatment or prophylaxis of thrombosis or embolism
CN103254211A (en) * 2012-02-17 2013-08-21 江苏威凯尔医药科技有限公司 Method for preparing vicagrel and derivatives thereof
CN103664990A (en) * 2012-09-12 2014-03-26 江苏威凯尔医药科技有限公司 Preparation method of Vicagrel
WO2015039577A1 (en) * 2013-09-17 2015-03-26 天士力控股集团有限公司 Thienopiperidine derivative and use thereof

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 (en) * 1991-09-09 1993-07-21 三共株式会社 Tetrahydrothienopyridine derivatives, furo and pyrrolo analogs thereof and their preparation and uses for inhibiting blood platelet aggregation
CN102120744A (en) * 2010-02-02 2011-07-13 江苏威凯尔医药科技有限公司 Optical-activity 2-hydroxytetrahydrothienopyridine derivative, preparation method and application thereof in pharmacy
CN103068383A (en) * 2010-08-26 2013-04-24 Ipca实验室有限公司 Methods for the treatment or prophylaxis of thrombosis or embolism
CN102199163A (en) * 2011-04-01 2011-09-28 中国药科大学 2-hydroxy tetrahydrothiophene derivative, preparation method thereof and application thereof in pharmacy
CN103254211A (en) * 2012-02-17 2013-08-21 江苏威凯尔医药科技有限公司 Method for preparing vicagrel and derivatives thereof
CN103664990A (en) * 2012-09-12 2014-03-26 江苏威凯尔医药科技有限公司 Preparation method of Vicagrel
WO2015039577A1 (en) * 2013-09-17 2015-03-26 天士力控股集团有限公司 Thienopiperidine derivative and use thereof

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