CN116744921A - Optically active 2-hydroxy tetrahydrothiophene pyridine derivative and preparation method and application thereof - Google Patents

Optically active 2-hydroxy tetrahydrothiophene pyridine derivative and preparation method and application thereof Download PDF

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CN116744921A
CN116744921A CN202380008078.5A CN202380008078A CN116744921A CN 116744921 A CN116744921 A CN 116744921A CN 202380008078 A CN202380008078 A CN 202380008078A CN 116744921 A CN116744921 A CN 116744921A
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compound
clopidogrel
tetrahydrothiophene
derivative
optically active
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刘军华
王衡新
邓俐丽
宋志林
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Tiandi Hengyi Pharmaceutical Co ltd
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Tiandi Hengyi Pharmaceutical Co ltd
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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

Abstract

The invention provides an optically active 2-hydroxy tetrahydrothiophene pyridine derivative, which introduces various novel 2-hydroxy tetrahydrothiophene pyridine derivatives by modifying the structure of clopidogrel and mainly comprises derivatives forming esters with indobufen. The compound can be rapidly metabolized into effective metabolites and indobufen after entering the body to exert the drug effect, and is applied to the preparation of medicines for preventing and/or treating embolic diseases caused by thrombus. The compound can effectively improve the pharmacokinetic property, improve the bioavailability of the clopidogrel active metabolite, and hopefully realize that the side effects of quick effect, high curative effect, bleeding of an anti-platelet aggregation medicine and the like can be reduced by obviously reducing the medicine dosage. Meanwhile, the compound has better aqueous solution stability and can meet the requirement of developing into liquid preparations (such as injection).

Description

Optically active 2-hydroxy tetrahydrothiophene pyridine derivative and preparation method and application thereof
The present application claims priority from China patent application No. 202210026839.7 entitled "an optically active 2-hydroxy tetrahydrothiophene and pyridine derivative, and preparation method and use thereof", filed on 1 month 11 2022, the entire contents of which are incorporated herein by reference.
Technical Field
The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to an optically active 2-hydroxy tetrahydrothiophene pyridine derivative, a preparation method and application thereof.
Background
Clopidogrel (Clopidogrel) is one of the most widely used antiplatelet aggregation drugs worldwide at present, and is sold in China for more than 100 hundred million in 2019 and clinically used for treating atherosclerosis, acute coronary syndrome, thrombotic complications and the like. Clinical trials have demonstrated the efficacy and safety of clopidogrel against thrombotic cardiovascular and cerebrovascular diseases (Lancet, 1996, 348:1329). Clopidogrel is a prodrug which is metabolized in vivo by two-step oxidation of the liver P450 enzyme system to produce an active metabolite which forms a covalent bond with the platelet surface P2Y12 receptor and inhibits platelet aggregation by antagonizing the P2Y12 receptor (Thromb Haemost,2000,84,891). However, in the study of its metabolic processes, two disadvantages were found: 1) 85% of clopidogrel Lei Yuanxing is decomposed into inactive clopidogrel carboxylic acid derivatives (J Pharmacol Exp Ther,2006, 319:1467) through human liver carboxylesterase1 (hCE 1) ester in the liver, so that the oral bioavailability of clopidogrel is greatly reduced, and the clinical dosage of clopidogrel (300 mg clopidogrel is loaded), the effect is slow, and the defects of delay, bleeding risk and the like of platelet inhibition are caused (Cardiovascular drug reviews,1993, 11:180); 2) Because of the difference of P450 enzyme system expression in livers of different individuals, clopidogrel which depends on the metabolic effect of the P450 enzyme system generates larger individual difference in clinical treatment effect, such as the phenomenon of 'clopidogrel resistance', cardiovascular events including thrombus formation in a bracket still occur (Circulation, 2004, 109:166).
In view of the limitations and drawbacks of clopidogrel, there is a need to develop new clopidogrel derivatives having better pharmacokinetic and pharmacodynamic properties with fewer side effects.
At present, one of the hot spots of research on new drugs for resisting platelet aggregation is the development of water-soluble injectable pharmaceutical preparations, and attempts have been made in the prior art to develop clopidogrel which is already marketed into injection preparations to improve the curative effect and shorten the onset time, but none of the drugs has been successful, such as ASD-002 nanoemulsion of Ascencia company, MDCO-157 (cyclodextrin inclusion) injection of CyDex company and JIN-2013 nanoliposome injection of Jina Pharmaceuticals company. The main reasons for this are that MDCO-157, although improving the stability of clopidogrel against hydrolytic, thermal and photodegradation, has insufficient threshold for active metabolite production after injection administration, insufficient platelet inhibition effect until the dose is increased to 300mg, and the adverse reaction is significantly larger than that of oral formulations. In addition, clopidogrel free base is oily, the oily matter is unstable, needs to be salified with strong acid such as hydrochloric acid and sulfuric acid, and the product is unstable and easy to degrade, and has the defects of low solubility in water at neutral pH, and the like, so that the development of an injection product with high bioavailability and good physical stability is very difficult.
Patent CN103554132B, CN107304215a and the like also report a series of clopidogrel derivative compounds, but these compounds have a certain problem, and although the bioavailability or efficacy of these compounds is improved to some extent compared with clopidogrel or prasugrel, the improvement is not significant.
The application aims to introduce various novel derivatives of 2-hydroxy tetrahydrothiophene pyridine by modifying the structure of clopidogrel, which mainly comprise derivatives forming esters with indobufen and derivatives forming esters with ozagrel Lei Cheng; the inventors have surprisingly found that the obtained derivative compound can be rapidly metabolized into an effective metabolite and indobufen or ozagrel to exert the drug effect after entering the body, wherein the indobufen and ozagrel have the anti-platelet effect and can form a synergistic effect so as to solve the defect of clopidogrel. Compared with clopidogrel or the existing clopidogrel derivative, the compound provided by the application has the advantages of better pharmacokinetics and pharmacodynamics, quicker onset time, larger therapeutic index, and effectively reduced side effects such as bleeding, and the obtained derivative is in a solid form, has better physical and chemical properties such as stability of aqueous solution, and the like, can meet the requirement of developing into an oral preparation, and can also meet the requirement of developing into a liquid preparation (such as an injection).
Disclosure of Invention
In order to achieve the above object, the present application has been made in an intensive study on thienopyridine derivatives, and provides an optically active 2-hydroxytetrahydrothienopyridine derivative represented by formula (i):
wherein G is selected from the group consisting of a bond,
n is an integer from 0 to 12;
the broken lines each represent a linking site with a thiophene ring, and the wavy lines each represent a linking site with R;
r is selected from:
wherein,
wavy lines indicate ligation sites;
R 1 selected from halogen;
R 2 selected from CH 3 、CD 3 。
In some preferred embodiments, an optically active 2-hydroxytetrahydrothienopyridine derivative or a pharmaceutically acceptable salt thereof is selected from any one of the following compounds:
in other embodiments provided herein, an optically active 2-hydroxytetrahydrothienopyridine derivative or a pharmaceutically acceptable salt thereof, wherein the derivative is any one selected from the following compounds:
another aspect of the present application is to provide a pharmaceutical composition comprising any of the compounds described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. And further, the compound or the pharmaceutical composition thereof is applied to the preparation of medicines for preventing and/or treating embolic diseases caused by thrombus.
The compound can effectively improve the pharmacokinetic property, improve the bioavailability of clopidogrel active metabolites, and the generation amount of the active metabolites is obviously higher than that of clopidogrel or the existing clopidogrel derivatives, so that the side effects of quick acting, high curative effect, reduction of bleeding of platelet aggregation resisting drugs, reduction of cardiovascular events caused by thrombus formation in a stent and the like can be achieved by obviously reducing the drug dosage. Meanwhile, the compound disclosed by the application has better aqueous solution stability, can meet the requirements of developing an oral preparation and liquid preparations (such as injection), and has greater clinical potential advantage and meets the medication requirements of more clinical patients compared with clopidogrel which can only be developed into an oral preparation.
Detailed Description
The present application will be further described in detail with reference to the following examples, in order to make the objects, technical solutions, and advantages of the present application more apparent. It will be apparent that the described embodiments are only some, but not all, embodiments of the application. All other embodiments, which are derived by a person skilled in the art based on the embodiments of the application, fall within the scope of protection of the application.
The following is a detailed description of the present application by way of examples. In the present application, the following examples are given for better illustration of the present application and are not intended to limit the scope of the present application.
As used herein, room temperature refers to about 20-30 ℃; "overnight" means about 10 to 16 hours; 1N is 1mol/L;
yield = actual synthetic product mass/theoretical synthetic product mass x 100%;
purity test: the purity of the product was checked by High Performance Liquid Chromatography (HPLC).
Example 1
Synthesis of (S) -5- (1- (2-chlorophenyl) -2- (tridecylmethoxy) -2-oxoethyl) -4,5,6, 7-tetrahydrothiophen [3,2-c ] pyridin-2-yl ((3, 5, 6-trimethylpyrazin-2-yl) methyl) maleate (Compound 1)
Step one: in a 100mL three-necked flask, compound f (5 g,32.90 mmol), dichloromethane (50 mL), triethylamine (6.65 g,65.80 mmol) and Compound b (3.22 g,32.90 mmol) were added, reacted overnight at room temperature, after completion of the reaction by Thin Layer Chromatography (TLC) spot plate detection, a suitable amount of water was added, the solution was separated, the organic phase was washed successively with water (30 mL. Times.2), a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and silica gel column chromatography (V) Petroleum ether ：V Acetic acid ethyl ester =1:1) to give compound 1-1 (3.67 g, purity 95%, yield 44.6%).
Characterization data: [ M+H ]] + ：251.2； 1 H NMR(400MHz,Chloroform-d)δ6.49(d,J＝11.9Hz,1H),5.93(d,J＝11.9Hz,1H),5.22(s,2H),2.52(s,3H),2.48(d,J＝4.8Hz,6H)。
Step two: in a 100mL three-necked flask, compound 1-1 (2 g,8 mmol), methylene chloride (40 mL), compound c (2.72 g,8 mmol), 4-Dimethylaminopyridine (DMAP) (0.51 g,4 mmol) and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI) (3.07 g,16 mmol) were added, reacted overnight at room temperature, after completion of the TLC plate detection reaction, an appropriate amount of water was added, the liquid was separated, the organic phase was washed successively with water (20 mL. Times.2), saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and silica gel column chromatography (V) Petroleum ether ：V Acetic acid ethyl ester =3:1) to give compound 1 as an oil (1.5 g, purity 95%, yield 39.27%).
Characterization data: [ M+H ]] + ：573.1； 1 H NMR(400MHz,Chloroform-d)δ7.72–7.67(m,1H),7.45 –7.40(m,1H),7.33–7.22(m,2H),6.65(s,2H),6.15(s,1H),5.45(s,2H),4.84(s,1H),3.70–3.61(m,1H),3.54(dt,J＝14.3,1.8Hz,1H),2.95–2.83(m,2H),2.80(ddd,J＝7.5,6.1,1.3Hz,2H),2.53–2.49(m,9H)。
Example 2
Synthesis of (S) -5- (1- (2-chlorophenyl) -2- (tridecylmethoxy) -2-oxoethyl) -4,5,6, 7-tetrahydrothiophen [3,2-c ] pyridin-2-yl ((3, 5, 6-trimethylpyrazin-2-yl) methyl) fumarate (Compound 2)
Step one: in a 250mL three-port flask, compound f (5 g,32.90 mmol), dichloromethane (100 mL), compound d (5.66 g,32.9 mmol), DMAP (2.09 g,16.45 mmol), EDCI (12.61 g,65.80 mmol) were added, reacted overnight at room temperature, after completion of the TLC plate detection reaction, an appropriate amount of water was added, the solution was separated, the organic phase was washed successively with water (50 mL. Times.2), a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and silica gel column chromatography (V after spin drying Petroleum ether ：V Acetic acid ethyl ester =5:1) to give compound 2-1 (4.2 g, purity 96%, yield 41.75%). Characterization data: [ M+H ]] + ：307.3。
Step two: in a 100mL three-necked flask, compound 2-1 (4 g,13.1 mmol), methylene chloride (20 mL) and trifluoroacetic acid (20 mL) were added, the reaction was carried out at room temperature for 4 hours, and after completion of the TLC detection, the reaction was directly dried by spin to give Compound 2-2 (3.2 g, purity 95%, yield 98%).
Characterization data: [ M+H ]] + ：251.2； 1 H NMR(400MHz,Chloroform-d)δ6.81(d,J＝1.9Hz,2H),5.26(d,J＝1.8Hz,2H),2.53–2.40(m,9H)。
Step three: in a 100mL three-necked flask, compound 2-2 (2 g,8 mmol), dichloromethane 40mL, compound c (2.72 g,8 mmol), DMAP (0.51 g,4 mmol), EDCI (3.07 g,16 mmol) were added, reacted overnight at room temperature, after the TLC plate detects the completion of the reaction, a proper amount of water was added, the separated liquid was separated, the organic phase was washed successively with water (20 mL. Times.2), saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and silica gel column chromatography after spin-drying (V Petroleum oilEthers ：V Acetic acid ethyl ester =3:1) to give compound 2 as an oil (2.1 g, purity 95%, yield 54.98%).
Characterization data: [ M+H ]] + ：573.1； 1 H NMR(400MHz,Chloroform-d)δ7.72–7.67(m,1H),7.45–7.40(m,1H),7.33–7.22(m,2H),6.40(s,2H),6.15(s,1H),5.44(s,2H),4.85(s,1H),3.70–3.60(m,1H),3.55(dt,J＝14.3,1.8Hz,1H),2.94–2.83(m,2H),2.81(ddd,J＝7.5,6.1,1.3Hz,2H),2.54–2.49(m,9H)。
Example 3
Synthesis of 5- ((S) -1- (2-chlorophenyl) -2- (tridecylmethoxy) -2-oxoethyl) -4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridin-2-yl-2- (4- (1-oxoisoquinolin-2-yl) phenyl) butanoate (Compound 3)
In a 250mL three-necked flask, compound c (3 g,8.8 mmol), dichloromethane 100mL, compound e (2.61 g,8.8 mmol), DMAP (0.56 g,4.4 mmol), EDCI (3.39 g,17.6 mmol) were added, the reaction was carried out at room temperature for 2 hours, after the TLC plate detection was completed, a proper amount of water was added, the solution was separated, the organic phase was washed successively with water (50 mL. Times.2), a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and silica gel column chromatography (V) Petroleum ether ：V Acetic acid ethyl ester =2:1) to give compound 3 (1.7 g, purity 98%, yield 31.25%) as a white solid.
Characterization data: [ M+H ]] + ：618.2； 1 H NMR(400MHz,Chloroform-d)δ7.95(d,J＝7.6Hz,1H),7.88(d,J＝8.5Hz,2H),7.71–7.66(m,1H),7.66–7.60(m,1H),7.55(d,J＝7.5Hz,2H),7.46–7.38(m,3H),7.34–7.29(m,2H),6.25(s,1H),4.90(s,1H),4.88(s,2H),3.69(t,J＝7.8Hz,1H),3.62(s,1H),3.52(d,J＝14.4Hz,1H),2.88(t,J＝5.3Hz,2H),2.78(d,J＝5.9Hz,2H),2.21(dp,J＝14.6,7.2Hz,1H),1.93(dq,J＝14.1,7.3Hz,1H),0.98(t,J＝7.3Hz,3H)。
Example 4
Synthesis of (S) -5- (1- (2-chlorophenyl) -2- (tridecylmethoxy) -2-oxoethyl) -4,5,6, 7-tetrahydrothiophen [3,2-c ] pyridin-2-yl ((3, 5, 6-trimethylpyrazin-2-yl) methyl) glutarate (Compound 4)
The synthesis was carried out in the same manner as in example 1 to give compound 4 as an oil (HPLC purity 97.32%, yield 52.29%).
Characterization data: [ M+H ]] + ：589.2； 1 HNMR(400MHz,Chloroform-d)δ7.72–7.65(m,1H),7.45–7.39(m,1H),7.34–7.29(m,2H),6.26(s,1H),5.23(s,2H),4.92(s,1H),3.66(dt,J＝14.3,1.8Hz,1H),3.57–3.49(m,1H),2.89(t,J＝5.3Hz,2H),2.79(d,J＝5.8Hz,2H),2.65(t,J＝7.3Hz,2H),2.58–2.46(m,11H),2.09(d,J＝7.3Hz,2H)。
Example 5
Synthesis of (S) -5- (1- (2-chlorophenyl) -2- (tridecylmethoxy) -2-oxoethyl) -4,5,6, 7-tetrahydrothiophen [3,2-c ] pyridin-2-yl ((3, 5, 6-trimethylpyrazin-2-yl) methyl) adipate (Compound 5)
The synthesis was carried out in the same manner as in example 1 to obtain oily compound 5 (HPLC purity 98.15%, yield 58.08%).
Characterization data: [ M+H ]] + ：603.3； 1 HNMR(400MHz,Chloroform-d)δ7.69(dd,J＝7.1,2.4Hz,1H),7.42(dd,J＝7.3,2.0Hz,1H),7.35–7.28(m,2H),6.26(s,1H),5.21(s,2H),4.91(s,1H),3.66(d,J＝14.3Hz,1H),3.53(d,J＝14.3Hz,1H),2.89(t,J＝5.6Hz,2H),2.79(d,J＝5.7Hz,2H),2.59–2.49(m,11H),2.44(t,J＝6.6Hz,2H),1.77(dd,J＝7.1,3.6Hz,4H)。
Example 6
Synthesis of (S) -5- (1- (2-chlorophenyl) -2- (tridecylmethoxy) -2-oxoethyl) -4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridin-2-yl (10- (4, 5-dimethoxy-2-methyl-3, 6-dioxan-1, 4-dien-1-yl) decyl) succinate (Compound 6)
The synthesis was carried out in the same manner as in example 1 to obtain oily compound 6 (HPLC purity 97.21%, yield 42.70%).
Characterization data: [ M+H ]] + ：761.3； 1 HNMR(400MHz,Chloroform-d)δ7.72–7.63(m,1H),7.44–7.35(m,1H),7.34–7.29(m,1H),7.26(dd,J＝7.3,2.1Hz,1H),6.28(s,1H),4.90(s,1H),4.10–4.05(m,2H),4.00(d,J＝1.2Hz,6H),3.69–3.60(m,1H),3.56–3.48(m,1H),2.91–2.80(m,4H),2.78(d,J＝5.6Hz,2H),2.74–2.66(m,2H),2.45(t,J＝7.4Hz,2H),2.05(s,3H),1.62(t,J＝7.1Hz,2H),1.39–1.27(m,14H)。
Example 7
Synthesis of (S) -5- (1- (2-chlorophenyl) -2- (tridecylmethoxy) -2-oxoethyl) -4,5,6, 7-tetrahydrothiophen [3,2-c ] pyridin-2-yl ((3, 5, 6-trimethylpyrazin-2-yl) methyl) malonate (Compound 7)
The synthesis was carried out in the same manner as in example 2 to obtain compound 7 as an oil (HPLC purity 96.13%, yield 8.14%).
Characterization data: [ M+H ]] + ：561.2； 1 H NMR(400MHz,Chloroform-d)δ7.73–7.66(m,1H),7.43–7.39(m,1H),7.33–7.27(m,2H),6.15(s,1H),5.45(s,2H),4.84(s,1H),3.71–3.63(m,1H),3.56(dt,J＝14.3,1.8Hz,1H),3.22(s,2H),2.93–2.85(m,2H),2.55–2.50(m,9H),2.40(m,2H)。
Example 8
Synthesis of (S) -5- (1- (2-chlorophenyl) -2- (tridecylmethoxy) -2-oxoethyl) -4,5,6, 7-tetrahydrothiophen [3,2-c ] pyridin-2-yl (E) -4- (4- (1H-imidazol-1-yl) phenyl) but-2-enoic acid ester (Compound 8)
The synthesis was carried out in the same manner as in example 3 to obtain compound 8 (HPLC purity 98.13%, yield 70.10%) as a solid powder.
Characterization data: [ M+H ]] + ：551.2； 1 H NMR(400MHz,Chloroform-d)δ7.69-7.57(m,4H),7.47-7.45(m,1H),7.30-7.24(m,3H),7.20-7.11(m,3H),6.88(d,J＝5.7Hz,1H),6.35(d,J＝10.8Hz,1H),6.15(s,1H),5.39(s,2H),4.83(s,1H),3.66(d,J＝14.2Hz,1H),3.60-3.48(m,1H),2.95-2.90(m,2H),2.69-2.63(m,2H)。
Example 9
Synthesis of (S) -5- (1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl ((3, 5, 6-trimethylpyrazin-2-yl) methyl) succinate (Compound 9)
Step one: in a 100mL three-necked flask, compound f (1 g,6.6 mmol) and acetonitrile (30 mL) were added, the mixture was dissolved with stirring, anhydrous potassium carbonate (1.36 g,9.9 mmol) and Compound g (0.79 g,7.9 mmol) were added, the reaction was carried out overnight, after completion of the TLC detection, ethyl acetate (10 mL) was added, filtration was carried out, and the solid was collected, dissolved in 20mL of water, pH was adjusted to less than 3 with 2N HCl (20 mL) and V was used Dichloromethane (DCM) :V Methanol (MeOH) Three extractions were performed =4:1 (25 mL), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, spun to near dryness, ethyl acetate (20 mL) solution was added, petroleum ether (60 mL) was added dropwise, solids were precipitated, stirred for 1h, filtered, the solids were rinsed with petroleum ether, and dried to give compound 9-1 (1.1 g, 66% yield) as a white solid.
Characterization data: [ M+H ]] + ：253.1； 1 H NMR(400MHz,Chloroform-d)δ5.25(s,2H),2.72(s,4H),2.63–2.40(m,9H)。
Step two: in a 10mL single-necked flask, intermediate 9-1 (100 mg,0.40 mmoL), anhydrous dichloromethane (1 mL) and thionyl chloride (47.2 mg,0.40 mmoL) were added and reacted at room temperature for 20min to obtain an intermediate 9-2 reaction solution, which was directly used in the next step.
Step three: in a 10mL single-port flask, compound m (50 mg,0.15 mmoL) and anhydrous dichloromethane (0.5 mL) were added, the solution was stirred and dissolved, triethylamine (90 mg,0.90 mmoL) was added, the reaction solution of the intermediate 9-2 was slowly added dropwise, the reaction was carried out at room temperature for 2 hours, after completion of the TCL spot plate detection reaction, the mixture was subjected to spin-dry column chromatography on silica gel (V Petroleum ether ：V Acetic acid ethyl ester =5:1) to give compound 9 as an oil (15 mg, yield 18%).
Characterization data: [ M+H ]] + ：572.2； 1 H NMR(400MHz,Chloroform-d)δ7.70(dd,J＝7.3,2.2Hz,1H),7.47-7.39(m,1H),7.35-7.29(m,2H),6.26(s,1H),5.24(s,2H),4.93(s,1H),3.74(s,3H),3.66(d,J＝14.2Hz,1H),3.60-3.48(m,1H),2.95-2.85(m,4H),2.85-2.73(m,4H),2.56-2.47(m,9H)。
Example 10
Synthesis of (S) -5- (1- (2-chlorophenyl) -2- (tridecylmethoxy) -2-oxoethyl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridin-2-yl ((3, 5, 6-trimethylpyrazin-2-yl) methyl) succinate (Compound 10)
The synthesis method was referred to in step three of example 9 to give compound 10 as an oil (purity 97.12%, yield 44%).
Characterization data: [ M+H ]] + ：575.2； 1 H NMR(400MHz,Chloroform-d)δ7.73–7.67(m,1H),7.46–7.40(m,1H),7.35–7.29(m,2H),6.26(s,1H),5.25(s,2H),4.94(s,1H),3.71–3.63(m,1H),3.56(dt,J＝14.3,1.8Hz,1H),2.95–2.85(m,4H),2.80(ddd,J＝7.5,6.1,1.3Hz,4H),2.55– 2.50(m,9H)。
Example 11
Synthesis of 5- ((S) -1- (2-chlorophenyl) -2-methoxy-2-oxoethyl) -4,5,6, 7-tetrahydrothiophene [3,2-c ] pyridin-2-yl-2- (4- (1-oxoisoquinolin-2-yl) phenyl) butanoate (Compound 11)
The synthesis was carried out in the same manner as in example 3 to obtain solid compound 11 (HPLC purity 98.13%, yield 70.10%).
Characterization data: [ M+H ]] + ：615.2； 1 H NMR(400MHz,Chloroform-d)δ7.95(d,J＝7.6Hz,1H),7.88(d,J＝8.5Hz,2H),7.71–7.66(m,1H),7.66–7.60(m,1H),7.55(d,J＝7.5Hz,2H),7.46–7.38(m,3H),7.34–7.29(m,2H),6.25(s,1H),4.90(s,1H),4.88(s,2H),3.77(s,3H),3.69(t,J＝7.8Hz,1H),3.62(s,1H),3.52(d,J＝14.4Hz,1H),2.88(t,J＝5.3Hz,2H),2.78(d,J＝5.9Hz,2H),2.21(dp,J＝14.6,7.2Hz,1H),1.93(dq,J＝14.1,7.3Hz,1H),0.98(t,J＝7.3Hz,3H)。
Example 12
Pharmacokinetic studies of the Compounds of the application
Research background: clopidogrel is not active as a prodrug, and most of clopidogrel is rapidly metabolized in the liver to form an inactive carboxylic acid metabolite via carboxylesterase1 (CES 1) accounting for 85% of the total amount. Only less than 15% of the crude drug is oxidized by cytochrome oxidase P450 (CYP enzyme), mainly CYP3A4, CYP2C19, etc. 2 steps to produce the final active metabolite. The active metabolite exerts antiplatelet activity by irreversibly binding to the P2Y12 receptor on the surface of platelets, and the concentration of clopidogrel active metabolite is extremely important for exerting antiplatelet efficacy. The structure of the clopidogrel active metabolite contains active sulfhydryl groups, and the structure is very unstable in organisms, so that the sulfhydryl groups must be protected in a derivatization way, and the derivatization product of the clopidogrel active metabolite is measured to express the content of the clopidogrel active metabolite.
Rat pharmacokinetic study
The following compounds of formula were prepared as a control group 1 sample set as per the method of the application patent CN103554132 a.
The experimental method comprises the following steps: female SD rats (200-300 g) were randomized into six groups (n=10): clopidogrel group, compound 3, compound 4, compound 8, compound 10 and control group 1. Clopidogrel sulfate (0.73 mg/kg), compound 3 (1.07 mg/kg), compound 4 (1.02 mg/kg), compound 8 (0.95 mg/kg), compound 10 (1.00 mg/kg), and control group 1 (0.66 mg/kg) were administered intravenously, wherein the above groups were administered at equimolar doses and the administration volumes of the groups were 5 mL.kg -1 . Blood is taken out at 0.083h, 0.25h, 0.5h, 1.0h, 2.0h, 3.0h, 4.0h, 8.0h and 12h respectively before and after administration, derivatization protection treatment is carried out, plasma is centrifugally taken out, and the concentration of a derivatization product of the clopidogrel Lei Huoxing metabolite in the plasma is detected. The experimental results are shown in Table 1.
TABLE 1 pharmacokinetic parameters for intravenous administration in rats (mean+ -SD)
Conclusion of experiment:
experimental results show that the compound provided by the application has excellent pharmacokinetic properties, wherein the compound 3, the compound 4, the compound 8, the compound 10 and the clopidogrel groups and the AUC of the derivative product of the clopidogrel Lei Huoxing metabolite in the plasma of rats in the control group 1 (equimolar intravenous injection administration) 0-t (h × ng/mL) 220, 225, 164, 204 and 40.8, and 69, respectively, illustrate that the degree of conversion of the compounds provided by the present application to clopidogrel active metabolite is significantly better than the degree of conversion of clopidogrel or a similar deuterated analog control group 1 compound.
Dog pharmacokinetic studies
The experimental method comprises the following steps: male beagle dogs (8-12 kg), randomized (n=3), clopidogrel sulfate (2.2 mg/kg), compound 3 (3.25 mg/kg), intravenous (3.25 mg/kg), and compound 10 (3.0 mg/kg) were each administered orally, with each of the above groups being given equimolar doses. Blood is taken at 0.083h, 0.25h, 0.5h, 1.0h, 2.0h, 3.0h, 4.0h, 6.0h, 8.0h, 12h and 24h respectively before and after administration, protection treatment is performed in a derivatization mode, plasma is taken through centrifugation, and the concentration of a derivatization product of the clopidogrel Lei Huoxing metabolite in the plasma is detected. The experimental results are shown in Table 2.
Table 2 pharmacokinetic parameters (mean±sd) after beagle administration
Conclusion of experiment:
experimental results indicate that the AUC of the derivative products of clopidogrel Lei Huoxing metabolites in beagle plasma are given orally, intravenously (equimolar) 3 0-t (h ng/mL) was 42, 548, 199 respectively, indicating that the conversion of compound 3 (orally or intravenously) to clopidogrel active metabolite was increased by more than 4.5 fold relative to oral clopidogrel.
The above study results show that: the compound has unexpected effect on improving the pharmacokinetic properties, improves the exposure of clopidogrel active metabolites, and has the production amount of the active metabolites obviously higher than that of clopidogrel or the existing clopidogrel derivatives, so that the compound is expected to achieve quick effect and high curative effect by obviously reducing the drug dosage, reduce the side effects of bleeding and the like of the anti-platelet aggregation drug, and simultaneously has potential to be developed into injection and oral preparations so as to meet the drug use requirements of clinical patients.
Example 13
Research on drug efficacy of the compound of the application
ADP-induced platelet aggregation assay
Female SD rats (200-300 g) were randomly divided into 7 groups (n=8), vehicle was 4vol% dimethyl sulfoxide (DMSO) +16vol% polyethylene glycol 400 (PEG 400) +80vol% physiological saline (salt), clopidogrel sulfate (0.73 mg/kg), control group 1 (0.66 mg/kg), ozagrel (0.40 mg/kg), indobufen (0.51 mg/kg), compound 3 (1.07 mg/kg), compound 8 (0.95 mg/kg), vehicle group was intravenously administered with equal volumes of 4vol% DMSO+16vol% PEG400+80vol% physiological saline, respectively, wherein the above groups were administered at equimolar doses. After 4 hours after administration, isoflurane was anesthetized, abdominal aorta was bled, anticoagulated with sodium citrate 1:9, and platelet rich plasma and platelet poor plasma were spun together at a mixing ratio of platelet poor plasma to platelet rich plasma=3:1. After the mixed platelet plasma was obtained, the platelet aggregation rate after Adenosine Diphosphate (ADP) addition was measured by using a platelet aggregation meter by using an "optical turbidimetry method". The experimental results are shown in Table 3.
TABLE 3 platelet aggregation Rate after rat administration
Group of Platelet aggregation Rate (%)
Solvent group 81.2±3.5###
Clopidogrel group 70.3±4.1**##
Control group 1 61.2±3.1**
Ozagrel group 75.9±2.8*##
Indolibufen group 74.8±2.4*##
Compound 3 38.5±4.5***###
Compound 8 51.5±5.9***##
Note that: p.ltoreq.0.05, p.ltoreq.0.01, p.ltoreq.0.001 compared to vehicle group; compared with the control group 1, the # P is less than or equal to 0.05, the # P is less than or equal to 0.01, and the # # P is less than or equal to 0.001
Conclusion of experiment:
experimental results show that in ADP-induced platelet aggregation experiments, each administration group has obvious effect of inhibiting platelet aggregation of rats, and can reverse platelet aggregation to cause depolymerization. The platelet aggregation degree of the compound 3 group and the compound 8 group is obviously lower than that of the clopidogrel group/the control group 1/ozagrel group/the indobufen group, and the platelet aggregation resistance is obviously stronger than that of the clopidogrel/the control group 1/ozagrel/indobufen. The compound has stronger anti-platelet aggregation activity, and is expected to reduce the side effects of bleeding and the like of the anti-platelet aggregation medicine while achieving quick effect and high curative effect by obviously reducing the medicine dosage. In addition, the experiment shows that the compound 3 group and the compound 8 group can be rapidly metabolized into effective metabolites and indobufen or ozagrel to exert the drug effect after entering the body, wherein the indobufen and ozagrel have the anti-platelet effect and form a synergistic effect with clopidogrel metabolites, so that better anti-platelet aggregation activity is generated.
Example 14
Safety study of the Compounds of the application
Acute toxicity test in rats
Single intravenous administration of the Compound (vehicle 5vol% DMSO+10vol% polyethylene glycol-15 Hydroxystearate (HS)15) +85vol% saline) in SD rats (4-6 dose groups per compound, 10 per dose group, male and female halves) were given for clinical observation after dosing. Clinical observations were made twice a day, once a day, starting on the second day, for 14 consecutive days. Including behavioral observations, autonomic activity and nervous system behavior and death, etc., to obtain maximum tolerance (MTD value) and half-Lethal (LD) of the compound 50 Values). The experimental results are shown in Table 4.
TABLE 4 acute toxicity test data for intravenous administration in rats
Numbering device MTD(mg/kg) LD50 value (mg/kg)
Clopidogrel 72 104
Compound 3 86 121
Conclusion of experiment:
experimental results show that the MTD value and LD of the compound of the application are administered to rats in a single vein 50 The value is improved to a certain extent compared with clopidogrel, which shows that the compound has good safety.
Example 15
Stability investigation of the inventive compounds: stability of the compound in different solutions (small amount of ethanol to aid in dissolution) and experimental results are shown in table 5.
Table 5 test table of stability of compounds
The stability of the compound in 20% aqueous sulfobutyl ether- β -cyclodextrin (SBECD) at room temperature was further examined and the experimental results are shown in table 6.
Table 6: stability of the Compounds at Room temperature in 20% SBECD aqueous solution
Numbering of compounds 0h(％) 2h(％) 4h(％) 6h(％)
Compound 10 97.06 96.55 / /
Compound 3 99.10 99.12 99.06 99.02
Compound 4 97.98 97.64 97.30 96.62
Note that: the stability results in tables 5 and 6 are both based on the purity of the compounds, as measured by High Performance Liquid Chromatography (HPLC), which is the relative purity of the liquid phases;
liquid phase conditions:
phase A: 0.1% phosphoric acid aqueous solution;
and B phase: acetonitrile;
gradient elution, elution procedure is shown in table 7;
TABLE 7 elution procedure
Time (min) A％ B％
0 90 10
20 20 80
30 20 80
31 90 10
40 90 10
Column temperature: 30 ℃;
flow rate: 1mL/min;
sample concentration: 0.5mg/mL;
detection wavelength: 210nm;
chromatographic column: titank C18.
Conclusion of experiment: the compound provided by the application has excellent stability in different solutions, particularly the compound 3 and the compound 4 show unexpected stability in aqueous solutions, meets the physicochemical property requirement of being capable of being developed into a liquid preparation (such as injection), solves the technical problems that clopidogrel salt is unstable in aqueous solutions and is severely degraded in the prior art, and is very difficult to prepare the injection of clopidogrel or the clopidogrel salt for injection, overcomes the technical problems that the prior art aims to develop the marketed antiplatelet aggregation drugs such as clopidogrel or prasugrel into injection preparations to improve the curative effect and shorten the effective time, but has no successful long-term technical difficulty, and is expected to become a new generation of antiplatelet anti-aggregation drug which has good curative effect and low side effect and is feasible for injection and oral administration.
The foregoing description of the preferred embodiments of the application is not intended to limit the application to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the application are intended to be included within the scope of the application.

Claims (5)

  1. An optically active 2-hydroxytetrahydrothienopyridine derivative represented by formula (I) or a pharmaceutically acceptable salt thereof:
    wherein G is selected from the group consisting of a bond,
    n is an integer from 0 to 12;
    the broken lines each represent a linking site with a thiophene ring, and the wavy lines each represent a linking site with R;
    the R is selected from:
    wherein,
    wavy lines indicate ligation sites;
    R 1 selected from halogen;
    R 2 selected from CH 3 、CD 3 。
  2. The optically active 2-hydroxytetrahydrothienopyridine derivative of claim 1, or a pharmaceutically acceptable salt thereof, wherein the derivative is any one selected from the following compounds:
  3. an optically active 2-hydroxytetrahydrothienopyridine derivative or a pharmaceutically acceptable salt thereof, characterized by being selected from any one of the following compounds:
  4. a pharmaceutical composition comprising the derivative of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.
  5. Use of a derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the prevention and/or treatment of embolic disorders caused by thrombosis.
CN202380008078.5A 2022-01-11 2023-01-10 Optically active 2-hydroxy tetrahydrothiophene pyridine derivative and preparation method and application thereof Pending CN116744921A (en)

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CN103694250B (en) * 2012-09-28 2016-02-10 武汉启瑞药业有限公司 Thiophene pyridine derivatives and preparation method thereof and medicinal use
CN103554132B (en) * 2013-10-31 2016-01-27 李纪宁 Deuterated derivative of tetrahydrothieno pyridines and preparation method thereof and pharmaceutical use
WO2016034103A1 (en) * 2014-09-02 2016-03-10 南京曼杰生物科技有限公司 Substituted tetrahydrothieno pyridine derivatives and use thereof
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CN114736215B (en) * 2022-04-19 2023-04-11 中荣凯特（北京）生物科技有限公司 Tetrahydrothienopyridine deuterated derivative and preparation method and pharmaceutical application thereof

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