CN111362970A - Benzofuran derivative and preparation method and application thereof - Google Patents
Benzofuran derivative and preparation method and application thereof Download PDFInfo
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- CN111362970A CN111362970A CN201811593419.7A CN201811593419A CN111362970A CN 111362970 A CN111362970 A CN 111362970A CN 201811593419 A CN201811593419 A CN 201811593419A CN 111362970 A CN111362970 A CN 111362970A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- 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
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- 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
Abstract
The invention provides a compound with a structure shown in a formula (I), a preparation method and application thereof, a pharmaceutical composition containing the compound, and application of the compound as a PAR4 inhibitor.
Description
Technical Field
The invention belongs to the technical field of medicines. In particular, the invention provides a compound with an anti-platelet aggregation effect, a preparation method and application thereof, and a pharmaceutical composition containing the compound. More specifically, the invention relates to a benzofuran derivative, a preparation method and application thereof and a pharmaceutical composition.
Background
The thromboembolic diseases have the characteristics of high morbidity, high mortality, high disability rate and the like, and myocardial infarction, cerebral infarction and pulmonary infarction caused by thromboembolism are the first causes of death. Platelet activation and aggregation play an important role in the formation of thrombi, and thus antiplatelet therapy is an important means for clinically preventing and treating thrombotic diseases. The antiplatelet drugs widely used in clinic at present still have certain limitations, such as incomplete effectiveness, bleeding risk and the like. Therefore, there is an urgent need to develop novel, safe and effective antiplatelet drugs.
Thrombin is the strongest platelet activator and it acts by binding to Protease Activated Receptors (PARs). Human platelets express PAR-1 and PAR-4, and thrombin cleaves the N-terminal portion of PAR-1 and PAR-4, thereby activating the platelets to function. The results of studies and clinical trials of the PAR-1 inhibitor Vorapaxar (Vorapaxar) found that it did not significantly reduce cardiovascular events while increasing the risk of bleeding. Previous studies have shown that binding of PAR-4 to thrombin at the site of injury requires a higher thrombin concentration. It has been demonstrated by researchers that PAR-4 plays a more important role than PAR-1 in platelet aggregation caused by thrombin. Therefore, the research of the antiplatelet medicament aiming at the PAR-4 target point is particularly important for finding safer and more effective antiplatelet medicaments.
Disclosure of Invention
The invention aims to provide benzofuran derivatives, a preparation method of the benzofuran derivatives, application of the benzofuran derivatives and a pharmaceutical composition containing the benzofuran derivatives.
The invention aims to provide a benzofuran derivative.
In particular, these substances are useful in the prevention and/or treatment of thromboembolic disorders while avoiding to some extent the disadvantages of the prior art, and provide compounds having the structure of formula (I):
wherein:
R1selected from methyl, methoxy;
R2is selected from
CH2-R8Or
R3、R4、R5、R6、R7、R8Each independently selected from
R9Selected from methoxy, H, F, Cl, Br, nitro and methyl;
R10is selected from C1-C3Alkyl radical, C1-C3An acyl group;
R11、R12each independently selected from methoxy, H, F, Cl, Br, nitro and methyl.
In a preferred embodiment of the present invention, a compound having the structure of formula (I) wherein:
R1selected from methyl, methoxy;
R2is selected from
-CH2-R8Or
R3Is selected from
R4Is selected from
R5Is selected from
R6Is selected from
R7Is selected from
R8Is selected from
R9Is selected from methyl;
R10selected from methyl, ethyl, acetyl;
R11selected from methoxy, H, nitro, methyl;
R12selected from Cl.
In a preferred embodiment of the invention, the compound is represented by the general formula (I), wherein the compound is selected from the compounds in the following table:
unless stated to the contrary, the terms used in the specification and claims have the following meanings.
When the present invention relates to a compound substituted with a plurality of substituents, each substituent may be the same or different.
When the present invention relates to a compound containing a plurality of hetero atoms, the hetero atoms may be the same or different.
The elemental carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention all include their isotopes, and the elemental carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include12C、13C、14C, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including16O、17O and18isotopes of O, sulfur including32S、33S、34S and36isotopes of S, nitrogen include14N and15isotopes of N, F19Isotopes of F, chlorine including35Cl and37cl, isotopes of bromine including79Br and81Br。
another object of the present invention is to provide a process for preparing the benzofuran derivative.
Reacting the compound (Ia) with a corresponding bromide in the presence of a base to obtain a compound having a structure shown in a formula (I):
wherein: r1、R2Is defined by the formula(I) are consistent;
the compound (Ia), bromide, may be prepared by conventional synthetic methods or may be obtained commercially.
In some embodiments, the solvent used in the preparation method of the present invention may be a solvent inert under the reaction conditions, including but not limited to: ethers such as tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, etc., but not limited thereto; halogenated hydrocarbons such as 1, 2-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, etc., but not limited thereto; alcohols such as methanol, ethanol, isopropanol, tert-butanol, etc., but not limited thereto; hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, etc., but not limited thereto; others such as dimethyl sulfoxide, dimethylformamide, acetonitrile, pyridine, water, hexamethylphosphoric triamide, etc., but not limited thereto. The solvent may also be a mixture of the above solvents.
In certain embodiments of the invention, the base may be a conventional inorganic or organic base, preferably: hydroxides of alkali metals, such as potassium hydroxide or sodium hydroxide, but not limited thereto; carbonates of alkali metals such as potassium carbonate or sodium carbonate, etc., but not limited thereto; alkoxides such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, or potassium tert-butoxide, but not limited thereto; amines such as methylamine, hydrazine hydrate, triethylamine, diisopropylethylamine, pyridine, etc., but not limited thereto.
In still another aspect, the present invention provides the use of the compound of formula (I) in the present invention in the preparation of a medicament for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, such as coronary syndrome, myocardial infarction, myocardial ischemia, etc., which are well known to those skilled in the art.
In still another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a pharmaceutically acceptable carrier or excipient.
By "pharmaceutical composition" is meant one or more of the compounds described herein, and other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.
Detailed Description
The technical solutions of the present invention are described in detail below with reference to examples, but the scope of the present invention includes, but is not limited to, the following.
The structure of the compound was confirmed by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a Bruker AV400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
MS was measured using Thermo scientific (finnigan lcq ad) (ESI).
The thin layer chromatography silica gel plate adopts a cigarette platform yellow sea GF254 silica gel plate, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials for the present invention may be synthesized by methods known in the art or may be purchased from companies such as the welfare technology, the alading technology, and the like.
The nitrogen atmosphere means that the reaction flask is connected with a nitrogen balloon with a volume of about 1L.
The hydrogen atmosphere refers to a hydrogen balloon with a reaction flask connected to about 1L of solvent.
In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is room temperature, unless otherwise specified.
The room temperature is the most suitable reaction temperature and is 20-30 ℃.
DMF: n, N-dimethylformamide
Example 1
2- ((6-methoxy-2- (2-methoxyimidazo [2,1-b ] [1,3,4] thiadiazol-6-) benzofuran-4-) oxy) -N- (tetrahydro-2H-pyran-4-) acetamide (Compound 1)
2-((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)-N-(tetrahydro-2H-pyran-4-yl)acetamide
Mixing 6-methoxy-2- (2-methoxyimidazole [2,1-b ]][1,3,4]Diazosulfide-6-) benzofuran-4-ol (0.3g,0.95mmol), 2-bromo-N- (tetrahydro-2H-pyran-4-) acetamide (0.2g,1.1mmol) and potassium carbonate (0.3g,2.2mmol) were added to 10mL DMF, stirred at room temperature for 3H, the reaction solution was poured into 50mL water and 50mL ethyl acetate, the phases were stirred and separated, the ethyl acetate layer was separated, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate gradient elution ethyl acetate 0% -100%) to give the title compound 2- ((6-methoxy-2- (2-methoxyimidazo [2, 1-b))][1,3,4]And thiadiazole-6-) benzofuran-4-) oxy) -N- (tetrahydro-2H-pyran-4-) acetamide (Compound 1) (0.4g, 91.8% yield).1H-NMR(400MHz,DMSO-d6):δ8.35(1H,s),8.07(1H,d),7.14(1H,s),6.83(1H,s),6.36(1H,s),4.59(2H,s),4.20(3H,s),3.85(3H,m),3.78(3H,s),3.35(2H,m),1.67(2H,d),1.56(2H,m)。MS m/z＝459.12[M+1]。
In a similar manner to that of example 1, starting with 6-methoxy-2- (2-methoxyimidazo [2,1-b ] [1,3,4] dithiadiazol-6-) benzofuran-4-ol, examples 2-4 were prepared:
in a similar manner to that of example 1, starting with 6-methoxy-2- (2-methoxyimidazo [2,1-b ] [1,3,4] thiadiazol-6-) benzofuran-4-ol, examples 5, 6:
example 7
6- (6-methoxy-4- ((2- (4-methylpiperazin-1-) thiazol-4-) methoxy) benzofuran-2-) -2-methylimidazo [2,1-b ] [1,3,4] thiadiazoles (Compound 7)
6-(6-methoxy-4-((2-(4-methylpiperazin-1-yl)thiazol-4-yl)methoxy)benzofuran-2-yl)-2-methylimidazo[2,1-b][1,3,4]thiadiazole
Mixing 6-methoxy-2- (2-methylimidazole [2,1-b ]][1,3,4]Thiadiazole-6-) benzofuran-4-ol (0.3g,1mmol), 4- (bromomethyl) -2- (4-methylpiperazine-1-) thiazole (0.3g,1.1mmol) and potassium carbonate (0.3g,2.2mmol) were added to 10mL dmf, stirred at room temperature for 3h, the reaction solution was poured into 50mL of water and 50mL of ethyl acetate, stirred for phase separation, the ethyl acetate layer was separated, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate gradient elution ethyl acetate 0% -100%) to yield the title compound 6- (6-methoxy-4- ((2- (4-methylpiperazin-1-) thiazole-4-) methoxy) benzofuran-2-) -2-methylimidazole [2,1-b ]][1,3,4]And thiadiazole (compound 7) (0.4g, 80.1% yield).1H-NMR(400MHz,DMSO-d6):δ8.45(1H,s),7.03(1H,s),6.93(1H,s),6.81(1H,s),6.56(1H,s),5.05(2H,s),3.80(3H,s),3.39(4H,t),2.73(3H,s),2.42(4H,t),2.21(3H,s)。MS m/z＝497.11[M+1]。
In a similar manner to that of example 7, starting with 6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-) benzofuran-4-ol, examples 8-12 are prepared:
examples 13-19 were prepared in a similar manner to example 7 starting from 6-methoxy-2- (2-methylimidazo [2,1-b ] [1,3,4] thiadiazol-6-) benzofuran-4-ol:
example 20:
inhibition of platelet aggregation induced by gamma-thrombin in rabbit blood by the compounds of the invention
The following method was used to determine the inhibitory effect of the compounds of the present invention on platelet aggregation induced by gamma-thrombin in rabbit blood in vitro, expressed as inhibition rate.
The weight of the rabbit is 2.5-3 kg, 4% chloral hydrate is used for anesthetizing the ear edge vein and is slowly injected until the blink reflex disappears, the abdominal aorta is used for taking blood, PRP is separated by centrifugation at 1100rpm/15min, and PPP is separated at 3500rpm/10 min. PRP300ul was incubated with 10ul of drug in a plastic cuvette for 5 min. When measured using a platelet aggregation meter (PRECIL, LBY-NJ4), gamma-thrombin (produced by Enzyme research Laboratories, Lot: HGT5230, 1.99mg/ml) was added at 10 to 50nM to the cuvette to cause aggregation, platelet adsorption and aggregation were observed for 3 minutes, the instrument automatically plots a platelet adsorption-aggregation curve, and the maximum aggregation rate was read at the end of 3 minutes.
The results are shown in table 1:
TABLE 1 inhibition of gamma-thrombin induced platelet aggregation by the compounds (concentration of compound 1.67. mu.M)
| Compound numbering | Inhibition rate |
| 1 | 19％ |
| 2 | 28％ |
| 3 | 20％ |
| 4 | 21％ |
| 5 | 24％ |
| 6 | 16％ |
| 7 | 100％ |
| 8 | 100％ |
| 9 | 83％ |
| 12 | 23％ |
| 13 | 100％ |
| 14 | 32％ |
| 19 | 21％ |
Example 21: the results were tested at a compound concentration of 3.33. mu.M using the same method as in example 20:
TABLE 2 inhibition of platelet aggregation induced by gamma-thrombin by the compounds (concentration of compound 3.33. mu.M)
| Compound numbering | Inhibition rate |
| 10 | 100％ |
| 11 | 90％ |
| 15 | 100％ |
| 16 | 70％ |
| 17 | 100％ |
Example 22: the IC was calculated by measuring the inhibition rate at different concentrations in the same manner as in example 2050The results are as follows:
inhibition of gamma-thrombin induced platelet aggregation by the compounds of Table 3
| Compound numbering | IC50(nM) |
| 7 | 288.8 |
| 8 | 26.0 |
| 9 | 480.9 |
Claims (8)
1. A compound having the structure of formula (I):
wherein:
R1selected from methyl, methoxy;
R2is selected from
CH2-R8Or
R3、R4、R5、R6、R7、R8Each independently selected from
R9Selected from methoxy, H, F, Cl, Br, nitro and methyl;
R10is selected from C1-C3Alkyl radical, C1-C3An acyl group;
R11、R12each independently selected from methoxy, H, F, Cl, Br, nitro and methyl.
2. A compound of formula (i) as claimed in claim 1 wherein:
R1selected from methyl, methoxy;
R2is selected from
-CH2-R8Or
R3Is selected from
R4Is selected from
R5Is selected from
R6Is selected from
R7Is selected from
R8Is selected from
R9Is selected from methyl;
R10selected from methyl, ethyl, acetyl;
R11selected from methoxy, H, nitro, methyl;
R12selected from Cl.
3. A compound of formula (i) according to any one of claims 1 to 2, wherein the compound is selected from:
4. a process for the preparation of a compound of formula (i) as defined in any one of claims 1 to 3, comprising the steps of:
wherein: r1、R2Is as defined in claim 1.
5. Use of a compound having a structure of formula (I) as claimed in claims 1 to 3 in the preparation of a medicament for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation.
6. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier or excipient.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is a solid oral formulation, a liquid oral formulation, or an injection.
8. The pharmaceutical composition of claim 7, wherein the solid oral formulation is a tablet, capsule or granule; the liquid oral preparation is syrup or oral solution; the injection is water injection, powder injection or small infusion.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811593419.7A CN111362970A (en) | 2018-12-25 | 2018-12-25 | Benzofuran derivative and preparation method and application thereof |
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| CN201811593419.7A CN111362970A (en) | 2018-12-25 | 2018-12-25 | Benzofuran derivative and preparation method and application thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104411713A (en) * | 2012-04-26 | 2015-03-11 | 百时美施贵宝公司 | PAR4 agonist peptides |
| CN104540835A (en) * | 2012-04-26 | 2015-04-22 | 百时美施贵宝公司 | Imidazothiadiazole derivatives as protease activated receptor 4 (par4) inhibitors for treating platelet aggregation |
| CN104583218A (en) * | 2012-04-26 | 2015-04-29 | 百时美施贵宝公司 | Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation |
| WO2017066863A1 (en) * | 2015-10-19 | 2017-04-27 | Universite De Montreal | Heterocyclic compounds as inhibitors of platelet aggregation |
-
2018
- 2018-12-25 CN CN201811593419.7A patent/CN111362970A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104411713A (en) * | 2012-04-26 | 2015-03-11 | 百时美施贵宝公司 | PAR4 agonist peptides |
| CN104540835A (en) * | 2012-04-26 | 2015-04-22 | 百时美施贵宝公司 | Imidazothiadiazole derivatives as protease activated receptor 4 (par4) inhibitors for treating platelet aggregation |
| CN104583218A (en) * | 2012-04-26 | 2015-04-29 | 百时美施贵宝公司 | Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation |
| WO2017066863A1 (en) * | 2015-10-19 | 2017-04-27 | Universite De Montreal | Heterocyclic compounds as inhibitors of platelet aggregation |
Non-Patent Citations (1)
| Title |
|---|
| 杨华 等: "3-取代-1（3H）-异苯并呋喃酮光学异构体的合成及抗血小板活性初步研究", 《中南药学》 * |
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Application publication date: 20200703 |