Imidazolidinyl vanillic acid ether derivatives and their uses

Abstract

The present invention provides an imidazolidinyl vanillic acid ether derivative represented by formula (I) and its use. The imidazolidinyl vanillic acid ether derivative of formula (I) according to the present invention has higher in vivo bioavailability and in vivo antiplatelet aggregation activity compared to the prior art, and is useful for the treatment and / or prevention of thromboembolic-related diseases. 【Chemical 1】 JPEG2025518969000037.jpg31170

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to imidazolidinyl vanillic acid ether derivatives and a method for producing the same, and further provides the use of the derivatives in the production of medicaments for the prevention and / or treatment of thrombus-related diseases.

Background Art

[0002] Thrombi caused by various causes can cause cardiovascular, cerebrovascular, and pulmonary circulation diseases such as myocardial infarction, stroke, and pulmonary embolism, collectively referred to as thrombus-related diseases. Since the incidence of such diseases is higher than that of various other diseases and seriously threatens human life and health, they have become the focus and hotspots of medical research and new drug development.

[0003] Currently, drugs clinically used for the prevention and treatment of thrombus-related diseases mainly include thrombolytic drugs, anticoagulants, and antiplatelet aggregation drugs. Thrombolytic therapy is mainly used for the treatment of acute ischemic stroke. However, most patients miss the timing of thrombolysis when they are admitted to the hospital, or are limited by various conditions and cannot undergo thrombolysis. The disadvantages of thrombolytic drugs themselves, such as being prone to causing allergies and needing to be stored at low temperatures, are also prominent. Therefore, the clinical application of such medicaments is greatly limited. Anticoagulants have a reliable therapeutic effect, but their action is limited to venous thrombi, and moreover, the risk of bleeding is high. Therefore, their application is narrower than that of antiplatelet aggregation drugs. On the other hand, antiplatelet aggregation drugs for arterial thrombi are the most common drugs. Representative ones include aspirin, a cyclooxygenase inhibitor, clopidogrel, ticagrelor, etc., which are P2Y 12 receptor inhibitors. Currently, P2Y 12 receptor inhibitors have become the main drugs clinically applied, but there are still problems such as insufficient therapeutic effect in some clinical patients and the risk of bleeding (Zhang Xia, Ke Yongsheng. Novel P2Y 12Clinical research progress of ticagrelol, a receptor inhibitor [J]. "Chinese Journal of Clinical Pharmacology and Therapeutics", 2014, 19(4): 459-465), the demand for new antiplatelet aggregation drugs remains strong.

[0004] Chinese Patent CN101851209B discloses a carboxylic acid compound (Compound A) of the following formula having antiplatelet aggregation activity, and its methyl ester intermediate in the synthesis scheme is disclosed. It has been found that the compound has a significant inhibitory effect on rabbit platelet aggregation induced by adenosine diphosphate (ADP) (there is no activity data for its methyl ester intermediate). However, due to its low oral bioavailability and weak ability to penetrate the blood-brain barrier, its development for clinical application has been limited.

Chemical formula

Summary of the Invention

Problems to be Solved by the Invention

[0005] In the prior art, there remains a need for pharmaceuticals with stronger antiplatelet aggregation activity and higher bioavailability.

Means for Solving the Problems

[0006] In order to solve the above problems in the prior art, the inventors designed an imidazolidinyl vanillic acid derivative having a structure represented by the following formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof.

Chemical formula

[0007] In one embodiment, R1 is C3-C 12 alkyl group, C3-C 12 cycloalkyl group, C6-C 14 selected from aryl groups, wherein the alkyl group and cycloalkyl group are halogen, C1-C 12 alkoxy group, C1-C 12 alkoxycarbonyl group, C1-C12 an alkoxycarbonyloxy group, C1-C 12 an alkylacyloxy group, which may be substituted with a carboxy group; the aryl group is C1-C 12 an alkyl group, C1-C 12 an alkoxy group, which may be substituted with OH, wherein the alkyl group and the alkoxy group may be substituted with OH, an amino group, or a carboxy group; or, R1 is C1-C 12 an alkoxycarbonyloxy group or C1-C 12 a C2 alkyl group substituted with an alkylacyloxy group, selected from a benzyl group substituted with a hydroxy group. 1-

[0008] In one embodiment, R1 is selected from a C3-C6 alkyl group, a C3-C8 cycloalkyl group, and a phenyl group, wherein the alkyl group and the cycloalkyl group may be substituted with a halogen, a C1-C6 alkoxy group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkoxycarbonyloxy group, a C1-C6 alkylacyloxy group, or a carboxy group; the phenyl group may be substituted with a C1-C6 alkyl group, a C1-C6 alkoxy group, or OH, wherein the alkyl group and the alkoxy group may be substituted with an amino group or a carboxy group; or, R1 is a C2 alkyl group substituted with a C1-C6 alkoxycarbonyloxy group or a C1-C6 alkylacyloxy group, selected from a benzyl group substituted with a hydroxy group. 1-

[0009] In one embodiment, R1 is an n-propyl group, an isopropyl group,

Chemical formula

[0010] In one embodiment, R2 is selected from H or a C1-C6 alkyl group; preferably, R2 is selected from H or a methyl group.

[0011] ​​In one embodiment, n is selected from 0 or 1; preferably, n is selected from 1.

[0012] In one embodiment, the compound of the present invention is selected from the following compounds, or pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, solvates thereof.

[0013]

Chemical formula

Chemical formula

[0014] The present invention further provides a pharmaceutical composition for the treatment and / or prevention of thrombus-related diseases, comprising a compound having a structure represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof, and a pharmaceutically acceptable carrier.

[0015] The present invention further provides the use of a compound having a structure represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof, in the manufacture of a medicament for the treatment and / or prevention of thrombus-related diseases.

[0016] The present invention further provides a method for the treatment and / or prevention of thrombus-related diseases, comprising administering to an individual in need thereof a therapeutically effective amount of a compound having a structure represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof.

[0017] In the pharmaceutical composition containing the compound of the present invention described above, the use of the compound of the present invention, or the method for treating or preventing thrombus-related diseases using the compound of the present invention, the thrombus-related disease is a disease caused by platelet aggregation.

Advantages of the Invention

[0018] The compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, or solvate thereof, has stronger in vivo antiplatelet aggregation activity, higher bioavailability, can meet the clinical needs of various thromboembolic diseases, and can maximize the advantages and application scope of clinical treatment.

Embodiments for Carrying Out the Invention

[0019] Definitions In this specification, the following terms and phrases generally have the meanings shown below, unless the context in which they are used indicates otherwise.

[0020] In this specification, the term "alkyl group" refers to a monovalent group of a branched or unbranched saturated hydrocarbon chain having 1 to 12 carbon atoms (more typically, 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 6 carbon atoms). Examples of groups of this term include, for example, methyl group, ethyl group, 1-propyl group (n-propyl group), 2-propyl group (isopropyl group), 1-butyl group (n-butyl group), 2-methyl-1-propyl group (isobutyl group), 2-butyl group (s-butyl group), 2-methyl-2-propyl group (t-butyl group), 1-pentyl group (n-pentyl group), 2-pentyl group, 3-pentyl group, 2-methyl-2-butyl group, 3-methyl-2-butyl group, 3-methyl-1-butyl group, 2-methyl-1-butyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 2-methyl-2-pentyl group, 3-methyl-2-pentyl group, 4-methyl-2-pentyl group, 3-methyl-3-pentyl group, 2-methyl-3-pentyl group, 2,3-dimethyl-2-butyl group, 3,3-dimethyl-2-butyl group, 1-heptyl group, 1-octyl group, 1-nonyl group, 1-decyl group, and the like.

[0021] As used herein, the term "alkenyl group" refers to a monovalent straight-chain or branched unsaturated hydrocarbon group having the indicated number of carbon atoms (e.g., 3 to 12 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 6 carbon atoms, etc.) and having a carbon-carbon double bond (e.g., 1, 2 or 3 carbon-carbon double bonds). In some embodiments, specific examples of alkenyl groups include, but are not limited to, ethenyl group (i.e., -CH=CH2), propen-1-yl (i.e., -CH=CHCH3), propen-3-yl (or allyl group, i.e., -CH2CH=CH2), propen-2-yl (i.e., -C(CH3)=CH2), butadienyl group (including 1,2-butadienyl group and 1,3-butadienyl group), etc.

[0022] As used herein, the term "alkynyl group" refers to a monovalent straight-chain or branched unsaturated hydrocarbon group having the indicated number of carbon atoms (e.g., 3 to 12 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 6 carbon atoms, etc.) and having a carbon-carbon triple bond (e.g., 1, 2 or 3 carbon-carbon triple bonds). In some embodiments, specific examples of alkynyl groups include, but are not limited to, ethynyl group (i.e., -C≡CH), propargyl group (i.e., -CH2C≡CH), propynyl group (i.e., -C≡CCH3), etc.

[0023] As used herein, the term "cycloalkyl group" refers to a monovalent saturated carbocyclic group having a monocyclic, multiple-fused ring or bridged ring and having 3 to 12 carbon atoms (more typically, 3 to 10 carbon atoms, or 3 to 8 carbon atoms). In some embodiments, cycloalkyl groups include monocyclic structures such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclooctyl group, etc.; polycyclic structures such as adamantyl group, bicyclo[2.2.1]heptyl group, etc.; cycloalkyl groups condensed with aryl groups such as indan group (the linkage point may be on the cycloalkyl group).

[0024] As used herein, the term "aryl group" refers to an aromatic carbocyclic group having a monocyclic ring (e.g., phenyl group), polycyclic ring (e.g., biphenyl group), or multiple fused rings (fused ring) (e.g., naphthyl group, fluorenyl group, and anthryl group) and having 6 to 14 carbon atoms (more typically, 6 to 10 carbon atoms, or 6 carbon atoms). Examples of groups of this term include, for example, phenyl group, fluorenyl group, naphthyl group, anthryl group, 1,2,3,4-tetrahydronaphthyl group (the linking point may be at the aryl group), etc.

[0025] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0026] As used herein, the term "alkoxy group" refers to an "alkyl-O-" group. Here, the alkyl group is as defined herein. Examples of groups of this term include, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, t-butoxy group, etc.

[0027] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to affect the treatment as defined below when administered to a mammal in need of such treatment. The therapeutically effective amount varies depending on the subject and condition being treated, the weight and age of the subject, the severity of the condition, the method of administration, etc., and can be readily determined by those skilled in the art.

[0028] As used herein, the term "stereoisomer" refers to compounds that have the same chemical composition and connectivity but differ in the three-dimensional orientation of their atoms (where this orientation cannot be interconverted by rotation about a single bond). "Stereoisomers" include "diastereomers" and "enantiomers". "Diastereomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectroscopic properties, and reactivity. A mixture of diastereomers can be separated by high-resolution analytical procedures (such as crystallization, electrophoresis, and chromatography). "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[0029] As used herein, the term "tautomer" means two (or more) coexisting compounds that differ in the position and electronic distribution of one (or more) active atoms with respect to each other, such as, for example, keto-enol tautomers.

[0030] As used herein, the term "pharmaceutically acceptable salt" refers to salts that retain the biological availability and properties of the particular compound, provided that the salts are not biologically or otherwise undesirable. Pharmaceutically acceptable salts can be prepared from inorganic acids and organic acids. Salts derived from inorganic acids include hydrochloride, hydrobromide, sulfate, nitrate, phosphate, carbonate, bisulfate, hydrogen phosphate, dihydrogen phosphate, bicarbonate, etc. Salts derived from organic acids include formate, acetate, propionate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, tartrate, citrate, benzoate, cinnamate, mandelate, mesylate, ethylsulfonate, tosylate, salicylate, etc.

[0031] As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the formulation and / or other components, including the mammalian subject being treated therewith.

[0032] As used herein, the term "prodrug" refers to a compound that is metabolized by one or more steps or processes upon in vivo administration or is otherwise converted into a biologically, pharmaceutically, or therapeutically active form of the compound. To produce a prodrug, a pharmaceutically active compound is modified such that the active compound can be regenerated by a metabolic process. By designing prodrugs to alter metabolic stability and drug transport properties, negative effects or toxicities can be masked, the flavor of a drug can be improved, or other properties or performance of the drug can be changed. One of ordinary skill in the art, with knowledge of the pharmacodynamic processes and drug metabolism in the body, can design prodrugs of a compound once the pharmaceutically active compound is known. (See, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pp. 388-392).

[0033] As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the invention. Specific examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0034] Pharmaceutical Compositions and Administration The compounds provided by the present invention, or pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, solvates thereof are generally administered as pharmaceutical compositions. Thus, the present invention provides a pharmaceutical composition comprising a compound provided by the present invention as an active ingredient and one or more pharmaceutically acceptable carriers. The pharmaceutical composition may be administered alone or in combination with other therapeutic agents. This composition can be manufactured by methods known in the art (e.g., Reminton’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985); and, Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0035] The pharmaceutically acceptable carriers may be solid or liquid. Among them, the solid carriers can be one or more substances used as excipients, diluents, sweeteners, solubilizers, lubricants, binders, tablet disintegrants, stabilizers, preservatives or encapsulating materials. The liquid carriers can be solvents or liquid dispersion media. Suitable solid carriers include, for example, cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, tragacanth, gum arabic, sodium alginate, parabens, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, etc., but are not limited thereto. Suitable liquid carriers include water, ethanol, polyols (e.g., glycerin, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycerides, agar, pyrogen-free water, isotonic saline, Ringer's solution, and mixtures thereof), but are not limited thereto.

[0036] The pharmaceutical composition according to the present invention can be in any form suitable for the desired administration method. For example, when used for oral administration, it can be manufactured as tablets, pills, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs, solutions, sprays. The composition intended for oral administration can be manufactured by any known method for manufacturing pharmaceutical compositions in the art. The pharmaceutical composition of the present invention may be in the form of a sterile injectable preparation such as a sterile aqueous or oily suspension for injection. Also, the pharmaceutical composition of the present invention can be manufactured as a preparation suitable for pulmonary or intranasal administration, for example, an aerosol or dry powder administration preparation, a nasal drop or nasal spray. Further, the pharmaceutical composition of the present invention can be manufactured as a suppository suitable for rectal administration. Note that the pharmaceutical composition of the present invention can be manufactured as a transdermal preparation for topical administration or an eye drop suitable for eye administration.

[0037] The pharmaceutical composition of the present invention can be administered once or multiple times by arterial injection, intravenous injection, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, or topical administration.

[0038] The effective dosage of the compound of the present invention depends at least on the nature of the disease to be treated, toxicity, delivery method, and pharmaceutical formulation, and is determined by the usual dose escalation studies by a clinician. It can be expected to be about 0.0001 to about 100 mg / kg body weight / day; usually about 0.01 to about 10 mg / kg body weight / day; more typically, about 0.01 to about 5 mg / kg body weight / day; and most typically, about 0.05 to about 0.5 mg / kg body weight / day. For example, the candidate dosage per day for an adult weighing about 70 kg is in the range of 1 mg to 1000 mg, preferably in the range of 5 mg to 500 mg, and can be in the form of single or multiple administrations.

[0039] Indications The compounds of the present invention, or pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, solvates thereof can be used for the prevention and / or treatment of thromboembolic diseases. In particular, the compounds of the present invention, or pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, solvates thereof can be used for the treatment and / or prevention of atherosclerosis, coronary heart disease, myocardial infarction, ischemic stroke, peripheral vascular disease, multiple sclerosis, scleroderma, Raynaud's phenomenon caused by multiple sclerosis, deep vein thrombosis, lower extremity venous thrombosis, intermittent claudication, etc.

[0040] Combined administration The compounds of the present invention may be administered as a single therapeutic agent to treat and / or prevent thromboembolic diseases, other diseases caused by platelet aggregation, or diseases selected from atherosclerosis, coronary heart disease, myocardial infarction, ischemic stroke, peripheral vascular disease, multiple sclerosis, scleroderma, Raynaud's phenomenon caused by multiple sclerosis, deep vein thrombosis, lower extremity venous thrombosis, intermittent claudication, etc. Further, the above-mentioned diseases may be treated by administering the compounds of the present invention in combination with one or more other therapeutic agents. The one or more other therapeutic agents may be any antithrombotic agent having the same or different mechanisms of action, for example, common heparin, low molecular weight heparin, other heparin derivatives, synthetic heparin derivatives (e.g., fondaparinux), vitamin K antagonists, synthetic or biological inhibitors of non-thrombin coagulation factors (e.g., synthetic FXa, FVIIa and FIXa inhibitors and rNAPc2), antiplatelet agents (acetylsalicylic acid, ticlopidine and clopidogrel); thromboxane receptor and / or synthase inhibitors; fibrinogen receptor antagonists; prostacyclin; phosphodiesterase inhibitors; ADP-receptor (P2X1, P2Y1, P2Y12 [P2T]) antagonists; and inhibitors of carboxypeptidase U inhibitor (CPU or TAFIa) and plasminogen activator inhibitor-1 (PAI-1).

[0041] In addition, by administering the compound of the present invention in combination with a thrombolytic agent, diseases selected from thromboembolic diseases, diseases caused by platelet aggregation, or arteriosclerosis, coronary heart disease, myocardial infarction, ischemic stroke, peripheral vascular disease, multiple sclerosis, scleroderma, Raynaud's phenomenon caused by multiple sclerosis, deep vein thrombosis, lower extremity venous thrombosis, intermittent claudication, etc. may be treated and / or prevented. Examples of thrombolytic agents include one or more (natural, recombinant, or modified) tissue-type plasminogen activators, streptokinase, urokinase, prourokinase, anisylated plasminogen streptokinase activator complex (APSAC), animal salivary gland plasminogen activator, and the like.

[0042] Treatment methods and uses In one embodiment, the present invention provides a method for treating and / or preventing a thromboembolic disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof, or a pharmaceutical composition containing the same. In another embodiment, the present invention provides a method for treating and / or preventing a disease caused by platelet aggregation, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof, or a pharmaceutical composition containing the same. In another embodiment, the present invention provides a method for treating and / or preventing arteriosclerosis, coronary heart disease, myocardial infarction, ischemic stroke, peripheral vascular disease, multiple sclerosis, scleroderma, Raynaud's phenomenon caused by multiple sclerosis, deep vein thrombosis, lower extremity venous thrombosis, and / or intermittent claudication, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof, or a pharmaceutical composition containing the same.

[0043] The present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof, as a therapeutic active substance in the manufacture of a medicament for the treatment and / or prevention of thromboembolic diseases. Further, the present invention particularly provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof, as a therapeutic active substance in the manufacture of a medicament for the treatment and / or prevention of diseases caused by platelet aggregation. Furthermore, the present invention particularly provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof, as a therapeutic active substance in the manufacture of a medicament for the treatment and / or prevention of diseases such as atherosclerosis, coronary heart disease, myocardial infarction, ischemic stroke, peripheral vascular disease, multiple sclerosis, scleroderma, Raynaud's phenomenon caused by multiple sclerosis, deep vein thrombosis, lower extremity venous thrombosis, and / or intermittent claudication.

[0044] Common synthetic methods The compounds of the present invention can be prepared using the methods disclosed herein, their routine modifications apparent from the disclosure herein, and methods well known in the art. Typical embodiments of the compounds of the present invention can be synthesized using the common reaction schemes described below. It will be apparent from the description herein that corresponding different products can be obtained by using other starting materials having similar structures instead of the starting materials for the reaction. The starting materials are typically obtained from commercial sources or synthesized by well-known methods.

[0045] Reaction Scheme I

Chemical formula

[0046] Reaction Scheme II [Chem.] React a carboxylic acid compound represented by formula (I-a) with a halogenating reagent (e.g., oxalyl chloride, sulfinyl chloride, etc.) in an inert solvent to produce an acid halide (e.g., a compound represented by formula (I-c). Here, X’ is chlorine or bromine.), and react this with R1XH to obtain a compound represented by formula (I).

[0047] Reaction Scheme III [Chem.] React a compound represented by formula (I-a) with R1XH under conditions suitable for forming an amide or an ester to obtain a compound represented by formula (I). For example, add a condensing agent (e.g., 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), and 1-hydroxybenzotriazole (HOBt), etc.) and a base (e.g., N-methylmorpholine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, etc.) to a mixture of the compound represented by formula (I-a) and R1XH in an inert solvent and react to obtain a compound represented by formula (I).

[0048] Reaction Scheme IV [Chem.] React a carboxylic acid represented by formula (I-a) with R1X’ in an inert solvent under basic conditions (e.g., cesium carbonate, potassium carbonate, etc.) to obtain a compound represented by formula (I).

Example

[0049] The following examples are provided to illustrate the production of the compounds of the present invention and are in no way intended to limit the present invention.

[0050] Example 1 Synthesis of Compound Propyl 4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxybenzoate

Chemical formula

[0051] 1 H NMR (400 MHz, CDCl3) δ (ppm): 7.70 - 7.61 (m, 2H, ArH), 7.58 (d, J = 1.71 Hz, 1H, ArH), 7.10 (d, J = 11.49 Hz, 2H, ArH), 6.80 (d, J = 8.56 Hz, 1H, ArH), 4.39 - 4.44 (m, 2H, CH2), 4.24 - 4.34 (m, 4H, CH2CH2), 3.93 (s, 3H, OCH3), 1.74 - 1.85 (m, 2H, CH2), 1.04 (t, J = 7.34 Hz, 3H, CH3).

[0052] Example 2 Synthesis of Compound Isopropyl 4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxybenzoate Hydrochloride Step 1

Chemical formula

[0053] Step 2

Chemical formula

[0054] Example 3 Synthesis of 6-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxybenzoyloxy)hexanoic acid Step 1

Chemical formula

[0055] Step 2

Chemical formula

[0056] Step 3

Chemical formula

[0057] Step 4

Chemical Structure

[0058] Example 4 Synthesis of (1R,4R)-4,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl 4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxybenzoate

Chemical Structure

[0059] Example 5 Synthesis of ((Isopropoxycarbonyl)oxy)methyl 4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxybenzoate

Chemical Structure

[0060] Example 6 Synthesis of 1 - acetoxyethyl - 4-(2-(1H - imidazol - 1 - yl)ethoxy)-3 - methoxybenzoate

Chemical Structure

[0061] Example 7 Synthesis of (S)-4-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxybenzamide)phenylalanine hydrochloride Step 1

Chemical formula

[0062] 1 1H NMR (600 MHz, CD3OD) δ (ppm): 8.14 (d, J = 8.2 Hz, 2H, ArH), 7.30 (d, J = 8.2 Hz, 2H, ArH), 5.04 (s, 1H, NH), 4.62 (s, 1H, CH), 3.72 (s, 3H, OCH3), 3.25 (s, 1H, CH2), 3.11 (s, 1H, CH2), 1.39 (s, 9H, 3CH3).

[0063] Step 2

Chemical formula

[0064] Step 3

Chemical formula

[0065] Step 4 [Chemical formula] To a 50 mL single-necked flask, intermediate 12 (2.00 g, 3.7 mmol), methanol (10 mL), water (2 mL), and LiOH . H2O (468 mg, 11.10 mmol) were added in this order, and the mixture was stirred at room temperature for 1 h. After monitoring by TLC (V ジクロロメタン :V メタノール = 5:1) to confirm that the raw material had completely reacted, the reaction solution was concentrated, diluted hydrochloric acid (1 N) was added to adjust the pH to 6, filtered, the filter cake was washed with water (20 mL), the filter cake was collected, and dried in an oven at 45 °C overnight to obtain 1.40 g of intermediate 13 as a white solid. The yield was 85.1%. 11H NMR (600 MHz, DMSO-d6) δ (ppm): 10.02 (s, 1H, NH), 7.71 (s, 1H, NH), 7.64 (d, J = 8.4 Hz, 2H, ArH), 7.57 (dd, J1 = 8.4 Hz, J2 = 2.1 Hz, 1H, ArH), 7.54 (d, J = 2.1 Hz, 1H, ArH), 7.27 (s, 1H, ArH), 7.20 (d, J = 8.3 Hz, 2H, ArH), 7.06 (d, J = 8.4, 2H, ArH), 6.90 (s, 1H, ArH), 4.40 (t, J = 5.2 Hz, 2H, CH2), 4.32 (t, J = 5.2 Hz, 2H, CH2), 4.09 - 4.05 (m, 1H, CH), 3.85 (s, 3H, CH3), 2.98 (dd, J1 = 13.9 Hz, J2 = 5.3 Hz, 1H, CH2), 2.80 (dd, J1 = 13.9 Hz, J2 = 10.1 Hz, 1H, CH2), 1.33 (s, 9H, 3CH3).

[0066] Step 5

Chemical formula

[0067] Example 8 Synthesis of (R)-3-(4-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxybenzamido)phenyl)-2-propionic acid hydrochloride

Chemical Structure

[0068] Example 9 Synthesis of (S)-4-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxybenzoyloxy)phenylalanine hydrochloride Step 1

Chemical Structure

[0069] Step 2

Chemical Structure

[0070] Step 3

Chemical formula

[0071] Example 10 Synthesis of Compound (R)-4-(4-(2-(1H-imidazol-1-yl)ethoxy)-3-methoxybenzoyloxy)phenylalanine Hydrochloride

Chemical Structure

[0072] Example 11 Biological Activity Measurement Study on the Antithrombotic Activity of the Compounds of the Present Invention in Rats After 7 days of adaptive breeding, 104 male Sprague-Dawley rats weighing 180 - 220 g (purchased from Victoria Experimental Animal Technology Co., Ltd., certificate number: 20211103Aazz0619000910) were randomly divided into 13 groups according to body weight, with 8 rats per group: a normal control group, a compound A group, a methyl ester of compound A group, and compound groups of Examples 1 - 10. Each group was intragastrically administered the corresponding drug (dosage 15 mg / kg), and the normal control group was administered an equal volume of solvent. All were administered intragastrically once. One hour after the final administration, the rats were anesthetized intraperitoneally with 3% chloral hydrate, fixed in the supine position, and the right common carotid artery and left external jugular vein were separated. A polyethylene tube with an inner diameter of 1.5 mm and a length of 10 cm was taken, containing a thread (pre-weighed) with a length of 6 cm, and the polyethylene tube was filled with a heparin saline solution (50 U / ml). After inserting one end of the polyethylene tube into the left external jugular vein, heparin (50 U / kg) was injected, and the other end was inserted into the right common carotid artery. After the blood flow was released for 15 min, the blood flow was interrupted, the thread was quickly taken out and weighed, the original thread weight was subtracted from the total weight to obtain the wet weight of the thrombus, then it was placed in an oven and dried at 70°C, and the original thread weight was subtracted from the thread weight to obtain the dry weight of the thrombus, and the inhibition rate was calculated. Wet weight inhibition rate (%) = (thrombus wet weight of normal control group - thrombus wet weight of administration group) / thrombus wet weight of normal control group × 100%. Dry weight inhibition rate (%) = (thrombus dry weight of normal control group - thrombus dry weight of administration group) / thrombus dry weight of normal control group × 100%.

[0073] The experimental results are shown in Table 1. Compared with the blank control group, each administration group could significantly reduce the wet weight and dry weight of the thrombus (P < 0.01), and had an obvious thrombus formation inhibitory effect; the antithrombotic effect of compound A was similar to that of its methyl ester, with no obvious difference; compared with compound A and its methyl ester, the compounds of the present invention had an obviously stronger effect of reducing the wet weight and dry weight of the thrombus, the wet weight inhibition rate of the thrombus reached 45% or more, and the dry weight inhibition rate of the thrombus reached 50% or more.

[0074]

Table 1

[0075] Pharmacokinetic Study of the Compounds of the Present Invention in Rats Eighteen male SD rats weighing 240 - 280 g (purchased from Victoria Experimental Animal Technology Co., Ltd., certificate number: 20211103Aazz0619000910) were randomly divided into 6 groups of 3 rats each. Before dosing, the animals were fasted overnight. On the day of dosing, the animals in each group were intragastrically administered the compounds of Examples 3, 4, 5, 6, Compound A, and the methyl ester of Compound A, respectively, at a dose of 15 mg / kg (calculated based on Compound A). The animals were bled 0.15 mL from the jugular vein at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h before and after dosing, and placed in an EDTA-K2 anticoagulation tube containing 3 μL of dichlorvos aqueous solution (10 mg / mL). Plasma was obtained by centrifugation, and the plasma was used as a sample. Then, 10 μL of the plasma sample was taken, and 500 μL of acetonitrile containing IS (verapamil 5 ng·mL -1 , glibenclamide 50 ng·mL -1 , tolbutamide 200 ng·mL -1 and diclofenac 200 ng·mL -1 ) was added, vortexed for 10 min, then centrifuged at a rotational speed of 3700 rpm for 10 min. Then, 70 μL of the supernatant and 70 μL of water were added, and vortexed for 10 min. An equal split sample of 2 μL of the mixture was injected into an LC-MS / MS system (Triple Quad 5500+: LC-MS-MS-022) to measure the blood drug concentration of the compound. Pharmacokinetic parameter analysis was performed using WinNonlin 8.0 software, and the analysis results are shown in Table 2.

[0076]

Table 2

[0077] As is clear from the experimental results, the compounds of Examples 3, 4, 5, and 6 of the present invention have an area under the concentration-time curve (AUC) that is significantly improved compared to Compound A and the methyl ester of Compound A, and the relative bioavailability reaches 200.37%, 169.97%, 179.28%, and 176.8% respectively, which is significantly higher than that of the methyl ester of Compound A. Also, the peak concentration (C max ) after oral administration is significantly improved compared to Compound A and the methyl ester of Compound A, and the peak arrival time (T max ) is significantly shortened. The compounds of the present invention have been shown to have significantly higher bioavailability, faster effects, and stronger actions compared to Compound A and the methyl ester of Compound A.

[0078] All references mentioned in this specification are hereby incorporated by reference into this specification. It will be understood that changes and modifications can be made to the technical means of the present invention without departing from the spirit and scope of the present disclosure.

Claims

1. A compound having a structure represented by the following formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, or solvate thereof. 【Chemical Formula 1】 [In formula (I), X is selected from O or NH; R １ is C ３ - C １２ an alkyl group, C ３ - C １２ an alkenyl group, C ３ - C １２ an alkynyl group, C ３ - C １２ a cycloalkyl group, C ６ - C １４ an aryl group, and here, the alkyl group, alkenyl group, alkynyl group, and cycloalkyl group are halogen, cyano group, C １ - C １２ an alkoxy group, C １ - C １２ an alkoxycarbonyl group, C １ - C １２ an alkoxycarbonyloxy group, C １ - C １２ an alkylacyloxy group, carboxy group, C １ - C １２ an alkylthio group, C １ - C １２ an alkylthiocarbonyl group, C １ - C １２ an alkylthiocarbonyloxy group, C １ - C １２ an alkylthiocarbonylthio group, C １ - C １２ an alkylacylthio group, C １ - C １２ an alkylamino group, C １ - C １２ an alkylaminocarbonyl group, C １ - C １２ an alkylaminoacyloxy group, C １ - C １２ an alkylamide group, C １ - C １２may be substituted with an alkylaminoamide group; the aryl group is C １ -C １２ alkyl group, C １ -C １２ alkoxy group, OH, halogen, cyano group, nitro group, carboxy group, and here, the alkyl group and alkoxy group may be substituted with OH, amino group, carboxy group, nitro group, cyano group, halogen, C １ -C １２ alkoxy group, C ３ -C １２ cycloalkyl group; or R １ is selected from C １ -C １２ alkoxycarbonyloxy group or C １ -C １２ alkylacyloxy group-substituted C １－ C ２ alkyl group, benzyl group substituted with a hydroxy group; R ２ is H or C １ -C １２ alkyl group; n is selected from 0, 1, 2, 3. ]

2. R １ is selected from C ３ -C １２ alkyl group, C ３ -C １２ cycloalkyl group, C ６ -C １４ aryl group, where the alkyl group and cycloalkyl group may be substituted with halogen, cyano group, C １ -C １２ alkoxy group, C １ -C １２ alkoxycarbonyl group, C １ -C １２ alkoxycarbonyloxy group, C １ -C １２ alkylacyloxy group, carboxy group, C １ -C １２ alkylthio group, C １ -C １２ alkylthiocarbonyl group, C １-C １２ an alkylthiocarbonyloxy group, C １ -C １２ an alkylthiocarbothio group, C １ -C １２ an alkylacylthio group, C １ -C １２ an alkylamino group, C １ -C １２ an alkylaminocarbonyl group, C １ -C １２ an alkylaminoacyloxy group, C １ -C １２ an alkylamide group, C １ -C １２ may be substituted with an alkylaminoamide group; wherein the aryl group is C １ -C １２ an alkyl group, C １ -C １２ an alkoxy group, OH, halogen, cyano group, nitro group, carboxy group, and wherein the alkyl group, alkoxy group may be substituted with OH, amino group, carboxy group, nitro group, cyano group, halogen, C １ -C １２ an alkoxy group, C ３ -C １２ a cycloalkyl group; or R １ is C １ -C １２ an alkoxycarbonyloxy group or C １ -C １２ a C substituted with an alkylacyloxy group １－ C ２ an alkyl group, a benzyl group substituted with a hydroxy group, the compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof.

3. R １ is C ３ -C １２ an alkyl group, C ３ -C １２ a cycloalkyl group, C ６ -C １４ an aryl group, and wherein the alkyl group, cycloalkyl group are halogen, C １-C １２ an alkoxy group, C １ -C １２ an alkoxycarbonyl group, C １ -C １２ an alkoxycarbonyloxy group, C １ -C １２ an alkylacyloxy group, which may be substituted with a carboxy group; said aryl group is C １ -C １２ an alkyl group, C １ -C １２ an alkoxy group, which may be substituted with OH, wherein said alkyl group and alkoxy group may be substituted with OH, an amino group, or a carboxy group; or, R １ is C １ -C １２ an alkoxycarbonyloxy group or C １ -C １２ a C alkyl group substituted with an alkylacyloxy group, a benzyl group substituted with a hydroxy group, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof. １－ C ２ selected from an alkyl group, a benzyl group substituted with a hydroxy group, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof.

4. R １ is selected from C ３ -C ６ an alkyl group, C ３ -C ８ a cycloalkyl group, a phenyl group, wherein said alkyl group and cycloalkyl group may be substituted with a halogen, C １ -C ６ an alkoxy group, C １ -C ６ an alkoxycarbonyl group, C １ -C ６ an alkoxycarbonyloxy group, C １ -C ６ an alkylacyloxy group, a carboxy group; said phenyl group is C １ -C ６ an alkyl group, C １ -C ６An alkoxy group may be substituted with OH, wherein the alkyl group and the alkoxy group may be substituted with an amino group or a carboxy group; or R １ is C １ -C ６ An alkoxycarbonyloxy group or C １ -C ６ A C substituted with an alkylacyloxy group １－ C ２ An alkyl group, a benzyl group substituted with a hydroxy group, the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof.

5. R １ is an n-propyl group, an isopropyl group, 【Chemical Formula 2】 Selected from the above, the compound according to the above claim, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof.

6. The compound according to claim 1, selected from the following compounds, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof. 【Chemical Formula 3(1)】 【Chemical Formula 3(2)】

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate thereof, and a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 to 6 in the manufacture of a medicament for the treatment and / or prevention of thromboembolic diseases.

9. Use of the compound according to any one of claims 1 to 6 in the manufacture of a medicament for the treatment and / or prevention of diseases caused by platelet aggregation.

10. The use according to claim 8 or 9, wherein the disease is selected from atherosclerosis, coronary heart disease, myocardial infarction, ischemic stroke, peripheral vascular disease, multiple sclerosis, scleroderma, Raynaud's phenomenon caused by multiple sclerosis, deep vein thrombosis, lower extremity venous thrombosis, and intermittent claudication.

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