CN103539709A

CN103539709A - N-(-1-hydro-indenyl-1-yl)sulfonamide compound and its preparation method and use

Info

Publication number: CN103539709A
Application number: CN201310476325.2A
Authority: CN
Inventors: 许勇; 乐洋; 郭涤亮; 李莉娥
Original assignee: Ren Fu Pharmaceutical Group Stock Co
Current assignee: Hubei Bio-Pharmaceutical Industrial Technological Institute Inc
Priority date: 2013-03-22
Filing date: 2013-10-11
Publication date: 2014-01-29
Anticipated expiration: 2033-10-11
Also published as: CN103539709B

Abstract

The invention provides a compound. The compound is an N-(-1-hydro-indenyl-1-yl)sulfonamide compound shown in the formula I, or its enantiomer, diastereoisomer, raceme, pharmaceutically acceptable salt, crystalline hydrate or solvate. The N-(-1-hydro-indenyl-1-yl)sulfonamide compound can be used for preparation of drugs for treating or preventing thromboxane receptor-related diseases or for treating or preventing thrombosis and/or hypertension.

Description

N- (-1-hydrogen-indene-1-yl) sulfonamide compound and preparation method and application thereof

Technical Field

The invention relates to the field of medicines, in particular to an N- (-1-hydrogen-indene-1-yl) sulfonamide compound and a preparation method and application thereof. More specifically, the invention relates to N- (-1-hydro-indene-1-yl) sulfonamide compounds and derivatives shown in a general formula I with a novel structure, a preparation method thereof, a pharmaceutical composition thereof and application thereof in preparing medicines for treating diseases related to thromboxane receptors, especially cardiovascular diseases such as thrombosis and hypertension.

Background

Cardiovascular disease is one of the most serious diseases threatening mankind in the world today, about 1700 thousands of people die from cardiovascular disease every year worldwide, and the morbidity and mortality rate thereof have surpassed the neoplastic disease and leaped the world first. According to WHO statistics, the number of cardiovascular disease deaths accounts for about 35% of the total deaths. Cardiovascular disease is the first cause of death in men over 45 years of age and the second cause of death in women in most countries. According to statistics, the ratio of urban population death from cardiovascular diseases in 2009 in China is 128.19 people/hundred thousand people.

The high prevalence also contributes to the enormous market size. In the clinical medication amount of China for many years, cardiovascular disease medication is always arranged behind antibiotics and anti-tumor drugs, and the first three are listed. The market sales in 2009 is close to 700 million yuan, and the average annual growth rate reaches 17%. Among them, the market for antithrombotic drugs has also increased rapidly. In 2011, the global market for antithrombotic agents is expected to exceed 180 billion dollars.

At present, the drugs clinically used for antithrombotic include anticoagulants, thrombolytic drugs and antiplatelet drugs. Among them, antiplatelet drugs are used most widely, and are important means for preventing and treating thrombotic diseases, accounting for more than 50% of antithrombotic drugs. However, the antiplatelet therapeutic drugs currently used still have various drawbacks, such as: weak inhibition of platelet function, blockage of ADP-mediated signaling pathways, long onset times, inability to convert intravenous integrin α IIb β 3 antagonist therapy to oral therapy, and inability to completely reduce the incidence of thrombosis, among others. Therefore, the development of more efficient and safer novel medicaments is a research hotspot of various large medicament enterprises at present.

Diseases caused by two pathological processes of thrombosis and thromboembolism are clinically called thrombotic diseases. Thrombotic diseases seriously threaten the life and health of human beings, the incidence rate of the thrombotic diseases is the first of various diseases, and the thrombotic diseases are increasing in recent years, and are one of the key points and hot points of modern medical research. In recent years, the market for antithrombotic drugs has been increasing rapidly driven by increasing clinical demand. In 2011, the global market size for antithrombotic drugs approaches 180 billion dollars.

At present, the most widely used drugs for clinical antithrombotic use are antiplatelet drugs, which account for more than 50% of antithrombotic drugs, so the antiplatelet drugs have great market potential. Meanwhile, the existing antiplatelet drugs on the market have the defects of a certain degree, and the drugs with good curative effect, high safety and convenient taking are very few, so that the successful development of new antiplatelet drugs has huge social value and economic benefit.

Disclosure of Invention

The present invention aims to solve at least one of the above technical problems to at least some extent or to at least provide a useful commercial choice. To this end, it is an object of the present invention to propose a compound which can be used for the preparation of a medicament.

The present invention has been completed based on the following findings of the inventors:

due to the central role of platelets in cardiovascular and cerebrovascular thrombosis, antiplatelet therapy is one of the effective methods in treating cardiovascular and cerebrovascular arterial diseases. However, the antiplatelet therapeutic drugs currently used still have different defects, and the drugs with good curative effect and safety and convenient taking are very few, so that the successful development of new antiplatelet drugs has huge social value and economic benefit.

Antiplatelet drugs can be classified as TXA according to their mechanism of action₂Inhibitors (COX)₁Inhibitors and TP receptor antagonists), ADP antagonists, GPIIb/IIIa receptor antagonists, PAR1 receptor antagonists, PDE inhibitors, platelet aggregation inhibitors, and the like. We selected TP receptor antagonists as the focus of the study. The reason is that:

TP receptor antagonists having TXA inhibiting properties₂The synthesis effect, so that the active inhibition effect can be achieved at the early stage of thrombosis;

TP receptor antagonists and similar TXA inhibition₂Synthetic COX₁Compared with the inhibitor, the inhibitor has stronger pertinence, thereby avoiding selecting COX₁The defect of poor selectivity at the action point, so the compound has better treatment potential;

the successful market of TP receptor antagonists is blank throughout the antiplatelet drugs in the market and under development, thus avoiding the competition with various pharmaceutical companies in the world and having larger research and development space.

In a first aspect of the invention, the invention features a compound. According to an embodiment of the invention, the compound is N- (-1-hydro-inden-1-yl) sulfonamide compound shown in formula I or enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof,

wherein,

x is selected from C, O and N, preferably X is C or O, more preferably X is O;

R¹selected from the group consisting of C1-C12 linear or branched alkyl unsubstituted or substituted with 1-3 halogens, C1-C12 linear or branched alkoxy unsubstituted or substituted with 1-3 halogens or phenyl, C3-C6 cycloalkyl unsubstituted or substituted with 1-3 halogens, C1-C6 linear or branched alkyl substituted with C1-C6 alkoxy, C1-C6 linear or branched alkyl substituted with C3-C6 cycloalkyl, hydroxyl, C1-C6 linear or branched hydroxyalkyl, substituted or unsubstituted benzene ring, and substituted or unsubstituted C5-C12 aromatic heterocyclic ring containing 1-4 heteroatoms, wherein the heteroatoms are independently selected from O, S and N;

R²selected from hydrogen or isotopes thereof, C1-C12 linear or branched alkyl which is unsubstituted or substituted by 1-3 halogens, C3-C6 cycloalkyl which is unsubstituted or substituted by 1-3 halogens, C1-C6 linear or branched alkyl which is substituted by C1-C6 alkoxy, C1-C6 linear or branched alkyl which is substituted by C3-C6 cycloalkyl, C1-C6 linear or branched carboxyl which is unsubstituted or substituted by 1-3 halogens or phenyl, hydroxyl, C1-C6 linear or branched hydroxyalkyl, carboxyl, sulfydryl, -N R⁴R⁵，-NCO R⁴R⁵，-SO₂R⁴，-SO₂NR⁴R⁵and-OCOR⁴；

R³Selected from hydrogen or isotopes thereof, halogen, C1-C12 linear or branched alkyl unsubstituted or substituted by 1-3 halogens, C1-C12 linear or branched alkoxy unsubstituted or substituted by 1-3 halogens or phenyl, C3-C6 cycloalkyl unsubstituted or substituted by 1-3 halogens, C1-C6 linear or branched alkyl substituted by C1-C6 alkoxy, C1-C6 linear or branched alkyl substituted by C3-C6 cycloalkyl, hydroxyl, cyano, nitro, C1-C6 linear or branched hydroxyalkyl, carboxyl, sulfydryl, -NR⁴R⁵，-NCO R⁴R⁵，-SO₂R⁴，-SO₂N R⁴R⁵and-OCOR⁴；

R⁴And R⁵Independently selected from hydrogen or isotopes thereof, halogen, C1-C6 linear or branched alkyl groups unsubstituted or substituted with 1-3 halogens, and C3-C6 cycloalkyl groups unsubstituted or substituted with 1-3 halogens;

the halogen is fluorine, chlorine, bromine or iodine.

The inventors have surprisingly found that the above compounds can be used for the treatment or prevention of a disease associated with a thromboxane receptor, or for the treatment or prevention of thrombosis and/or hypertension.

In one embodiment of the present invention, for the substituted benzene ring or substituted aromatic heterocycle, each ring comprises 1 to 3 substituents independently selected from hydrogen or isotopes thereof, halogen, C1-C12 linear or branched alkyl group unsubstituted or substituted with 1 to 3 halogens, C1-C12 linear or branched alkoxy group unsubstituted or substituted with 1 to 3 halogens and/or phenyl, C2-C12 linear or branched unsaturated hydrocarbon group unsubstituted or substituted with 1 to 3 halogens, C3-C6 cycloalkyl group unsubstituted or substituted with 1 to 3 halogens, C1-C6 linear or branched alkyl group substituted with C1-C6 alkoxy group, C1-C6 linear or branched alkyl group substituted with C3-C6 cycloalkyl group, hydroxyl, cyano, nitro, C1-C6 linear or branched hydroxyalkyl group, and mercapto group, -NR⁴R⁵，-NCOR⁴R⁵，-SR⁴，-SO₂R⁴，-SO₂NR⁴R⁵，-COR⁴，-CONR⁴R⁵or-OCOR⁵。

In one embodiment of the present invention, for the substituted benzene ring or the substituted aromatic heterocyclic ring, the substituted benzene ring or the substituted aromatic heterocyclic ring is substituted with a plurality of substituents, wherein two of the plurality of substituents together with the adjacent carbon atom or heteroatom form a 5-7 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, the 5-7 membered heterocyclic ring being optionally substituted with a substituent selected from the group consisting of: hydrogen or isotopes thereof, halogen, C1-C6 linear or branched alkyl groups unsubstituted or substituted with 1-3 halogens, C1-C6 linear or branched alkoxy groups unsubstituted or substituted with 1-3 halogens, and hydroxyl groups.

In one embodiment of the invention, R¹Is a substituted or unsubstituted group selected from: a benzene ring, pyrrole, furan, thiophene, pyrazole, oxazole, isoxazole, thiazole, imidazole, benzopyrazole, benzoxazole, benzisoxazole, indole, pyridine, pyrimidine, quinoline, isoquinoline, or purine.

In one embodiment of the invention, R¹Substituted with a substituent selected from the group consisting of: hydrogen, C1-C6 linear chain or branched chain alkyl which is unsubstituted or substituted by 1-3 halogens, C1-C6 linear chain or branched chain alkoxy which is unsubstituted or substituted by 1-3 halogens or phenyl, C2-C6 linear chain or branched chain unsaturated alkyl which is unsubstituted or substituted by 1-3 halogens, C3-C4 cycloalkyl which is unsubstituted or substituted by 1-3 halogens, C1-C6 linear chain or branched chain alkyl which is substituted by C1-C6 alkoxy, C1-C6 linear chain or branched chain alkyl which is substituted by C3-C4 cycloalkyl, hydroxyl, -SO₂R⁴，-COR⁴，-SO₂NR⁴R⁵，-OCOR⁴，-NR⁴R⁵and-NCO R⁴R⁵(ii) a Optionally, R¹Substituted with a plurality of substituents, two of which, together with their adjacent carbon atoms, form a 5-membered heterocyclic ring containing 2O atoms;

R²selected from hydrogen, carboxyl, C1-C6 linear chain or branched chain alkyl which is unsubstituted or substituted by 1-3 halogens, C1-C6 linear chain or branched chain alkoxy which is unsubstituted or substituted by 1-3 halogens or phenyl, and C1-C6 linear chain or branched chain carboxyl which is unsubstituted or substituted by 1-3 halogens or phenyl;

R³selected from hydrogen, halogen, C1-C6 linear chain or branched chain alkyl which is unsubstituted or substituted by 1-3 halogens, C1-C6 linear chain or branched chain alkoxy which is unsubstituted or substituted by 1-3 halogens or phenyl, hydroxyl, -NR⁴R⁵、-NCOR⁴R⁵、-SO₂R⁴、-SO₂NR⁴R⁵Or-OCOR⁴；

R⁴And R⁵Each independently is hydrogen, halogen, or C1-C4 straight chain or branched chain alkyl which is unsubstituted or substituted by 1-3 halogens;

the halogen is fluorine, chlorine or bromine.

In one embodiment of the invention, R¹Is a substituted or unsubstituted group selected from: benzene rings, pyrrole, furan, thiophene, and pyridine.

In one embodiment of the invention, R¹Substituted with a substituent selected from the group consisting of: hydrogen, halogen, C1-C4 linear or branched alkyl unsubstituted or substituted with 1-3 halogens, C1-C4 linear or branched alkoxy unsubstituted or substituted with 1-3 halogens or phenyl, C1-C4 linear or branched alkyl substituted with C3-C4 cycloalkyl, and hydroxyl; optionally, R¹Substituted with a plurality of substituents, two of which are linked together with their adjacent carbon atoms to form a 5-membered heterocyclic ring containing 2O atoms;

R²is selected from hydrogen and C1-C6 straight chain or branched chain carboxyl which is unsubstituted or substituted by 1-3 halogens or phenyl;

R³selected from hydrogen, halogen, C1-C4 linear or branched alkoxy unsubstituted or substituted by 1-3 halogens or phenyl groups, hydroxyl and-OCOR⁴；

R⁴And R⁵Each independently selected from hydrogen, halogen, and C1-C4 straight chain or branched chain alkyl which is unsubstituted or substituted by 1-3 halogens;

the halogen is fluorine or chlorine.

In one embodiment of the invention, R¹Is a substituted or unsubstituted benzene ring,

optionally, R¹Substituted with a substituent selected from the group consisting of: hydrogen, halogen, and hydroxyl;

optionally, R¹Substituted with a plurality of substituents, two of which, together with their adjacent carbon atoms, form a 5-membered heterocyclic ring containing 2O atoms;

R²is hydrogen;

R³selected from hydrogen, halogen, C1-C4 linear or branched alkoxy which is unsubstituted or substituted by 1-3 halogens or phenyl, and hydroxyl;

R⁴and R⁵Each independently hydrogen or methyl;

the halogen is fluorine or chlorine.

In one embodiment of the present invention, the compound is one selected from the group consisting of enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, crystalline hydrates and solvates thereof.

Thus, preferably, the N- (-1-hydro-inden-1-yl) sulfonamides of the invention are selected from the following compounds:

as used herein, the term "pharmaceutically acceptable salt" is a conventional non-toxic salt formed by the reaction of a compound of formula I with an inorganic or organic acid. For example, the conventional non-toxic salts can be prepared by reacting the compounds of formula I with inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid, phosphoric acid, and the like, or organic acids including citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid, and the like; or sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt formed by the compound of the general formula I and propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid after forming ester and then forming ester with inorganic base; or methylamine salt, ethylamine salt or ethanolamine salt formed by the compound of the general formula I and organic base; or the compound of the general formula I forms ester with lysine, arginine and ornithine and then forms corresponding inorganic acid salt with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid and phosphoric acid or forms corresponding organic acid salt with formic acid, acetic acid, picric acid, methanesulfonic acid and ethanesulfonic acid. The term "alkyl" as used herein may be a straight or branched chain alkyl group, and may be, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, octadecyl, etc.; substituted or unsubstituted cycloalkyl groups, which according to embodiments of the present invention contain 3 to 10 carbon atoms, may be saturated or unsaturated but not have aromatic character, and according to specific examples of the present invention may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; substituted or unsubstituted heterocycloalkyl groups, according to embodiments of the present invention, may contain at least one heteroatom selected from O, N and S.

In a second aspect, the present invention provides a process for the preparation of a compound as hereinbefore described, characterised in that it comprises the steps of:

condensing a compound represented by formula 1a with a compound represented by formula 2a to obtain a compound represented by formula 3 a;

subjecting said compound of formula 3a to a ring closure reaction to obtain a compound of formula 4 a;

subjecting the compound of formula 4a to a reductive amination reaction with a compound of formula 5a to obtain a compound of formula 6 a;

subjecting the compound represented by the formula 6a to a condensation reaction with diethyl malonate to obtain a compound represented by the formula 7 a;

subjecting the compound represented by the formula 7a to hydrolysis reaction so as to obtain a compound represented by the formula 8 a; and

obtaining the compound of formula I from the compound of formula 8a based on at least one of:

subjecting the compound of formula 8a and an amino acid ester or methyl malonate monopotassium salt to condensation reaction, and hydrolyzing the condensation reaction product under alkaline conditions to obtain the compound of formula I

Wherein,

R¹～R³as defined above.

The inventor finds that the compound can be effectively prepared by the method, and the preparation method has the advantages of mild reaction conditions, abundant and easily-obtained raw materials, simple operation and post-treatment, good corresponding selectivity and the like.

In a third aspect of the invention, a pharmaceutical composition is provided. According to an embodiment of the invention, the pharmaceutical composition comprises:

the compounds described hereinbefore; and

a pharmaceutically acceptable excipient which is capable of being used,

optionally the pharmaceutical composition is for use in the treatment or prevention of a thromboxane receptor associated disease, or for use in the treatment or prevention of thrombosis and/or hypertension. The pharmaceutical composition may further comprise conventional additives such as flavoring agents, etc.

The pharmaceutical composition provided by the invention preferably contains 1-99 wt% of the compound of the general formula (I) as an active ingredient, preferably, the compound of the general formula I as an active ingredient accounts for 65-99 wt% of the total weight of the pharmaceutical composition, and the balance is a pharmaceutically acceptable carrier and/or a conventional additive.

The compounds and pharmaceutical compositions provided herein may be in a variety of forms such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and the like, and may be presented in suitable solid or liquid carriers or diluents and in suitable sterile devices for injection or instillation.

Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dosage of the preparation formula comprises 0.05mg to 200mg of the compound of the general formula (I), preferably 0.1mg to 100mg of the compound of the general formula (I).

The compounds and pharmaceutical compositions of the present invention may be administered to mammals in clinical use, including humans and animals, by oral, nasal, dermal, pulmonary or gastrointestinal routes, among others. The most preferred route of administration is oral. The most preferable daily dose is 0.01mg/kg to 200mg/kg of body weight, which is taken once, or 0.01mg/kg to 100mg/kg of body weight, which is taken in divided portions. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment regimen. Usually starting with a small dose and gradually increasing the dose until the most suitable dose is found.

In a fourth aspect, the present invention proposes the use of a compound as described above for the preparation of a medicament for the treatment or prevention of a disease associated with a thromboxane receptor, or for the treatment or prevention of thrombosis and/or hypertension.

Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.

Detailed Description

The invention will be further illustrated in the following examples. These examples are intended to illustrate the invention, but not to limit it in any way. All parameters in the examples and the remaining descriptions are based on mass, unless otherwise specified. Various raw materials of the preparation method which are not described in the specification can be commercially obtained.

General procedure

The general process for preparing N- (-1-hydro-inden-1-yl) sulfonamides employed in the examples of the invention is described below:

the compounds to be synthesized are shown below:

the invention also provides a preparation method of the compound of the general formula I, and raw materials and reagents used in the invention are all purchased commercially if no special description is provided.

Compound a001-a014 was prepared according to reaction scheme one:

the reaction scheme I:

the preparation process of scheme one is detailed as follows:

route one, step a: preparation of compound 3 a: under the action of a catalyst, condensing the compound 1a and the compound 2a to obtain a compound 3 a; wherein the catalyst is a palladium catalyst, preferably palladium acetate;

specifically, dissolving a chemical dose of a compound 1a and a chemical dose of a compound 2a in a proper amount of anhydrous solvent, condensing at room temperature under the conditions of a proper amount of palladium catalyst, a proper amount of phase transfer catalyst and a proper amount of potassium carbonate, and purifying the product by column chromatography to obtain a compound 3 a; the solvent is preferably DMF;

route one step b: preparation of compound 4 a: under the action of acid, carrying out cyclization reaction on the compound 3a to obtain a compound 4 a; wherein the acid is PPA, concentrated sulfuric acid, aluminum trichloride and the like, and the condensing agent is preferably PPA;

specifically, 3a was dissolved in an appropriate amount of PPA, heated to 90 degrees celsius, and TLC monitored for completion of the reaction to give compound 4 a. Dropwise adding a proper amount of water in an ice bath, extracting for 3 times by using ethyl acetate, washing an organic phase to be neutral by using a saturated sodium bicarbonate aqueous solution, drying by using sodium sulfate, evaporating to dryness, and purifying a product by using column chromatography to obtain a compound 4 a;

a route one step c: preparation of compound 6 a: under the action of a catalyst and a reducing agent, carrying out reductive amination reaction on the compound 4a and the compound 5a to obtain a compound 6 a; wherein the catalyst is TiCl₄、AlCl₃And Lewis acids, etc.; wherein the reducing agent is sodium borohydride, sodium cyanoborohydride or sodium acetoxyborohydride.

Specifically, the obtained compound 4a and 5a are subjected to enamine reaction by using a proper amount of dichloromethane and toluene as solvents and a proper amount of Lewis acid catalysts to obtain an imine intermediate. The reaction is carried out at room temperature for 16 to 20 hours. Subsequently, an equivalent amount of acid is added to the reaction solution, and an appropriate amount of reducing agent is added to the reaction solution every 1 to 2 hours. After the reaction is finished, neutralizing the reaction solution with alkali liquor, adding water for dilution, extracting with ethyl acetate, drying with sodium sulfate, evaporating the solvent to dryness, and purifying by column chromatography. Wherein the Lewis acid catalyst is TiCl₄、AlCl₃The molar ratio to compound 4a is preferably 0.3: 1; reducing with proper amount of sodium borohydride, sodium cyanoborohydride or sodium acetoxyborohydride, reacting at room temperature for 7-12 hr, adding proper amount of water, extracting with ethyl acetate, drying with sodium sulfate, spin drying solvent, and purifying with column chromatography;

step d of route one: preparation of compound 7 a: under the action of alkali, carrying out condensation reaction on the compound 6a and diethyl malonate to obtain a compound 7 a; wherein the alkali is NaH or MeONa;

specifically, diethyl malonate is dissolved in a proper amount of solvent, alkali is added in an ice bath, and after 2 hours of reaction, 6a is added dropwise. Reacting for 6-8 hours at room temperature. Adjusting the post-treatment to be neutral, extracting by an organic solvent, spin-drying, and purifying by column chromatography to obtain a compound 7 a; the solvent is DMF or THF; the alkali is NaH or MeONa; the equivalent ratio of 6a to diethyl malonate and base was 1:3: 3.3.

Route one, step e: preparation of compound 8 a: under the action of acid, the compound 7a undergoes hydrolysis reaction to obtain a compound 8 a; wherein the acid is concentrated hydrochloric acid or concentrated sulfuric acid.

Specifically, 7a was dissolved in an appropriate solvent, 1 to 3 equivalents of an acid was added, and the reaction was refluxed for 48 hours. After the reaction, the reaction mixture was washed with brine, dried, spun-dried, and purified by column chromatography to obtain compound 8a (compound a001-a 014).

Compound a015-a028 was prepared according to reaction scheme two:

a second reaction line:

preparation of Compound 11a (A015-A028) Compound 8a was condensed with methyl malonate monopotassium salt in the presence of a base, followed by hydrolysis under alkaline conditions to give 11 a.

Specifically, 8a is dissolved in a proper solvent, alkali is added for activation for 2 hours, methyl malonate monopotassium salt is added, after 10 hours of reaction, an alkali water solution is added, after 2 hours of reaction at room temperature, the reaction liquid is adjusted to be neutral, ethyl acetate extraction is carried out, washing is carried out by saturated saline solution, drying and spin-drying are carried out, and column chromatography purification is carried out to obtain the compound 11a (A015-A028).

Compound a029-a076 is prepared according to reaction scheme three:

the reaction route is three:

the preparation process according to scheme three is detailed below: .

A route three step a: preparation of compound 9 a: under the action of alkali and a condensation reagent, carrying out condensation reaction on the compound 8a and amino acid ester to obtain a compound 9a, wherein the condensation reagent is TBTU or DCC or HOBt;

specifically, the solvent 8a prepared in the first route is added with proper alkali and condensation reagent in proper solvent, and then reacted for 2-16 hours at room temperature, after the reaction is finished, water is added to stop the reaction, and the mixture is extracted by dichloromethane and washed by saturated saline solution. Drying, spin-drying the solvent, and purifying by column chromatography to obtain compound 9 a.

A route three step b: preparing a compound 10a (A029-A076), and hydrolyzing the compound 9a under the action of alkali to obtain a compound 10 a; wherein the alkali is NaOH or KOH or LiOH;

specifically, 9a is dissolved in an appropriate solvent, an aqueous alkali solution is added thereto, and the mixture is stirred at room temperature for 1 to 2 hours. Adjusting the reaction solution to be neutral, extracting, drying, spin-drying the solvent, and purifying by column chromatography to obtain 10 a; the solvent is THF or dioxane.

Example 1: 2- (1- (4-fluorobenzenesulfonamido) -1-hydro-inden-4-yl) acetic acid (A001) (prepared according to scheme one)

1.13 preparation of methyl (2- (bromomethyl) phenyl) acrylate

2.97g of iodobenzyl bromide, 1.72g of methyl acrylate, 225mg of palladium acetate, 2.78g of tetrabutylammonium chloride, 4.14g of potassium carbonate and 50mL of anhydrous DMF were charged into a 250mL reaction flask, and the mixture was stirred overnight at room temperature while being substituted with nitrogen gas for 3 times. The reaction solution was poured into water, extracted 3 times with ethyl acetate, the organic phases were combined, washed 2 times with 0.1N HCl, washed 2 times with saturated brine, dried, filtered, the solvent was spin-dried, and purified by column chromatography to give 2.1g of a pale yellow oil.

¹H NMR(CDCl₃,400MHz):δ8.07(d,J=16.0Hz,1H),7.67-7.56(m,1H),7.42-7.31(m,3H),6.45(d,J=16.0Hz,1H),4.60(s,2H),3.84(s,3H).ESI-MSm/z:256[M+H]⁺.

Preparation of 24-bromomethyl-1-hydro-1-oxoindene

A100 mL reaction flask was charged with 2.1g of 3- (2- (bromomethyl) phenyl) acrylic acid methyl ester and 30mL of PP A, heated to 90 ℃ and reacted overnight. 50mL of water is dropwise added in an ice bath, ethyl acetate is used for extraction for 3 times, an organic phase is washed to be neutral by using a saturated sodium bicarbonate aqueous solution, sodium sulfate is dried and evaporated to dryness, and a product is purified by column chromatography to obtain 1.46g of a white solid.

ESI-MS m/z:245[M+Na]⁺.

1.1 preparation of 31- (4-fluorobenzenesulfonamido) -4-bromomethyl-1-hydro-indene

Into a 100mL reaction flask were placed 2.23g of 4-bromomethyl-1-hydro-1-oxoindene, 1.75g of 4-fluorobenzenesulfonamide, 190mg of TiCl₄And 20mL of DCM and 20mL of toluene, stirring at room temperature for 16 hours, and adding 3.78g of sodium cyanoborohydride three times at intervals of 1-2 hours. After the addition was completed, the reaction was continued at room temperature for 2 hours. After the reaction is finished, neutralizing the reaction solution with alkali liquor, adding water for dilution, extracting with ethyl acetate, drying with sodium sulfate, evaporating the solvent to dryness, and purifying by column chromatography. 2.3g of a pale yellow solid are obtained.

¹H NMR(d⁶-DMSO,400MHz):δ7.96-7.87(m,2H),7.42-7.10(m,6H),6.53(d,J=2.4Hz,1H),6.33(d,J=2.4Hz,1H),4.69(s,2H).ESI-MS m/z:404[M+Na]⁺.

1.42 preparation of diethyl- ((1- (4-fluorobenzenesulfonamido) -1-hydro-inden-4-yl) methyl) malonate

2.4g of diethyl malonate was dissolved in an appropriate amount of anhydrous THF, 0.66g of NaH (60%) was added under ice-bath, and after 2 hours of reaction, a solution of 1.91g of 1- (4-fluorobenzenesulfonamido) -4-bromomethyl-1-hydro-indene in THF was added dropwise. Reacting for 6-8 hours at room temperature. Adjusting the post-treatment to be neutral, extracting by an organic solvent, and spin-drying to obtain a crude product which is directly used for the next step without purification.

ESI-MS m/z:484[M+Na]⁺.

1.2 preparation of 52- (1- (4-fluorobenzenesulfonamido) -1-hydro-inden-4-yl) acetic acid

The product of the previous step was dissolved in THF, 3 equivalents of concentrated HCl were added, and the reaction was refluxed for 48 hours. After the reaction is finished, washing with saturated saline solution, drying, spin-drying and purifying by column chromatography to obtain the off-white solid.

¹H NMR(d⁶-DMSO,400MHz):δ12.14(br,1H),7.96-7.87(m,2H),7.42-7.10(m,6H),6.53(d,J=2.4Hz,1H),6.33(d,J=2.4Hz,1H),4.69(s,2H),2.85-2.37(m,4H).ESI-MS m/z:384[M+Na]⁺.

Example 2: 2- (1- (4-fluorobenzenesulfonamido) -1-hydro-inden-4-yl) -3-oxobutyric acid (A015) (prepared according to reaction scheme two)

Dissolving 3.6g of compound A001 in THF, adding EDCI to react for 2 hours, adding 1.1 equivalent of methyl malonate monopotassium salt to react for 10 hours, adding a 2N NaOH aqueous solution to react at room temperature for 2 hours, adjusting the reaction solution to be neutral, extracting with ethyl acetate, washing with saturated saline solution, drying, spin-drying, and purifying by column chromatography to obtain an off-white solid.

¹H NMR(d⁶-DMSO,400MHz):δ12.34(br,1H),7.96-7.87(m,2H),7.42-7.10(m,6H),6.53(d,J=2.4Hz,1H),6.33(d,J=2.4Hz,1H),4.69(s,2H),3.45-3.37(m,4H).ESI-MS m/z:412[M+Na]⁺.

Example 3: 2- (2- (1- (4-fluorobenzenesulfonyl) -h-inden-4-yl) acetylamino) acetic acid (A029) (prepared according to scheme three)

Preparation of ethyl 12- (2- (1- (4-fluorobenzenesulfonyl) -h-inden-4-yl) acetylamino) acetate

3.6g of compound A001, 1.37g of glycine methyl ester hydrochloride, 1.1 equivalent of TBTU, 1.1 equivalent of triethylamine and 40mL of DCM were added to a reaction flask, and after reacting for 2 hours at room temperature, washed 3 times with 0.1N HCl, washed 2 times with saturated saline, dried, filtered and the solvent was spin-dried to obtain a crude product. Used directly in the next step.

ESI-MS m/z:455[M+Na]⁺.

Preparation of 22- (2- (1- (4-fluorobenzenesulfonyl) -h-inden-4-yl) acetamido) acetic acid

The product of the previous step was dissolved in 40mL THF, 40mL2N in aqueous NaOH was added and stirred vigorously for 2 hours. Adjusting the reaction liquid to be neutral, extracting, drying, spin-drying the solvent, and purifying by column chromatography to obtain the off-white solid.

¹H NMR(d⁶-DMSO,400MHz):δ12.37(br,1H),7.96-7.87(m,2H),7.42-7.10(m,7H),6.53(d,J=2.4Hz,1H),6.33(d,J=2.4Hz,1H),4.69(s,2H),4.4.52-4.37(m,4H),2.85-2.37(m,4H).ESI-MS m/z:441[M+Na]⁺.

Pharmacological study

Example 4: testing of platelet aggregation in rats

The experimental method comprises the following steps:

SD rats were randomly grouped: blank control group 5.0mL/kg, aspirin 25mg/kg, sample group 25mg/kg dose group. The gavage administration of each group of rats is carried out 1 time a day for 11 days continuously, after the last administration, the rats are fasted and are not forbidden to be watered for 12 hours, and in the next morning, after 3% sodium pentobarbital is anesthetized, blood is taken from abdominal aorta, and the platelet aggregation rate is determined.

Sodium citrate solution (0.109 mol/l) anticoagulated (blood: anticoagulant =9: 1), centrifuged at 800r/min for 5min, the supernatant fraction was collected as Platelet Rich Plasma (PRP), the remaining fraction was centrifuged at 3000r/min for 10min, and the supernatant fraction was collected as Platelet Poor Plasma (PPP). Platelet count in PRP was 3.00/mm³Left and right. Platelet Rich Plasma (PRP) was stored at room temperature for use within 4 hours after blood draw.

According to the Born's turbidimetry, a turbidimetric tube containing 200. mu.L of PRP and 1 small magnetic bar is placed in a platelet aggregation apparatus, and is subjected to heat preservation at 37 ℃ for 1min, and after being calibrated by PPP, an inducer is added under the stirring condition to induce aggregation. The final concentrations of the inducers used were: adenosine Diphosphate (ADP) 5.67. mu.g/mL, Arachidonic Acid (AA) 78.2. mu.g/mL, Platelet Activating Factor (PAF) 0.41. mu.g/mL. The effect of the drug on platelet aggregation was analyzed according to the maximum aggregation rate.

And (3) data analysis:

the maximum aggregation rate of platelets was determined, and the platelet aggregation inhibition rate was calculated:

platelet aggregation inhibition rate = (normal control group platelet aggregation rate-administration group platelet aggregation rate)/normal control group platelet aggregation rate

The response rates of different dosages of the same drug are subjected to nonlinear regression analysis by GraphPad Prism software to obtain a dose response curve and measure IC₅₀The value is obtained. Data are expressed as mean ± standard deviation as results of three independent experiments, each experiment being triplicated.

The results obtained are shown in Table 4:

TABLE 4

Serial number	Numbering	IC₅₀（nM）
			1	A001	516.4±84.5
2	A003	91.5±51.1
			3	A005	25.7±10.6
4	A007	413.3±164.2
			5	A010	600.1±167.2
6	A012	20.3±16.1

7	A016	105.0±27.4
			8	A017	268.1±88.1
9	A020	360.5±115.5
			10	A023	134.1±84.2
11	A024	110.1±28.5
			12	A025	908.1±123.7
13	A026	61.1±51.3
			14	A031	261.5±101.6
15	A032	366.1±101.3
			16	A035	612.6±202.2
17	A036	1009.9±255.3
			18	A041	81.9±18.2
19	A052	852.1±119.8
			20	A063	455.0±120.0
21	A070	1516.1±196.2
			22	A074	122.3±56.1

The compounds of the invention are all highly active antagonists of platelets, with an IC of 9 compounds₅₀Levels below 200nM, IC of 5 compounds₅₀Less than 100 nM. In vitro tests show that the compound of the invention has obvious inhibition effect on rabbit platelet aggregation stimulated by ADP (adenosine diphosphate), PAF (platelet activating factor) and AA (arachidonic acid).

Example 5: testing of platelet aggregation in vitro in rabbits

The experimental method comprises the following steps:

randomly grouping the big-ear white rabbits: blank control group 5.0mL/kg, aspirin 25mg/kg, sample group 25mg/kg dose group. The administration group is administered by intragastric administration according to the dose, the control group is administered by intragastric administration with an isovolumetric solvent once a day, the administration is continuously carried out for 7d, 1h after the last administration, 3% sodium pentobarbital is anesthetized and then blood is taken by puncturing middle artery of ear, and the platelet aggregation rate is determined.

And (3) data analysis:

The response rates of different dosages of the same drug are subjected to nonlinear regression analysis by GraphPad Prism software to obtain a dose response curve and measure IC₅₀The value is obtained. Data are expressed as mean ± sd as three independent experimentsAnd (4) testing results, wherein each experiment is carried out by three times of wells.

The results obtained are shown in Table 5:

TABLE 5

Serial number	Numbering	IC₅₀（nM）
			1	A001	301.0±77.5
2	A003	141.5±35.6
			3	A005	43.2±18.3
4	A007	502.3±195.4
			5	A010	552.3±218.5
6	A012	25.1±11.7
			7	A016	80.3±19.4
8	A017	531.6±105.3
			9	A020	257.1±95.3
10	A023	267.7±164.6
			11	A024	83.7±34.8
12	A025	798.7±196.7
			13	A026	90.1±46.3
14	A031	306.1±79.1
			15	A036	921.3±181.3
16	A041	76.6±9.7
			17	A052	1720.1±120.3
18	A063	160.2±54.6
			19	A070	2017.5±89.1

The compounds of the invention are all highly active antagonists of platelets, with an IC of 8 compounds₅₀IC of 6 compounds at levels below 200nM₅₀Less than 100 nM. Can inhibit rabbit platelet aggregation stimulated by ADP (adenosine diphosphate), PAF (platelet activating factor) and AA (arachidonic acid) in vitro and show obvious dose dependence. And (4) conclusion: the compounds have obvious platelet aggregation resisting effect.

The compounds have good antithrombotic application prospect, thereby having good commercial value.

Example 6: assay for in vitro platelet aggregation in dogs

The experimental method comprises the following steps:

beagle dogs were randomly given in groups, anesthetized with sodium pentobarbital (30 mg/kg i.v.), subjected to arterial blood draw, anticoagulated with sodium citrate solution (0.109 moles/liter) (blood: anticoagulant =9: 1), centrifuged at 800r/min for 5min, the supernatant fraction, Platelet Rich Plasma (PRP), centrifuged at 3000r/min for 10min, and the supernatant fraction, Platelet Poor Plasma (PPP). Platelet count in PRP was 3.00/mm³Left and right. Platelet Rich Plasma (PRP) was stored at room temperature for use within 4 hours after blood draw.

And (3) data analysis:

The response rates of different dosages of the same drug are subjected to nonlinear regression analysis by GraphPad Prism software to obtain a dose response curve and measure IC₅₀The value is obtained. Data are expressed as mean ± standard deviation as three independent experimental results.

The results obtained are shown in Table 8:

TABLE 8

Serial number	Numbering	IC₅₀（nM）
			1	A005	27.6±16.3
2	A012	12.6±12.2
			3	A026	106.1±19.9
4	A041	173.1±96.4

The results show that the compounds A005 and A012 have obvious inhibition effect on the Beagle dog platelet aggregation caused by the agonist.

The experimental results show that the preparation methods of the N- (-1-hydro-indene-1-yl) sulfonamide compound and the derivative have the advantages of mild reaction conditions, abundant and easily-obtained raw materials, simple operation and aftertreatment, good corresponding selectivity and the like.

The N- (-1-hydrogen-indene-1-yl) sulfonamide compound and the derivative are high-activity antagonists of platelet aggregation.

Therefore, the N- (-1-hydrogen-indene-1-yl) sulfonamide compound and the derivative can be used for preparing medicaments for treating diseases related to thromboxane receptors, in particular cardiovascular diseases such as thrombosis, hypertension and the like.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made in the above embodiments by those of ordinary skill in the art without departing from the principle and spirit of the present invention.

Claims

1. A compound is characterized in that the compound is an N- (-1-hydrogen-indene-1-yl) sulfonamide compound shown in a formula I or an enantiomer, a diastereoisomer, a racemate, a pharmaceutically acceptable salt, a crystal hydrate or a solvate thereof,

wherein,

x is selected from C, O and N, preferably X is C or O, more preferably X is O;

R¹selected from the group consisting of C1-C12 linear or branched alkyl unsubstituted or substituted with 1-3 halogens, C1-C12 linear or branched alkoxy unsubstituted or substituted with 1-3 halogens or phenyl, C3-C6 cycloalkyl unsubstituted or substituted with 1-3 halogens, C1-C6 linear or branched alkyl substituted with C1-C6 alkoxy, C1-C6 linear or branched alkyl substituted with C3-C6 cycloalkyl, hydroxyl, C1-C6 linear or branched hydroxyalkyl, a substituted or unsubstituted benzene ring, and a substituted or unsubstituted C5-C12 aromatic heterocyclic ring containing 1-4 heteroatoms, wherein the heteroatoms are independently selected from O, S and N;

R²selected from hydrogen or isotopes thereof, C1-C12 linear or branched alkyl groups unsubstituted or substituted with 1-3 halogens, C3-C6 cycloalkyl groups unsubstituted or substituted with 1-3 halogens, C1-C6 linear or branched alkyl groups substituted with C1-C6 alkoxy groups, C1-C6 linear or branched alkyl groups substituted with C3-C6 cycloalkyl groups, C1-C6 linear or branched carboxyl groups unsubstituted or substituted with 1-3 halogens or phenyl groups, hydroxyl groups, C1-C6 linear or branched hydroxyalkyl groups, carboxyl groups, mercapto groups, -N R⁴R⁵，-NCO R⁴R⁵，-SO₂R⁴，-SO₂NR⁴R⁵and-OCOR⁴；

R³Selected from hydrogen or isotopes thereof, halogen, C1-C12 linear or branched alkyl unsubstituted or substituted by 1-3 halogens, C1-C12 linear or branched alkoxy unsubstituted or substituted by 1-3 halogens or phenyl, C3-C6 cycloalkyl unsubstituted or substituted by 1-3 halogens, C1-C6 linear or branched alkyl substituted by C1-C6 alkoxy, C1-C6 linear or branched alkyl substituted by C3-C6 cycloalkyl, hydroxyl, cyano, nitro, C1-C6 linear or branched hydroxyalkyl, carboxyl, mercapto, -NR⁴R⁵，-NCO R⁴R⁵，-SO₂R⁴，-SO₂N R⁴R⁵and-OCOR⁴；

R⁴And R⁵Each independently selected from hydrogen or its isotope, halogen, C1-C6 linear chain unsubstituted or substituted by 1-3 halogensOr branched alkyl, and C3-C6 cycloalkyl unsubstituted or substituted with 1-3 halogens;

the halogen is fluorine, chlorine, bromine or iodine.

2. The compound of claim 1, wherein for said substituted benzene or substituted aromatic heterocycle, each ring comprises 1 to 3 substituents independently selected from hydrogen or isotopes thereof, halogen, C1-C12 linear or branched alkyl unsubstituted or substituted with 1 to 3 halogens, C1-C12 linear or branched alkoxy unsubstituted or substituted with 1 to 3 halogens and/or phenyl, C2-C12 linear or branched unsaturated hydrocarbon unsubstituted or substituted with 1 to 3 halogens, C3-C6 cycloalkyl unsubstituted or substituted with 1 to 3 halogens, C1-C6 linear or branched alkyl substituted with C1-C6 alkoxy, C1-C6 linear or branched alkyl substituted with C3-C6 cycloalkyl, hydroxyl, cyano, nitro, C1-C6 straight or branched hydroxyalkyl, and mercapto, -NR⁴R⁵，-NCOR⁴R⁵，-SR⁴，-SO₂R⁴，-SO₂NR⁴R⁵，-COR⁴，-CONR⁴R⁵or-OCOR⁵。

3. The compound of claim 1, wherein for said substituted phenyl ring or substituted aromatic heterocycle, said substituted phenyl ring or substituted aromatic heterocycle is substituted with a plurality of substituents, wherein two of said plurality of substituents together with its adjacent carbon or heteroatom form a 5-7 membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, said 5-7 membered heterocycle being optionally substituted with a substituent selected from the group consisting of: hydrogen or isotopes thereof, halogen, C1-C6 linear or branched alkyl groups unsubstituted or substituted with 1-3 halogens, C1-C6 linear or branched alkoxy groups unsubstituted or substituted with 1-3 halogens, and hydroxyl.

4. The compound of claim 1,

R¹is a substituted or unsubstituted group selected from: a benzene ring, pyrrole, furan, thiophene, pyrazole, oxazole, isoxazole, thiazole, imidazole, benzopyrazole, benzoxazole, benzisoxazole, indole, pyridine, pyrimidine, quinoline, isoquinoline or purine,

optionally, R¹Substituted with a substituent selected from the group consisting of: hydrogen, C1-C6 linear or branched alkyl unsubstituted or substituted by 1-3 halogens, C1-C6 linear or branched alkoxy unsubstituted or substituted by 1-3 halogens or phenyl, C2-C6 linear or branched unsaturated hydrocarbon unsubstituted or substituted by 1-3 halogens, C3-C4 cycloalkyl unsubstituted or substituted by 1-3 halogens, C1-C6 linear or branched alkyl substituted by C1-C6 alkoxy, C1-C6 linear or branched alkyl substituted by C3-C4 cycloalkyl, hydroxyl, -SO₂R⁴，-COR⁴，-SO₂NR⁴R⁵，-OCOR⁴，-NR⁴R⁵and-NCO R⁴R⁵(ii) a Optionally, R¹Substituted with a plurality of substituents, two of which, together with their adjacent carbon atoms, form a 5-membered heterocyclic ring containing 2O atoms;

R²selected from hydrogen, carboxyl, C1-C6 linear or branched alkyl unsubstituted or substituted by 1-3 halogens, C1-C6 linear or branched alkoxy unsubstituted or substituted by 1-3 halogens or phenyl, C1-C6 linear or branched carboxyl unsubstituted or substituted by 1-3 halogens or phenyl;

R³selected from hydrogen, halogen, C1-C6 linear or branched alkyl unsubstituted or substituted by 1-3 halogens, C1-C6 linear or branched alkoxy unsubstituted or substituted by 1-3 halogens or phenyl, hydroxy, -NR⁴R⁵、-NCOR⁴R⁵、-SO₂R⁴、-SO₂NR⁴R⁵or-OCOR⁴；

R⁴And R⁵Each independently hydrogen, halogen, or C1-C4 straight or branched chain alkyl unsubstituted or substituted with 1-3 halogens;

the halogen is fluorine, chlorine or bromine.

5. The compound of claim 1, wherein,

R¹is a substituted or unsubstituted group selected from: benzene rings, pyrrole, furan, thiophene, and pyridine;

optionally, R¹Substituted with a substituent selected from the group consisting of: hydrogen, halogen, C1-C4 linear or branched alkyl unsubstituted or substituted with 1-3 halogens, C1-C4 linear or branched alkoxy unsubstituted or substituted with 1-3 halogens or phenyl, C1-C4 linear or branched alkyl substituted with C3-C4 cycloalkyl, and hydroxy; optionally, R¹Substituted with a plurality of substituents, two of which are linked together with their adjacent carbon atoms to form a 5-membered heterocyclic ring containing 2O atoms;

R²is selected from hydrogen, and C1-C6 straight chain or branched chain carboxyl unsubstituted or substituted by 1-3 halogens or phenyl groups;

R³selected from hydrogen, halogen, C1-C4 linear or branched alkoxy unsubstituted or substituted with 1-3 halogens or phenyl groups, hydroxy and-OCOR⁴；

R⁴And R⁵Each independently selected from hydrogen, halogen, and C1-C4 straight or branched chain alkyl unsubstituted or substituted with 1-3 halogens;

the halogen is fluorine or chlorine.

6. The compound of claim 1,

R¹is a substituted or unsubstituted benzene ring,

R²is hydrogen;

R³selected from hydrogen, halogen, C1-C4 unsubstituted or substituted by 1-3 halogens or phenyl groupsLinear or branched alkoxy, and hydroxy;

R⁴and R⁵Each independently hydrogen or methyl;

the halogen is fluorine or chlorine.

7. The compound according to claim 1, wherein the compound is one selected from the group consisting of enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, crystalline hydrates and solvates thereof

8. A process for the preparation of a compound according to any one of claims 1 to 7, comprising the steps of:

subjecting the compound of formula 8a and an amino acid ester or methyl malonate monopotassium salt to condensation reaction, and hydrolyzing the condensation reaction product under alkaline conditions to obtain the compound of formula I,

wherein,

R¹～R³is as defined in any one of claims 1 to 7.

9. A pharmaceutical composition, comprising:

a compound according to any one of claims 1 to 7; and

a pharmaceutically acceptable excipient which is capable of being used,

optionally the pharmaceutical composition is for use in the treatment or prevention of a thromboxane receptor associated disease, or for use in the treatment or prevention of thrombosis and/or hypertension.

10. Use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment or prophylaxis of a disease associated with a thromboxane receptor or for the treatment or prophylaxis of thrombosis and/or hypertension.