CN1730475B - Aromatic amine ketene compounds, its synthesis method, pharmaceutical composition containing same and uses - Google Patents

Abstract

The invention provides arylamine alkenone compounds having a general formula (I), the preparation of the compounds, the medicinal composition containing them and the use of these compounds in preventing and/or treating platelet activating factor related diseases, especially the use in antiphlogistic immunization, in particular for treating acute or chronic inflammation, such as osteoarthritis, chronic infectious arthritis etc.

Description

Arylamine ketene compounds, synthesis method thereof, pharmaceutical composition containing arylamine ketene compounds and application of arylamine ketene compounds

Technical Field

The invention relates to arylamine ketene compounds shown in a general formula (I), a preparation method of the compounds, a pharmaceutical composition containing the compounds and application of the compounds in preventing and/or treating diseases related to platelet activating factor.

Background

The arylamine ketene compounds are Platelet Activating Factor (PAF) receptor antagonists with novel structures, which are designed and synthesized by the inventor, and the arylamine ketene compounds are proved to be compounds with brand-new structures by the retrieval of the national intellectual property bureau (finding new reports are shown in the attached component I). Experiments prove that the arylamine ketene compound has stronger anti-inflammatory immunocompetence on various animal models for evaluating the curative effect of the anti-arthritis drug, such as models of mouse skin vascular permeability, rat carrageenan foot swelling, rat adjuvant arthritis and the like, and a radioligand receptor combination experiment and other biochemical and molecular biological experiments show that the arylamine ketene compound has a definite action mechanism and lower acute toxicity.

Rheumatoid Arthritis (RA) is a persistent worldwide disease, is a systemic autoimmune disorder, has a high incidence rate, a long course of disease, is refractory, has a poor long-term treatment effect, and is easy to relapse. The chronic inflammation of multiple facet joints, abnormal pain of the diseased joints, bone destruction of the joints in the later period of the disease, joint deformity and rigidity influence the normal working and living ability of the patients and cause great pain to the patients.

So far, no ideal medicine for treating rheumatoid arthritis exists at home and abroad. The currently used drugs mainly include two anti-inflammatory drugs, namely Steroid (SAID) and non-steroid (NSAID), and although many drugs are available, the drugs have serious side effects. Steroidal anti-inflammatory drugs have the side effects of producing hormone dependence, immunosuppression and influencing the whole body metabolism, and cause irreparable damage after long-term application. Non-steroidal anti-inflammatory drugs act by inhibiting arachidonic acid epoxidase and reducing the production of Prostaglandin (PG), which is a protective factor for the gastric mucosa, and therefore, the application of such anti-inflammatory drugs is likely to cause damage to the gastrointestinal mucosa.

With the intervention of biochemistry and molecular biology, it has been revealed that the pathological process of rheumatoid arthritis involves numerous inflammatory mediators, Platelet Activating Factor (PAF), an important one thereof, is a phospholipid inflammatory mediator, which can be produced by various inflammatory cells, and PAF acts to activate signal transduction pathways by binding to PAF receptors on target cells, coupling to G proteins, and causing subsequent effects. PAF receptor antagonists compete with PAF for receptors on target cells and are therefore effective in inhibiting inflammatory responses. The research shows that the PAF not only has the function of activating and inducing inflammatory cells, but also promotes the generation of other small molecular mediators related to inflammation, the expression of cytokines and the activation of nuclear transcription factors, thereby influencing a plurality of pathological processes related to inflammation. Therefore, PAF receptor becomes an important new target for developing anti-inflammatory immune drugs in recent years, and the PAF receptor antagonist can effectively inhibit the generation and development of inflammation. Meanwhile, as PAF is also a gastric mucosa injury factor, the PAF receptor antagonist not only has the anti-inflammatory effect, but also has the gastrointestinal mucosa protection effect, which is the most promising characteristic of the medicine over the prior anti-inflammatory medicine.

In recent years, researchers have found some natural and synthetic compounds with PAF receptor antagonism and have been demonstrated in a number of in vitro and in vivo models and clinical trials. Currently, a total of 60 pharmaceutical companies or research units are invested in the study of PAF receptor antagonists internationally, synthesizing 550 compounds and entering biological studies, 18 of which enter phase I, 17 of which enter phase II, and 2 (BN52021, Y-24180) enter phase III. Two more compounds are currently in preclinical biological research for the treatment of rheumatoid arthritis. Such compounds as CV-6209 inhibit swelling of rat feet caused by various inflammatory agents (PAF, carrageenan, histamine, 5-hydroxytryptamine); BN 50730 takes medicine for 4 weeks to obviously improve symptoms of patients with rheumatic arthritis; WEB 2170 can inhibit the increase of new blood vessels in mouse angiogenesis model caused by synovial fluid of rheumatoid arthritis patients; WEB 2170 can inhibit TNF-alpha level increase in synovial fluid of ankle joint of rat caused by immune complex; a-85783 obviously inhibits inflammation of rat ears caused by PAF and PMA; BN 50730 can obviously inhibit the joint swelling of the collagen mouse arthritis and reduce the precipitation of fibronectin and the loss of cartilage proteoglycan; BN50739 reduces the early activity of NF- κ B and the expression of TNF- α mRNA in mice under infection; LDP-392 obviously inhibits the inflammation of mouse ears caused by arachidonic acid.

There is still a great need to find and develop new anti-inflammatory drugs.

Disclosure of Invention

The invention aims to provide a compound shown in a general formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, an ester and a prodrug thereof.

It is another object of the present invention to provide a process for preparing the compounds of formula (I), stereoisomers thereof and pharmaceutically acceptable salts thereof.

A further object of the present invention is a pharmaceutical composition comprising at least one compound of general formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier and/or excipient.

The invention also aims to provide application of the compound shown in the general formula (I), the stereoisomer thereof and the medicinal salt thereof in preparing medicaments for preventing and/or treating inflammation.

According to the invention, the arylamine alkenone compounds are represented by the general formula (I)

Wherein,

AL is hydrogen atom, hydroxyl, halogen atom, trifluoromethyl, nitrile group, nitro, amino, C_1-6Alkyl radical, C_1-6Alkoxy, methylenedioxy, 3, 4-C_1-6Alkoxy, 3, 4, 5-tri-C_1-6Alkoxy, 3-methoxy-4-hydroxy, 3, 4-methylenedioxy-5-methoxy, 3-hydroxy-4-methoxy;

n＝0、1；

y is CH₂、NH、O；

X＝H、C_1-6Alkyl, COOR (R ═ H, C)_1-6Alkyl, C (CH)₃)₃Substituted or unsubstituted aryl), CO-Ph, CH₂Ph、CH₂CH₂OH、CONR₁R₂(R₁、R₂＝C_1-6Alkyl groups).

Preferred compounds of formula (I) according to the present invention include, but are not limited to, compounds of formula (Ia),

wherein,

r1 is selected from hydrogen, hydroxyl, halogen atom, trifluoromethyl, nitrile group, nitro, amino, C_1-6Alkyl radical, C_1-6Alkoxy, methylenedioxy, 3, 4-di-C_1-6Alkoxy, 3, 4, 5-tri-C_1-6Alkoxy, 3-methoxy-4-hydroxy, 3, 4-methylenedioxy-5-methoxy, 3-hydroxy-4-methoxy;

r2 is selected from C_1-6Alkyl, ethoxycarbonyl, C_1-6Alkoxy, benzyl, 2, 3, 4-trimethoxy (benzyl), 3, 4-methylenedioxy (benzyl), benzoyl, carboxy;

preferred compounds of formula (Ia) include, but are not limited to, compounds of formula (Iaa),

wherein R'₃，R’₄And R'₅Independently selected from hydrogen, C_1-6Alkyl, methylenedioxy, C_1-6Alkoxy, halogen, hydroxyl, nitro, nitrile;

preferred compounds of formula (Ia) include, but are not limited to, compounds of formula (Iab),

wherein R'₃And R’₄Independently selected from hydrogen, C_1-6Alkyl, methylenedioxy, C_1-6Alkoxy, halogen, hydroxyl, nitro, nitrile;

r2 is selected from C_1-6Alkyl, carboxyl, benzyl, ethoxycarbonyl, C_1-6Alkoxy, 2, 3, 4-trimethoxy (benzyl), 3, 4-methylenedioxy (benzyl), benzoyl;

preferred compounds of formula (I) according to the present invention include, but are not limited to, compounds of formula (Ib),

r1 is selected from hydrogen, hydroxyl, halogen atom, trifluoromethyl, nitrile group, nitro, amino, C_1-6Alkyl radical, C_1-6Alkoxy, methylenedioxy, 3, 4-di-C_1-6Alkoxy, 3, 4, 5-tri-C_1-6Alkoxy, 3-methoxy-4-hydroxy, 3, 4-methylenedioxy-5-methoxy, 3-hydroxy-4-methoxy;

r2 is selected from C_1-6Alkyl, ethoxycarbonyl, C_1-6Alkoxy, benzyl, 2, 3, 4-trimethoxy (benzyl), 3, 4-methylenedioxy (benzyl), benzoyl, carboxy;

preferred compounds of formula (I) according to the present invention include, but are not limited to, compounds of formula (Ic),

wherein R1 is independently selected from hydrogen and C_1-6Alkyl, methylenedioxy, C_1-6Alkoxy, halogen, hydroxyl, nitro, nitrile;

r2 is selected from C_1-6Alkyl radical, C_1-6Alkoxy, R2 may be substituted on any carbon atom of the ring;

preferred compounds of formula (I) according to the present invention include, but are not limited to, compounds of formula (Id),

r1 is selected from hydrogen, hydroxyl, halogen atom, trifluoromethyl, nitrile group, nitro, amino, C_1-6Alkyl radical, C_1-6Alkoxy, methylenedioxy, 3, 4-di-C_1-6Alkoxy, 3, 4, 5-tri-C_1-6Alkoxy, 3-methoxy-4-hydroxy, 3, 4-methylenedioxy-5-methoxy, 3-hydroxy-4-methoxy;

r2 is selected from C_1-6Alkyl, ethoxycarbonyl, C_1-6Alkoxy, benzyl, 2, 3, 4-trimethoxy (benzyl), 3, 4-methylenedioxy (benzyl), benzoyl, carboxy;

preferred compounds of formula (Id) include, but are not limited to, compounds of formula (Ida),

wherein R'₃，R’₄And R'₅Independently selected from hydrogen, C_1-6Alkyl, methylenedioxy, C_1-6Alkoxy, halogen, hydroxyl, nitro, nitrile;

in the above definitions, a pharmaceutically acceptable salt of a compound of formula (la) containing a basic center is a salt with a pharmaceutically acceptable acid. Examples thereof include hydrochloride, hydrobromide, sulfate or bisulfate, succinate, maleate and the like.

Also provided according to the invention are methods of making the compounds of the invention.

The compounds of the present invention and their pharmaceutically acceptable salts can be prepared by the following reaction routes:

1. synthesis of substituted benzylidene acetone 1:

preparation of compound 1:

raw materials: substituted or unsubstituted benzaldehyde derivative and acetone, and the excessive acetone also serves as a solvent for the reaction.

Reaction conditions are as follows: the reaction is preferably carried out under alkaline conditions, the preferred bases being alkaline earth metal hydroxides, such as potassium hydroxide and sodium hydroxide, and alumina, and the preferred alkaline earth metal hydroxides being potassium hydroxide and sodium hydroxide.

Solvent: excess acetone is used as solvent, and other solvents, ethanol and/or water, are optionally added depending on the solubility of the different benzaldehyde derivatives and the base used. The amount of the solvent is appropriately adjusted depending on the solubility of the reactants.

Temperature: the temperature of the reaction is preferably 5 to 40 ℃, more preferably 10 to 30 ℃, and most preferably 15 to 25 ℃.

Time: the reaction time is 1 to 40 hours, preferably 5 to 30 hours, more preferably 14 to 25 hours.

The progress of the reaction can be monitored by Thin Layer Chromatography (TLC) or High Performance Liquid Chromatography (HPLC), and after completion of the reaction, it is acidified to neutrality with an acid, preferably an inorganic acid, more preferably hydrochloric acid. The product is obtained by extracting or filtering with an organic solvent, and then selectively washing, drying and purifying to ensure that the purity of the product meets the requirements of the next reaction.

Preparation of substituted acetophenone:

raw materials: substituted or unsubstituted benzoic acid derivatives, thionyl chloride and diethyl malonate;

reaction conditions are as follows: heating and refluxing the reaction under anhydrous condition;

solvent: when reacting with thionyl chloride, anhydrous benzene is used as a solvent, and when reacting with diethyl malonate, anhydrous ethanol is used as a solvent;

temperature: the temperature of the reaction is preferably heated under reflux at 5 to 40 ℃, more preferably 10 to 30 ℃, most preferably 15 to 25 ℃;

time: the reaction time is 1 to 40 hours, preferably 5 to 30 hours, more preferably 14 to 25 hours.

The progress of the reaction can be monitored by Thin Layer Chromatography (TLC) or High Performance Liquid Chromatography (HPLC), after the reaction is completed, the product is obtained by extracting or filtering with an organic solvent, and then is selectively washed, dried and purified to ensure that the purity of the product meets the requirements of the next reaction.

2. The secondary amines (2) are all commercially available products:

secondary amines such as substituted or unsubstituted piperazine, substituted or unsubstituted piperidine, substituted or unsubstituted morpholine; substituted piperidine formates and the like are commercially available or prepared according to conventional techniques of the art and those of ordinary skill in the art; the secondary amine hydrochloride is the corresponding hydrochloride salt of the secondary amine prepared according to the techniques of the prior art and conventional techniques of those of ordinary skill in the art:

3.1-substituted phenyl-1-pentene-4-methylene-5- [ substituted secondary amino ] -3-ketone hydrochloride synthesis:

raw materials: reacting substituted or unsubstituted benzylidene acetone 1, paraformaldehyde and secondary amine hydrochloride 2 (such as substituted or unsubstituted piperazine hydrochloride, substituted or unsubstituted piperidine hydrochloride, substituted or unsubstituted morpholine hydrochloride),

reaction conditions are as follows: the reaction is preferably carried out under acidic or near-neutral conditions, the preferred acid is hydrochloric acid, the preferred base is triethylamine, and the pH value of the reaction solution is preferably 4-5.

Solvent: anhydrous acetonitrile or anhydrous ethanol is used as a solvent, and the dosage of the solvent is properly adjusted according to the solubility of reactants.

Temperature: the temperature of the reaction is preferably a temperature at which the solvent is refluxed.

Time: the reaction time is 10 to 25 hours, preferably 15 to 20 hours, and more preferably 16 hours. After the reaction is completed, the reaction solution is decompressed and concentrated, solid is separated out, filtered and dried, and the crude product is recrystallized.

The substituent Al in the compound can be introduced through raw material benzalacetone, namely, benzalacetone with corresponding AL substituent, secondary amine hydrochloride and paraformaldehyde are selected in the reaction and react in acidic or near-neutral anhydrous acetonitrile or anhydrous ethanol.

The invention therefore also relates to pharmaceutical compositions containing a compound of the invention as active ingredient and conventional pharmaceutical excipients or auxiliaries. Typically, the pharmaceutical compositions of the present invention contain 0.1 to 95% by weight of a compound of the present invention.

Pharmaceutical compositions of the compounds of the invention may be prepared according to methods well known in the art. For this purpose, the compounds of the invention can, if desired, be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants and brought into a suitable administration form or dosage form for use as human or veterinary medicine.

The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intramuscular, subcutaneous, nasal, oromucosal, dermal, peritoneal or rectal administration.

The route of administration of the compounds of the invention or the pharmaceutical compositions containing them may be by injection. The injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection, etc.

The administration dosage form can be liquid dosage form or solid dosage form. For example, the liquid dosage form can be true solution, colloid, microparticle, emulsion, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.

The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various microparticle drug delivery systems.

In order to prepare the unit dosage form into tablets, various carriers well known in the art can be widely used. Examples of the carrier are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; wetting agents and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrating agents such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.

For example, to form the administration units into pills, various carriers well known in the art are widely used. Examples of the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc.

For example, to encapsulate the administration unit, the active ingredient of the compounds of the present invention is mixed with the various carriers described above, and the mixture thus obtained is placed in hard gelatin capsules or soft gelatin capsules. The effective component of the compound can also be prepared into microcapsules, and the microcapsules can be suspended in an aqueous medium to form a suspension, and can also be filled into hard capsules or prepared into injections for application.

For example, the compounds of the present invention may be formulated as injectable preparations, such as solutions, suspensions, emulsions, lyophilized powders, which may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid ester, etc. In addition, for the preparation of isotonic injection, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, pH adjusters and the like may also be added. These adjuvants are conventional in the art

In addition, colorants, preservatives, flavors, flavorings, sweeteners or other materials may also be added to the pharmaceutical preparation, if desired.

For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

The dosage of the pharmaceutical composition of the compound of the present invention to be administered depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight, character and individual response of the patient or animal, the administration route, the number of administrations and the therapeutic purpose, and thus the therapeutic dosage of the present invention can be widely varied. Generally, the dosage of the pharmaceutical ingredients of the present invention is well known to those skilled in the art. The prophylactic or therapeutic objectives of the present invention can be accomplished by appropriate adjustment of the actual amount of drug contained in the final formulation of the compound composition of the present invention to achieve the desired therapeutically effective amount. A suitable daily dosage range of the compound of the invention is 0.001 to 150mg/Kg body weight, preferably 0.1 to 100mg/Kg body weight, more preferably 1 to 60mg/Kg body weight, most preferably 2 to 30mg/Kg body weight. The above-mentioned dosage may be administered in a single dosage form or divided into several, e.g., two, three or four dosage forms which is limited by the clinical experience of the administering physician and by dosage regimens which include the use of other therapeutic means.

The total dose required for each treatment can be divided into multiple doses or administered as a single dose. The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents and adjusted in dosage.

Experiments prove that the arylamine ketene compound has stronger anti-inflammatory activity on various animal models for evaluating the curative effect of the anti-arthritis medicament, such as models of mouse skin vascular permeability, rat adjuvant arthritis and the like, and a radioligand receptor binding experiment and other biochemical and molecular biological experiments show that the arylamine ketene compound has a definite action mechanism and lower acute toxicity.

The arylamine ketonic compounds of the present invention are apparently capable of reacting with [ alpha ], [ alpha ]³H]PAF competes for PAF receptors on polymorphonuclear leukocytes and platelets, inhibits release of polymorphonuclear leukocyte lysosomal enzymes, and inhibits polymorphonuclear activityLeukocyte LTB₄And 5-HETE production, inhibit the production of polymorphonuclear leukocyte PAF, inhibit polymorphonuclear leukocyte O₂ ^-Inhibiting chemotactic reaction of polymorphonuclear leukocytes, inhibiting calcium level increase in polymorphonuclear leukocytes, inhibiting skin permeability increase of mice caused by irritant, and inhibiting adjuvant arthritis of rats.

The indications of the compound pharmaceutical composition mainly comprise all acute and chronic inflammatory diseases and immune inflammatory diseases, such as: acute and chronic rheumatic arthritis, acute and chronic ankylosing spondylitis, and osteoarthritis. Scapulohumeral periarthritis, bursitis, tendonitis and tenosynovitis. Sprains, strains and other soft tissue injuries; severe infectious inflammation of ear, nose and throat (such as tonsillitis, otitis, sinusitis, etc.), and should be accompanied by anti-infective drugs. In addition, the compound medicine composition can also treat vascular embolism caused by platelet aggregation, such as myocardial infarction, cerebral infarction and the like.

Detailed Description

The following examples further illustrate the invention but are not intended to limit the invention in any way.

The process for preparing the compounds of the present invention will be described more specifically with reference to the experimental examples. The purity of the compound was routinely checked. Melting points were determined using a Yanaco micro melting point apparatus, the temperature not being corrected. The nuclear magnetic resonance spectrometer is FX-300 type, BRUKER-AM500 type and TMS is an internal standard. The mass spectrometer is a ZAB-2F type mass spectrometer, the measurement is carried out by a CI method, and the model of the HRMS mass spectrometer is an MAZ711 mass spectrometer. The infrared spectrometer is PERKIN-ELMER 683 type, KBr tablet method or film method. Elemental analysis was determined on a Carlo Erbr 1106 elemental analyzer with errors in the 0.3% range. Column chromatography and thin layer chromatography silica gel (GF254) are products of Qingdao maritime chemical plants. The reagents used in the experiments were either chemically pure or analytically pure. These spectra are in all cases consistent with the structure of the hypothesis.

The starting compounds used in the examples of the present invention may be prepared according to conventional methods in the art and/or methods well known to those skilled in the art, and may be prepared as exemplified below.

All secondary amines in the examples, such as substituted or unsubstituted piperazines, substituted or unsubstituted piperidines, substituted or unsubstituted morpholines, and the like, are commercially available products; they may also be conveniently prepared according to techniques well known in the art and conventional techniques known to those of ordinary skill in the art. Likewise, the secondary amine salts used in the examples, such as the hydrochloride salt, may also be conveniently prepared according to techniques well known in the art and conventional techniques familiar to those of ordinary skill in the art.

Preparation example

Preparation example 1.1 preparation of- (4-chloro) phenyl-1-buten-3-one:

8.43g of p-chlorobenzaldehyde, 60ml of acetone and 6ml of ethanol are added into a 500ml beaker, 240ml of water and 48ml of 10% aqueous sodium hydroxide solution are added under stirring, under rapid stirring,

solid is gradually generated, the reaction is carried out at about 25 ℃, after the reaction is checked to be complete by TLC (developing agent: cyclohexane: ethyl acetate is 2: 1), 6N hydrochloric acid is dripped to acidify until ph is 5-6 under the cooling of ice water bath, and then the mixture is rapidly stirred for 30 minutes. Standing at room temperature overnight, performing suction filtration the next day, washing the solid with a large amount of water, and drying to obtain 10.5g, mp.: 56-57 ℃ and the yield is 96.9%.

Preparation example 2.1 Synthesis of- (4-hydroxy) phenyl-1-buten-3-one:

in a 500ml three-necked flask were added 10g of 4-hydroxybenzaldehyde and 28ml of freshly prepared 10% aqueous sodium hydroxide, and most of the solids were dissolved with rapid stirring to give a light brown solution, which was immediately clear in dark brown after addition of 20g of acetone. 40ml of 10% aqueous sodium hydroxide solution were added and checked by TLC until the reaction was complete. Diluting with distilled water until the solid is completely dissolved, dropwise adding hydrochloric acid for acidification, separating out a large amount of light yellow solid, standing for a moment, performing suction filtration, washing the solid with water, draining, washing the solid with 50% ethanol for 2-3 times to obtain the light yellow solid, and drying to obtain 11.06g of mp.: and (2) at the temperature of 98-101 ℃, with the yield of 83.7%, recrystallizing with 50% ethanol, decoloring with activated carbon, putting the product in a refrigerator to separate out crystals, filtering, and drying to obtain light yellow crystals 9.3g, wherein mp: 104-105 ℃ and the yield is 70.4%

Preparation example 3.preparation of 1- (4-methyl) phenyl-1-buten-3-one:

dissolving 1.2g (10mmol) of 4-methylbenzaldehyde in 10ml of acetone, adding 20ml of water while stirring, slowly dropping 4ml of 10% NaOH solution (inner temperature not exceeding 20 ℃), continuing the reaction at room temperature for 14 hours, TLC showing completion of the reaction, neutralizing with 10% HCI to neutrality, and adding CH₂Cl₂The extraction, water washing, drying and concentration gave 0.73g of a pale yellow viscous substance.

Preparation example 4.1- (4-methoxy-3-ethoxy) phenyl-1-buten-3-one preparation

6.2g (30mmol) of 4-hydroxy-3-ethoxyphenyl-1-buten-3-one and 3.98g of anhydrous sodium carbonate are dissolved in 40ml of acetone, 3.78g (30mmol) of dimethyl sulfate is added, heating and stirring reflux are carried out for 8 hours, a yellow solid is separated out, filtration is carried out, washing liquid and filtrate are combined, reduced pressure concentration is carried out till about 20ml, a refrigerator is placed, the yellow solid is separated out, filtration and drying are carried out, recrystallization is carried out by using anhydrous ethanol, and 4.3g of yellow crystals are obtained, and the yield is as follows: 65.3%, mp: 95-96 ℃.

Preparation example 5.1- (3-ethoxy-4-hydroxy) phenyl-1-buten-3-one preparation

16.6g (100mmol) of 3-methoxy-4-hydroxybenzaldehyde was dissolved in 50ml of acetone and 50ml of 95% ethanol, 400ml of water was added with stirring to precipitate a white solid, 80ml of 10% NaOH solution was slowly dropped (inner temperature not exceeding 20 ℃) to continue the reaction at room temperature for 24 hours to precipitate a large amount of pale yellow solid, TLC showed completion of the reaction, neutralized to neutrality with 6N HCI, filtered, washed with a small amount of ethanol, dried, and recrystallized with 95% ethanol to obtain 14.5g of pale yellow crystals, yield: 70.4%, mp: 98-100 ℃.

Preparation 6.1- (3-methoxy-4-ethoxy) phenyl-1-buten-3-one synthesis:

dissolving 9.09g (50mmol) of 3-methoxy-4-ethoxybenzaldehyde in 25ml of acetone and 25ml of 95% ethanol, adding 200ml of water while stirring to precipitate a white solid, slowly dropping 40ml of 10% NaOH solution (internal temperature does not exceed 20 ℃), continuing reaction at room temperature for 24 hours to precipitate a large amount of light yellow solid, TLC shows that the reaction is complete, neutralizing with 6N HCI to neutrality, filtering, washing with ethanol, drying, recrystallizing with 95% ethanol to obtain 7.38g of light yellow solid, mp.: 95-97 ℃, yield: 66.5 percent.

Preparation 7.1 Synthesis of- (3, 4, 5-trimethoxy) phenyl-1-buten-3-one:

6.62g (33.7mmol) of 3, 4, 5-trimethoxybenzaldehyde were dissolved in 105ml (1.43mol) of acetone, and 11.65g (114.7mmol) of Al was added₂O₃And (3) reacting for 24 hours under heating and stirring to precipitate a large amount of light yellow solid, wherein TLC shows that the reaction is complete, neutralizing the mixture to be neutral by 6N HCI, filtering the mixture, washing the mixture by a small amount of ethanol, recrystallizing the mixture by 95% of ethanol, and drying the mixture to obtain 3.33g of light yellow solid, mp.: 90.0-91.5 ℃.

Preparation example 8.1- (4-cyano) phenyl-1-buten-3-one synthesis:

7g of 4-cyanobenzaldehyde (80.6mmol) was added to 40ml of acetone and 25ml of water, and under rapid stirring, 4.5ml of a 10% aqueous solution of sodium hydroxide was added, followed by addition of 150ml of water, reaction at 14 ℃ for 2 hours and checking by TLC until the reaction was completed. Acidifying with hydrochloric acid at pH 7-8, filtering, drying, and recrystallizing with anhydrous ethanol to obtain needle crystal 4.8g, yield 49.25%, mp: 102 ℃ to 103 DEG C

Preparation example 9.1 Synthesis of- (4-nitro) phenyl-1-buten-3-one:

1- (4-Nitro) phenyl-1-buten-3-one was prepared by the method of preparation example 1 except that p-chlorobenzaldehyde was replaced with 4-nitrobenzaldehyde.

Preparation example 10.1 synthesis of- (3-methoxy-4-hydroxy) phenyl-1-buten-3-one:

dissolving 7.6g (50mmol) of 3-methoxy-4-hydroxybenzaldehyde in 25ml of acetone and 25ml of 95% ethanol, adding 200ml of water while stirring to precipitate a white solid, slowly dropping 40ml of 10% NaOH solution (the internal temperature does not exceed 7 ℃), continuing to react for 3.0 hours at room temperature to precipitate a light yellow solid, TLC shows that the reaction is complete, neutralizing with 6NHCl to neutrality, filtering, washing with a small amount of ethanol, drying, recrystallizing the crude product with 95% ethanol to obtain 4.7g of light yellow crystals, and obtaining the yield: 48.9%, mp.: 126-128 ℃.

Preparation example 11.1- (3, 4-methylenedioxy) phenyl-1-buten-3-one synthesis:

8.20g (50mmol) of 3, 4-methylenedioxybenzaldehyde was dissolved in 25ml of acetone and 25ml of 95% ethanol, 200ml of water was added with stirring to precipitate a white solid, 40ml of a 10% NaOH solution was slowly dropped (inner temperature not exceeding 20 ℃ C.), the reaction was continued at room temperature for 8 hours to precipitate a large amount of pale yellow solid, TLC showed completion of the reaction, neutralized to neutrality with 6N HCl, filtered, washed with a small amount of ethanol, dried, and recrystallized with 95% ethanol to obtain 7.26g of pale yellow flaky crystals, yield: 76.4 percent. mp: 108 temperature 109 deg.C

Preparation example 12.1 synthesis of (3, 4-methylenedioxy-5-methoxy) acetophenone:

39.23g (0.2mol) of 3, 4-methylenedioxy-5-methoxybenzoic acid is added with 140ml of anhydrous benzene (molecular sieve drying) and 47.6g (28.8ml, 0.4mol) of thionyl chloride, the mixture is heated for 15 hours under reflux and stirring, reduced pressure distillation is carried out to remove excessive thionyl chloride and benzene, 50ml of anhydrous benzene is added after the mixture is dried to dryness, the reduced pressure distillation is continued to remove excessive thionyl chloride, 50ml of anhydrous benzene is added to be dried to dryness under reduced pressure, and the acyl chloride white solid is obtained.

5.35g (0.22mol) of magnesium turnings were added to 2ml of CCl₄And 6ml absolute ethyl alcohol, slightly heating, adding 170ml absolute ethyl ether after the reaction is started, dropwise adding a solution of 35.24g (0.22mol) diethyl malonate, 28ml absolute ethyl ether and 28ml absolute ethyl alcohol after the reaction is carried out for a few minutes, controlling the dropwise adding speed to keep the reaction solution boiling, and continuously heating and refluxing after the addition is finished until all the metal magnesium is used up. Then is atFilling acyl chloride prepared by the above reaction between a reaction bottle and a condenser tube, dissolving the acyl chloride by condensed diethyl ether, gradually dripping into the reaction bottle, after dripping for 1 hour, the reaction solution turns turbid into yellow green, after all the acyl chloride is dripped, continuously heating and refluxing for 3 hours, standing overnight, adding 120ml of water, and then adding 20% H₂SO₄Stirring thoroughly until all solid is dissolved, pH 2-3, separating ether layer, and adding CH into water layer₂Cl₂Extracting, mixing organic layers, and sequentially adding saturated NaCO₃Washing the aqueous solution with NaCl aqueous solution, drying, filtering, evaporating to dryness under reduced pressure to obtain white solid, recrystallizing with 95% ethanol to obtain 20.12g white crystal, and obtaining the yield: 50.8%, mp: 81-82 ℃.

Preparation example 13.1 Synthesis of (4-chloro) acetophenone:

1- (4-chloro) acetophenone was prepared by the method of preparation 14, except that 3, 4-methylenedioxy-5-methoxybenzoic acid was replaced with 4-chlorobenzoic acid.

Examples

Example 1

1- (4-chloro) phenyl-1-pentene-4-methylene-5- [ (N)₄-ethoxycarbonyl) piperazinyl]-3-keto hydrochloric acid

Compound 1

0.59g (3mmol) of N₄-ethoxycarbonylpiperazine hydrochloride (commercially available) was dissolved in 5ml of previously prepared absolute ethanol having a pH of 4.5 to 5.0, 0.9g of paraformaldehyde was added, the mixture was heated under stirring and refluxed for 4 hours, 0.54g (3mmol) of 1- (4-chloro) phenyl-1-buten-3-one prepared in preparation example 1 was added, the reflux was continued for 18 hours, the mixture was concentrated under reduced pressure to obtain an oily substance, and the oily substance was recrystallized from acetone-ethyl ether to precipitate a white solid, which was filtered, dried, and the crude product was recrystallized from absolute ethanol to obtain 0.34g of a white crystal, with a yield of 28.6%, mp.: 187-190 ℃.

¹HNMRδppm(DMSO-d₆)：1.20(t，J＝7.2Hz，3H，COOCH₂CH ₃)，3.00-3.60(m，6H，3CH₂N)，3.84-4.24(m，6H，2NCH₂+COOCH ₂CH₃)，6.76(s，1H，C＝CH_2f)，7.04(s，1H，C＝CH_2g)，7.45(d，J＝8.1Hz，2H，ArH_AA′)， 7.64(s，1H，＝CHCO)，7.69(s，1H，CH＝)，7.86(d，J＝8.1Hz，2H，ArH_BB’)。MS(m/z)：362(M⁺，65)，345(22)，333(2)，317(4)。

Anal.Cald.for C₁₉H₂₄N₂O₃Cl₂％：C：57.15，H：6.02，N：7.01；Found％：C：57.19，H：6.15，N：6.87。

Example 2

1- (4-methyl) phenyl-1-pentene-4-methylene-5- [ (N)₄-ethoxycarbonyl) piperazinyl]-3-keto hydrochloride

Compound 2

0.38g (2mmol) of N₄-ethoxycarbonylpiperazine hydrochloride (commercially available) was dissolved in 5ml of anhydrous acetonitrile, 0.3g of paraformaldehyde and 2 drops of triethylamine were added, heating and stirring were performed under reflux for 3 hours, 0.16g (1mmol) of 1- (4-methyl) phenyl-1-buten-3-one prepared in preparation example 3 was added, reflux was continued for 15 hours, insoluble matter was filtered off while hot, the filtrate was cooled and then ground with a small amount of anhydrous ether to precipitate a pale yellow solid, which was filtered, dried, and the crude product was recrystallized with anhydrous acetonitrile to obtain 0.22g of white crystals, yield: 58.8%, mp.: 194 ℃ and 196 ℃.

¹HNMRδppm(DMSO-d₆)：1.22(t，J＝7.2Hz，3H，COOCH₂CH ₃)，3.00-3.60(m，6H，3CH₂N)，3.84-4.20(m，6H，2NCH₂+COOCH ₂CH₃)，6.68(s，1H，C＝CH_2f)，7.00(s，1H，C＝CH_2g)，7.24(d，J＝7.2Hz，2H，ArH_AA′)，7.62(s，2H，HC＝CH)，7.70(d，J＝7.2Hz，2H，ArH_BB′)。MS(m/z)：342(M⁺，100)，325(25)，313(3)，297(5)，269(10)。Anal.Cald.for C₂₂H₃₁N₂O₅Cl％：C：63.40，H：7.18，N7.39；Found％：C：63.29，H：7.02，N：7.15。

2a was synthesized by the method of example 2.

1- (4-chloro) phenyl-1-pentene-4-methylene-5- [ (4-ethoxycarbonyl) piperidinyl ] -3-one hydrochloride

Synthesis of 2a by the method used in example 2, except that (4-ethoxycarbonyl) piperidine hydrochloride was used instead of N₄Ethoxycarbonylpiperazine hydrochloride (commercially available), replacing 1- (4-methyl) phenyl-1-buten-3-one with 1- (4-chloro) phenyl-1-penten-3-one prepared in preparation example 1, mp.: 185 ℃ and 187 ℃.

¹HNMR δppm(DMSO-d₆)：1.17(t，J＝7Hz，3H，-COOCCH₃)， 1.81-3.33(m，11H，-CH₂C-N(CH₂)₄CH-)，2.64(t，J＝5Hz，2H，-CCH₂-N-)，4.14(q，J＝7Hz，2H，-COOCH ₂CH₃)，6.73(s，1H，C＝CH_2f)，7.07(s，1H，C＝CH_2g)，7.53(d，J＝8.1Hz，2H，ArH)，7.64(d，J＝15.9Hz，1H，＝CHCO)，7.80(d，J＝15.3Hz，1H，Ar-CH＝)，7.90(d，J＝8.4Hz，2H，ArH)。MS(m/z)：361.5(M⁺，87)，332.4(M⁺-29，10)，316.4(M⁺-45，40)，288.4(M⁺-73，12)，206.2(M⁺-156，20)，156.2(100)。

Example 3

1- (4-methoxy-3-ethoxy) phenyl-1-pentene-4-methylene-5- [ (N)₄-ethoxycarbonyl) piperazinyl]-3-keto hydrochlorideCompound 3

0.76g (4mmol) of N₄-ethoxycarbonylpiperazine hydrochloride (commercially available) was dissolved in 5ml of absolute ethanol, 0.9g of paraformaldehyde and 6 drops of concentrated hydrochloric acid were added, and the mixture was heated under stirring and refluxed until most of the solid was dissolved, 0.66g (3mmol) of 1- (4-methoxy-3-ethoxy) phenyl-1-buten-3-one prepared in preparation example 4 was added, and the reflux reaction was continued for 20 hours, and the mixture was concentrated under reduced pressure to obtain an oily substance, which was then recrystallized from acetone-diethyl etherCrystallizing to separate out light yellow solid, filtering, drying, recrystallizing the crude product with anhydrous ethanol to obtain 0.53g light yellow powdery crystal, and obtaining the yield: 40.3%, mp.: 206 ℃ and 209 ℃.

¹HNMRδppm(DMSO-d₆)：1.18(t，J＝7.2Hz，3H，COOCH₂CH ₃)，1.35(t，J＝7.2Hz，3H，OCH₂CH ₃)，3.32-3.37(m，6H，3CH₂N)，3.80(s，3H，OCH₃)，4.00-4.11(m，8H，2NCH₂+OCH ₂CH₃+COOCH ₂CH₃)，6.62(s，1H，C＝CH_2f)，7.01(d，J＝8.1Hz，1H，ArH)，7.05(s，1H，C＝CH_2g)，7.35(d，J＝8.1Hz，1H，ArH)，7.46(s，1H，ArH)，7.61(s，2H，HC＝CH)。MS(m/z)：402(M+，100)，385(15)，246(32)，216(35)。

Anal Cald for C22H31N2O5Cl％：C：60.20，H：7.12，N：6.38；Found％：C：60.27，H：7.00，N：6.52。

Example 4

1- (3-ethoxy-4-hydroxy) phenyl-1-pentene-4-methylene-5- [ (N)₄-ethoxycarbonyl) piperazinyl]-3-keto hydrochlorideCompound 4

0.76g (3.9mmol) of N₄Ethoxycarbonylpiperazine hydrochloride (commercially available) was dissolved in 5ml of absolute ethanol, 0.9g of paraformaldehyde and 6 drops of concentrated hydrochloric acid were added, the mixture was heated under stirring and refluxed until most of the solid was dissolved, 0.62g (3mmol) of 1- (3-ethoxy-4-hydroxy) phenyl-1-buten-3-one prepared in preparation example 5 was added, the reflux reaction was continued for 20 hours, the mixture was concentrated under reduced pressure to obtain an oily substance, and the oily substance was recrystallized from acetone-ether to precipitate a yellow solid, which was filtered, dried and recrystallized from absolute ethanol to obtain 0.33g of pale yellow crystals, yield: 24.4%, mp.: 120 ℃ and 123 ℃.

¹HNMRδppm(DMSO-d₆)：1.18(t，J＝7.2Hz，3H，COOCH₂CH ₃)，1.35(t，J＝7.2Hz，3H，OCH₂CH ₃)，3.32-3.37(m，6H，3CH₂N)，3.80(s，3H，OCH₃)，4.00-4.11(m，8H，2NCH₂+OCH ₂CH₃+COOCH ₂CH₃)，6.62(s，1H，C＝CH_2f)，7.01(d，J＝8.1Hz，1H，ArH)，7.05(s，1H，C＝CH_2g)，7.35(d，J＝8.1Hz，1H，ArH)，7.46(s，1H，ArH)，7.61(s，2H，HC＝CH)。MS(m/z)：388(M+，100)，371(20)，232(30)，191(25)，171(35)。

Example 5

1- (3-methoxy-4-ethoxy) phenyl-1-pentene-4-methylene-5- [ (N)₄-ethoxycarbonyl) piperazinyl]-3-keto hydrochlorideCompound 5

0.59g (3mmol) of N₄-ethoxycarbonylpiperazine hydrochloride (commercially available) was dissolved in 15ml of anhydrous acetonitrile, 0.6g of paraformaldehyde and 3 drops of triethylamine were added, heating and stirring were performed under reflux for 3 hours, 0.66g (3mmol) of 1- (3-methoxy-4-ethoxy) phenyl-1-buten-3-one prepared in preparation example 6 was added, reflux was continued for 9 hours, cooling was performed, a large amount of pale yellow solid was precipitated, filtration and drying were performed, and the crude product was recrystallized from anhydrous acetonitrile to obtain 0.90g of pale yellow crystals, yield: 68.5%, mp.: 172 ℃ and 175 ℃.

¹HNMRδppm(DMSO-d₆)：1.18(t，J＝7.2Hz，3H，COOCH₂CH ₃)，1.33(t，J＝7.2Hz，3H，OCH₂CH ₃)，3.00-3.40(m，6H，3CH₂N)，3.82(s，3H，OCH₃)，3.92-4.20(m，8H，2NCH₂+OCH ₂CH₃+COOCH ₂CH₃)，6.70(s，1H，C＝CH_2f)，6.95(d，J＝8.1Hz，1H，ArH)，7.00(s，1H，C＝CH_2g)，7.30(d，J＝8.1Hz，1H，ArH)，7.42(s，1H，ArH)，7.56(s，2H，CH＝CH)。MS(m/z)：402(M+，100)，385(16)，373(6)，357(5)，329(6)。Anal Cald for C₂₂H₃₁N₂O₅Cl％：C：60.20，H：7.12，N：6.38；Found ％：C：60.11，H：7.06，N：6.36。

Example 6

1- (3, 4, 5-trimethoxy) phenyl-1-pentene-4-methylene-5- [ (N)₄-ethoxycarbonyl) piperazinyl]-3-keto hydrochlorideCompound 6

0.59g (3mmol) of N₄Dissolving ethoxycarbonylpiperazine hydrochloride (commercially available) in 5ml of anhydrous ethanol prepared in advance, wherein the pH value of the absolute ethanol is 4.5-5.0, adding 0.9g of paraformaldehyde, heating, stirring, refluxing for 4 hours, adding 0.70g (3mmol) of 1- (3, 4, 5-trimethoxy) phenyl-1-buten-3-one prepared in preparation example 7, continuously refluxing for 20 hours, concentrating under reduced pressure to obtain an oily substance, separating by VLC (visible light) to obtain a developing solvent of dichloromethane and methanol which are 50: 1, and obtaining 0.22g of light yellow powder crystals, wherein the yield is as follows: 16.2%, mp.: 78-81 ℃.

¹HNMRδppm(DMSO-d₆)：1.22(t，J＝7.2Hz，3H，COOCH₂ CH ₃)，3.00-3.60(m，6H，3CH₂N)，3.74(s，3H，OCH₃)，3.88(s，6H，2OCH₃)，3.92-4.20(m，6H，2NCH₂+COOCH ₂CH₃)，6.70(s，1H，C＝CH_2f)，7.00(s，1H，C＝CH_2g)，7.16(s，2H，ArH)，7.62(s，2H，HC＝CH)。MS(m/z)：418(M⁺，35)，401(5)，373(2)。

Example 7

1- (3, 4-methylenedioxy) phenyl-1-pentene-4-methylene-5- [ (N)₄-ethoxycarbonyl) piperazinyl]-3-keto hydrochlorideCompound 7

0.59g (3mmol) of N₄Ethoxycarbonylpiperazine hydrochloride (commercially available) was dissolved in 15ml of anhydrous acetonitrile, 0.6g of paraformaldehyde and 3 drops of triethylamine were added, heating and stirring were performed under reflux for 3 hours, 0.59g (3mmol) of 1- (3, 4-methylenedioxy) phenyl-1-buten-3-one prepared in preparation example 11 was added, reflux was continued for 9 hours, cooling was performed to precipitate a large amount of pale yellow solid, which was filtered, dried, and the crude product was recrystallized from anhydrous acetonitrile to obtain 0.95g of pale yellow granular crystals, yield: 77.6%, mp.: 179 ℃ and 182 ℃.

¹HNMRδppm(DMSO-d₆)：1.20(t，J＝7.2Hz，3H，COOCH₂ CH ₃)，3.20-3.60(m，6H，3CH₂N)，3.80-4.16(m，6H，2NCH₂+COOCH ₂CH₃)， 6.08(s，2H，OCH₂O)，6.70(s，1H，C＝CH_2f)，6.96(d，J＝7.2Hz，1H，ArH)，7.03(s，1H，C＝CH_2g)，7.27(d，J＝7.2Hz，1H，ArH)，7.60(s，3H，HC＝CH+ArH)。MS(m/z)：372(M⁺，100)，355(20)，299(5)，216(38)。HRMS Cald for C₂₀H₂₄O₅N₂·HCl：372.4200(M⁺)，found：372.1689(M⁺，100)，355.1643(15)，327.1346(3.6)，299.1376(3.8)，216.0769(29.1)。

Example 8

1- (4-Nitro) phenyl-1-pentene-4-methylene-5- [ (N)₄-ethoxycarbonyl) piperazinyl]-3-keto hydrochlorideCompound 8

0.38g (2mmol) of N₄-ethoxycarbonylpiperazine hydrochloride (commercially available) was dissolved in 5ml of anhydrous ethanol (pH 4.5-5.0) prepared in advance, 0.3g of paraformaldehyde was added, heating and stirring were performed under reflux for 4 hours, 0.19g (1mmol) of 1- (4-nitro) phenyl-1-buten-3-one prepared in preparation example 9 was added, reflux was continued for 12 hours, concentration under reduced pressure was performed to obtain an oily substance, acetone-diethyl ether was used for recrystallization to precipitate a pale yellow solid, filtration and drying were performed, and the crude product was recrystallized with anhydrous ethanol to obtain 0.18g of pale yellow crystals, yield: 43.9%, mp.: 192 ℃ to 195 ℃ (dec).

¹HNMRδppm(DMSO-d₆)：1.20(t，J＝7.2Hz，3H，COOCH₂ CH ₃)，3.00-3.60(m，6H，3NCH₂)，3.82-4.16(m，6H，2NCH₂+COOCH ₂CH₃)，6.76(s，1H，C＝CH_2f)，7.08(s，1H，C＝CH_2g)，7.74(s，1H，＝CHCO)，7.84(s，1H，CH＝)，8.08(d，J＝9.0Hz，2H，ArH_AA′)，8.26(d，J＝9.0Hz，2H，ArH_BB′)。MS(m/z)：373(M⁺，50)，356(45)，328(9)，300(8)。

Example 9

1- (4-nitrile) phenyl-1-pentene-4-methylene-5- [ (N)₄-ethoxycarbonyl) piperazinyl]-3-keto hydrochlorideCompound 9

0.38g (3mmol) of N₄-ethoxycarbonylpiperazine hydrochloride (commercially available) was dissolved in 5ml of previously prepared absolute ethanol having pH 4.5 to 5.0, 0.3g of paraformaldehyde was added, the mixture was heated under stirring and refluxed for 4 hours, 0.17g (1mmol) of 1- (4-nitrile) phenyl-1-buten-3-one prepared in preparation example 8 was added, the reflux was continued for 20 hours, insoluble matter was filtered off while hot, and the mixture was concentrated under reduced pressure to give an oily substance, and a small amount of anhydrous ether was added and ground to precipitate a pale yellow solid, and the crude product was recrystallized from absolute ethanol to give 0.17g of a white crystal, yield: 44.7%, mp.: 195 ℃ and 198 ℃ (dec).

¹HNMRδppm(DMSO-d₆)：1.22(t，J＝7.2Hz，3H，COOCH₂ CH ₃)，3.00-3.60(m，6H，3CH₂N)，3.82-4.16(m，6H，2NCH₂+COOCH ₂CH₃)，6.78(s，1H，C＝CH_2f)，7.08(s，1H，C＝CH_2g)，7.72(s，1H，＝CHCO)，7.82(s，1H，CH＝)，7.88(d，J＝8.1Hz，2H，ArH_AA′)，8.06(d，J＝8.1Hz，2H，ArH_BB′)。MS(m/z)：353(M⁺，18)，336(5)，308(3)，280(3)。

Example 10

1- (3, 4-methylenedioxy) phenyl-1-pentene-4-methylene-5- [ (4-benzyl) piperidinyl ] -3-one hydrochloride

Compound 10

Dissolving 0.48g (2mmol) of 4-benzylpiperidine hydrochloride (sold in the market) in 5ml of anhydrous acetonitrile, adding 0.3g of paraformaldehyde and 2 drops of triethylamine, heating, stirring, refluxing for 3 hours, adding 0.19g (1mmol) of 1- (3, 4-methylenedioxy) phenyl-1-buten-3-one prepared in preparation example 11, continuously refluxing for 15 hours, filtering out insoluble substances while hot, cooling the filtrate, adding a small amount of anhydrous ether, grinding, precipitating light yellow solid, filtering, drying, recrystallizing the crude product with anhydrous acetonitrile, and obtaining 0.22g of light yellow powder crystals, wherein the yield is as follows: 51.8%, mp.: 198 ℃ and 200 ℃ (dec).

¹HNMRδppm(DMSO-d₆)：1.66(brs，5H，2CH₂+CH)，2.88(s，2H，CH₂Ph)，3.24-3.40(m，4H，2NCH₂)，3.89(s，2H，CH₂N)，6.04(s，2H，OCH₂O)，6.63(s，1H，C＝CH_2f)，6.92(d，J＝7.2Hz，1H，Ar(a)H)，6.93(s，1H，C＝CH_2g)，7.18(m，6H，Ar(b)5H+Ar(a)H)，7.52(s，3H，HC＝CH+ArH)。MS(m/z)：389(M⁺，42)，372(10)，260(52)，216(55)。

Example 11

1- (4-chloro) phenyl-1-pentene-4-methylene-5- [ (4-benzyl) piperidinyl ] -3-one hydrochloride

Compound 11

Dissolving 0.48g (2mmol) of 4-benzylpiperidine hydrochloride (sold in the market) in 5ml of anhydrous acetonitrile, adding 0.3g of paraformaldehyde and 2 drops of triethylamine, heating, stirring and refluxing for 3 hours, adding 0.18g (1mmol) of 1- (4-chloro) phenyl-1-buten-3-one prepared in preparation example 1, continuously refluxing for 15 hours, filtering out insoluble substances while hot, cooling the filtrate, adding a small amount of anhydrous ether for grinding, separating out a light yellow solid, filtering, drying, recrystallizing the crude product with anhydrous acetonitrile, obtaining 0.17g of white crystals, and obtaining the yield: 40.9%, mp.: 175 ℃ and 179 ℃.¹HNMRδppm(DMSO-d₆)：1.74(brs，5H，2CH₂+CH)，2.88(s，2H，CH₂Ph)，3.00-3.48(m，4H，2NCH₂)，3.94(s，2H，CH₂N)，6.74(s，1H，C＝CH_2f)，7.00(s，1H，C＝CH_2g)，7.16-7.20(m，5H，Ar(b)5H)，7.46(d，J＝8.1Hz，2H，ArH_AA’)7.62(s，1H，＝CHCO)，7.66(s，1H，CH＝)，7.84(d，J＝8.1Hz，2H，ArH_BB’)。MS(m/z)：379(M+，60)，362(30)，344(4)，288(10)，254(25)。

Example 12

1- (3, 4-methylenedioxy) phenyl-1-pentene-4-methylene-5- [ (N)₄-benzyl) piperazinyl]-3-keto hydrochloride

Compound 12

0.48g (2mmol) of N₄-benzylpiperazine hydrochloride (commercially available) was dissolved in 5ml of anhydrous acetonitrile, 0.3g of paraformaldehyde and 2 drops of triethylamine were added, heating and stirring were carried out under reflux for 3 hours, 0.59g (3mmol) of 1- (3, 4-methylenedioxy) phenyl-1-buten-3-one prepared in preparation example 11 was added, reflux was continued for 15 hours, insoluble matter was filtered off while hot, the filtrate was cooled and then ground with a small amount of anhydrous ether to precipitate a solid, which was filtered, dried and the crude product was recrystallized from anhydrous acetonitrile to obtain 0.20g of pale yellow powdery crystals, yield: 43.3%, mp.: 189 deg.C and 191 deg.C (dec).

¹HNMRδppm(DMSO-d6)：3.00-3.60(m，10H，4NCH₂+CH₂Ph)，3.92(s，2H，CH₂N)，6.08(s，2H，OCH₂O)，6.60(s，1H，C＝CH_2f)，6.95(d，J＝7.2Hz，1H，Ar(a)H)，6.95(s，1H，C＝CH_2g)，7.25(m，6H，Ar(b)5H+Ar(a)H)，7.56(s，3H，HC＝CH+Ar(a)H)。MS(m/z)：390(M⁺，8)，373(1)，314(2)。

Example 13

1- (3, 4-methylenedioxy) phenyl-1-pentene-4-methylene-5- (2, 6-dimethylmorpholinyl) -3-one hydrochloride

Compound 13

Dissolving 0.30g (2mmol) of 2, 6-dimethylmorpholine hydrochloride (commercially available) in 5ml of anhydrous ethanol prepared in advance and having a pH value of 4.5-5.0, adding 0.15g of paraformaldehyde, heating, stirring, refluxing for 3 hours until most of the solid is dissolved, adding 0.38g (2mmol) of 1- (3, 4-methylenedioxy) phenyl-1-buten-3-one prepared in preparation example 11, continuing to reflux for 24 hours, cooling, adding a small amount of anhydrous ether, grinding to separate out a pale yellow solid, filtering, drying, and recrystallizing with anhydrous ethanol to obtain 0.15g of pale yellow crystals, wherein the yield is as follows: 41.6%, mp.: 203 ℃ and 206 ℃.

¹HNMRδppm(DMSO-d₆)：1.08(s，3H，CH₃)，1.16(s，3H，CH₃)，3.30(brs，4H，2NCH₂)，4.00(brs，4H，CH₂N+2CHCH₃)，6.08(s，2H，OCH₂O)，6.70(s，1H，C＝CH_2f)，6.91(d，J＝7.2Hz，1H，ArH)，7.00(s，1H，C＝CH_2g)，7.28(d，J＝7.2Hz，1H，ArH)，7.56(s，3H，HC＝CH+ArH)。MS(m/z)：329(M⁺，100)，312(10)，216(45)，202(25)。

Example 14

1- (3-methoxy-4-ethoxy) phenyl-1-pentene-4-methylene-5- (2, 6-dimethylmorpholinyl) -3-one hydrochloride

Compound 14

Dissolving 0.30g (2mmol) of 2, 6-dimethylmorpholine hydrochloride (commercially available) in 5ml of anhydrous acetonitrile, adding 0.3g of paraformaldehyde and 1 drop of triethylamine, heating, stirring, refluxing for 4 hours, adding 0.22g (1mmol) of 1- (3-methoxy-4-ethoxy) phenyl-1-buten-3-one prepared in preparation example 6, refluxing for 11 hours, cooling, adding a small amount of anhydrous ether, grinding to precipitate a pale yellow solid, filtering, drying, recrystallizing with anhydrous acetonitrile to obtain 0.17g of pale yellow crystals, yield: 43.0%, mp.: 183 ℃ and 186 ℃.

¹HNMRδppm(DMSO-d₆)：1.14(s，3H，CH₃)，1.20(s，3H，CH₃)，1.40(t，J＝7.2Hz，3H，OCH ₂CH₃)，3.36(br，4H，2NCH₂)，3.88(s，3H，OCH₃)，4.00(m，6H，CH₂N+OCH ₂CH₃+2CHCH₃)，6.74(s，1H，C＝CH_2f)，7.02(d，J＝8.1Hz，1H，ArH)，7.07(s，1H，C＝CH_2g)，7.38(d，J＝8.1Hz，1H，ArH)，7.44(s，1H，ArH)，7.64(s，2H，HC＝CH)。MS(m/z)：359(M⁺，100)，342(12)，330(12)，258(10)，246(35)。

Example 15

1- (3, 4-methylenedioxy) phenyl-1-pentene-4-methylene-5- [ (N)₄-methyl) piperazinyl]-3-keto hydrochloride

Compound 15

0.20g (1.5mmol) of N₄-methylpiperazine hydrochloride (commercially available) was dissolved in 5ml of absolute ethanol, 0.15g of paraformaldehyde and 3 drops of hydrochloric acid-ethanol solution were added, and after heating under stirring and refluxing for 3 hours, 0.29g (1.5mmol) of 1- (3, 4-methylenedioxy) phenyl-1-buten-3-one prepared in preparation example 11 was added, and refluxing was continued for 23 hours, cooling was carried out, insoluble matter was removed by filtration, the filtrate was ground with a small amount of absolute ethyl ether, and a pale yellow solid was precipitated, filtered, dried, and recrystallized from absolute ethanol to obtain 0.13g of cream yellow crystals, yield: 25.6%, mp.: 192 ℃ and 196 ℃.

¹HNMRδppm(DMSO-d₆)：2.72(s，3H，NCH₃)，3.20-3.40(m，10H，4NCH₂+CH₂N)，6.05(s，2H，OCH₂O)，6.40(s，1H，C＝CH_2f)，6.91(d，J＝7.2Hz，1H，ArH)，6.96(s，1H，C＝CH_2g)，7.23(dd，J＝7.2Hz，J＝1.8Hz，ArH)，7.42(s，2H，HC＝CH)，7.47(d，J＝1.8Hz，1H，ArH)。MS(m/z)：314(85)，299(9)，297(8)，258(12)。

Example 16

1- (3, 4-methylenedioxy) phenyl-1-pentene-4-methylene-5- [ (4-methyl) piperidinyl ] -3-one hydrochloride

Compound 16

Dissolving 0.27g (2mmol) of 4-methylpiperidine hydrochloride (commercially available) in 5ml of previously prepared absolute ethanol having a pH of 4.5 to 5.0, adding 0.3g of paraformaldehyde and 2 drops of triethylamine, stirring under heating and refluxing for 3 hours, adding 0.19g (1mmol) of 1- (3, 4-methylenedioxy) phenyl-1-buten-3-one prepared in preparation example 11, refluxing for 15 hours, filtering off insoluble matter while hot, cooling the filtrate, adding a small amount of anhydrous ether, and grinding to precipitate 0.14g of pale yellow powder crystals, yield: 40.1%, mp.: 147 ℃ and 150 ℃.

¹HNMRδppm(DMSO-d₆)：0.88(brs，3H，CH₃)，1.64(brs，5H，2CH₂+CH)，3.00-3.60(m，4H，2NCH₂)，4.40(s，2H，CH₂N)，6.07(s，2H， OCH₂O)，6.72(s，1H，C＝CH_2f)，6.94(d，J＝7.2Hz，1H，ArH)，6.98(s，1H，C＝CH_2g)，7.26(d，J＝7.2Hz，1H，ArH)，7.56(s，3H，HC＝CH+ArH)。MS(m/z)：313(M⁺，50)，298(5)，296(32)，216(33)。

Example 17

1- (3, 4-methylenedioxy) phenyl-1-pentene-4-methylene-5- [ (4-carboxy) piperidinyl ] -3-one hydrochloride

Compound 17

Dissolving 0.38g (2mmol) of 4-carboxypiperidine hydrochloride (commercially available) in 5ml of anhydrous acetonitrile, adding 0.3g of paraformaldehyde and 2d of triethylamine, heating, stirring, refluxing for 3 hours, adding 0.19g (1mmol) of 1- (3, 4-methylenedioxy) phenyl-1-buten-3-one prepared in preparation example 11, refluxing for 9 hours, filtering off insoluble substances while hot, cooling the filtrate, adding a small amount of anhydrous diethyl ether, grinding to precipitate 0.28g of light yellow solid, filtering, drying, recrystallizing the crude product with anhydrous acetonitrile to obtain 0.12g of light yellow powdery crystals, and obtaining the yield: 31.9%, mp.: 191 ℃ and 194 ℃.

¹HNMRδppm(DMSO-d₆)：2.00(brs，5H，2CH₂+CH)，2.80-3.60(m，4H，2NCH₂)，3.96(s，2H，CH₂N)，6.08(s，2H，OCH₂O)，6.60(s，1H，C＝CH_2f)，6.91(d，J＝7.2Hz，1H，ArH)，6.98(s，1H，C＝CH_2g)，7.26(d，J＝7.2Hz，1H，ArH)，7.56(s，3H，HC＝CH+ArH)；MS(m/z)：343(M⁺，40)，326(15)，298(3)，216(100)。

Example 18

1- (4-chloro) phenyl-1-pentene-4-methylene-5- [ (4-carboxy) piperidinyl ] -3-one hydrochloride

Compound 18

Dissolving 0.38g (2mmol) of 4-carboxypiperidine hydrochloride (commercially available) in 5ml of anhydrous acetonitrile, adding 0.3g of paraformaldehyde and 2 drops of triethylamine, heating, stirring and refluxing for 3 hours, adding 0.18g (1mmol) of 1- (4-chloro) phenyl-1-buten-3-one prepared in preparation example 1, continuously refluxing for 15 hours, filtering off insoluble substances while hot, cooling the filtrate, adding a small amount of anhydrous ether for grinding, separating out a white solid, filtering, drying, recrystallizing the crude product with anhydrous acetonitrile, obtaining 0.13g of white crystals, yield: 35.1%, mp.: 171 ℃ and 173 ℃.

¹HNMRδppm(DMSO-d₆)：1.93(brs，5H，2CH₂+CH)，2.80-3.40(br，4H，2NCH₂)，3.96(s，2H，CH₂N)，6.74(s，1H，C＝CH_2f)，7.00(s，1H，C＝CH_2g)，7.47(d，J＝8.1Hz，2H，ArH)，7.64(s，1H，＝CHCO)，7.67(s，1H，CH＝)，7.86(d，J＝8.1Hz，2H，ArH)。MS(m/z)：333(M⁺，10)，316(8)，288(3)，206(20)。

Example 19

1- (3, 4-methylenedioxy-5-methoxy) phenyl-2-methylene-3- [ (N)₄-ethoxycarbonyl) piperazinyl]-1-oxopropane hydrochlorideCompound 19

0.38g (2mmol) of N₄Ethoxycarbonylpiperazine hydrochloride (commercially available) dissolved in 5ml of anhydrous acetonitrile, 0.3g of paraformaldehyde and 1 drop of triethylamine added, heated, stirred under reflux for 3 hours, 0.16g (1mmol) of 3, 4-methylenedioxy-5-methoxyacetophenone prepared in preparation example 12 added, refluxed for 11 hours, cooled and ground with a small amount of anhydrous ether to precipitate a milky white solid, filtered, dried, and the crude product recrystallized from anhydrous acetonitrile to give 0.13g of white crystals, yield: 30.8%, mp: 172 ℃ and 175 ℃.

¹HNMRδppm(DMSO-d₆)：1.16(t，J＝7.2Hz，3H，COOCH₂ CH ₃)，3.00-3.60(m，6H，3CH₂N)，3.84(s，3H，OCH₃)，3.88-4.16(m，6H，2NCH₂+COOCH ₂CH₃)，6.08(s，2H，OCH₂O)，6.12(s，1H，C＝CH_2F)，6.59(s，1H，C＝CH_2g)，7.00(s，1H，ArH)，7.06(s，1H，ArH)。MS(m/z)：376(M⁺，42)，359(62)，331(10)，303(9)，274(9)。HRMS Cald for C₁₉H₂₄O₆N₂·HCl：376.4012(M⁺)，found：376.1624(M⁺，77)，359.1601(74)，331.1283(10)，303.1378(6)，274.1067(8)。

Example 20

1- (4-chloro) phenyl-2-methylene-3- [ N₄-ethoxycarbonyl) piperazinyl]-1-oxopropane hydrochloride

Compound 20

0.38g (2mmol) of N₄-ethoxycarbonylpiperazine hydrochloride (commercially available) was dissolved in 5ml of anhydrous acetonitrile, 0.3g of paraformaldehyde and 1 drop of triethylamine were added, heating, stirring under reflux for 3 hours, 0.15g (1mmol) of 4-chloroacetophenone prepared in preparation 13 was added, reflux was continued for 11 hours, after cooling, a small amount of anhydrous ether was added and triturated to precipitate a milky white solid, which was filtered, dried, and the crude product was recrystallized from anhydrous acetonitrile to obtain 0.18g of white powdery crystals, yield: 48.4%, mp.: 165-167 ℃.

¹HNMRδppm(DMSO-d₆)：1.20(t，J＝7.2Hz，3H，COOCH₂CH₃)，3.00-3.40(m，6H，3CH₂N)，3.92-4.16(m，6H，2NCH₂+COOCH₂CH₃)，6.18(s，1H，C＝CH_2f)，6.70(s，1H，C＝CH_2g)，7.58(d，J＝9.0Hz，2H，ArH_AA′)，7.78(d，J＝9.0Hz，2H，ArH_BB′)。MS(m/z)：336(M⁺，20)，319(85)，307(4)，291(10)，263(5)。

Pharmacological experiments

Experimental example 1

Inhibition of rat thoracic polymorphonuclear leukocyte beta-glucuronidase release in vitro

1% Carrageenan was injected into the thoracic cavity to induce Wistar rat polymorphonuclear leukocytes, and a cell suspension was prepared with Dulbeccoo's buffer solution adjusted to a cell concentration of 2.5X 10⁶cells·ml^-1. Adding compound or equal volume of solvent into the tube, and 2.5X 10⁶cells·mL^-1250 μ l of cell suspension, incubating in 37 deg.C water bath for 15min, adding 1 × 10^-3mol·L^-12.5 μ l cytochalasin B, incubating for 5min, and adding 1 × 10^-4mol·L^-12.5 mul PAF, continuously incubating for 5min, stopping the reaction in ice bath, centrifuging, and taking supernatant as released enzyme solution. Adopting 96-hole enzyme label plate, adding released enzyme liquid 25 μ L, 2.5 mmol.L per hole^-1Phenolphthalein glucuronic acid 25. mu.l, 0.1 mol. L^-1Acetic acid buffer (pH4.6) 100. mu.l. Placing in an incubator at 37 deg.C for 18 hr. Adding 0.3mol per hole^-1NaOH 150. mu.l, the reaction was stopped and developed. The readings were taken on a microplate reader with 550nm filters. The results show that: the compound has obvious inhibition effect on the release of rat thoracic polymorphonuclear leukocyte beta-glucuronidase caused by PAF. The compounds are suggested to exert anti-inflammatory effects by inhibiting lysosomal enzyme release and may also be potential PAF receptor antagonists.

TABLE 1 beta-glucosidase enzyme assay results

Compound (I)	Agent for treating cancerAmount (mol. L)-1)	Irritant (mol. L)-1)	Inhibition ratio (%)
				2 3 4 5 7 8 9 12 13 14 15 18 20	1×10-4 ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ··	2×10-7 ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ·· ··	47.9 36.8 62.7 54.4 64.8 66.8 66.0 29.9 32.0 61.2 57.2 54.0 52.5

Preferred compounds of part 2 para-beta-glucuronidase

Half maximal inhibitory concentration released (IC50)

Compound (I)	IC50(mol·L-1)
		4 5 7 14 15	6.69×10-5 1.51×10-5 3.30×10-5 1.29×10-5 5.70×10-6

Experimental example 2

In vitro pair [ 2 ]³H]Competitive binding of PAF to rat polymorphonuclear leukocyte receptors

A suspension of Wistar rat polymorphonuclear leukocytes was prepared and 240. mu.l (2X 10) of the cell suspension was added to each reaction well⁶cells ml-1), and [ 2 ]³H]5 μ L (1.16 nmol. L-1) of PAF, 5 μ L (5 μmol. L-1) of unlabeled PAF is added to the nonspecific binding wells, compounds with different concentrations are added to the competitive binding wells, corresponding volumes of drug solvents are added to the total binding wells and the nonspecific binding wells, incubation is carried out in a water bath at 37 ℃ for 30min, the reaction is stopped in an ice bath, suction filtration and washing are carried out, and free labeled ligand is separated. The filter was dried at 80 ℃ and placed in a scintillation vial containing 5ml of scintillation fluid and the radiation intensity on the filter was measured with a liquid scintillation counter.

The results show that: compound pair [ alpha ], [ alpha³H]PAF has a clear competitive effect on the binding of rat polymorphonuclear leukocyte receptors. Suggesting that the compounds meet the characteristics of PAF receptor antagonists. Has anti-inflammatory effect.

Compound pair [ alpha ], [ alpha³H]Competitive binding of PAF to rat polymorphonuclear leukocyte receptors

Compound (I)	IC50(mol·L-1)
		7 5	1.08×10-6 6.49×10-6

Experimental example 3

In vitro pair [ 2 ]³H]Competition for the binding of PAF to the rabbit platelet receptor

Collecting blood from middle artery of rabbit ear, anticoagulating, sucking platelet-rich plasma from upper layer, preparing platelet suspension with buffer solution A, and adjusting platelet concentration to 1 × 10⁸Ml-1. Each reaction well was charged with 240. mu.l of a platelet suspension, and [ 2 ]³H]5 μ L (1.16 nmol. L-1) of PAF, adding 5 μ L (5 μmol. L-1) of unlabeled PAF into a non-specific binding well, adding compounds with different concentrations into a competitive binding well, adding corresponding volumes of drug solvents into a total binding well and a non-specific binding well, incubating at 25 ℃ for 30min, stopping reaction in an ice bath, rapidly performing suction filtration, washing, drying a filter membrane, and counting. The results show that: compound pair [3H]The binding of PAF to rabbit platelet receptors has a clear competitive effect. Suggesting that the compounds meet the characteristics of PAF receptor antagonists. Has antithrombotic effect.

Compound pair [ alpha ], [ alpha³H]Competitive binding of PAF to rabbit platelet receptor

Compound (I)	IC50(mol·L-1)
		7 5	1.97×10-6 7.48×10-7

[0243] Experimental example 4

Inhibition of chemotactic response of rat neutrophils in vitro

The rat carotid artery was bled, anticoagulated, and neutrophils were isolated with 5% dextran and lymphocyte isolate. After 27. mu.l of stimulating agent per well was added to the lower well of the 48-well cytochemotactic plate, the filter was placed, the upper cytochemotactic plate was mounted, the compound or the corresponding solvent was added to the cell suspension at various concentrations, and the cell suspension was added to the upper chamber of the 48-well cytochemotactic plate at 50. mu.l per well, and incubated at 37 ℃ in an incubator for 4 hours. The filter membrane is taken out, stained with hematoxylin stain, dehydrated, and the number of cells chemotactic to the other side of the filter membrane in a unit area is counted under a microscope equipped with a micrometer.

The results show that: the compound has obvious inhibition effect on rat neutrophil chemotactic reaction. Suggesting that the compounds may exert anti-inflammatory effects by inhibiting chemotactic responses of neutrophils.

Inhibition of rat neutrophil chemotaxis

Compound (I)	IC50(mol·L-1)
		7	4.26×10-7

Experimental example 5

PAF-activated neutrophil LTB in vitro₄And influence of 5-HETE Generation

1% carrageenan induced Wistar rat thoracic polymorphonuclear leukocytes. Adding different compounds or control solvents into leukocyte suspension at 1 × 10^-6mol.L^-1After PAF stimulation, the column was separated by Sep-PakC18 column, and the LTB was separated by RP-HPLC and detected by UV₄And 5-HETE content.

The results show that: compound on rat polymorphonuclear leukocyte LTB₄And 5-HETE generation has obvious inhibition effect. Suggesting that compounds may be useful for inhibiting LTB₄And 5-HETE production exerts an anti-inflammatory effect.

Compound on rat neutrophil LTB₄And inhibition of 5-HETE production

Compound (I)	IC50(mol·L-1)
			LTB4	5-HETE
5	8.71×10-8	3.08×10-8
			7	2.29×10-6	5.25×10-6

Experimental example 6

Neutrophil superoxide anion (O) activated in vitro on PAF₂ ^-) Influence of generation

1% carrageenan induced Wistar rat thoracic polymorphonuclear leukocytes. Adding different compounds or control solvents into leukocyte suspension at 2 × 10^-6mol.L^-1After PAF stimulation, O was measured by cytochrome C reduction method₂ ^-And (4) content.

The results show that: compound on rat polymorphonuclear leucocyte O₂ ^-Has obvious inhibiting effect on the generation. The compounds are useful for inhibiting O₂ ^-Can be used for relieving inflammation.

Compound on rat neutrophil O₂ ^-Inhibition of production

Compound (I)	IC50(mol·L-1)
		7 5	3.24×10-6 2.51×10-6

Experimental example 7

Effect on PAF-activated neutrophil PAF production in vitro

1% carrageenan InductionWistar rat thoracic polymorphonuclear leukocytes. Adding different compounds or control solvents into leukocyte suspension at 1 × 10^-6mol.L^-1After PAF stimulation, PAF content was determined by radiolabelling.

The results show that: the compound has obvious inhibition effect on rat polymorphonuclear leukocyte PAF generation. Suggesting that the compounds may exert anti-inflammatory effects by inhibiting PAF production.

Inhibition of rat neutrophil PAF production by compounds

Compound (I)	Conc.(mol·L-1)	Inhibition(％)
			7 5	1×10-5 1×10-5	26 29

Experimental example 8

In vitro inhibition of calcium ion elevation in PAF-stimulated rat polymorphonuclear leukocytes

1% carrageenan induced Wistar rat thoracic polymorphonuclear leukocytes. Fura-2/AM was added to the cell suspension to a final concentration of 3X 10^-6mol·L^-1. Adding 1ml of cell suspension into a glass test tube containing the drug or corresponding solvent in advance, and performing warm bath on the cell suspension in a constant-temperature oscillating water bath for 45min, standing at room temperature for 15min, and washing twice with HBSS solution to remove residual extracellular Fura-2/AM. And adding the cell suspension loaded with the Fura-2/AM into an absorption cell of a Hitachi F-4010 type fluorescence spectrophotometer, and measuring the fluorescence intensity at constant temperature of 37 ℃ under the condition of keeping the cells in a suspension state. The fluorescence intensity in the resting state was measured and then 1X 10 was added^-4mol·L^-1PAF 20. mu.l, 10% Triton X-10020. mu.l and 500 mmol.L^-1Fluorescence intensity of 100. mu.l EGTA (3 mol. L-1 Tris adjusted to pH 8.7). The experimental data were treated with the computer program for Ca2+ measurement (F-4010) Quin 2 Fura2 Indol. And calculating the change values of the resting state and the intracellular calcium ion concentration after adding the stimulant.

The results show that: the compound can remarkably reduce the increase of the polymorphonuclear leukocyte intracellular free calcium level caused by PAF stimulation. Suggesting that the mechanism of action of the compounds may be related to antagonism of PAF receptor binding and subsequent signal transduction. Has anti-inflammatory effect.

Intracellular stimulation of PAF by compounds

Inhibition of elevated free calcium levels

Compound (I)	IC50(mol.·L-1)
		7 5	1.24×10-5 6.59×10-6

[0274] Experimental example 9

Inhibition of PAF-induced increase in skin vascular permeability in mice

18-22 g of Kunming male mice are randomly divided into a control group and an administration group. Oral administration, control group with equal volume of drug solvent. After 1h, 0.25ml of 1% Evans blue was injected into tail vein, and after 10min, 1X 10 was injected into the skin of the back of the mouse^-8mol.L-1 PAF0.1ml, killing the mice after 1h, separating the skin, cutting off the position of the inner side of the skin where the blue spot is formed, cutting into pieces, putting into a centrifuge tube with a ground plug, adding 0.8ml of acetone/normal saline solution (7: 3), oscillating on an oscillator for 30min, 3000rpm, and centrifuging for 5 min. 0.25ml of the supernatant was taken, transferred to a 96-well microplate, and the absorbance value was measured on a microplate reader with a 620nm filter. The value of the absorbance of the evans blue extract is used to express the value of the skin vascular permeability.

The results show that: the compound is orally taken, 50mg/kg, and can obviously inhibit the increase of the skin vascular permeability of mice caused by PAF. Has anti-inflammatory effect.

Inhibition of PAF-induced increase in skin vascular permeability in mice

Compound (I)	Inhibition ratio (%)
		5 7	58.90 46.60

Experimental example 10

Inhibition of adjuvant arthritis in rats

SD rats, male, body weight 190 + -10 g, day 0, each rat right hind foot plantar intradermal injection Freund's complete adjuvant 0.1 ml. Prophylactic experiments were administered from day 0 to day 11 starting with each group. The circumference of the ankle joint of the left hind foot is measured and the efficacy is judged by scoring the forefoot, the ear, the tail, etc. 1 time every 3 days till 28 days.

The results show that: the compound is orally taken, 100mg/kg, and can obviously inhibit the adjuvant arthritis of rats. Has anti-inflammatory effect.

Inhibitory Effect (preventive Effect) of Compounds on rat adjuvant-induced arthritis

Compound (I)	Inhibition ratio (%)
			15 days	22 days
7 5	57.1 56.8	53.2 55.5

Claims (8)

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof

Wherein:

AL is selected from hydrogen atom, hydroxyl, halogen atom, trifluoromethyl, nitrile group, nitro, amino and C_1-6Alkyl radical, C_1-6Alkoxy, 3, 4-methylenedioxy, 3, 4-di-C_1-6Alkoxy radical, 34, 5-tri-C_1-6Alkoxy, 3-methoxy-4-hydroxy, or 3, 4-methylenedioxy-5-methoxy;

n＝1；

y is selected from CH₂NH or O;

X＝C_1-6alkyl, COOR, CO-Ph, CH₂Ph、CH₂CH₂OH or CONR₁R₂，

Wherein:

r ═ H or C_1-6An alkyl group, a carboxyl group,

R₁、R₂＝C_1-6an alkyl group;

with the proviso that the compound does not comprise:

2. a compound according to claim 1, wherein R is C (CH)₃)₃。

3. The compound according to claim 1, wherein said compound is selected from the group consisting of:

4. a pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of claims 1, 2 or 3, and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is in the form of a tablet, capsule, pill, injection, sustained release formulation, controlled release formulation, or various particulate delivery systems.

6. Use of a compound according to claim 1 or 2 or 3 for the preparation of a medicament for the prophylaxis and/or treatment of inflammation.

7. The use according to claim 6, wherein said inflammation is acute or chronic rheumatoid arthritis, acute or chronic ankylosing spondylitis, osteoarthritis, scapulohumeral periarthritis, bursitis, tendonitis, or tenosynovitis.

8. Use of a compound according to claim 1 or 2 or 3 for the manufacture of an antithrombotic medicament.