CN100420677C - Substituted aryl methylene sulfonylated azacyclopentanone compounds, pharmaceutical composition thereof, preparation method and use thereof - Google Patents

Abstract

The invention discloses a class of substituted aryl methylene sulfonylated azacyclopentanones (I), a preparation method thereof, a pharmaceutical composition containing an effective dose of the compound of the general formula (I), and the compound and the combination Application of substances in the preparation of anti-inflammatory and analgesic drugs.

Description

Substituted aryl methylene sulfonylated azacyclopentanone compounds, pharmaceutical composition thereof, preparation method and use thereof

Technical field

The invention belongs to the field of medicine, and relates to a non-steroidal anti-inflammatory and analgesic drug, in particular to a class of substituted aryl methylenesulfonylated azacyclopentanone compounds (I), a preparation method thereof, and a general medicine containing an effective dose. A pharmaceutical composition of the compound of formula (I), and the application of the compound and the composition in the field of non-steroidal anti-inflammatory analgesia.

Background technique

Non-steroidal anti-inflammatory drugs (NSAIDs for short) are widely used in the prevention and treatment of various inflammatory diseases and pain due to their definite anti-inflammatory and analgesic effects. These ailments include migraine, biliary colic, bursitis, tenosynovitis, joint capsulitis, low back pain, gout, headache, toothache, neuralgia, joint pain, muscle pain, menstrual pain, fever, rheumatism, acute and chronic rheumatoid arthritis And rheumatoid arthritis, soft tissue diseases and sports injuries. Although traditional non-steroidal anti-inflammatory drugs (NSAIDs) have strong antipyretic, analgesic and anti-inflammatory effects, about 20% of patients who take NSAIDs for a long time have gastrointestinal adverse reactions, such as nausea, vomiting, ulcers, etc. , bleeding and perforation. Studies have shown that the pharmacological effects of NSAIDs are related to the inhibition of cyclooxygenase-2 (cox-2) activity, while gastrointestinal adverse reactions are related to the inhibition of cyclooxygenase-1 (cox-1) activity (Ao Gui Zhen, Zhang Yubin, Zhang Yihua, Research progress of cyclooxygenase-2, the target of new non-steroidal anti-inflammatory drugs [J]. Chinese Journal of New Drugs, 2001, 10(7): 492-496). To this end, a series of selective cox-2 inhibitors have been developed and put on the market. It is disclosed in the prior art that highly selective cox-2 inhibitors can cause enzyme imbalance in the body. Although they can overcome gastrointestinal side effects, long-term use is likely to cause cardiovascular damage. For example, rofecoxib (Vioxx) has been withdrawn from the market by the US FDA; while celecoxib (Celebrex) has been questioned. The prior art further reveals that another important enzyme, 5-esteroxygenase (5-LO), is involved in the inflammatory process. Inhibiting 5-LO and moderately inhibiting cox-2 may not only avoid gastrointestinal side effects, but also avoid cardiovascular damage, and produce better anti-inflammatory and analgesic effects. The prior art also discloses that in addition to selectively inhibiting cox-2 to prevent the synthesis of inflammatory mediator prostaglandin (PG), substituted phenolic compounds can also inhibit 5-esteroxygenase (5-LO), preventing another The synthesis of inflammatory mediator leukotrienes (LT), so this kind of compound may have a good prospect of pharmaceutical application. For example, compound (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-imino-4-thiazolidinone (darbufelone) is a dual inhibitor of It has good anti-inflammatory and analgesic activity (Yuntao S, David TC, Robert D, et al, Synthesis, Structure-Activity Relationships, and in VivoEvaluations of substituted Di-tert-butylphenols as a Novel Class of Potent, Selective, and Orally Active Cyclooxygenase-2 Inhibitors. 1. Thiazolone and Oxazolone Series [J]. J. Med. Chem., 1999, 42: 1151-1160).

Contents of the invention

The object of the present invention is to provide a new class of substituted aryl methylenesulfonylated azacyclopentanones with anti-inflammatory and analgesic activities. The compound of the present invention is a sulfonylated structure of a substituted azacyclopentanone.

Another object of the present invention is to provide a method for preparing azocyclopentanones containing substituted aryl methylenesulfonates.

Another object of the present invention is to provide a pharmaceutical composition containing one or more of these compounds.

Another object of the present invention is to provide a use of the above-mentioned compound and composition in the preparation of a drug for preventing and treating neuropsychiatric diseases, especially analgesic effect.

Another object of the present invention is to provide a use of the above compounds and compositions in the preparation of medicines for treating and preventing inflammation.

In order to accomplish the purpose of the present invention, the present invention takes following technical scheme:

The new substituted aryl methylene sulfonylated cyclopentanones provided by the present invention have a structure as a compound shown in general formula I and pharmaceutically acceptable salts or hydrates or prodrugs thereof,

In formula (I), R ¹ and R ² each independently represent hydrogen, hydroxyl, straight chain or branched chain alkyl containing 1 to 6 carbons, or straight chain or branched chain alkoxy containing 1 to 6 carbons , R ¹ and R ² are the same or different; R ³ represents hydrogen, arylsulfonyl, or alkylsulfonyl; X represents CH ₂ , NH, O, or S group; Y represents O, S, NH, aryl Sulfonimide, or alkylsulfonimide; and wherein when R ³ represents hydrogen, Y only represents arylsulfonimide or alkylsulfonimide.

Among the above-mentioned compounds, preferably ^R1 and ^R2 each independently represent hydrogen, hydroxyl, methoxy, ethoxyl or tert-butyl; more preferably ^R1 and ^R2 represent tert-butyl respectively; X represents NH or S group ; The configuration of the compound is the Z configuration.

In the present invention, the new compound is a series of compounds formed by sulfonylation of aryl or alkyl substituted aryl methylene azolone intermediates. Specifically, it can be: (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-p-toluenesulfonylimide-4-thiazolidinone, (Z)- 5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-benzenesulfonylimido-4-thiazolidinone, (Z)-5-(3,5-di-tert Butyl-4-hydroxyphenylmethylene)-2-methylsulfonimido-4-thiazolidinone, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenyl Methylene)-2-ethylsulfonylimido-4-thiazolidinone, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-propane Sulfonimide-4-thiazolidinone, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-butylsulfonimide-4 -thiazolidinone, (Z)-5-(4-hydroxyphenylmethylene)-2-benzenesulfonylimide-3-benzenesulfonyl-4-thiazolidinone, (Z)-5-( 4-hydroxyphenylmethylene)-3-p-toluenesulfonyl-2,4-imidazolidinedione, (Z)-5-(4-hydroxyphenylmethylene)-3-benzenesulfonyl-2 , 4-imidazolidinedione, (Z)-5-(4-hydroxyphenylmethylene)-3-ethanesulfonyl-2,4-imidazolidinedione, (Z)-5-(3,5 -Di-tert-butyl-4-hydroxyphenylmethylene)-3-methylsulfonyl-2,4-imidazolidinedione, (Z)-5-(3,5-di-tert-butyl-4- Hydroxyphenylmethylene)-3-ethylsulfonyl-2,4-imidazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)- 3-Propylsulfonyl-2,4-imidazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-butylsulfonyl-2 , 4-imidazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-p-methylphenylsulfonyl-2,4-imidazolidine Diketone, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-phenylsulfonyl-2,4-imidazolidinedione, (Z)-5 -(3-methoxy-4-hydroxyphenylmethylene)-2-p-toluenesulfonyl-3-p-toluenesulfonyl-4-thiazolidinone, (Z)-5-( 3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-p-toluenesulfonylimide-3-p-methylbenzenesulfonyl-4-thiazolidinone, (Z)-5- (3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-benzenesulfonylimide-3-benzenesulfonyl-4-thiazolidinone, (Z)-5-(3, 5-di-tert-butyl-4-hydroxyphenylmethylene)-2-methanesulfonyl-3-methylsulfonyl-4-thiazolidinone, (Z)-5-(3,5-di tert-butyl-4-hydroxyphenylmethylene)-2-ethanesulfonylimido-3-ethanesulfonyl-4-thiazolidinone, (Z)-5-(3,5-di-tert-butyl -4-Hydroxyphenylmethylene)-2-propanesulfonylimido-3-propanesulfonyl-4-thiazolidinone, (Z)-5-(3,5-di-tert-butyl-4- Hydroxyphenylmethylene)-2-butanesulfonylimide-3-butanesulfonyl-4-thiazolidinone, (Z)-5-(3-methoxy-4-hydroxyphenylmethylene )-2-ethanesulfonylimido-4-thiazolidinone, (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-3-p-toluenesulfonyl-2,4 -Thiazolidinedione, (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-3-benzenesulfonyl-2,4-thiazolidinedione, (Z)-5- (3-methoxy-4-hydroxyphenylmethylene)-3-ethanesulfonyl-2,4-thiazolidinedione, (Z)-5-(3,5-di-tert-butyl-4- Hydroxyphenylmethylene)-3-p-methylbenzenesulfonyl-2,4-thiazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene )-3-Benzenesulfonyl-2,4-thiazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-methylsulfonyl- 2,4-thiazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-ethylsulfonyl-2,4-thiazolidinedione , (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-propylsulfonyl-2,4-thiazolidinedione, (Z)-5-( 3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-butylsulfonyl-2,4-thiazolidinedione, (Z)-5-(3-methoxy-4- Hydroxyphenylmethylene)-3-p-toluenesulfonyl-2,4-imidazolidinedione, (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-3-benzene Sulfonyl-2,4-imidazolidinedione, (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-3-methanesulfonyl-2,4-imidazolidinedione, (Z)-5-(4-hydroxyphenylmethylene)-3-p-toluenesulfonyl-2,4-thiazolidinedione, (Z)-5-(4-hydroxyphenylmethylene)- 3-Benzenesulfonyl-2,4-thiazolidinedione, (Z)-5-(4-hydroxyphenylmethylene)-3-benzenesulfonyl-2,4-thiazolidinedione, (Z) -5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-p-methylbenzenesulfonyl-2,4-thiazolidinedione, (Z)-5-(3, 5-di-tert-butyl-4-hydroxyphenylmethylene)-3-benzenesulfonyl-2,4-thiazolidinedione, (Z)-5-(3,5-di-tert-butyl-4- Hydroxyphenylmethylene)-3-methylsulfonyl-2,4-thiazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)- 3-Ethylsulfonyl-2,4-thiazolidinedione, or (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-propylsulfonyl- 2,4-thiazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-butylsulfonyl-2,4-thiazolidinedione , and the pharmaceutically acceptable salts formed by these compounds, such as potassium salts, hydrates and prodrugs.

It has been verified by experiments that the outstanding advantage of the above compound is that it exhibits excellent anti-inflammatory and analgesic effects. In addition, the introduction of sulfonylated groups may make the compounds safer when administered.

The method for preparing substituted aryl methylene sulfonylated azacyclopentanone compounds of the present invention uses substituted aromatic aldehydes as raw materials, adds a catalyst, and reacts with azacyclopentanone intermediates to firstly prepare a dehydration condensation intermediate; and then Add a basic catalyst and react with arylsulfonyl chloride or alkylsulfonyl chloride to prepare a sulfonylated product. In the preparation process, the dehydration condensation catalyst is selected from amine reagents such as ethanolamine, isopropanolamine, pyridine or piperidine, etc.; the basic catalyst is selected from acylation catalysts such as dimethylaminopyridine (DMAP ), 2,4,6-collidine, pyridine or triethylamine, etc.

Aromatic formaldehyde and azacyclopentanone are condensed in water under the catalysis of 1/10 molar amount of isopropanolamine, which can replace other organic catalysts and traditional inorganic base-catalyzed condensation reactions. The reaction product is single, the post-treatment is simple and the yield is high. higher. In the presence of an acid scavenger such as triethylamine, the compound of the present invention can be obtained by reacting the condensation product with a substituted sulfonyl chloride in tetrahydrofuran.

The present invention also provides the substituted benzylidenesulfonylated cyclopentanone-containing drugs, including substituted arylmethylenesulfonylated azocyclopentanone compounds and one or more of these compounds as medicinal ingredients. The pharmaceutical composition is used in the preparation of anti-inflammatory and analgesic drugs.

The standard acetic acid-induced mouse writhing model commonly used to screen non-narcotic analgesics was used to evaluate the analgesic activity of these compounds. Darbufelone and the newly listed selective cox-2 inhibitor valdecoxib (Valdecoxib) were selected As a control drug, it was found that at the same dose, the compound of the present invention has obvious analgesic activity. The anti-inflammatory activity of the compound was screened by the xylene inflammatory test, and it was found that the compound exhibited strong anti-inflammatory activity at the same dose. It shows that these compounds are effective non-steroidal anti-inflammatory and analgesic active compounds.

The present invention also includes providing one or more pharmaceutical compositions containing the substituted benzylidenesulfonylated azacyclopentanone compound and one or more pharmaceutically acceptable carriers or excipients.

Detailed ways

The present invention will be further described below in conjunction with examples, but the scope of the present invention is not limited.

The structural feature of the compounds of the present invention is that the nitrogen substituting the azacyclopentanone is sulfonylated, thereby forming a new class of compounds. The inventors have found through research that the sulfonylated group, especially the sulfonamide group, is the key pharmacophore of non-steroidal anti-inflammatory analgesic drugs, such as meloxicam, ampiraxicam, JET-522, piroxicam and Celecoxib, etc.; and sulfonamide-substituted structures such as celecoxib may have better cardiovascular safety than non-sulfonamide-substituted structures such as rofecoxib (Vioxx). (The cardiovascular safety of the two coxib COX-2 inhibitors is different. Chinese Medical Information Herald, 2004; 22: 15). Based on this, the present invention designs and obtains a series of p-hydroxyaryl methylenesulfonylated azacyclopentanone derivatives.

The compound of the present invention is a compound shown in general formula I and its pharmaceutically acceptable salt or hydrate or prodrug:

In formula (I), R ¹ and R ² each independently represent hydrogen, a hydroxyl group, a linear or branched chain alkyl or alkoxy group containing 1 to 6 carbons, and R ¹ and R ² can be the same or different; R ³ Represents hydrogen, arylsulfonyl or alkylsulfonyl; X represents CH ₂ , NH, O or S group; Y represents O, S, NH, arylsulfonyl or alkylsulfonyl; The configuration of the compound represented by general formula (I) can be E configuration or Z configuration. Wherein when R ³ represents hydrogen, Y does not include O, S or NH groups.

The specific compound can be: (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-p-toluenesulfonylimide-4-thiazolidinone, (Z )-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-benzenesulfonylimido-4-thiazolidinone, (Z)-5-(3,5- Di-tert-butyl-4-hydroxyphenylmethylene)-2-methylsulfonimido-4-thiazolidinone, (Z)-5-(3,5-di-tert-butyl-4-hydroxy Phenylmethylene)-2-ethylsulfonylimido-4-thiazolidinone, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2 -Propylsulfonimide-4-thiazolidinone, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-butylsulfonimide -4-thiazolidinone, (Z)-5-(4-hydroxyphenylmethylene)-2-benzenesulfonylimide-3-benzenesulfonyl-4-thiazolidinone, (Z)-5 -(4-hydroxyphenylmethylene)-3-p-toluenesulfonyl-2,4-imidazolidinedione, (Z)-5-(4-hydroxyphenylmethylene)-3-benzenesulfonyl -2,4-imidazolidinedione, (Z)-5-(4-hydroxyphenylmethylene)-3-ethanesulfonyl-2,4-imidazolidinedione, (Z)-5-(3 , 5-di-tert-butyl-4-hydroxyphenylmethylene)-3-methylsulfonyl-2,4-imidazolidinedione, (Z)-5-(3,5-di-tert-butyl- 4-hydroxyphenylmethylene)-3-ethylsulfonyl-2,4-imidazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene )-3-propylsulfonyl-2,4-imidazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-butylsulfonyl -2,4-imidazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-p-methylphenylsulfonyl-2,4- Imidazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-phenylsulfonyl-2,4-imidazolidinedione, (Z) -5-(3-methoxy-4-hydroxyphenylmethylene)-2-p-toluenesulfonylimide-3-p-methylbenzenesulfonyl-4-thiazolidinone, (Z)-5 -(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-p-toluenesulfonyl-3-p-toluenesulfonyl-4-thiazolidinone, (Z)- 5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-benzenesulfonylimide-3-benzenesulfonyl-4-thiazolidinone, (Z)-5-( 3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-methanesulfonyl-3-methylsulfonyl-4-thiazolidinone, (Z)-5-(3,5 -Di-tert-butyl-4-hydroxyphenylmethylene)-2-ethanesulfonylimide-3-ethanesulfonyl-4-thiazolidinone, (Z)-5-(3,5-di-tert Butyl-4-hydroxyphenylmethylene)-2-propanesulfonylimide-3-propanesulfonyl-4-thiazolidinone, (Z)-5-(3,5-di-tert-butyl- 4-hydroxyphenylmethylene)-2-butanesulfonylimide-3-butanesulfonyl-4-thiazolidinone, (Z)-5-(3-methoxy-4-hydroxyphenylene Methyl)-2-ethanesulfonylimido-4-thiazolidinone, (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-3-p-toluenesulfonyl-2 , 4-thiazolidinedione, (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-3-benzenesulfonyl-2,4-thiazolidinedione, (Z)- 5-(3-methoxy-4-hydroxyphenylmethylene)-3-ethanesulfonyl-2,4-thiazolidinedione, (Z)-5-(3,5-di-tert-butyl- 4-hydroxyphenylmethylene)-3-p-methylbenzenesulfonyl-2,4-thiazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylene Methyl)-3-benzenesulfonyl-2,4-thiazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-methylsulfonate Acyl-2,4-thiazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-ethylsulfonyl-2,4-thiazolidine Diketone, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-propylsulfonyl-2,4-thiazolidinedione, (Z)-5 -(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-butylsulfonyl-2,4-thiazolidinedione, (Z)-5-(3-methoxy- 4-hydroxyphenylmethylene)-3-p-toluenesulfonyl-2,4-imidazolidinedione, (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-3 -Benzenesulfonyl-2,4-imidazolidinedione, (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-3-methylsulfonyl-2,4-imidazolidinedione Ketone, (Z)-5-(4-hydroxyphenylmethylene)-3-p-toluenesulfonyl-2,4-thiazolidinedione, (Z)-5-(4-hydroxyphenylmethylene )-3-benzenesulfonyl-2,4-thiazolidinedione, (Z)-5-(4-hydroxyphenylmethylene)-3-benzenesulfonyl-2,4-thiazolidinedione, ( Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-p-methylbenzenesulfonyl-2,4-thiazolidinedione, (Z)-5-( 3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-benzenesulfonyl-2,4-thiazolidinedione, (Z)-5-(3,5-di-tert-butyl- 4-hydroxyphenylmethylene)-3-methylsulfonyl-2,4-thiazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene )-3-ethylsulfonyl-2,4-thiazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-propylsulfonyl -2,4-thiazolidinedione, (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-3-butylsulfonyl-2,4-thiazolidinedione Ketones etc.

The compounds of the present invention also include pharmaceutically acceptable salts formed from these compounds, such as potassium salts, hydrates and prodrugs.

The present invention also includes providing one or more pharmaceutical compositions containing the medicine of the substituted benzylidenesulfonylated azacyclopentanone compound and a pharmaceutically acceptable carrier or excipient.

The present invention also provides the drug containing substituted benzylidenesulfonylated cyclopentanones, including substituted arylmethylenesulfonylated azacyclopentanones and a pharmaceutical composition using it as a medicinal component. Use of anti-inflammatory analgesic drugs.

The anti-inflammatory and analgesic medicines made from the compounds and compositions of the present invention are used in the treatment, prevention, suppression or alleviation of the above-listed diseases in mammals, preferably humans. A dose that provides a palliative or preventive effect on disease.

The compounds of the present invention or compositions thereof can be administered orally or parenterally. Oral administration can be in the form of tablets, pills, powder mixtures, capsules, coatings, solutions, emulsions, dispersions, injections and suppositories, or other appropriate forms. These formulations are prepared according to methods well known to those skilled in the art. The excipients used in the manufacture of tablets, capsules and coatings are commonly used auxiliaries, such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents used in liquid dosage forms such as water, ethanol, propylene glycol, vegetable oils Such as corn oil, peanut oil, olive oil, etc. The preparation containing the compound of the present invention may also contain other auxiliary agents, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, pigments and the like.

The method for preparing substituted aryl methylene sulfonylated azacyclopentanones used in the present invention is to use substituted aromatic aldehydes as raw materials, add a catalyst, and react with azacyclopentanones intermediates to first prepare a dehydration condensation intermediate; Then add a basic catalyst to react with arylsulfonyl chloride or alkylsulfonyl chloride to prepare a sulfonylated product. In the preparation process, the dehydration condensation catalyst is selected from amine reagents such as ethanolamine, isopropanolamine, pyridine or piperidine, etc.; the basic catalyst is selected from acylation catalysts such as dimethylaminopyridine (DMAP ), 2,4,6-collidine, pyridine or triethylamine, etc.

The condensation reaction of aromatic formaldehyde and azacyclopentanone in water under the catalysis of isopropanolamine can replace the traditional condensation reaction catalyzed by inorganic base, and the single-post-treatment of the reaction product is simple and the yield is high. In the presence of an acid scavenger such as triethylamine, the compound of the present invention can be obtained by reacting the condensation product with a substituted sulfonyl chloride in tetrahydrofuran.

The following specific examples illustrate the preparation and properties of the compounds of the present invention, and the examples are not exhaustive. The reagents used in the examples are commercially available; Measuring instrument: RY-1 type electric melting point instrument for melting point, thermometer reading without correction, nuclear magnetic resonance spectrum with JNM-ECA-400 type nuclear magnetic resonance instrument, mass spectrometry with Zabspec type mass spectrometer .

Example 1: Preparation of (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-p-toluenesulfonimide-4-thiazolidinone (A1)

Add 2.34g (10mmol) 3,5-di-tert-butyl-4-hydroxybenzaldehyde, 1.16g (10mmol) 2-imino-4-thiazolidinone and 20ml water in a 50ml round-bottomed flask, and add under stirring 0.075 g (1 mmol) isopropanolamine. Reflux for 10 h, cool to room temperature, and filter with suction, wash the filter cake with cold water, and dry to obtain 2.69 g of yellow solid, mp 283-286°C, yield 81.0%. is (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-imino-4-thiazolidinone (intermediate A).

Dissolve 0.198g (0.6mmol) of the intermediate A in 10ml of dry tetrahydrofuran, and add 0.120g (1.2mmol) of triethylamine (1.2mmol) and 0.228g (1.2mmol) of p-toluenesulfonyl chloride while stirring. Reaction at 50°C for 12h, preparative thin-layer separation, the developing solvent was dichloromethane:methanol=15:1, and 0.102g of yellow solid was obtained, mp 264-267°C, yield 35.0%.

Example 2: Preparation of (Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-benzenesulfonimide-4-thiazolidinone (A2)

Carry out by the method for embodiment 1.

The intermediate A is obtained first, the raw materials used in the condensation reaction are 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 2-imino-4-thiazolidinone, and the catalyst is ethanolamine.

The reagent used in the sulfonylation process is benzenesulfonyl chloride, and the basic catalyst used is dimethylaminopyridine.

The obtained product A2(Z)-5-(3,5-di-tert-butyl-4-hydroxyphenylmethylene)-2-benzenesulfonimido-4-thiazolidinone is a yellow solid, mp 252 -255°C, yield 18.9%.

Example 3: Preparation of (Z)-5-(4-hydroxyphenylmethylene)-2-benzenesulfonylimide-3-benzenesulfonyl-4-thiazolidinone (A3)

The same method as in Example 1 was used.

First synthesize (Z)-5-(4-hydroxyphenylmethylene)-2-imino-4-thiazolidinone, the raw materials used are 4-hydroxybenzaldehyde and 2-imino-4-thiazolidine Ketones, the catalyst is isopropanolamine. A yellow solid was obtained, mp > 300°C, and the yield was 82.4%.

The reagent used in the sulfonylation process is benzenesulfonyl chloride, and the basic catalyst used is pyridine.

The product A3 was obtained as light yellow solid, mp 222-226°C, yield 22.5%.

Example 4: Preparation of (Z)-5-(4-hydroxyphenylmethylene)-3-p-toluenesulfonyl-2,4-imidazolidinedione (A4)

The same method as in Example 1 was used.

First synthesize (Z)-5-(4-hydroxyphenylmethylene)-2,4-imidazolidinedione. The raw materials used are 4-hydroxybenzaldehyde and 2,4-imidazolidinedione, and the catalyst is piperidine. A yellow solid was obtained, mp>300°C. Then it was synthesized according to the method for preparing compound A1. The reagent used in the sulfonylation process is p-toluenesulfonyl chloride, and the basic catalyst used is pyridine. The obtained product A4 was a white solid, mp 245-247°C, yield 55.9%.

Example 5: Preparation of (Z)-5-(4-hydroxyphenylmethylene)-3-benzenesulfonyl-2,4-imidazolidinedione (A5)

The same method as in Example 4 was used.

First synthesize (Z)-5-(4-hydroxyphenylmethylene)-2,4-imidazolidinedione. The raw materials used are 4-hydroxybenzaldehyde and 2,4-imidazolidinedione, and the catalyst is isopropanolamine. A yellow solid was obtained, mp>300°C. Then it was synthesized according to the method for preparing compound A1. The reagent used in the sulfonylation process is benzenesulfonyl chloride, and the basic catalyst used is pyridine. The obtained product A5 was a white solid, mp 237-239°C, yield 34.9%.

Example 6: Preparation of (Z)-5-(4-hydroxyphenylmethylene)-3-ethanesulfonyl-2,4-imidazolidinedione (A6)

The same method as in Example 4 was used.

First synthesize (Z)-5-(4-hydroxyphenylmethylene)-2,4-imidazolidinedione. The raw materials used are 4-hydroxybenzaldehyde and 2,4-imidazolidinedione, and the catalyst is isopropanolamine. Then it was synthesized according to the method for preparing compound A1. The reagent used in the sulfonylation process is ethylsulfonyl chloride, and the basic catalyst used is pyridine. The obtained product A6 is a white solid, mp223-224°C, yield 47.3%.

Example 7: Preparation of (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-2-p-toluenesulfonylimide-3-p-toluenesulfonyl-4-thiazolidinone (A7)

First synthesize (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-2-imino-4-thiazolidinone according to the method for preparing intermediate A, and the raw material used is 3-methyl Oxy-4-hydroxybenzaldehyde and 2-imino-4-thiazolidinone, the catalyst is ethanolamine. A yellow solid was obtained, mp 280°C (dec.).

Then it was synthesized according to the method for preparing compound A1. The reagent used in the sulfonylation process is p-toluenesulfonyl chloride, and the basic catalyst used is 2,4,6-collidine. The obtained product A7 was a yellow solid, mp 262-264°C, yield 30.2%.

Example 8: Preparation of (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-2-ethanesulfonylimido-4-thiazolidinone (A8)

Synthesized according to the method for preparing compound A1. The reagent used in the sulfonylation process is ethanesulfonyl chloride, and the basic catalyst used is pyridine. The product A8 was obtained as light yellow solid, mp 225°C (dec.), yield 15.4%.

Example 9: Preparation of (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-3-p-toluenesulfonyl-2,4-thiazolidinedione (A9)

First synthesize (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-2,4-thiazolidinedione according to the method for preparing intermediate A, and the raw material used is 3-methoxy- 4-hydroxybenzaldehyde and 2,4-thiazolidinedione, the catalyst is isopropanolamine. A yellow solid was obtained, mp 228-230°C, yield 77.7%. Then it was synthesized according to the method for preparing compound A1. The reagent used in the sulfonylation process is p-toluenesulfonyl chloride, and the basic catalyst used is triethylamine. The product A9 was obtained as a yellow solid, mp 210-214°C, yield 31.6%.

Example 10: Preparation of (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-3-benzenesulfonyl-2,4-thiazolidinedione (A10)

First synthesize (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-2,4-thiazolidinedione according to the method for preparing intermediate A, and the raw material used is 3-methoxy- 4-hydroxybenzaldehyde and 2,4-thiazolidinedione, the catalyst is isopropanolamine. A yellow solid was obtained. Then it was synthesized according to the method for preparing compound A1. The reagent used in the sulfonylation process is benzenesulfonyl chloride, and the basic catalyst used is triethylamine. The obtained product A10 was a light yellow solid, mp 199-202°C, and the yield was 38.4%.

Example 11: Preparation of (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-3-ethanesulfonyl-2,4-thiazolidinedione (A11)

First synthesize (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-2,4-thiazolidinedione according to the method for preparing intermediate A, and the raw material used is 3-methoxy- 4-hydroxybenzaldehyde and 2,4-thiazolidinedione, the catalyst is pyridine. A yellow solid was obtained. Then it was synthesized according to the method for preparing compound A1. The reagent used in the sulfonylation process is ethylsulfonyl chloride, and the basic catalyst used is dimethylaminopyridine. The product A11 was obtained as light yellow solid, mp 187-191°C, yield 25.7%.

Example 12: Preparation of (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-3-p-toluenesulfonyl-2,4-imidazolidinedione (A12)

1.52g (10mmol) of vanillin, 1.2g (10mmol) of 2,4 imidazolidinedione and 20ml of water were added to a 50ml round bottom flask, and 0.09g (1.5mmol) of isopropanolamine was added with stirring. Reflux for 12 hours, cool to room temperature, and filter with suction, wash the filter cake with cold water, and dry to obtain 1.5 g of a light yellow solid with a yield of 84.1%, which is (Z)-5-(3-methoxy-4-hydroxyphenylmethylene base)-2,4-imidazolidinedione (intermediate B).

Take 0.117g (0.5mmol) of the intermediate B and dissolve it in 6ml of dry tetrahydrofuran, and add 0.15g (1.5mmol) of triethylamine (1.5mmol) and 0.228g (1.2mmol) of p-toluenesulfonyl chloride under stirring. Reaction at 50°C for 12h, preparative thin-layer separation, the developing solvent was dichloromethane:methanol=15:1, to obtain 50 mg of light yellow solid, mp 255-258°C, yield 25.7%.

Example 13: Preparation of (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-3-benzenesulfonyl-2,4-imidazolidinedione (A13)

According to the synthesis method for preparing intermediate B, (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-2,4-imidazolidinedione was first synthesized, and the catalyst used was ethanolamine. Then it was synthesized according to the method for preparing compound A12. The sulfonylation reagent is benzenesulfonyl chloride, and the basic catalyst is pyridine. The product A13 was obtained as a white solid, mp 240-242°C, yield 48.1%.

Example 14: Preparation of (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-3-methylsulfonyl-2,4-imidazolidinedione (A14)

According to the synthesis method for preparing intermediate B, (Z)-5-(3-methoxy-4-hydroxyphenylmethylene)-2,4-imidazolidinedione was first synthesized, and the catalyst used was piperidine. Then it was synthesized according to the method for preparing compound A12. The sulfonylation reagent is methanesulfonyl chloride, and the basic catalyst is triethylamine. The product A14 was obtained as a white solid, mp 250-251°C, yield 16.1%.

Example 15: Preparation of (Z)-5-(4-hydroxyphenylmethylene)-3-p-toluenesulfonyl-2,4-thiazolidinedione (A15)

1.22g (10mmol) of p-hydroxybenzaldehyde, 1.17g (10mmol) of 2,4-thiazolidinedione and 20ml of water were added to a 50ml round bottom flask, and 0.09g (1.5mmol) of isopropanolamine was added with stirring. Refluxed for 12 hours, cooled to room temperature and suction filtered. The filter cake was washed with cold water and dried to obtain 1.3 g of a yellow solid with a yield of 78.8%. It was (Z)-5-(4-hydroxyphenylmethylene)-2,4- Thiazolidinedione (Intermediate C).

Take 0.111g (0.5mmol) of the intermediate C and dissolve it in 5ml of dry tetrahydrofuran, and add 0.12g (1.2mmol) of triethylamine (1.2mmol) and 0.228g (1.2mmol) of p-toluenesulfonyl chloride under stirring. Reaction at 50°C for 22h, preparative thin layer separation, the developing solvent was dichloromethane:methanol=15:1, 80 mg of yellow solid was obtained, mp 187-190°C, yield 42.7%.

Example 16: Preparation of (Z)-5-(4-hydroxyphenylmethylene)-3-benzenesulfonyl-2,4-thiazolidinedione (A16)

According to the synthesis method for preparing intermediate C, (Z)-5-(4-hydroxyphenylmethylene)-2,4-thiazolidinedione was first synthesized, and the catalyst used was ethanolamine. Then it was synthesized according to the method for preparing compound A15. The sulfonylation reagent is benzenesulfonyl chloride, and the basic catalyst is pyridine. Product A16 is a yellow solid, mp 179-182°C, yield 41.6%.

Example 17: Preparation of (Z)-5-(4-hydroxyphenylmethylene)-3-methylsulfonyl-2,4-thiazolidinedione (A17)

According to the synthesis method for preparing intermediate C, (Z)-5-(4-hydroxyphenylmethylene)-2,4-thiazolidinedione was first synthesized, and the catalyst used was piperidine. Then it was synthesized according to the method for preparing compound A15. The sulfonylation reagent is methanesulfonyl chloride, and the basic catalyst is triethylamine. Product A17 is a white solid, mp 201-204°C, yield 20.1%.

After determination, the physical and chemical data of the compounds in the examples of the present invention are shown in Table 1.

Table 1 Physicochemical data of compounds A1-A17

compound Mp(°C) MS(m/z) ¹ H-NMR(δ) A1 264-267 487(M+1) 1.48(s, 18H), 2.44(s, 3H), 5.77(s, 1H), 7.33(d, 2H, J=8.1Hz), 7.41(s, 2H), 7.87(d, 2H, J=8.2Hz ) A2 252-255 473(M+1) 1.47(s, 18H), 5.76(s, 1H), 7.39(s, 2H), 7.52(m, 2H, J=7.2Hz), 7.59(m, 1H, J=7.2Hz), 7.99(d, 2H , J=7.7Hz) A3 222-226 501(M+1) 7.25(d, 2H, J=8.8Hz), 7.63(d, 2H, J=8.0Hz), 7.67(s, 1H), 7.70(m, 4H, J=8.3Hz), 7.86(m, 2H, J = 8.4Hz), 7.91 (d, 4H, J = 8.5Hz) A4 245-247 359(M+1) 2.51(s, 3H), 6.38(s, 1H), 7.03(dd, 2H, J=8.7Hz, J’=1.8Hz), 7.49(d, 2H, J=7.8Hz), 7.61(dd, 2H, J=8.7Hz, J'=1.8Hz), 7.76(d, 2H, J=8.2Hz) A5 237-239 345(M+1) 6.38(s, 1H), 7.03(d, 2H, J=8.8Hz), 7.61(d, 2H, J=8.5Hz), 7.69(m, 2H, J=7.8Hz), 7.83(m, 1H, J =7.4Hz), 7.88(d, 2H, J=7.2Hz), 10.59(s), 11.32(s) A6 223-224 297(M+1) 1.38(t, 3H, J=7.4Hz), 3.55(q, 2H, J=7.4Hz), 6.44(s, 1H), 7.35(d, 2H, J=8.8Hz), 7.72(d, 2H, J =8.8Hz), 10.65(s), 11.32(s) A7 262-264 559(M+1) 2.39(s, 3H), 2.43(s, 3H), 3.59(s, 3H), 7.22(dd, 1H, J=8.2Hz, J’=2.0Hz), 7.32(d, 1H, J=8.2Hz) , 7.37(d, 1H, J=1.8Hz), 7.42(d, 2H, J=8.0Hz), 7.48(d, 2H, J=8.0Hz), 7.71(s, 1H), 7.74(d, 2H, J=8.4Hz), 7.79(d, 2H, J=8.3Hz) A8 225(dec.) 343(M+1) 1.39(t, 3H, J=7.4Hz), 3.52(q, 2H, J=7.4Hz), 3.90(s, 3H), 7.09(dd, 1H, J=8.6Hz, J'=2.1Hz), 7.43 (d, 1H, J=8.3Hz) 7.42(s, 1H), 7.62(s, 1H) A9 211-214 406(M+1) 2.43(s, 3H), 3.55(s, 3H), 7.16(dd, 1H, J=8.5Hz, J’=1.9Hz), 7.25(d, 1H, J=8.5Hz), 7.30(d, 1H, J=1.9Hz), 7.47(d, 2H, J=8.3Hz), 7.72(d, 2H, J=8.2Hz), 7.76(s, 1H) A10 199-202 392(M+1) 3.55(s, 3H), 7.17(dd, 1H, J=8.4Hz, J'=2.0Hz), 7.27(d, 1H, J=8.4Hz), 7.28(d, 1H, J=2.0Hz), 7.67 (m, 2H, J=7.6Hz), 7.75(s, 1H), 7.82(m, 1H, J=7.6Hz), 7.85(d, 2H, J=7.3Hz) A11 187-191 344(M+1) 1.39(t, 3H, J=7.3Hz), 3.49(q, 2H, J=7.3Hz), 3.85(s, 3H),

5.32(s, 1H), 7.03(dd, 1H, J=8.2Hz, J’=2.0Hz), 7.32(d, 1H, J=8.2Hz), 7.15(d, 1H, J=2.0Hz) A12 255-258 389(M+1) 2.43(s, 3H), 3.57(s, 3H), 6.36(s, 1H), 7.05(d, 1H, J=8.9Hz), 7.18(d, 1H, J=8.7Hz), .19(s, 1H), 7.46(d, 2H, J=7.9Hz), 7.71(d, 2H, J=8.4Hz), 10.64(s, 1H), 11.29(s, 1H) A13 240-242 375(M+1) 2.54(s, 3H), 6.37(s, 1H), 7.08(d, 1H, J=8.4Hz), 7.17(s, 1H), 7.20(m, 1H), 6.67(m, 2H), 7.81(d , 1H, J=8.9Hz), 7.83(d, 2H, J=7.3Hz), 10.65(s, 1H), 11.30(s, 1H) A14 250-251 313(M+1) 3.37(s, 3H), 3.92(s, 3H), 6.43(s, 1H), 7.27(dd, 1H, J=8.4Hz, J’=2.0Hz), 7.29(s, 1H), 7.32(d, 1H, J=8.1Hz), 10.70(s, 1H), 11.30(s, 1H) A15 187-190 376(M+1) 2.47(s, 3H), 7.12(d, 2H, J=9.0Hz), 7.34(d, 2H, J=8.4), 7.43(d, 2H, J=8.7Hz), 7.73(d, 2H, J= 8.4), 7.78(s, 1H) A16 179-182 362(M+1) 7.20(d, 2H, J=8.7Hz), 7.61(d, 2H, J=8.7Hz), 7.69(m, 2H), 7.76(s, 1H), 7.84(m, 1H), 7.89(d, 2H , J=8.4Hz), 12.67(s, 1H) A17 201-204 300(M+1) 3.44(s, 3H), 7.51(d, 2H, J=8.7Hz), 7.72(d, 2H, J=8.7Hz), 7.83(s, 1H), 12.68(s, 1H)

Experiment 1: Analgesic activity test in mice

Kunming mice, half male and half male, weighing 18-22 g, were randomly divided into groups with 8 animals in each group. A blank control group, a Darbufelone control group, a Valdecoxib (valdecoxib, a newly marketed selective cox-2 inhibitor) group and 17 new compound groups were set up. The blank control group was 0.2% carboxymethylcellulose sodium (CMCNa) physiological saline solution, and all the drugs were dispersed with 0.2% CMCNa physiological saline solution with a concentration of 0.1 mg/ml.

The analgesic activity of the compound was evaluated by using the acetic acid-induced mouse writhing model commonly used by non-narcotic analgesics. The mice in each group were injected with 0.2ml of blank or drug, and then injected with 0.6% acetic acid saline solution 0.2ml after 1h. ml, after 5 minutes, start counting the number of times the mouse writhes within 10 minutes, the mice with the number of writhing less than or equal to 5 times are recorded as pain suppression, and the mice with more than 5 times are recorded as pain suppression, and the pain suppression is calculated based on this Rate. The screening results are shown in Table 2.

Table 2 Analgesic activity screening results

compound The number of mice that completed the experiment (only) Mouse pain inhibition rate blank control 8 25% Darbufelone group 7 70.7% Valdecoxib group 8 62.5%

A1 8 75.0% A2 7 28.6% A3 8 87.5% A4 8 72.5% A5 8 62.5% A6 8 25% A7 8 65.5% A8 7 42.9% A9 8 12.5% A10 8 72.5% A11 8 61.5% A12 8 70.5% A13 8 71.3% A14 8 62.2% A15 8 52.5% A16 8 78.1% A17 8 61.2%

As can be seen from the results in Table 2, compared with the blank group, 14 of the 17 compounds used in the experiment of the present invention have very significant analgesic activity, and the other 3 pain suppression rates are relatively low, which may be related to the application amount; positive The control results showed that the analgesic activity of 12 of the 17 compounds was equivalent to or better than that of Valdecoxib group, and 7 of them were equivalent or better than that of Darbufelone. Among them, the pain inhibition rate of A1, A3, and A16 was significantly higher than that of Darbufelone, with The experimental results of A3 are the most prominent, the pain suppression rate is 17% higher than Darbufelone, and 25% higher than Valdecoxib.

Experiment 2: Xylene Inflammation Test in Mice

Male mice weighing 18-22 g were randomly divided into groups of 8 animals. A blank group (0.2% CMCNa normal saline solution), a positive control group (Darbufelone group and Valdecoxib group) and an administration test group were set up. Intraperitoneal injection 60 minutes before inflammation. Weigh 0.5 mg of the drug respectively and place it in a 5 ml volumetric flask, and prepare a solution with 0.2% CMCNa normal saline solution. Each mouse was injected with 0.3ml of blank or drug respectively. 50 microliters of xylene was dropped on the right ear of the mouse, and the left ear was the control. After 30 minutes, the mice were sacrificed, and the two ears were cut off along the base line of the auricles, and round ear pieces were respectively punched in the same part of the two ears with a puncher with a diameter of 6 mm, weighed, and the weight difference between the left and right ear pieces was calculated as the degree of swelling, Compare the significance of the difference between groups. The results show that compared with the blank group, the swelling degree of the compound of the present invention is significantly reduced, and there is a significant difference; compared with the positive control group, the swelling degree of the compound of the present invention has no significant difference, indicating that the compound of the present invention has comparable anti-inflammatory properties with Darbufelone and Valdecoxib .

Experiment 3: Mouse Toxicity Experiment

It is carried out according to the routine toxicity test methods well known to those skilled in the art.

18-22g healthy mice were selected for toxicity experiment. A blank group (0.2% CMCNa physiological saline solution), a positive control group (Darbufelone group and Valdecoxib group) and an administration test group were set up with 10 rats in each group. Dissolve the test drug in normal saline and prepare a solution with a certain concentration. The route of administration is oral gavage, daily administration, group observation for 7 consecutive days, and observe whether the experimental mice have poisoning symptoms and death after administration. The results showed that during the observation period, the mice in each group had no obvious abnormality or death, indicating that the toxicity of the compound of the present invention was not significantly different from that of the positive control group.

Claims (8)

1. contain the substituted aryl methylene sulfonylated aza cyclo-pentanone compound, be the compound of structure shown in general formula I:

In the formula (I), R ¹And R ²Represent hydrogen, hydroxyl independently of one another, contain the straight or branched alkyl of 1 to 6 carbon or contain the straight or branched alkoxyl group of 1 to 6 carbon, R ¹And R ²Identical or different; R ³Represent hydrogen, aryl sulfonyl or alkyl sulphonyl; X represents CH ₂, NH, O or S group; Y represents O, S, NH, arylsulfonyl imido grpup or alkyl sulfonyl imido grpup; And wherein work as R ³When representing hydrogen, Y only represents arylsulfonyl imido grpup or alkyl sulfonyl imido grpup.

2. the substituted aryl methylene sulfonylated aza cyclo-pentanone compound that contains as claimed in claim 1 is characterized in that R ¹And R ²Represent hydrogen, hydroxyl, methoxyl group, oxyethyl group or the tertiary butyl independently of one another.

3. the substituted aryl methylene sulfonylated aza cyclo-pentanone compound that contains as claimed in claim 1 or 2 is characterized in that R ¹And R ²Represent the tertiary butyl respectively; X represents NH or S group; Compound be configured as the Z configuration.

4. the substituted aryl methylene sulfonylated aza cyclo-pentanone compound that contains as claimed in claim 1 is characterized in that, is specially:

(Z)-5-(3,5-di-tert-butyl-hydroxy phenyl methylene radical)-2-tolysulfonyl imido grpup-4-thiazolidone,

(Z)-5-(3,5-di-tert-butyl-hydroxy phenyl methylene radical)-2-benzenesulfonimide base-4-thiazolidone,

(Z)-5-(4-hydroxy phenyl methylene radical)-2-benzenesulfonimide base-3-benzenesulfonyl-4-thiazolidone,

(Z)-5-(4-hydroxy phenyl methylene radical)-3-p-toluenesulfonyl-2, the 4-imidazolidimedione,

(Z)-5-(4-hydroxy phenyl methylene radical)-3-benzenesulfonyl-2, the 4-imidazolidimedione,

(Z)-5-(4-hydroxy phenyl methylene radical)-3-ethylsulfonyl-2, the 4-imidazolidimedione,

(Z)-5-(3-methoxyl group-4-hydroxy phenyl methylene radical)-2-tolysulfonyl imido grpup-3-p-toluenesulfonyl-4-thiazolidone,

(Z)-5-(3-methoxyl group-4-hydroxy phenyl methylene radical)-2-second sulfimide base-4-thiazolidone,

(Z)-5-(3-methoxyl group-4-hydroxy phenyl methylene radical)-3-p-toluenesulfonyl-2, the 4-thiazolidinedione,

(Z)-5-(3-methoxyl group-4-hydroxy phenyl methylene radical)-3-benzenesulfonyl-2, the 4-thiazolidinedione,

(Z)-5-(3-methoxyl group-4-hydroxy phenyl methylene radical)-3-ethylsulfonyl-2, the 4-thiazolidinedione,

(Z)-5-(3-methoxyl group-4-hydroxy phenyl methylene radical)-3-p-toluenesulfonyl-2, the 4-imidazolidimedione,

(Z)-5-(3-methoxyl group-4-hydroxy phenyl methylene radical)-3-benzenesulfonyl-2, the 4-imidazolidimedione,

(Z)-5-(3-methoxyl group-4-hydroxy phenyl methylene radical)-3-methylsulfonyl-2, the 4-imidazolidimedione,

(Z)-5-(4-hydroxy phenyl methylene radical)-3-p-toluenesulfonyl-2, the 4-thiazolidinedione,

(Z)-5-(4-hydroxy phenyl methylene radical)-3-benzenesulfonyl-2, the 4-thiazolidinedione or

(Z)-and 5-(4-hydroxy phenyl methylene radical)-3-methylsulfonyl-2, the 4-thiazolidinedione.

5. pharmaceutical composition wherein contains arbitrary described substituted aryl methylene sulfonylated aza cyclo-pentanone compound, its pharmacologically acceptable salt or its hydrate of containing of claim 1 to 4 as effective constituent, and contains pharmaceutically acceptable carrier or vehicle.

6. arbitrary described preparation method who contains the substituted aryl methylene sulfonylated aza cyclo-pentanone compound of claim 1 to 4, it is characterized in that, step 1: to replace aromatic aldehyde is raw material, add amine reagents such as thanomin, Yi Bingchunan, pyridine or piperidines and make catalyzer, obtain the dehydrating condensation intermediate earlier with aza cyclo-pentanone class back flow reaction; Step 2: add dimethylamino pyridine, 2, pyridine or triethylamine again and make basic catalyst, with aryl sulfonyl chloride or alkyl sulfonyl chloride prepared in reaction sulfonylation product.

7. preparation method as claimed in claim 6 is characterized in that, is reactant with aromatic formaldehyde and aza cyclo-pentanone in the step 1, and Yi Bingchunan is a catalyzer, and the condensation reaction that refluxes obtains the condensation intermediate.

8. arbitrary described substituted aryl methylene sulfonylated aza cyclo-pentanone compound, its pharmacologically acceptable salt or its hydrate application in preparation non_steroidal anti_inflammatory drug thing that contains of claim 1 to 4.