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CN1309717C - 4-aryl group-5H-thoifuran-2-ketone derivative, producing method and use thereof - Google Patents

4-aryl group-5H-thoifuran-2-ketone derivative, producing method and use thereof Download PDF

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CN1309717C
CN1309717C CNB031412742A CN03141274A CN1309717C CN 1309717 C CN1309717 C CN 1309717C CN B031412742 A CNB031412742 A CN B031412742A CN 03141274 A CN03141274 A CN 03141274A CN 1309717 C CN1309717 C CN 1309717C
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李小虎
沈小宁
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
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Abstract

The present invention relates to a novel 4-aryl-5H-thiophene-2-one derivative of the formula I with therapeutic action and a medical composition containing novel 4-aryl-5H-thiophene-2-one derivative, a using method of the 4-aryl-5H-thiophene-2-one derivative and the medical composition containing novel 4-aryl-5H-thiophene-2-one derivative on treating disease mediated by II(COX-2) and a preparation method thereof.

Description

4-aryl-5H-thiophene-2-ketone derivatives, its method for making and purposes
Technical field
The present invention relates to new 4-aryl-5H-thiophene-2-ketone derivatives, contain the pharmaceutical composition of this derivative, their using method in the disease of treatment cyclooxygenase II (COX-2) mediation, and method for making with treatment effectiveness.
Background technology
Non-steroid antiinflammatory drug (NSAIDs) is widely used in anti-inflammatory, brings down a fever and relieves the pain.The mechanism of action usually is summed up as them and suppresses energy catalysis from arachidonic acid biosynthesizing prostaglandin(PG) such as PGG 2, PGH 2And PGE 2The ability of cyclooxygenase (COX).Recently invention shows two kinds of distinct enzymes, cyclooxygenase I (COX-1) and cyclooxygenase II (COX-2).COX-1 is consistent with the initial enzyme of determining, constitutive expression in majority tissue and organ (as stomach, intestines and kidney), and prostaglandin(PG) has cytoprotection to keeping normal physiological processes in these tissues and organ.Owing to this reason, most known non-steroidal anti-inflammatory drugs produce adverse side effect behind long-term large dose oral administration, often cause stomach ulcer, gastrorrhagia etc.On the contrary, COX-2 is a kind of derivable enzyme, and its content is subjected to the stimulation of factors such as inflammation, intracellular toxin, mitogen, cytokine and hormone or significantly raise (Proc.Natl.Acad.Sci.USA, 89,7384,1992).Because its vital role in inflammatory process, optionally suppress the COX-2 enzyme, can suppress the anti-inflammatory, fever, analgesic effect of prostaglandin(PG) and do not have the adverse side effect of traditional non-steroidal anti-inflammatory drug.
AlzheimerShi patient cerebral tissue, neurodegenerative disorders (as multiple sclerosis disease) patient, among the patients such as osteoporosis, asthma, lupus and psoriasis, all found the COX-2 enzyme that content raises.Optionally cox 2 inhibitor can be used for treating the disease of all these COX-2 enzyme mediations.
In addition, in colon, lung, esophagus, bladder cancer patients body, found excessive COX-2 (American J.of Pathology, 2001,158,1411-1422).In zooscopy, cox 2 inhibitor suppress significantly the propagation of colorectal carcinoma and invasion (International Journal of Cancer, 2002,100:515-519).Optionally cox 2 inhibitor may be useful as anticarcinogen, perhaps use separately or with known anticarcinogen such as taxol and carbon platinum (carboplatin) coupling.
Optionally the potential utility of cox 2 inhibitor is at Nature, Vol.367, and 215-216,1994 and Drug News and Perspectives, vol.7,501-512 described in 1994.
In recent years, optionally cox 2 inhibitor was on the books in the literature.In animal model and human clinical trial, optionally cox 2 inhibitor has same purpose for inflammatory diseasess such as rheumatic arthritis, osteoarthritis, urarthritis and autoimmune diseases, and has reduced the side effect to gastrointestinal toxicity and kidney.The example of putting down in writing in the prior art is as follows:
Patent WO95/15316 discloses the compound (IIa) of following molecular formula
Figure C0314127400091
One of them is as following molecular formula (IIb)
Patent WO95/00501 discloses the phenyl-heterocycles as the molecular formula of selective COX-2-2 inhibitor (IIc)
One of them example is shown in molecular formula (IId)
Figure C0314127400094
International patent application no WO 97/34882 discloses as 2-(3H)- trazodone derivative cox 2 inhibitor, that have general formula (IIe):
One of them example is shown in molecular formula (IIf)
Figure C0314127400102
U.S. patent No.5,859,036 disclose 3 of the following molecular formula of tool (IIg), 4-diaryl thiazole-2-ketone or 40 thione derivatives
Figure C0314127400103
X=O or S.
One of them example is shown in molecular formula (IIh)
U.S. patent No.6,020,343 discloses the cox 2 inhibitor of (methylsulfonyl) phenyl-2-(the 5H)-Furanones of the following molecular formula of tool (IIi):
Figure C0314127400111
One of them example is shown in molecular formula (IIj)
Yet the curative effect of existing C OX-2 inhibitor is also very not satisfactory, so this area presses for the new higher cox 2 inhibitor of curative effect of exploitation.
Summary of the invention
Purpose of the present invention just provides the 4-aryl shown in the new molecular formula of a class (I)-5H-thiophene-2-ketone derivatives, and they can be used as the COX-2 selective depressant and effectively treatment and COX-2 diseases associated:
R in the formula 1From following groups, select:
(a) alkyl of 1-6 carbon atom;
(b) haloalkyl of 1 to 6 carbon atom;
(c) NH 2Group;
(d) NHC (O) R 5, R wherein 5Be the alkyl of 1-6 carbon atom, or the low-grade halogenated alkyl of 1-6 carbon atom;
(e) NR 6R 7, R wherein 6And R 7Respectively from the low alkyl group of hydrogen or 1-6 carbon atom, or the low-grade halogenated alkyl of 1-6 carbon atom is selected;
R wherein 2And R 3From following groups, select respectively:
(a) hydrogen;
(b) low alkyl group of 1-6 carbon atom;
(c)OH；
R wherein 4From following groups, select:
(a) hydrogen;
(b) halogen;
(c) low alkyl group of 1-6 carbon atom;
(d) low-grade halogenated alkyl of 1-6 carbon atom;
(e) lower alkoxy of 1-6 carbon atom;
(f) NR 8R 9R wherein 8And R 9It is respectively the low alkyl group of 1-6 carbon atom;
(g) unsubstituted phenyl, or the phenyl that is replaced by 1 to 3 following group: halogen atom (chlorine, fluorine, bromine), CN, NH 2, OH, CF 3, the low alkyl group of 1-6 carbon atom, the alkoxyl group of the low-grade halogenated alkyl of 1-6 carbon atom, a 1-6 carbon atom.Substituting group position on the phenyl ring can be the optional position.
(h) pyridine (or its N-oxide compound) group that does not replace or replace, wherein substituting group is selected from the low alkyl group of 1 to 3 halogen atom (chlorine, fluorine, bromine) or 1-6 carbon atom, CN, NH 2, OH, CF 3Substituting group position on the pyridine ring can be the optional position.
(i) singly-, two-or three-substituted aroma heterocycle, wherein aromatic heterocycle is 5 yuan of single heterocycles of fragrance, and it is S that this ring has a heteroatoms, and O or N perhaps randomly have 1,2,3 additional nitrogen-atoms; Perhaps aromatic heterocycle is 6 yuan of single heterocycles, and this ring has a heteroatoms N or 1,2,3 optional additional nitrogen-atoms, and wherein substituting group is selected from following groups: hydrogen, 1 to 3 halogen atom, the low alkyl group of 1-6 carbon atom, CN, CF 3, NH 2, OH, the low-grade halogenated alkyl of 1-6 carbon atom.Substituting group position can be the optional position on the heterocycle.
(j) have two heterocycles of 8,9,10 atoms, this heterocycle comprises 2 to 5 heteroatomss, and heteroatoms is respectively from O, and S selects among the N, and wherein substituting group is selected from following groups: hydrogen, 1 to 3 halogen atom, the low alkyl group of 1-6 carbon atom, CN, CF 3, NH 2, OH, the low-grade halogenated alkyl of 1-6 carbon atom.Substituting group position can be the optional position on the heterocycle.
The X substituting group is selected from following groups in the formula:
(a) hydrogen atom;
(b) be positioned at the halogen atom of commutable position;
(c) alkyl of 1-6 carbon atom;
(d)CN；
(e)NO 2；
(f)OH；
(g)CF 3；
(h)CO 2H；
(i)NH 2。
In a preference, R 1It is the alkyl of 1-6 carbon atom.
In another preference, R 2And R 3It is respectively the low alkyl group of a hydrogen or 1-6 carbon atom.
In another preference, R 4Be unsubstituted phenyl, or the phenyl that is replaced by 1 to 3 following group: halogen atom, CN, NH 2, OH, CF 3, the low alkyl group of 1-6 carbon atom, the alkoxyl group of the low-grade halogenated alkyl of 1-6 carbon atom, a 1-6 carbon atom.
In another preference, X is hydrogen atom or halogen atom.
In a second aspect of the present invention, a kind of pharmaceutical composition is provided, it contains the described compound of claim 1 or its pharmacy acceptable salt, and pharmaceutically acceptable carrier.
In a third aspect of the present invention, the purposes of The compounds of this invention is provided, it is used to prepare the medicine of the disease for the treatment of the COX-2 mediation.
In a fourth aspect of the present invention, the preparation method of The compounds of this invention is provided, comprise step:
(a) catalyst A lCl 3Exist down, acyl group is introduced the thioanisole derivative and the ketone of acquisition formula (III) by the Friedel-Crafts reaction;
Figure C0314127400131
(b) ketone (III) generates corresponding sulfone (IV) by the oxidation of sulfide group,
(c), form bromoketone (V) with bromine halogenation sulfone (IV);
Figure C0314127400141
(c) bromoketone (V) and CH 3COSK reacts acquisition formula VII compound in organic solvent;
(d) (VII) in organic solvent, make the VIII compound with concentrated hydrochloric acid hydrolysis;
(e) formula VIII compound and acyl chlorides carry out linked reaction, make formula VI compound;
Figure C0314127400144
(f) compound of formula VI dewaters in organic solvent in the presence of alkali, forms formula I compound.
In another preference, R 2And R 3The preparation method who is the formula I compound of H comprises step:
(a) with nitrile and MeLi at low-temp reaction, use acid hydrolysis then, the ketone of production (III);
(b) ketone of formula (III) generates sulfone (IV) with two normal mCPBA oxidations;
Figure C0314127400146
(c) sulfone (IV) is with bromine bromination and obtain the bromoketone of formula V in acidic medium;
Figure C0314127400151
(d) formula V bromoketone and thioic acid sulfoacid reaction acquisition formula VI monothioester compound;
Figure C0314127400152
(e) formula VI monothioester dewaters in organic solvent in the presence of alkali, forms formula I compound.
Embodiment
The term alkyl perhaps adopts separately or when being used for other terms such as haloalkyl, represents straight chain, side chain or cyclic group and their combination.The example of alkyl group comprises methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl and the tertiary butyl, amyl group, hexyl etc.
Term halogen is represented fluorine, chlorine, bromine, iodine.
Amount of carbon atom shown in the term alkoxyl group is represented to have, the alkoxy base of straight chain, side chain and ring texture.The alkoxyl group example comprises: methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, cyclohexyloxy etc.
Compound of the present invention be effectively, COX-2 enzyme inhibitors optionally.Select the COX-2 enzyme inhibitors of pool property more superior than COX-1 enzyme, this is adverse side effect (J.Pharmacol.Exp.Ther.1995,274, the 1531-37 that does not have traditional non-steroidal anti-inflammatory drug because of its existing antiphlogistic effects; Proc.Natl.Acad.Sci.USA, 1994,91,12013-12017).The present invention includes the pharmaceutical composition of the disease that suppresses COX-2 enzyme and the mediation of treatment COX-2 enzyme.These diseases comprise: headache, arthrodynia, have a toothache, sprain, muscle inflammation, fever, sacroiliitis, synovitis, sacroiliitis, rheumatic arthritis, osteitis and urarthritis.
The compounds of this invention can be used for treating the disease of other COX-2 enzyme mediations.AlzheimerShi patient cerebral tissue, neurodegenerative disorders (as multiple sclerosis disease) patient, among the patients such as osteoporosis, asthma, lupus and psoriasis, all found the COX-2 enzyme that content raises.The compounds of this invention can use separately or with the other medicines coupling, thereby treat above-mentioned disease.
Therefore The compounds of this invention conversion and the metastatic tumor growth with tumour capable of inhibiting cell can be used to treat cancer, perhaps use separately or with other medicines (as taxol and cis-platinum) coupling.
Pharmaceutical composition of the present invention comprises at least a molecular formula I compound or its acceptable pharmaceutical salt, also may comprise a kind of pharmaceutical vehicle, vehicle or carrier; Term " acceptable pharmaceutical salt " is meant by the made salt of the acceptable nontoxic bronsted lowry acids and bases bronsted lowry of medicine.Unless indicate in addition, the The compounds of this invention of mentioning comprises its salt; Term " salt " refers to acid and/or the alkali salt with inorganic and/or organic bronsted lowry acids and bases bronsted lowry formation; In addition, salt may comprise zwitter-ion (inner salt), for example, and when formula I compound had both comprised basic moiety such as amine or pyrimidine, when comprising acid moieties such as carboxylic acid again.Medicine acceptable (nontoxic, physiology is acceptable) salt, the positively charged ion in for example acceptable metal and the amine salt does not produce big toxicity and biological activity.Yet other salt also may be useful, for example, and the separation that may in preparation process, adopt and purification step, so other salt is also within the scope of the present invention.The salt that can prepare molecular formula I compound for example, reacts suitable getting in the solvent with stoichiometric quantity or excessive organic or inorganic acid by ion-exchange chromatography or by the free base of molecular formula I compound.The acceptable non-toxic salt of medicine comprises and is obtained from mineral acid for example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid etc.The salt that makes with organic acid comprises that YI salt (resembles with acetic acid or three halogen acetic acid and constitutes, trifluoroacetic acid for example), adipate, alginate, ascorbate salt, aspartate, the phenylformic acid hydrochlorate, benzene sulfonate, hydrosulfate, borate, butyrates, Citrate trianion, camphorate, camsilate, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, fumarate, gluceptate, glycerophosphate, Hemisulphate (hemisulfates), enanthate, hexanoate, the 2-isethionate, lactic acid salt, maleate (generating) with toxilic acid, mesylate (generating) with methylsulfonic acid, the 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectate, persulphate, the 3-phenpropionate, phosphoric acid salt, picrate, Pivalate, propionic salt, salicylate, succinate, vitriol (generating) with sulfuric acid, sulfonate, tartrate, thiocyanate-, tosylate such as tosilate, undecylate etc.
Similarly, the salt of acidic cpd is formed by itself and the reaction of suitable inorganic or organic bases.Typical salt group comprises ammonium salt, an alkali metal salt such as sodium, lithium, sylvite; Alkaline-earth metal such as calcium and magnesium salts, barium, zinc and aluminium salt; The salt that forms with organic bases (for example organic amine) has trialkylamine, as triethylamine, PROCAINE HCL, PHARMA GRADE, dibenzylamine, N-benzyl-β-phenylethylamine, 1-Chinese ephedra amine, N, N '-dibenzylidene diamines, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexyl amine or similar medical acceptable amine and the salt that forms with amino acid such as arginine, Methionin etc.It is quaternized that the alkalescence nitrogen-containing group can use lower halogenated hydrocarbon (for example muriate of methyl, ethyl, propyl group, butyl, bromide, iodide), dialkylsulfates (for example sulfuric ester of dimethyl, dihexyl, dibutyl and diamyl), long-chain halohydrocarbon (for example the muriate of decyl, dodecyl, tetradecyl, octadecyl, bromide, iodide), halogenated aryl hydrocarbon (for example bromide of benzyl, styroyl) etc. to carry out.
Suitable salt comprises mono-hydrochloric salts, hydrosulfate, mesylate, phosphoric acid salt or nitrate.
The precursor and the solvent of this compound also mentioned in invention.Term " medical precursor " refers to that a compound generates molecular formula I by metabolism or chemical process conversion, and/or salt and/or solvent.Multiple medical precursor is mentioned in this invention.The example of relevant these precursor-derived things, referring to:
(a) Design of Prodrugs, H.Bundgaard compiles, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p.309-396, people such as K.Widder compile. and (Acamedic Press, 1985);
(b) A Textbook of Drug Design and Development, Krosgaard-Larsen and H.Bundgaard compile, the 5th chapter, " Design and Application of Prodrugs, " H.Bundgaard, p.113-191 (1991);
(c)H.Bundgaard，Advanced Drug Delivery Reviews，8，1-38(1992)
Above-mentioned document is introduced into this paper as a reference.
But comprise the ester that carboxylic compound can form biological hydrolysis, it as medical precursor in vivo hydrolysis produce molecular formula I compound.Owing to hydrolysis in most of the cases is taken place by the influence of digestive ferment, so medical precursor preferably passes through oral administration.If itself has activity ester, perhaps hydrolysis can take place in blood, can adopt the parenterai administration mode so.But the biological hydrolysis ester of molecular formula I compound comprises C 1-6The alkane benzyl, 4-methoxybenzyl, 2,3-dihydro indenyl (C 9H 9-), phthalyl, methoxyl methyl, C 1-6Alkyloyloxyethyl-C 1-6Alkyl is as acetyl-o-methyl, pivalyl oxygen methyl or propionyl oxygen methyl, C 1-6Carbalkoxyl oxygen-C 1-6Alkyl, as methoxycarbonyl oxygen methyl or methylamino ethoxy acyl-oxygen methyl, glycyl oxygen methyl, benzene glycyl oxygen methyl, (5-methyl-2-oxygen-1,3-dioxolane-4-)-methyl and other physiology ester hydrolysis that in for example penicillin and cynnematin technology, uses of knowing.These esters can be by common process preparation of the prior art.
Molecular formula I compound and salt may exist with isomeric forms, and hydrogen atom transforms to other position of molecule, and atom and intermolecular chemical bond rearrange.The present invention includes the isomeric forms that might exist.In addition, the compound of invention has cis or trans isomer and one or more chiral centres is arranged, thereby the form with raceme and diastereomer exists, the present invention has comprised all these isomer, and the mixture and the racemic enantiomorph mixture (optically active isomer) of the mixture of cis-trans-isomer, diastereomer.When compound (or an asymmetric carbon) structure not being indicated (suitable, anti-or R, S) especially, then refer to any isomer or a plurality of mixture of isomers.Preparation process can adopt racemize hydrochlorate, enantiomorph or diastereomer as starting raw material.When preparation mapping or diastereo-isomerism product, can adopt ordinary method to separate, for example chromatography or Steppecd crystallization.
Compound of the present invention may be free form or hydrate forms.
Compound of the present invention can be formulated together with pharmaceutical carrier or thinner, with the dosage unit formulation form, and by oral, local, parenterai administration, for example muscle, vein or subcutaneous injection, or suck spraying.Can adopt the solid-state or liquid carrier, diluent and the additive that adapt with required administering mode, with ordinary method preparation pharmaceutical composition of the present invention.When oral, can tablet, mode such as capsule, particle, pulvis, lozenge, water-based or oily suspensions gives compound.The composition of formula of oral can be according to the preparation of known drug compound method, and said composition may comprise one or more components of selecting from sweeting agent, toning agent and sanitas.For example, comprise the formula I compound of above-mentioned definition or the tablet of its medical acceptable salt at least, can with vehicle such as lactose, starch, Magnesium Stearate, derivatived cellulose mixed together.Tablet can not have dressing or dressing is arranged, and decomposes and absorbs delaying in the stomach deferent, thereby long continuous action is provided.
Pharmaceutical composition of the present invention can be with hard capsule or soft capsule form oral administration, wherein effective constituent and inert solid diluent such as lime carbonate, calcium phosphate mix in the hard capsule, and in soft capsule effective constituent and water, miscible solvent such as propylene glycol, polyoxyethylene glycol and ethanol, or oil-based solvent such as peanut oil or whiteruss mixing.Depend on method for making, the content of The compounds of this invention in preparation can from 0.01% to 100%, and content can change with factors such as the object for the treatment of administration, route of administration, indication and diseases.
Compound among the present invention is oral with tablet or capsule form, dosage for the adult of mean body weight 60-70 kilogram at about 1mg in the 1000mg scope, or with injection mode parenterai administration, dosage is about 0.1mg to 500mg, can once a day or divide administration several times.The dosage unit of pharmaceutical composition generally includes the activeconstituents that scope is 1mg-500mg, 1mg, 5mg, 10mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg typically.
The quantity and the dosage regimen of used therapeutic activity composition depend on multiple factor when treating concrete illness with the present composition, comprise medical symptom, disease weight, route of administration and the frequency of body weight, age, sex, certainty.
General synthesis program
The compound of invention can be synthetic according to following method.R 2=H, R 3The molecular formula I compound of=H can synthesize by the low-temp reaction of nitrile and MeLi, uses acid hydrolysis then, the ketone of production (III).The ketone of formula (III) generates sulfone (IV) with two normal mCPBA oxidations.By obtain the bromoketone of formula V with bromine bromination in acidic medium.Monothioester compound (VI) is to obtain by bromoketone and thioic acid sulfoacid reaction.The dehydration of monothioester (VI) is that alkali exists down, at organic solvent such as THF, DMF, acetone, two  alkane, CH 3Realize in CN and the ethanol.
Method A
Can be at catalyzer such as AlCl 3Exist down, acyl group is introduced the thioanisole derivative and the ketone of acquisition formula (III) by the Friedel-Crafts reaction.Ketone (III) can generate corresponding sulfone by the oxidation of sulfide group, further adopts the universal method of describing among the method A to carry out halogenation with bromine again, thereby is converted into bromoketone.Molecular formula (VII) compound can pass through bromoketone (V) and CH 3COSK reacts acquisition in organic solvent such as acetone and ethanol.Sulfo-thing (VIII) can make with concentrated hydrochloric acid hydrolysis in organic solvent by (VII).Monothioester (VI) can make by the linked reaction with sulfydryl and acyl chlorides.The dehydration of molecular formula (VI) compound was described in method A.
Method B
Figure C0314127400201
Embodiment is used for setting forth the preparation method of representation compound of the present invention, is not limited to the scope of the invention.
Embodiment 1:4-(4-methylsulfonyl phenyl)-3-phenyl-5H-thiophene-2-ketone (compound 1)
The preparation of step 1:1-(4-first sulfur phenenyl)-ethyl ketone
500ml is contained 4-methylthio phenyl formonitrile HCN, and (100g, tetrahydrofuran solution 0.671mol) are cooled to-78 ℃, and (336mL, 2.1M), lasting dropping is no less than 1h to drip lithium methide by dropping funnel while stirring.After dropwising, reaction mixture is slowly heated to 0 ℃, adds saturated NH 4Cl solution.With ethyl acetate extraction three times.Merge organic phase, use the salt water washing, Na 2SO 4Drying is filtered the back and is concentrated.Residue is dissolved among the THF (250mL), handles 2h with 6N HCl (100mL).Removal of solvent under reduced pressure gets crude product after the filtration, (2 * 50mL) washings get 83g (productive rate 75%) title compound after the vacuum-drying with IPA.The analytical pure sample can pass through silica gel column chromatography, and 20～40% ethyl acetate-normal hexane wash-out makes.
1H-NMR(400MHz，CDCl 3)δ7.86(2H，d，J＝7.9Hz)，7.26(2H，d，J＝8.4Hz)，2.56(3H，s)，2.51(3H，s)。
The preparation of step 2:1-(4-methylsulfonyl phenyl)-ethyl ketone
From step 1 make thick 1-(4-methylsulfonyl phenyl)-(83g 0.5mol) is dissolved in CH to ethyl ketone 2Cl 2(400mL), be chilled to 0 ℃, divide (portionwise) adding solid m-CPBA (315g) for several times, reaction mixture stirs 2h under room temperature, add saturated Na 2S 2O 3And NaHCO 3The solution termination reaction, the mixture vigorous stirring 1h that obtains tells organic layer, water layer CH 2Cl 2Extracting twice merges organic layer, salt water washing, Na 2SO 4Drying is filtered, and gets title compound (88g, productive rate 89%) after concentrating.Crude product need not be further purified and be directly used in next step reaction.The analytical pure sample makes by silica gel column chromatography.
1H-NMR(400MHz，CDCl 3)δ：8.10(2H，d，J＝8.4Hz)，8.02(2H，d，J＝8.4Hz)，3.06(3H，s)，2.64(3H，s)。
The preparation of step 3:2-bromo-1-(4-methylsulfonyl phenyl)-ethyl ketone
1-(4-methylsulfonyl phenyl)-ethyl ketone crude product (88g 0.444mole) is dissolved in HOAc (450mL), and adding HBr (48%, 1.0mL).In dropping funnel, put into Br in addition 2(71.1g 0.444mole), adds about 2.0mL Br in reaction mixture 2, at room temperature stir 30min then, dropwise add remaining Br 2, dropwise, continue to stir 2h.Filtration obtains crude product, uses H successively 2O: HOAc (1: 1) and H 2The O washing, vacuum-drying 18h obtains required white solid product (109g, 89%).
1H NMR(400MHz，CDCl 3)δ8.14(2H，d，J＝8.4Hz)，8.05(2H，d，J＝8.4Hz)，4.44(2H，s)，3.08(3H，s)。
Step 4: phenyl thioacetic acid S-[2-(4-methylsulfonyl phenyl)-2-oxoethyl] preparation of ester
(2.0g, THF 13.2mmole) (30mL) solution adds Et while stirring under the room temperature at the phenyl thioacetic acid 3N (1.33g, 13.2mmole), add then 2-bromo-1-(4-methylsulfonyl phenyl)-ethyl ketone (3.64g, 13.2mmole).Reaction mixture at room temperature stirs 2h, adds H 2O.With EtOAc extraction three times, merge organic layer, salt water washing, Na 2SO 4Drying is filtered, and concentrates.The crude product purification by silica gel column chromatography, with 30%, 40%, 50%EtOAc/ normal hexane wash-out gets white solid title compound (3.54g, productive rate 77%).
1H-NMR(400MHz，CDCl 3)δ：8.10(2H，d，J＝8.4Hz)，8.02(2H，d，J＝8.4Hz)，7.37-7.24(5H，m)，4.32(2H，s)，3.88(2H，s)，3.06(3H，s)； 13C NMR(500MHz，CDCl 3)δ193，192，144，139，129，128，44，36.5，30.1。
The preparation of step 5:4-(4-methylsulfonyl phenyl)-3 phenyl-5H-thiophene-2-ketone
Thiophenyl acetate S-[2-(4-methylsulfonyl phenyl)-2-oxoethyl] ester (2.1g, THF 6.03mmol) (45mL) solution N 2Degassing 30min, (1.83g, 18.1mmol), reaction mixture is heated to 60 ℃ then and keeps 3h in 23 ℃ of stirring 20min to add triethylamine.Reaction mixture is cooled to 23 ℃, add at leisure HCl (18.1mL 1N), with EtOAc extraction mixture three times, merges organic layer, the salt water washing, drying, after concentrating residue.The crude product purification by silica gel column chromatography gets yellow solid (832mg, productive rate 42%).
1H-NMR(400MHz，CDCl 3)δ7.83(2H，d，J＝8.2Hz)，7.38(2H，d，J＝8.3Hz)，7.32-7.30(3H，m)，7.13-7.11(2H，m)，4.34(2H，s)，3.03(3H，s)； 13C NMR(500MHz，CDCl 3)δ197.6，157.3，141.4，141.0，140.7，130.8，129.8，128.9，128.8，128.7，127.6，44.2，36.9。
Embodiment 2:3-(4-chloro-phenyl-)-4-(4-methylsulfonyl phenyl)-5H-thiophene-2-ketone
Figure C0314127400221
Step 1:(4-chloro-phenyl-)-thiacetic preparation
To NaHS (1.78g, 1.78mL H 31.8mmole) 2Add EtOH (18mL) in the O solution, the solution that obtains is cooled to 0 ℃, control internal temperature simultaneously and slowly add (4-chloro-phenyl-)-Acetyl Chloride 98Min. below 5 ℃.Stir the mixture and show acyl chlorides completely consumed (being approximately 15 minutes) at 0 ℃ until HPLC.Add the NaOH aqueous solution (1N) then and regulate pH about 10.Use Et 2O extracts mixture, discards organic layer, and water layer is regulated pH to～2 with 1N HCl, with EtOAc (4 * 20mL) extractions.Merge organic layer, salt solution (20mL) washing, anhydrous Na 2SO 4Drying, be concentrated into after doing 2.3g yellow oily crude product.LC-MS and HPLC analyze the display-object product and are about 65AP.This crude product need not be further purified and be directly used in next step reaction.
Step 2:(4-chloro-phenyl-)-and thioacetic acid S-[2-(4-methylsulfonyl phenyl)-2-oxo-ethyl] preparation of ester
THF (4.6mL) solution of (4-the chloro-phenyl-)-thioacetic acid (2.3g, 65AP, about 8.0mmole) of previous step preparation is cooled to 0 ℃, adds Et 3(808mg 8.0mmole) forms slurries to N.Dripped through 10 minutes 2-bromo-1-(4-methylsulfonyl phenyl)-ethyl ketone (embodiment 1 step 3) (and 2.21g, THF 8mmole) (28mL) mixture is observed more solid in the dropping process, behind the 10min, two kinds of reactants of HPLC indication have all reacted.Add H 2O (30mL), reaction mixture with EtOAc extraction (3 * 30mL), organic layer Na 2SO 4Drying is filtered, and concentrates.Residue rapid column chromatography purifying with 30%～40%EtOAc/ normal hexane wash-out, gets the title compound (2.0g, productive rate 65%) of white solid.
1H NMR(400MHz，CDCl 3)δ8.06(2H，d，J＝8.8Hz)，8.00(2H，d，J＝8.8Hz)，7.22(2H，d，J＝8.8Hz)，7.14(2H，d，J＝8.8Hz)，4.29(2H，s)，3.80(2H，s)，3.00(3H，s). 13C NMR(400MHz，CDCl 3)δ195.3，192.1，144.6139.5，131.2，130.9，129.3，129.0，127.9，49.2，44.3，36.7。
The preparation of step 3:3-(4-chloro-phenyl-)-4-(4-methylsulfonyl phenyl)-5H-thiophene-2-ketone
(4-chloro-phenyl-)-thioacetic acid S-[2-(4-methylsulfonyl phenyl)-2-oxo-ethyl] ester (1.0g, 2.61mmole) the following limit of stirring of DMF (20mL) solution room temperature add triethylamine (923mg, 9.14mmole), reaction mixture stirs 30min in 40 ℃, HPLC indicates most of raw material reaction intact, and form two kinds of new compounds, keep this temperature then and continue to stir 30min, be cooled to 0 ℃, neutralize with HOAc (224 μ L), with EtOAc (40mL) dilution, salt solution (10ml) washing, anhydrous Na 2SO 4Drying, vacuum concentration gets dark-brown oily crude product after doing.With column chromatography (purifying of 1: 1 normal hexane/EtOAC), 320mg yellow oily foam (productive rate 33.5%).Be further purified available preparation scale HPLC.
1H-NMR(400MHz，CDCl 3)δ7.83(2H，d，J＝8.3Hz)，7.33(2H，d，J＝8.3Hz)，7.24(2H，d，J＝8.8Hz)，7.04(2H，d，J＝8.8Hz)，4.29(2H，s)，3.00(3H，s). 13C NMR(400MHz，CDCl 3)δ197.3，157.7，141.4，140.5，135.1，131.2，129.1，128.9，127.9，127.8，44.2，37.1，26。
Embodiment 3:4-(4-methylsulfonyl phenyl)-3-(4-methoxyphenyl)-5H-thiophene-2-ketone
Step 1:(4-methoxyphenyl)-thiacetic preparation
To NaHS (1.82g, 1.82mL H 32.5mmole) 2Add EtOH (18mL) in the O solution, this solution is cooled to 0 ℃, (2.0g, 10.83mmole) more than the 20min, HPLC shows that acyl chloride reaction is intact, adds 1N HCl then and regulates pH to about 2, uses CH to drip 4-(p-methoxy-phenyl) Acetyl Chloride 98Min. 2Cl 2(3 * 30mL) purging compounds.Merge organic layer, salt solution (20mL) washing, anhydrous Na 2SO 4Drying, be concentrated into after doing crude product.LC-MS and HPLC analyze and show that yellow target product is about 75AP.This crude product need not be further purified and be directly used in next step reaction.
Step 2:(4-methoxyphenyl)-and thioacetic acid S-[2-(4-methylsulfonyl phenyl)-2-oxo-ethyl] preparation of ester
THF (20mL) solution of thick thioic acid sulfoacid (75AP, about 8.1mmole) is cooled to 0 ℃, adds Et 3(818mg 8.1mmole) forms slurries to N.((2.2g is more than THF 8mmole) (15mL) the solution 10min for embodiment 1 step 3) to drip 2-bromo-1-(4-methylsulfonyl phenyl)-ethyl ketone.Behind the 30min, two kinds of reactants of HPLC indication have all reacted.Mixture is used 0.5N HCl (20ml), saturated NaHCO respectively 3Washing, Na 2SO 4Drying, concentrating under reduced pressure gets brown oil.Crude product is handled with silica gel bolt (2: 1 EtOAc/ normal hexanes), gets 2.2g, the title compound of white solid (productive rate 73%).
1H-NMR(400MHz，CDCl 3)δ8.08(2H，d，J＝8.4Hz)，7.97(2H，d，J＝8.4Hz)，7.20(1H，m)，6.80(3H，m)，4.33(2H，s)，3.80(2H，s)，3.75(3H，s)，3.00(3H，s). 13C NMR(400MHz，CDCl 3)δ195.6，192.4，159.8144.6，139.5，134.1，129.8，129.3，127.8，121.9，115.3，113.1，55.2，49.9，44.2，36.6。
The preparation of step 3:4-(4-methylsulfonyl phenyl)-3-(4-methoxyphenyl)-5H-thiophene-2-ketone
(4-methoxyphenyl)-thioacetic acid S-[2-(4-methylsulfonyl phenyl)-2-oxo-ethyl] and ester (1.0g, 2.65mmole) and Et 3N (934mg, THF 9.25mmole) (20mL) mixture stirs 1.5h for 45 ℃, and the HPLC indication reaches 80% and transforms, and after continuing to stir 1h, does not observe further reaction.Reaction mixture is cooled to 0 ℃, and with HOAc (224 μ L) neutralization, vacuum concentration is to 7mL.With the solution that EtOAc (40mL) dilution obtains, salt solution (10mL) washing, anhydrous Na 2SO 4Drying, vacuum concentration gets dark-brown oily crude product after doing.With column chromatography (purifying of 1: 1 normal hexane/EtOAC), 200mg yellow oily foam (productive rate 21%).Be further purified available preparation scale HPLC.
1H-NMR(400MHz，CDCl 3)δ7.88(2H，d，J＝8.4Hz)，7.44(2H，d，J＝8.4Hz)，7.26(1H，m)，6.88(1H，m)，6.72(2H，m)，4.37(2H，s)，3.74(3H，s)，3.07(3H，s). 13C NMR(400MHz，CDCl 3)δ199.0，160.1，157.8，141.85，141.5，141.1，132.6，130.3，129.4，128.1，122.5，115.8，114.8，55.6，44.7，37。
Embodiment 4:4-(4-methylsulfonyl phenyl)-5,5-dimethyl-3-phenyl-5H-thiophene-2-ketone.
Figure C0314127400251
The preparation of step 1:2-methyl isophthalic acid-(4-first sulfur phenenyl)-third-1-ketone
In the flask of 2L, adding AlCl under the exsiccant nitrogen 3(100g, 0.75mol) and CH 2Cl 2(800mL), suspension stirring at room 20min.(80g 0.75mol) more than the 1h, gets a homogeneous phase solution to drip isobutyryl chloride.Solution is chilled to-10 ℃, and (77.6g, 0.625mol), after dropwising, reaction mixture is in-10 ℃ of ageing 1h, slowly the saturated NH of impouring to drip thioanisole 4Cl: ice (500ml: in mixture 500g), flask H 2O (100mL) and CH 2Cl 2(100mL) fully swing and wash for several times, tell lower floor's organic layer, water CH 2Cl 2(300mL) extraction once merges organic layer, uses the salt water washing, Na 2SO 4Drying, vacuum concentration gets the white solid title compound after doing.Crude product need not be further purified direct application.
The preparation of step 2:1-(4-methylsulfonyl phenyl)-2-methyl-third-1-ketone
The CH of the product that makes in step 1 2Cl 2(800mL) add m-CPBA (380g) in the solution, add the back and show that up to HPLC parent material all is converted into required product, add saturated Na with the HPLC monitoring 2S 2O 3And NaHCO 3The solution termination reaction, the mixture vigorous stirring 1h that obtains tells organic layer, water layer CH 2Cl 2(2 * 500mL) extractions merge organic layer, salt water washing, MgSO 4Drying is filtered, and gets the white solid crude product after concentrating, and uses H 2O (200ml) and IPA (100ml) washing, vacuum-drying is spent the night, and gets white solid 1-(4-methylsulfonyl phenyl)-2-methyl-third-1-ketone (109g, two step overall yields 77%).
1H-NMR(500MHz，CDCl 3)δ8.06-8.04(m，2H)，8.02-7.90(m，2H)，3.54-3.51(m，1H)，3.04(s，3H)，1.17(s，3H)，1.16(s，3H)； 13C NMR(500MHz，CDCl 3)δ203.07，143.73，140.21，129.0，127.65，44.16，35.89，18.70。
The preparation of step 3:2-bromo-1-(4-methylsulfonyl phenyl)-2-methyl-third-1-ketone
(109g in HOAc 0.482mol) (500ml) solution, adds dense HCl (1.0mL) while stir under the room temperature at the ketone sulfone.In dropping funnel, put into Br in addition 2(74.8g 0.468mole), adds 2.0mL Br earlier 2, the about 20min of decomposition induction time, rapidly disappearing with bromine brown is indication.After inductive phase, dropwise added remaining Br through 1 hour 2, room temperature ageing reactant 2 hours, product is separated out from solution, and filter reaction mixture, solid product are used H respectively 2O (100ml) and IPA (100ml) washing once get white solid title compound (127g, 89%).
1H-NMR(500MHz，CDCl 3)δ8.06-8.04(m，2H)，8.02-7.90(m，2H)，3.02(s，3H)，1.17(s，3H)，1.16(s，3H)； 13C NMR(500MHz，CDCl 3)δ196.08，143.22，139.72，130.54，127.19，59.99，44.20，30.92。
Step 4: thioacetic acid S-[2-(4-methylsulfonyl phenyl)-1,1-dimethyl-2-oxo-ethyl] preparation of ester
With 2-bromo-1-(4-methylsulfonyl phenyl)-2-methyl-third-1-ketone (8.12g, 26.6mmol), CH 3COSK (3.03g, 26.6mmol) mixture with anhydrous EtOH (30ml) at room temperature stirs 16h, and vacuum is removed EtOH, and residue dilutes with EtOAc (100mL), water, salt water washing, the anhydrous MgSO of organic phase 4Drying is filtered, and vacuum boils off solvent and gets crude product.
1H-NMR(500MHz，CDCl 3)δ8.02(d，J＝8.25Hz，2H)，7.90(d，J＝8.8Hz，2H)，3.02(s，3H)，2.09(s，3H)，1.64(s，6H)； 13C NMR(125MHz，CDCl 3)δ200.36，194.30，142.41，141.22，129.07，126.70，55.30，44.08，29.89，26.39。
The preparation of step 5:2-sulfydryl 1-(4-methylsulfonyl phenyl)-2-methyl-third-1-ketone
1.5g being dissolved in the solution of MeOH (20ml), stirs on one side thioacetic acid, with concentrated hydrochloric acid (2.0ml) handle on one side, reaction mixture is in 60 ℃ of heating 16h.Except that desolvating and handling residue totally three times, get faint yellow oily thing (800mg) with the PhMe azeotropic method.
1H-NMR(CDCl 3)δ3.04(s，3H)； 13C NMR(125MHz，CDCl 3)δ200.9，142.3，141.4，129.5，126.9，48.6，44.3，29.0。
Step 6: phenyl thioacetic acid S-[2-(4-methylsulfonyl phenyl)-1,1-dimethyl-2-oxo-ethyl] preparation of ester
CH in mercaptan (MW 258 for 800mg, 3.1mmol) 2Cl 2(10ml) in the solution, drip while stirring under the room temperature phenyllacetyl chloride (529mg, 3.41mmol), add then pyridine (363mg, 4.65mmol).Reaction mixture stirring at room 4h uses the EtOAc diluted reaction mixture, uses saturated NH successively 4Cl, salt water washing, MgSO 4Drying is filtered, and concentrating under reduced pressure gets the title compound (productive rate 94%) of 1.1g.
1H-NMR(500MHz，CDCl 3)δ7.90(d，J＝8.25Hz，2H)，7.76(d，J＝8.8Hz，2H)，7.15-7.14(m，3H)，6.90(m，2H)，3.53(s，2H)，2.96(s，3H)，1.61(s，6H)； 13C NMR(500MHz，CDCl 3)δ200.0，195.5，142.2，140.6，132.3，129.0，128.7，128.3，127.2，126.6，55.1，49.4，43.8，26.1。
The preparation of step 7:4-(4-methylsulfonyl phenyl)-5,5 dimethyl-3-phenyl-5H-thiophene-2-ketone
To 2-sulfydryl 1-(4-methylsulfonyl phenyl)-2-methyl-third-1-ketone (1.1g, add in THF 2.92mmol) (30ml) solution triethylamine (1.01g, 10mmole), reaction mixture is at 50-55 ℃ of heating 3h, reaction mixture is cooled to room temperature, and (10mL 10mmol) handles with 1N HCl.Vacuum concentration, residue dilutes with EtOAc, water washing, organic phase MgSO 4Drying is filtered and is concentrated, residue silica gel column chromatography purifying, and with 25%, 40%, 55%EtOAc/ normal hexane wash-out gets white solid title compound (MW 358 for 188mg, productive rate 18%).
1H-NMR(400MHz，CDCl 3)δ7.90(d，J＝16.4Hz，2H)，7.34(d，J＝16.5Hz，2H)，7.20-7.18(m，3H)，7.07-7.05(m，2H)，3.05(s，3H)，1.72(s，6H)； 13C NMR(500MHz，CDCl 3)δ195.7，167.6，139.7，130.3，129.5，128.1，127.8，127.2，56.4，44.0，27.9.
Biological activity test
Among the present invention compound to the extracorporeal extracorporeal suppression of COX-1 and COX-2 pressed document (InflammationResearch, 1996,45:68-74) method has been carried out the human whole blood test.COX-1 is a constitutive expression in the great majority tissue, is responsible for keeping the biosynthesizing of prostaglandin(PG) in the physiological process (prostanoid).On the contrary, the expression of COX-2 is at the different factors such as Buddhist ripple ester, is induction type in the cell that cytokine and lipopolysaccharides (LPS) are handled.COX-1 and COX-2 enzyme have 60% sequence homology, a large amount of COX-1 enzymes be present in the thrombocyte of human whole blood (Drug Development Research, 1992,25:249), for blood coagulation  alkane B 2(TxB 2) produce, after blood coagulation, measure the COX-1 enzymic activity, after lipopolysaccharides (LPS) insulation, induce the COX-2 enzyme from people's whole blood.The time that COX-2 expresses in the normal human blood and the dependency of concentration are induced (Inflammation Research, 1999,48; 133-138).Available this experimental evaluation cox 2 inhibitor is to PGE 2The restraining effect of producing.These experiments provide the intrinsic inhibition of the most reliable COX-1 and COX-2 enzyme, also predict the vivo effect of selective COX-2-2 inhibitor better than other experiment in vitro.
The activity of COX-1 in people's whole blood
The fresh blood of gathering the healthy volunteer places the glass test tube that does not contain antithrombotics.Quantitatively draw blood sample (500 μ l) and 5 μ l carriers (DMSO) or the tested compound of 5 μ l, making ultimate density is 1 to 50 μ M, keeps 1h in 37 ℃.Each compound repeats three parts with 5 kinds of different concns.After hatching finishes, centrifugal (5min, 12,000 * g) separation of serum.Get 100 μ l serum and 400 μ l methanol mixed with protein precipitation, supernatant liquor is measured TxB with enzyme immunoassay test kit (Amersham) 2Level.IC 50Value is by InPlot, and GraphPad software obtains with non-linear regression.
The activity of COX-2 in people's whole blood
Gather the test tube that healthy volunteer's fresh blood places heparin to handle, immediately from 2mL blood separated plasma as PGE 2Basal level.Remaining blood in room temperature insulation 5min, is quantitatively drawn the tested compound insulation from 50nM to 5 μ M of 500 μ l blood samples and 5 μ l carriers (DMSO) or 5 μ l ultimate densities with LPS (100g/mL ultimate density), keeps 24h in 37 ℃.With an amount of phosphate buffered saline buffer (non-LPS) as blank.After insulation finished, blood sample obtained blood plasma in the centrifugal 5min of 12,000 * g.Get 100 μ l blood plasma and 400 μ l methanol mixed with protein precipitation, supernatant liquor is measured the level of PGE2 with radioimmunology (ELISA) test kit (Amersham).IC 50Value is by InPlot, and GraphPad software obtains with non-linear regression.
In vivo test
Embodiment 1 compound is suspended in oral administration in 1.5% methylated cellulose aqueous solution, is 10ml/kg for this suspension dosage of rat.Rat is fixed before administration, can feed water, and continues 18h.The positive contrast of Ibuprofen BP/EP.Be used in the different animal models realize with the Ibuprofen BP/EP same volume in the dosage indication usefulness of embodiment 1 compound of effect.
Mycobacterium inductive oedema in the rat
Select the SD male rat of 200 ± 20g for use, be divided into 5 groups at random, 10 every group.In time of origin 0 oral administration embodiment 1 compound (3,9,27mg/kg), Ibuprofen BP/EP (200mg/kg) and carrier.After one hour, (0.05ml GIBCOBRL), behind the 18h, measures the rat paw volume with plethysmometer's (IITC 585 types), and the result represents with the mean value of back swelling degree of the paw the left back sufficient plantar subcutaneous injection mycobacterium of rat.(table 1).
The inhibition of table 1 pair big mycobacterium muris-inductive foot sole of the foot oedema
Group Foot sole of the foot oedema (ml ± SD)
Contrast 0.278±0.127
Ibuprofen BP/EP, 200mg/kg 0.152±0.109
Compound 1,27mg/kg 0.162±0.109
Compound 1,9mg/kg 0.256±0.147
Compound 1,3mg/kg 0.329±0.075
Mycobacterium inductive sacroiliitis in the rat
Select the SD male rat of 200 ± 20g for use, be divided into 5 groups at random, 10 every group.First day, every rat through right back vola subcutaneous injection mycobacterium suspension (0.05ml, GIBCOBRL), after causing sacroiliitis 19 days, Orally administered embodiment 1 compound (3,9,27mg/kg), Ibuprofen BP/EP (200mg/kg) and carrier, once a day, successive administration 7 days.Behind the last administration 18h, measure sufficient sole of the foot volume with plethysmometer's (IITC 585 types).(table 2)
The inhibition of table 2 pair mycobacterium inductive rat assist agent arthritis
Group Foot sole of the foot oedema (ml ± SD)
Contrast 0.283±0.079
Ibuprofen BP/EP, 200mg/kg 0.161±0.073
Compound 1,27mg/kg 0.183±0.063
Compound 1,9mg/kg 0.206±0.068
Compound 1,3mg/kg 0.229±0.106
The hyperpathia that machinery causes in the rat
In the hyperpathia model that rat machinery causes, measure the analgesic activity of compound among the embodiment 1.Threshold value when the right foot of rat bounces back after the record mechanical stimulus.In the increase that compound 1 back 20,40,90 and the 150min of oral administration embodiment 1 measure threshold value, represent anaesthetic effect with following formula.
Figure C0314127400301
Hyperalgesic threshold value in table 4. rat
Group 0min 20min 40min 90min 150min
Contrast 59.7± 10.7 58.8± 11.1 61.3± 9.5 55.5± 10.2 56.2± 12.3
Ibuprofen BP/EP, 200 mg/kg 63.5± 17.0 96.3± 17.7 93.7± 15.4 89.8± 19.2 69.0± 14.1
Compound 1,27 mg/kg 50.3± 11.4 100.0± 24.2 116.7± 26.0 114.2± 26.7 64.8± 9.7
Compound 1,9 mg/kg 56.8± 12.6 72.8± 12.0 91.0± 23.9 77.5± 20.0 59.3± 13.8
Compound 1,3 mg/kg 57.7± 8.8 64.7± 7.4 74.2± 7.7 65.0± 5.8 57.7± 7.4
The hyperalgesic anesthetic action of table 5. pair rat mechanical induction
Group 20min 40min 90min 150min
Ibuprofen BP/EP, 200mg/kg 57.9％ 56.7％ 46.5％ 10.6％
Compound 1,27mg/kg 109.4％ 139.2％ 132.8％ 31.8％
Compound 1,9mg/kg 31.5％ 61.2％ 40.6％ 4.3％
Compound 1,3mg/kg 13.2％ 30.6％ 13.8％ 0.7％
Toxicological test
For the single administration acute toxicity test, the compound among the embodiment 1 is suspended in 1.5% methocel solution the administration of DW rat, compound 1 maximum tolerated dose reaches 7,200mg/kg (per os), with 4,200mg/kg (abdominal cavity) does not see dead and other obvious toxic-side effects.This studies prompting, and compound of the present invention has good security.

Claims (10)

1. the 4-aryl shown in the formula (I)-5H-thiophene-2-ketone compound, or its pharmacy acceptable salt:
R in the formula 1From following groups, select:
(a) alkyl of 1-6 carbon atom;
(b) haloalkyl of 1 to 6 carbon atom;
(c) NH 2Group;
(d) NHC (O) R 5, R wherein 5Be the alkyl of 1-6 carbon atom, or the low-grade halogenated alkyl of 1-6 carbon atom;
(e) NR 6R 7, R wherein 6And R 7Respectively from the low alkyl group of hydrogen or 1-6 carbon atom, or the low-grade halogenated alkyl of 1-6 carbon atom is selected;
R 2And R 3From following groups, select respectively:
(a) hydrogen;
(b) low alkyl group of 1-6 carbon atom;
(c)OH；
R 4From following groups, select:
Unsubstituted phenyl, or the phenyl that is replaced by 1 to 3 following group: halogen atom, CN, NH 2, OH, the low alkyl group of 1-6 carbon atom, the alkoxyl group of the low-grade halogenated alkyl of 1-6 carbon atom, a 1-6 carbon atom;
The X substituting group is selected from following groups:
(a) hydrogen atom;
(b) be positioned at the halogen atom of commutable position;
(c) alkyl of 1-6 carbon atom;
(d)CN；
(e)NO 2；
(f)OH；
(g)CF 3；
(h)CO 2H；
(i)NH 2。
2. compound as claimed in claim 1 is characterized in that R 1It is the alkyl of 1-6 carbon atom.
3. compound as claimed in claim 1 is characterized in that R 2And R 3It is respectively the low alkyl group of a hydrogen or 1-6 carbon atom.
4. compound as claimed in claim 1 is characterized in that R 4Be unsubstituted phenyl, or the phenyl that is replaced by 1 to 3 following group: halogen atom, CN, CF 3
5. compound as claimed in claim 1 is characterized in that, X is hydrogen atom or halogen atom.
6. compound as claimed in claim 1, it is characterized in that, be 4-(4-methylsulfonyl phenyl)-3-phenyl-5H-thiophene-2-ketone, 3-(4-chloro-phenyl-)-4-(4-methylsulfonyl phenyl)-5H-thiophene-2-ketone or 4-(4-methylsulfonyl phenyl)-3-(4-methoxyphenyl)-5H-thiophene-2-ketone.
7. a pharmaceutical composition is characterized in that, contains the described compound of claim 1 or its pharmacy acceptable salt, and pharmaceutically acceptable carrier.
8. the purposes of the described compound of claim 1 is characterized in that, is used to prepare the medicine of the disease for the treatment of the COX-2 mediation.
9. the preparation method of the 4-aryl shown in the formula (I)-5H-thiophene-2-ketone compound,
Figure C031412740003C1
R in the formula 1From following groups, select:
(a) alkyl of 1-6 carbon atom;
(b) haloalkyl of 1 to 6 carbon atom;
(c) NH 2Group;
(d) NHC (O) R 5, R wherein 5Be the alkyl of 1-6 carbon atom, or the low-grade halogenated alkyl of 1-6 carbon atom;
(e) NR 6R 7, R wherein 6And R 7Respectively from the low alkyl group of hydrogen or 1-6 carbon atom, or the low-grade halogenated alkyl of 1-6 carbon atom is selected;
R 2And R 3From following groups, select respectively:
(a) hydrogen;
(b) low alkyl group of 1-6 carbon atom;
(c)OH；
R 4From following groups, select:
Unsubstituted phenyl, or the phenyl that is replaced by 1 to 3 following group: halogen atom, CN, NH 2, OH, CF 3, the low alkyl group of 1-6 carbon atom, the alkoxyl group of the low-grade halogenated alkyl of 1-6 carbon atom, a 1-6 carbon atom;
The X substituting group is selected from following groups:
(a) hydrogen atom;
(b) be positioned at the halogen atom of commutable position;
(c) alkyl of 1-6 carbon atom;
(d)CN；
(e)NO 2；
(f)OH；
(g)CF 3；
(h)CO 2H；
(i)NH 2，
It is characterized in that, comprise step:
(a) catalyst A lCl 3Exist down, acyl group is introduced the thioanisole derivative and the ketone of acquisition formula (III) by the Friedel-Crafts reaction;
Figure C031412740004C1
(b) ketone (III) generates corresponding sulfone (IV) by the oxidation of sulfide group,
Figure C031412740004C2
(c), form bromoketone (V) with bromine halogenation sulfone (IV);
Figure C031412740005C1
(d) bromoketone (V) and CH 3COSK reacts acquisition formula VII compound in organic solvent;
Figure C031412740005C2
(e) (VII) in organic solvent, make the VIII compound with concentrated hydrochloric acid hydrolysis;
(f) formula VIII compound and acyl chlorides carry out linked reaction, make formula VI compound;
(g) compound of formula VI dewaters in organic solvent in the presence of alkali, forms formula I compound.
10. the preparation method of a formula I compound,
R in the formula 1From following groups, select:
(a) alkyl of 1-6 carbon atom;
(b) haloalkyl of 1 to 6 carbon atom;
(c) NH 2Group;
(d) NHC (O) R 5, R wherein 5Be the alkyl of 1-6 carbon atom, or the low-grade halogenated alkyl of 1-6 carbon atom;
(e) NR 6R 7, R wherein 6And R 7Respectively from the low alkyl group of hydrogen or 1-6 carbon atom, or the low-grade halogenated alkyl of 1-6 carbon atom is selected;
R 2And R 3All be H;
R 4From following groups, select:
Unsubstituted phenyl, or the phenyl that is replaced by 1 to 3 following group: halogen atom, CN, NH 2, OH, CF 3, the low alkyl group of 1-6 carbon atom, the alkoxyl group of the low-grade halogenated alkyl of 1-6 carbon atom, a 1-6 carbon atom;
The X substituting group is selected from following groups:
(a) hydrogen atom;
(b) be positioned at the halogen atom of commutable position;
(c) alkyl of 1-6 carbon atom;
(d)CN；
(e)NO 2；
(f)OH；
(g)CF 3；
(h)CO 2H；
(i)NH 2，
It is characterized in that, comprise step:
(a) with nitrile and MeLi at low-temp reaction, use acid hydrolysis then, the ketone of production (III);
Figure C031412740006C1
(b) ketone of formula (III) generates sulfone (IV) with two normal mCPBA oxidations;
Figure C031412740006C2
(c) sulfone (IV) is with bromine bromination and obtain the bromoketone of formula V in acidic medium;
Figure C031412740007C1
(d) formula V bromoketone and thioic acid sulfoacid reaction acquisition formula VI monothioester compound;
Figure C031412740007C2
(e) formula VI monothioester dewaters in organic solvent in the presence of alkali, forms formula I compound.
CNB031412742A 2003-06-03 2003-06-03 4-aryl group-5H-thoifuran-2-ketone derivative, producing method and use thereof Expired - Fee Related CN1309717C (en)

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