IE911942A1 - New thiophene derivatives - Google Patents

Abstract

This invention relates to new thiophene derivatives having antiinflammatory and analgesic activities and represented by general formula (I), wherein R<1> is hydrogen, halogen, cyano, substituted lower alkyl, substituted or unsubstituted lower alkenyl, acyl, nitro, substituted or unsubstituted amino, sulfo, substituted or unsubstituted sulfamoyl, N-containing heterocyclic sulfonyl, hydroxy, substituted or unsubstituted heterocyclic group, R<2> is substituted or unsubstituted aryl, and R<3> is substituted or unsubstituted aryl, provided that R<3> is aryl substituted with substituent(s) selected from the group consisting of amino, mono(lower)-alkylamino, acylamino, lower alkyl(acyl)amino and sulfamoyl when R<1> is hydrogen, halogen or cyano, and pharmaceutically acceptable salts thereof, to processes for the preparation thereof and to a pharmaceutical composition comprising the same.

Description

NEW THIOPHENE DERIVATIVES The present invention relates to new thiophene derivatives and pharmaceutically acceptable salts thereof.

More particularly, it relates to new thiophene derivatives and pharmaceutically acceptable salts thereof which have antiinflammatory and analgesic activities, to processes for preparation thereof, to a pharmaceutical composition comprising the same, and to methods of using the same therapeutically in the treatment and/or prevention of inflammatory conditions and various pains, collagen diseases, autoimmune diseases and various immunity diseases in human beings or animals, and more particularly to methods for the treatment and/or prevention of inflammation and pain in joint and muscle [e.g. rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, etc.], inflammatory skin condition [e.g. sunburn, eczema, etc.], inflammatory eye condition [e.g. conjunctivitis, etc.], lung disorder in which inflammation is involved [e.g. asthma, bronchitis, pigeon fancier's disease, farmer's lung, etc.], condition of the gastrointestinal tract associated with inflammation [e.g. aphthous ulcer, Chrohn’s disease, atropic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, etc.], gingivitis, inflammation, pain and tumescence after □ operation or injury, pyresis, pain and other conditions associated with inflammation, particularly those in which lipoxygenase and cyclooxygenase products are a factor, systemic lupus erythematosus, scleroderma, polymyositis, periarteritis nodosa, rheumatic fever, Sjogren's syndrome, Behcet disease, thyroiditis, type I diabetes, naphrotic syndrome, aplastic anemia, myasthenia gravis, uveitis contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Hodgkin's disease, and the like.

One object of this invention is to provide new and useful thiophene derivatives and pharmaceutically acceptable salts thereof which possess antiinflammatory and analgesic activities.

Another object of this invention is to provide processes for the preparation of said thiophene derivatives and salts thereof.

A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said thiophene derivatives and pharmaceutically acceptable salts thereof.

Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of inflammatory conditions, various pains, and the other diseases mentioned above, using said thiophene derivatives and pharmaceutically acceptable salts thereof.

Some thiophene derivatives having antiinflammatory and analgesic activities have been known as described, for example, in European Patent Application Publication Nos. 042 and 87 629, U.S. Patent 4,749,712 and Research Disclosure 266015.

The object thiophene derivatives of this invention are new and can be represented by the following general formula [I] : wherein R^ is hydrogen; halogen; cyano; lower alkyl substituted with substituent(s) selected from the group consisting of halogen, hydroxy, amino, acylamino, lower alkylamino, lower alkyl(acyl)amino, acyl, aryl optionally substituted with hydroxy, a heterocyclic group, hydroxyimino and lower alkoxyimino; lower alkenyl optionally substituted with cyano; acyl; nitro; amino optionally substituted with substituent(s) selected from the group consisting of acyl and lower alkylsulfonyl; sulfo; sulfamoyl optionally substituted with substituent (s) selected from the group consisting of lower alkyl, halo(lower)alkyl, aryl, hydroxy, lower alkylamino(lower) alkyl, a heterocyclic group and (esterified carboxy) lower alkyl; N-containing heterocyclicsulfonyl; hydroxy; or a heterocyclic group optionally substituted with substituent(s) selected from the group consisting of hydroxy, oxo, amino and lower alkylamino; R is aryl optionally substituted with substituent (s) selected from the group ' consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower akylsulfonyl, nitro, amino, sulfamoyl and lower alkylsulfonylamino; and 3 R is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro, amino, lower alkylamino, acylamino, lower alkyl(acyl) amino, lower alkylsulfonylamino and sulfamoyl; provided that R is aryl substituted with substituent (s) selected from the group consisting of amino, mono(lower)alkylamino, acylamino, lower alkyl(acyl) amino and sulfamoyl when is hydrogen, halogen or cyano, and pharmaceutically acceptable salts thereof.

The object compound [I] or its salt can be prepared by the following processes.

Process 1 CHO I 3 R -C=C-R HSCH2-Ra [III] or its salt [II] or its salt [I-l] or its salt Process 2 haloalkylation R3 S r£ [IV] or its salt [1-2] or its salt •E 911942 Process 3 [V] or its salt Process 4 .IX R3 S (CH2)nCCH3 [1-4] or its salt Process 5 R3 S r1 acylation R -OH [VI] deesterification Rk R3' S' ' r1 [1-3] or its salt S' (CH2)n+1C°R [1-5] or its salt [1-6] or its salt [1-7] or its salt β Process 6 R“ amidation > -► r3^S^a.0H [1-8] or its reactive derivative at the carboxy or sulfo group or a salt thereof [1-9] or its salt Process 7 CO-.R I 4 co7r* [VII] OH [1-10] or its salt [1-113 or its salt Process 8 [1-12] or its salt [1-13] or its salt Process 9 [1-14] or its salt Process 10 [1-15] or its salt [1-3] or its salt [1-16] or its salt Process 11 g [1-17] or its salt Process 12 H2NO-R6 [VIII] [1-18] or its salt [1-19] or its salt [1-3] or its salt IE 911942 Process 13 nitration or sulfonation [V] or its salt Process 14 [1-20] or its salt [1-21] or its salt Process 15 [1-22] or its salt -CI-23] or its salt [1-24] or its salt Process 16 acylation or sulfonylation [1-25] or its salt [1-26] Process 17 sulfonylation [1-28] [1-27] or its salt Process 18 reduction .3 S' [1-29] or its salt [1-30] or its salt Process 19 formylation -..... .....'-fr [V] or its salt [1-31] or its salt IE 911®42 Process 20 [Va] Process 21 [1-33] or its salt [1-34] or its salt Process 22 [1-35] or its salt [1-36] or its salt Process 23 [1-37] or its salt [1-38] or its salt Process 24 acylation S^R1Rk s>XRk [1-39] or its salt [1-40] Process 25 alkylation S R1 Rk [1-40] Process 26 dehydration S^R1 Rk [1-41] [1-42] or its salt [1-43] or its salt Process 27 gA deacylation Al i [1-41] [1-44] or its salt lE 911942 Process 28 [1-431 or its salt [1-45] or its salt 3 wherein R , R and R are each as defined above; is cyano or acyl; CL X is halogen; is halo(lower) alkyl; R^ is lower alkanoyl optionally substituted with halogen; or aroyl optionally substituted with hydroxy; n is an integer of 0 to 6; R is lower alkyl; is lower alkyl substituted with esterified carboxy; esterified carboxy; or (esterified carboxy)lower alkylcarbamoyl optionally substituted with lower alkyl; R^ is lower alkyl substituted with carboxy; carboxy; or carboxy(lower)alkylcarbamoyl optionally substituted with lower alkyl; A is -(CH2)nCO- or -SO2-; R5 is amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl, halo(lower)alky1, aryl, hydroxy, lower alkylamino(lower) alkyl, a heterocyclic group and (esterified carboxy)lower alkyl; or N-containing heterocyclic group; R is lower alkylthio-substituted aryl optionally Cl substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, nitro, amino,sulfamoyl and lower alkylsulfonylamino; R is aryl optionally substituted with cl substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylsulfinyl, lower alkylsulfonyl, nitro, amino, lower alkylamino, acylamino, lower alkyl(acyl)amino and sulfamoyl; R£ is lower alkylsulfinyl- or lower alkylsulfonylsubstituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, nitro, amino, sulfamoyl and lower alkylsulfonylamino; R is aryl optionally substituted with c substituent(s) selected from the group consisting of halogen, lower alkoxy, nitro, amino, sulfamoyl and lower alkylsulfonylamino; R£ is lower alkylthio-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, nitro, amino, lower alkylamino, acylamino, lower alkyl(acyl)amino and sulfamoyl; R is lower alkylsulfinyl- or lower alkylsulfonylc substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, nitro, amino, lower alkylamino, acylamino, lower alkyl(acyl) amino and sulf amoyl; R^ is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylsulfonyl, nitro, amino, sulfamoyl and IE lower alkylsulfonylamino; R^ is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylsulfonyl, nitro, amino, lower alkylamino, acylamino, lower alky1(acyl)amino and sulfamoyl; is carboxy; esterified carboxy; lower alkyl substituted with carboxy or esterified carboxy; or lower alkanoyl optionally substituted with halogen; Rg is hydroxy(lower)alkyl optionally substituted with halogen; is lower alkoxyimino(lower) alkyl optionally 15 substituted with halogen; or lower alkyl substituted with hydroxyimino and aryl optionally substituted with hydroxy; R6 is hydrogen or lower alkyl; R^ is nitro or sulfo; R2 is nitro-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl and lower alkylsulfonylamino; R^ is amino-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl and lower alkylsulfonylamino; Rg is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro, sulfamoyl and lower alkylsulfonylamino; Rj is amino substituted with substituent (s) selected from the group consisting of acyl and lower alkylsulfonyl; Rj^ is hydrogen, halogen; cyano; lower alkyl substituted with substituent(s) selected from the group consisting of halogen, acylamino, lower alky1(acyl) amino, acyl, aryl, a heterocyclic group and lower alkoxyimino; lower alkenyl optionally substituted with cyano; acyl; nitro; amino substituted with substituent(s) selected from the group consisting of acyl and lower alkylsulfonyl; sulfo; sulfamoyl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, halo(lower)alkyl, aryl, a heterocyclic group and (esterified carboxy)lower alkyl; N-containing heterocyclicsulfonyl; or a heterocyclic group optionally substituted with oxo; R£ is lower alkylsulfonylamino-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl and sulfamoyl; R^ is N-containing heterocycliccarbonyl; carbamoyl optionally substituted with lower alkyl; or lower alkyl substituted with carbamoyl optionally substituted with lower alkyl; R1 is lower alkyl substituted with N-containing heterocyclic group, amino or lower alkylamino; R/ is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro, acylamino, lower alkyl(acyl)amino, lower alkylsulfonylamino and sulfamoyl; is sulfamoyl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, halo(lower)alky1, aryl, hydroxy, lower alkylamino(lower)alkyl, a heterocyclic group and (esterified carboxy)lower alkyl; or N-containing heterocyclicsulfonyl; r1 is thiazolyl substituted with amino or lower alkylamino; R·}· is lower alkanoyl; ί P R is lower alkenyl optionally substituted with cyano; B is di-esterified phosphono or substituted phosphonium salt; and R is lower alkyl optionally substituted with cyano; Rf is nitro-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylamino, acylamino, lower alkyl(acyl)amino and sulfamoyl; R3 is amino-substituted aryl optionally < substituted with substituent (s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylamino, acylamino, lower alkyl(acyl)amino and sulfamoyl; R^ is acylamino-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkyl(acyl)amino and sulfamoyl; R? is lower alkyl(acyl)amino-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulf inyl, lower alkylsulfonyl and. sulfamoyl; and Rj is mono(lower)alkylamino-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl and sulfamoyl.

In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following.

The term ’’lower is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.

The lower moiety in the term lower alkenyl is intended to mean a group having 2 to 6 carbon atoms.

Suitable lower alkyl and lower alkyl moiety in the terms lower alkylamino, lower alkyl(acyl)amino, lower alkylsulfonyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonylamino may be straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in which preferable one is methyl or ethyl The lower alkyl group for R1 may be substituted with /£ 911942 substituent(s) as mentioned above, wherein the preferable number of the substituent(s) is 1 or 2.

Suitable aryl” may be phenyl, naphthyl, phenyl substituted with lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, di(tert-butyl)phenyl, etc.] and the like, in which preferable one is phenyl.

The aryl group for R may be substituted with 1 to 5 substituent (s) as mentioned above and the aryl group for R may be substituted with 1 to 5 substituent (s) as stated above, wherein the preferable number of the substituent(s) is 1 or 2.

Suitable heterocyclic group may be one containing at least one hetero atom selected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group, and preferable heterocyclic group may be N-containing heterocyclic group such as unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-1,2,3triazolyl, etc.], tetrazolyl [e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.], etc.; saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[l,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1.2.4- oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.], etc.; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1.2.4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.], etc.; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like.

Said heterocyclic group may have 1 to 3 substituents such as lower alkyl as exemplified above, hydroxy, oxo, amino and lower alkylamino.

Preferable one is lower alkyl substituted with a heterocyclic group for R1 is pyrrolidinylmethyl.

Preferable one in a heterocyclic group optionally substituted with substituent(s) selected from the group consisting of hydroxy, oxo, amino and lower alkylamino for R1 is 4-hydroxy-2,5-dioxo-3-pyrrolin-3-yl, 2-aminothiazol-4-yl or 2-methylaminothiazol-4-yl.

Suitable halogen may be fluorine, chlorine, bromine and iodine, in which preferable one is fluorine or chlorine.

Suitable acyl and acyl moiety in the terms ίΕ 911942 acylamino and lower alkyl(acyl)amino may be carboxy; esterified carboxy; carbamoyl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, halo(lower)alkyl, aryl, hydroxy, lower alkylamino(lower)alkyl, a heterocyclic group, (esterified carboxy)lower alkyl and carboxy(lower) alkyl [e.g. lower alkyl-carbamoyl; aryl-carbamoyl; carbamoyl substituted with a heterocyclic group, (esterified carboxy)lower alkyl or carboxy(lower) alkyl; lower alkylcarbamoyl substituted with hydroxy, lower alkylamino, (esterified carboxy) lower alkyl or carboxy(lower) alkyl; etc.]; lower alkanoyl; aroyl; a heterocycliccarbonyl and the like.

The esterified carboxy may be substituted or unsubstituted lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl, 2.2.2- trichloroethoxycarbonyl, etc.], substituted or unsubstituted aryloxycarbonyl [e.g. phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.], substituted or unsubstituted ar(lower)alkoxycarbonyl [e.g. benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.] and the like.

The lower alkyl-carbamoyl may be substituted with halogen or unsubstituted one such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl, 2.2.2- trifluoroethylcarbamoyl or the like.

The aryl-carbamoyl may be phenylcarbamoyl, naphthylcarbamoyl, tolylcarbamoyl, xylylcarbamoyl, mesitylcarbamoyl, cumenylcarbamoyl, and the like, in which preferable one is phenylcarbamoyl.

The carbamoyl substituted with a heterocyclic group may be one substituted with a heterocyclic group as mentioned above, in which preferable one is tetrazolylcarbamoyl.

The carbamoyl substituted with (esterified carboxy)lower alkyl may be methoxycarbonylmethylcarbamoyl, methoxycarbonylethylcarbamoy1, ethoxycarbonylmethylcarbamoyl, ethoxycarbonylethylcarbamoyl, benzyloxycarbonylmethylcarbamoyl and the like.

The carbamoyl substituted with carboxy(lower) alkyl may be carboxymethylcarbamoyl, carboxyethylcarbamoyl and the like.

The lower alkylcarbamoyl substituted with hydroxy may 10 be N-hydroxy-N-methylcarbamoyl, N-ethyl-N-hydroxycarbamoyl, N-hydroxy-N-propylcarbamoyl, N-hydroxy-N-isopropylcarbamoyl and the like, in which preferable one is N-hydroxy-N-methylcarbamoyl.

The lower alkylcarbamoyl substituted with lower 15 alkylamino may be methylaminomethylcarbamoy1, dimethylaminomethylcarbamoyl, dimethylaminoethylcarbamoyl, diethylaminoethylcarbamoyl, isopropylaminomethylcarbamoyl, isopropylaminoisobutylcarbamoyl and the like, in which preferable one is dimethylaminoethylcarbamoyl.

The lower alkylcarbamoyl substituted with (esterified carboxy)lower alkyl may be (methoxycarbonylmethyl)ethycarbamoyl, (ethoxycarbonylmethyl)methylcarbamoy1, (benzyloxycarbonylmethyl)methylcarbamoyl, (benzyloxycarbonylethyl)ethylcarbamoyl and the like, in which preferable one is (ethoxycarbonylmethyl)methylcarbamoyl.

The lower alkylcarbamoyl substituted with carboxy(lower) alkyl may be (carboxymethyl)ethylcarbamoyl, (carboxymethyl)methylcarbamoyl, (carboxyethyl)ethylcarbamoyl and the like, in which preferable one is (carboxymethyl)methylcarbamoyl.

The lower alkanoyl may be substituted or unsubstituted one such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl or the like, in which preferable one is formyl, acetyl, propionyl or trifluoroacetyl.

The aroyl may be benzoyl, naphthoyl, toluoyl, di(tert-butyl)benzoyl and the like and the aryl in said aroyl may be substituted with hydroxy.

The heterocyclic moiety in the term a heterocycliccarbonyl may be one mentioned above as a heterocyclic group and preferable one in said heterocycliccarbonyl is morpholinocarbonyl, pyrrolidinylcarbonyl or methylpiperazinylcarbonyl.

Suitable ’’lower alkoxy” and lower alkoxy moiety in term ’’lower alkoxyimino may be methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like, in which preferable one is methoxy.

Preferable ’’lower alkyl substituted with halogen is trifluoromethyl or pentafluoroethyl.

Preferable aryl substituted with hydroxy” is di (tert-butyl)hydroxyphenyl.

Suitable lower alkenyl” may be a straight or 20 branched one such as vinyl, allyl, isopropenyl, propenyl, butenyl, pentenyl or the like, in which preferable one is isopropenyl. Said lower alkenyl may be substituted with cyano.

Suitable lower alkylamino may be mono or di(lower 25 alkyl)amino such as methylamino, ethylamino, dimethylamino, diethylamino or the like.

Suitable sulfamoyl substituted with lower alkyl may be methylsulfamoyl, ethylsulfamoyl, isopropylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl and the like, in which preferable one is methylsulfamoyl or dimethylsulfamoyl.

Suitable ester moiety in the term di-esterified phosphono can be referred to the ester moiety as exemplified for esterified carboxy.

In this respect, the ester group of the di-esterified 35 phosphono may be the same or different. 'Ε 911942 Suitable ’’substituted phosphonium salt” can be referred to the phosphonium salt conventionally used in the Wittig reaction [e.g. triphenylphosphoniura bromide, tri (n-butyl)phosphonium chloride, etc.].

Suitable pharmaceutically acceptable salts of the object compound [I] are conventional non-toxic salts and include acid addition salt such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], a salt with an amino acid [e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.], a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base addition salt [e.g. trimethylamine salt, triethylamine salt, etc.] and the like.

The processes for preparing the object compound [I] are explained in detail in the following.

Process 1 The compound [1-1] or its salt can be prepared by reacting a compound [II] or its salt with a compound [III] or its salt.

Suitable salt of the compound [II] may be acid addition salt as exemplified for the compound [I].

Suitable salts of the compound [III] may be base salt as exemplified for the compound [I].

Suitable salt of the compound [1-1] may be the same as those exemplified for the compound [I].

This reaction is preferably carried out in the presence of a base such as alkali metal [e.g. lithium, sodium, potassium, etc.], alkaline earth metal [e.g. •Ε 911942 calcium, magnesium, etc.], alkali metal hydride [e.g. sodium hydride, etc.], alkaline earth metal hydride [e.g. calcium hydride, etc.], alkali metal alkoxide [e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.], alkaline earth metal alkoxide [e.g. magnesium methoxide, magnesium ethoxide, etc.], trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane, l,8-diazabicyclo[5,4,0]undec-7-ene, or the like.

The reaction is usually carried out in a conventional solvent such as dioxane, tetrahydrofuran, pyridine or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 2 The compound [1-2] or its salt can be prepared by 20 reacting a compound [IV] or its salt with a haloalkylating agent.

Suitable salts of the compounds [IV] and [1-2] may be acid addition salts as exemplified for the compound [I].

Suitable haloalkylating agent may be a metal salt of 25 halo(lower)alkanoic acid [e.g. sodium trifluoroacetate, sodium pentafluoropropionate, etc.] and the like.

The present reaction is preferably carried out in the presence of a copper salt [e.g. cuprous iodide, etc.] and the like.

The reaction is usually carried out in a solvent Ν,Ν-dimethylacetamide, Ν,Ν-diraethylformamide or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under warming or heating.

,E 911942 Process 3 The compound [1-3] or its salt can be prepared by reacting a compound [V] or its salt with an acylating agent.

Suitable salts of the compounds [V] and [1-3] may be acid addition salts as exemplified for the compound [I].

Suitable acylating agent may be a conventional one used in the Friedel-Crafts acylation reaction such as an acid halide [e.g. acid chloride, acid bromide, etc.], an acid anhydride or the like.

This reaction is preferably carried out in the presence of a Lewis acid such as aluminum halide [e.g. aluminum chloride, aluminum bromide, etc.], titanium halide [e.g. titanium tetrachloride, etc.] or the like.

The reaction is usually carried out in a conventional solvent such as carbon disulfide, dichloroethane, benzene or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 4 The compound [1-5] or its salt can be prepared by reacting a compound [1-4] or its salt with a compound [VI].

Suitable salts of the compounds [1-4] and [1-5] may be acid addition salts as exemplified for the compound [13.

The present reaction is preferably carried out in the 30 presence of a thallium(III) salt [e.g. thallium(III) nitrate,, etc.], an acid [e.g. perchloric acid, etc.] and the like.

The reaction is usually carried out in a solvent such as dioxane, tetrahydrofuran or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is preferably carried out at ambient temperature or under warming to heating.

Process 5 The compound [1-7] or its salt can be prepared by subjecting a compound [1-6] or its salt to deesterification reaction.

Suitable salt of the compound [1-6] may be acid 10 addition salt as exemplified for the compound [I].

Suitable salt of the compound [1-7] may be the same as those exemplified for the compound [I].

The reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.

The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid. Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane, 1,8-diazabicyclo[5,4,0]25 undec-7-ene, or the like. Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.].

The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to wanning. The reduction can be applied preferably for elimination of the ester moiety such as 4-nitrobenzyl, 2-iodoethyl, 2,2,2-trichloroethyl, or the like. The reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].

Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalyst [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalyst [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], nickel catalyst [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalyst [e.g. reduced cobalt, Raney cobalt, etc.], iron catalyst [e.g. reduced iron, Raney iron, etc.], copper catalyst [e.g. reduced copper, Raney copper, Ullman copper, etc.] or the like.

The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, Ν,Ν-dimethylformamide, or a mixture thereof.

Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.

Process 6 The compound [1-9] or its salt can be prepared by reacting a compound [1-8] or its reactive derivative at the carboxy or sulfo group or a salt thereof with an amine, or formamide and alkali metal alkoxide.

Suitable salts of the compound [1-8] and its reactive derivative at the carboxy or sulfo group may be acid addition salts as exemplified for the compound [I].

Suitable ’’amine” may be ammonia, lower alkylamine, halo(lower)alkylamine, arylamine, lower alkylhydroxylamine, lower alkylamino(lower)alkylamine, amine substituted with a heterocyclic group, an amino acid ester, N-containing heterocyclic compound and the like.

The lower alkylamine may be mono or di(lower)20 alkylamine such as methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, pentylamine, hexylamine, dimethylamine, diethylamine, dipropylamine, dibutylamine, di-isopropylamine, dipentylaraine, dihexylamine, N-methylethylamine, N-methylpropylamine or the like, in which preferable one is methylamine, dimethylamine, ethylamine, diethylamine, isopropylamine, N-methylethylamine or N-methylpropylamine.

The halo (lower)alkylamine may be fluoromethylamine, chloroethylamine, difluoroethylamine, dichloroethylamine, trichloroethylamine, trifluoroethylamine and the like, in which preferable one is trifluoroethylamine.

The arylamine may be aniline, naphthylamine and the like, in which preferable one is aniline.

The lower alkylhydroxylamine may be methylhydroxylamine, ethylhydroxylamine, propylhydroxylamine, butylhydroxylamine, isopropylhydroxylamine and the like, in which preferable one is methylhydroxylamine.

The lower alkylamino(lower) alkylamine may be 5 dimethylaminomethylamine, diethylaminomethylamine, dimethylaminoethylamine, diethylaminoethylamine and the like, in which preferable one is“ dimethylaminoethylamine.

The amine substituted with a heterocyclic group may be aminothiazole, aminothiadiazole, aminotriazole, aminotetrazole and the like, in which preferable one is aminotetrazole.

The amino acid ester may be amino acid lower alkyl ester [e.g. glycine methyl ester, N-methylglycine ethyl ester, β-alanine methyl ester, isoleucine ethyl ester, etc.], amino acid ar(lower)alkyl ester [e.g. glycine benzyl ester,N-methylglycine benzyl ester, β-alanine benzyl ester, etc.] and the like, in which preferable one is N-methylglycine ethyl ester.

The N-containing heterocyclic compound may be saturated 5 or 6-membered N-, or N- and S-, or N- and Ocontaining heterocyclic compound such as pyrrolidine, imidazolidine, piperidine, piperazine, N-(lower)alkylpiperazine [e.g. N-methylpiperazine, N-ethylpiperazine, etc.],morpholine, thiomorpholine or the like, in which preferable one is morpholine, N-methylpiperazine or pyrrolidine.

Suitable alkali metal alkoxide may be sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like.

Suitable reactive derivative at the carboxy or sulfo group of the compound [1-8] may include an ester, an acid halide, an acid anhydride and the like. The suitable examples of the reactive derivatives may be an acid halide [e.g. acid chloride, acid bromide, etc.]; a symmetrical acid anhydride; a mixed acid anhydride with 1,1'-carbonyl diimidazole or an acid such as aliphatic carboxylic acid [e.g. acetic acid, pivalic acid, etc.], substituted phosphoric acid [e.g. dialkylphosphoric acid, diphenylphosphoric acid, etc.]; an ester such as lower alkyl ester [e.g. methyl ester, ethyl ester, propyl ester, hexyl ester, etc.], substituted or unsubstituted ar(lower)alkyl ester.[e.g. benzyl ester, benzhydryl ester, p-chlorobenzyl ester, etc.], substituted or unsubstituted aryl ester [e.g. phenyl ester, tolyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, naphthyl ester, etc.], or an ester with N,N-dimethylhydroxylamine, N-hydroxysuccinimide, N-hydroxyphthalimide or l-hydroxy-6-chloro-lH-benzotriazole, or the like.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, Ν,Ν-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. Among these solvents, hydrophilic solvents may be used in a mixture with water.

When the compound [1-8] is used in a free acid form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-ethyl-N'(3-dimethylaminopropyl) carbodiimide, thionyl chloride, oxalyl chloride, lower alkoxycarbonyl halide [e.g. ethyl 30 chloroformate, isobutyl chloroformate, etc.], l-(pchlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole, or •the like. The reaction is also preferably carried out in the presence of a conventional base such as triethylamine, pyridine, sodium hydroxide or the like.

The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.

Process 7 The compound [I—11] or its salt can be prepared by 5 reacting a compound [1-10] or its salt with a compound [VII].

Suitable salt of the compound [1-10] may be acid addition salt as exemplified for the compound [I].

Suitable salt of the compound [1-11] may be the same as those exemplified for the compound [I].

This reaction is preferably carried out in the presence of a base such as alkali metal [e.g. lithium, sodium, potassium, etc.], alkaline earth metal [e.g. calcium, magnesium, etc.], alkali metal hydride [e.g. sodium hydride, etc.], alkaline earth metal hydride [e.g. calcium hydride, etc.], alkali metal alkoxide [e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.], alkaline earth metal alkoxide [e.g. magnesium methoxide, magnesium ethoxide, etc.] or the like.

The reaction is usually carried out in a conventional solvent such as an alcohol [e.g. methanol, ethanol, etc.], dioxane, tetrahydrofuran, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 8 The compound [1-13] or its salt can be prepared by reacting a compound [1-12] or its salt with an oxidizing agent. -..

Suitable salts of the compounds [1-12] and [1-13] may be the same as those exemplified for the compound [I].

Suitable oxidizing agent may be hydrogen peroxide, Jones reagent, peracid [e.g. peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, etc.], chromic acid, potassium permanganate, alkali metal periodate [e.g. sodium periodate, etc.] and the like.

This reaction is usually carried out in a solvent 5 which does not adversely influence the reaction such as acetic acid, dichloromethane, acetone, ethyl acetate, chloroform, water, an alcohol [e.g. methanol, ethanol, etc.], a mixture thereof or the like.

The reaction temperature is not critical, and the 10 reaction is usually carried out under cooling to warming.

In this reaction, in case that the compound [1-12] having acylamino(lower)alkyl or lower alkyl(acyl)amino(lower)alkyl for R^ is used as a starting compound, the compound [1-13] having amino(lower) alkyl or lower alkylamino(lower)alkyl for R^ may be obtained respectively according to reaction conditions. These cases are included within the scope of the present reaction.

Process 9 The compound [1-15] or its salt can be prepared by reacting a compound [1-14] or its salt with an oxidizing agent.

Suitable salts of the compounds [1-14] and [1-15] may be the same as those exemplified for the compound [I].

Suitable oxidizing agent may be the same as those exemplified in Process 8.

This reaction can be carried out in substantially the same manner as Process 8, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as. explained in Process 8.

Process 10 The compound [1-16] or its salt can be prepared by 35 reacting a compound [1-3] or its salt with an oxidizing agent.

Suitable salts of the compounds [1-3] and [1-16] may be the same as those exemplified for the compound [I].

Suitable oxidizing agent may be the same as those 5 exemplified in Process 8.

This reaction can be carried out in substantially the same manner as Process 8, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to 10 those as explained in Process 8.

Process 11 The compound [1-18] or its salt can be prepared by reacting a compound [1-17] or its salt with a reducing agent.

Suitable salts of the compounds[1-17] and [1-18] may be the same as those exemplified for the compound [I].

Suitable reducing agent may be aluminum hydride compound [e.g. lithium aluminum hydride, lithium tri-t-butoxyaluminum hydride, etc.], borohydride compound [e.g. sodium borohydride, etc.], aluminum alkoxide [e.g. aluminum isopropoxide, etc.] and the like.

The reaction is usually carried out in a conventional solvent, such as water, an alcohol [e.g. methanol, ethanol, propanol, isopropanol, etc.], chloroform, diethyl ether, dioxane, or any other organic solvent which does not adversely influence the reaction, or a mixture thereof.

The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.

Process 12 The compound [1-19] or its salt can be prepared by reacting a compound [1-3] or its salt with a compound [VIII] or its salt.

IE 91 Suitable salts of the compounds [1-3], [1-19] and [VIII] may be acid addition salts as exemplified for the compound [I].

The reaction is usually carried out in a conventional 5 solvent such as water, an alcohol [e.g methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, Ν,Ν-dimethylformamide, dioxane or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.

The reaction is preferably carried out in the presence of an inorganic or organic base such as alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], tri(lower)alkylamine [e.g. triethylamine, etc.], pyridine, or the like.

The reaction temperature is not critical, and the 20 reaction is usually carried out under cooling to heating.

Process 13 The compound [1-20] or its salt can be prepared by reacting a compound [V] or its salt with a nitrating agent or a sulfonating agent.

Suitable salts of the compounds [1-20] and [V] may be acid addition salts as exemplified for the compound [I].

Suitable nitrating agent may be nitric acid, fuming nitric acid, potassium nitrate, nitronium tetrafluoroborate and the like.

Suitable sulfonating agent may be sulfuric acid, fuming sulfuric acid and the like.

The reaction is usually carried out in an acid or an acid anhydride such as sulfuric acid, acetic acid, acetic anhydride or the like.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 14 The compound [1-22] or its salt can be prepared by subjecting a compound [1-21] or its salt to reduction.

Suitable salts of the compounds [1-21] and [1-22] may be acid addition salts as exemplified for the compound [I].

The present reduction is carried out by chemical reduction, catalytic reduction, or the like.

Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].

Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalyst [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalyst [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], nickel catalyst [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalyst [e.g. reduced cobalt, Raney cobalt, etc.], iron catalyst [e.g. reduced iron, Raney iron, etc.], copper catalyst [e.g. reduced copper, Raney copper, Ullman copper, etc.] or the like.

The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, an alcohol [e.g. methanol, ethanol, propanol, etc.], Ν,Ν-dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent and other conventional solvent such as diethyl ether, methylene chloride, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not 10 critical and the reaction is usually carried out under cooling to warming.

In this reaction, in case that the compound [1-21] having aryl substituted with nitro for R and/or aryl 3 substituted with nitro for R is used as a starting compound, the compound [1-22] having aryl substituted with 3 amino for R and/or aryl substituted with amino for R may be obtained according to reaction conditions. This case is included within the scope of the present reaction.

Process 15 The compound [1-24] or its salt can be prepared by subjecting a compound [1-23] or its salt to reduction.

Suitable salts of the compounds [1-23] and [1-24] may be the same as those exemplified for the compound [I].

This reaction can be carried out in substantially the same manner as Process 14, and therefore the reducing agent, the reaction mode and the reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 14.

In this reaction! in case that the compound [1-23] having nitro for R^ and/or aryl substituted with nitro for R3 is used as a starting compound, the compound [1-24] having amino for R1 and/or aryl substituted with amino for R3 may be obtained according to reaction conditions. This case is included within the scope of the present reaction. Ε911942 Process 16 The compound [1-26] can be prepared by reacting a compound [1-25] or its salt with an acylating or sulfonylating agent.

Suitable salt of the compound [1-25] may be acid addition salt as exemplified for the compound [ I ].

The acylating or sulfonylating agent may include an Q organic acid represented by the formula : R -OH, in which g R is acyl or lower alkylsulfonyl as illustrated above, or a reactive derivative thereof, a compound of the formula : 4 R -N=C=O, wherein R is as defined above, and the like.

Suitable reactive derivative of the organic acid may be a conventional one such as an acid halide [e.g. acid chloride, acid bromide, etc.], an acid azide, an acid anhydride, an activated amide, an activated ester, etc.

When free acid is used as an acylating or sulfonylating agent, the present reaction may preferably be carried out in the presence of conventional condensing agent such as N,N’-dicyclohexylcarbodiimide, acetic anhydride or the like.

This reaction is usually carried out in a conventional solvent such as dioxane, chloroform, methylene chloride, tetrahydrofuran, pyridine or any other organic solvent which does not adversely influence the reaction.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], tri{lower)alkylamine [e.g. triethylamine, etc.], or the like.

The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.

In this reaction, in case that the compound [1-25] having aryl substituted with amino for R is used a IE 911942 starting compound, the compound [1-26] having aryl substituted with acylamino or lower alkylsulfonylamino for R may be obtained according to reaction conditions. This case is included within the scope of the present reaction.

Process 17 The compound [1-28] can be prepared by reacting a compound [1-27] or its salt with a sulfonylating agent.

Suitable salt of the compound [1-27] may be acid 10 addition salt as exemplified for the compound [I].

This reaction can be carried out in substantially the same manner as Process 16, and therefore the sulfonylating agent, the reaction mode and the reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 16.

In this reaction, in case that the compound [1-27] having aryl substituted with amino for R3 is used as a starting compound, the compound [1-28] having aryl 3 substituted with lower alkylsulfonylamino for R may be 20 obtained according to reaction conditions. This case is included within the scope of the present reaction.

Process 18 The compound [1-30] or its salt can be prepared by reacting a compound [1-29] or its salt with a reducing agent.

Suitable salts of the compounds [1-29] and [1-30] may be acid addition salts as exemplified for the compound [I].

Suitable reducing agent may be diborane, a metal hydride-[e.g. lithium aluminum hydride, etc.] and the like.

The reaction is usually carried out in a conventional solvent such as diethyl ether, tetrahydrofuran or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.

Process 19 The compound [1-31] or its salt can be prepared by reacting a compound [V] or its salt with a formylating agent.

Suitable salts of the compounds [V] and [1-31] may be acid addition salts as exemplified for the compound [I].

Suitable formylating agent may be Ν,Ν-dimethylformamide; so-called Vilsmeir reagent prepared by the reaction of Ν,Ν-dimethylformamide with phosphorus oxychloride, phosgene, etc.; and the like.

When a formylating agent is Ν,Ν-dimethylformamide, the reaction is preferably carried out in the presence of a base such as lower alkyl alkali metal [e.g. n-butyl lithium, etc.], or the like.

The reaction is usually carried out in a solvent such as dioxane, tetrahydrofuran, Ν,Ν-dimethylformamide, methylene chloride, chloroform, or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 20 The compound [1-32] can be prepared by the following methods. Namely, 1) the compound [Va] is firstly reacted with a chlorosulfonylating agent, and then 2) reacting the resultant product- with an amine.

Suitable amine may be the same as those exemplified in Process 6.

In the first step, suitable chlorosulfonylating agent may be chlorosulfonic acid, and the like. In this reaction, the chlorosulfonylating agent is usually used as a solvent. The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

In the second step, the reaction is carried out in a solvent such as water, ethyl acetate, tetrahydrofuran or any other solvent which does not adversely influence the reaction. This reaction temperature is not critical, and the reaction is usually carried out under cooling.

Process 21 The compound [1-34] or its salt can be prepared by reacting a compound [1-33] or its salt with thiourea or lower(alkyl) thiourea.

Suitable salts of the compounds [1-33] and [1-34] may be acid addition salts as exemplified for the compound [I] The reaction is usually carried out in a solvent such as an alcohol [e.g. methanol ethanol, etc.], chloroform, methylene chloride, tetrahydrofuran, dioxane or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.

Process 22 The compound [1-36] or its salt can be prepared by reacting a compound [1-35] or its salt with a compound [IX].

Suitable salts of the compounds [1-35] and [1-36] may 30 be acid addition salts as exemplified for the compound [I).

This reaction is preferably carried out in the presence of an inorganic or organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate thereof, alkali metal hydride [e.g. sodium hydride, etc.], alkali metal amide [e.g. sodium amide, etc.], alkaline earth metal hydride [e.g. calcium hydride, etc.], alkali metal alkoxide [e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.], alkaline earth metal alkoxide [e.g. magnesium methoxide, magnesium ethoxide, etc.], lower alkyl alkali metal [e.g. n-butyl lithium, etc.], trialkylamine [e.g. trimethylamine, triethylamine, etc.], pyridine, piperidine, picoline, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,0]octane, l,8-diazabicyclo[5,4,0]undec-7-ene, or the like.

The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], chloroform, methylene chloride, nitromethane, benzene, tetrahydrofuran, diethyl ether, Ν,Ν-dimethylformamide, dimethylsulfoxide or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the 20 reaction can be carried out under cooling to heating.

In this reaction, in case that the corresponding phosphorane compound derived from the compound [IX] is stable, the phosphorane compound may be used instead of the compound [IX]. This case is also included within the scope of the present reaction.

Process 23 The compound [1-38] or its salt can be prepared by subjecting a compound [1-37] or its salt to reduction.

Suitable salts of the compounds [1-37] and [1-38] may be the same as those exemplified for the compound [I].

This reaction can be carried out. in substantially the same manner as Process 14, and therefore the reducing agent, the reaction mode and the reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 14.

In this reaction, in case that the compound [1-37] having nitro for R1 and/or aryl substituted with nitro for R is used as a starting compound, the compound [1-38] having amino for R^ and/or aryl substituted with amino for R may be obtained according to reaction conditions. This case is included within the scope of the present reaction.

Process 24 IQ The compound [1-40] can be prepared by reacting a compound [1-39] or its salt with an acylating agent.

Suitable salt of the compound [1-39] may be acid addition salt as exemplified for the compound [I].

This reaction can be carried out in substantially the same manner as Process 16, and therefore the acylating agent, the reaction mode and the reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 16.

ZQ Process 25 The compound [1-41] can be prepared by reacting a compound [1-40] with an alkylating agent.

Suitable alkylating agent may be lower alkyl halide [e.g. methyl iodide, ethyl bromide, etc.] and the like.

When lower alkyl halide is used as alkylating agent, the reaction is preferably carried out in the presence of a base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydride thereof or the like. 3Q The reaction is usually carried out in a conventional solvent'.which does not adversely influence the reaction such as dioxane, tetrahydrofuran, Ν,Ν-dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned alkylating agent are in liquid, they can also be used as a solvent.

The reaction temperature is not critical and the reaction can be carried out under cooling to heating.

Process 26 The compound [1-43] or its salt can be prepared by reacting a compound [1-42] or its salt with a dehydrating agent.

Suitable salts of the compounds [1-42] and [1-43] may 10 be acid addition salts as exemplified for the compound [I].

Suitable dehydrating agent may be phosphorus compound [e.g. phosphorus pentoxide, phosphorus pentachloride, phosphorus oxychloride, etc.], thionyl chloride, acid anhydride [e.g. acetic anhydride, etc.], phosgene, arylsulfonyl chloride [e.g. benzenesulfonyl chloride, p-toluenesulfonyl chloride, etc.], methanesulfonyl chloride, sulfamic acid, ammonium sulfamate, N,N’dicyclohexylcarbodiimide, lower alkoxycarbonyl halide [e.g. ethyl chloroformate, etc.) and the like.

The reaction is usually carried out in a conventional solvent such as acetonitrile, methylene chloride, ethylene chloride, benzene, Ν,Ν-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.

Additionally in case that the above-mentioned dehydrating agents are in liquid, they can also be used as a solvent.

The reaction temperature is not critical and the 30 reaction is preferably carried out under warming or heating» Process 27 The compound [1-44] or its salt can be prepared by 35 subjecting a compound [1-41] to deacylation reaction.

Suitable salt of the compound [1-44] may be acid addition salt as exemplified for the compound [I].

This reaction may preferably be conducted in the presence of an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, etc.] and an organic acid [e.g. trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, etc.].

The reaction is usually carried out in a conventional solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], tetrahydrofuran, dioxane or any other organic solvent which does not adversely influence the reaction, or a mixture thereof.

The reaction temperature is not critical, and the reaction can be carried out cooling to heating.

Process 28 The compound [1-45] or its salt can be prepared by reacting a compound [1-43] or its salt with an azide compound.

Suitable salts of the compounds [1-43] and [1-45] may be the same as those exemplified for the compound [I].

Suitable azide compound may be alkali metal azide [e.g. sodium azide, potassium azide, etc.], alkaline earth metal azide [e.g. calcium azide, etc.], hydrogen azide and the like.

The reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, Ν,Ν-dimethylformamide or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction can be carried out warming to heating.

The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.

It is to be noted that the compound [I] and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention.

The object compound [I] and pharmaceutically acceptable salts thereof possess strong antiinflammatory and analgesic activities, and are useful for the treatment and/or prevention of inflammatory conditions and various pains, collagen diseases, autoimmune diseases and various immunity diseases in human beingsor animals, and more particularly to methods for the treatment and/or prevention of inflammation and pain in joint and muscle [e.g. rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, etc.], inflammatory skin condition [e.g. sunburn, eczema, etc.], inflammatory eye condition [e.g. conjunctivitis, etc.], lung disorder in which inflammation is involved [e.g. asthma, bronchitis, pigeon fancier's disease, farmer's lung, etc.], condition of the gastrointensinal tract associated with inflammation [e.g. aphthous ulcer, Chrohn's disease, atropic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, etc.], gingivitis, inflammation, pain and tumescence after operation or injury, pyresis, pain and other conditions associated with inflammation, particularly those in which lipoxygenase and cyclooxygenase products are a factor, systemic lups erythematosus, scleroderma, polymyositis, periarteritis nodosa, rheumatic fever, Sjogren's syndrome, Behcet disease, thyroiditis, type I diabetes, nephrotic syndrome, aplastic anemia, myasthenia gravis, uveitis contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Hodgkin’s disease, and the like.

In order to illustrate the usefulness of the object compound [I], the pharmacological test data of the compound [I] are shown in the following.

[A] ANTIINFLAMMATORY ACTIVITY : Effect on adjuvant arthritis in rats : (i) Test Method : Ten female Sprague-Dawley rats were used per group. A dose of 0.5 mg of Mycobacterium tuberculosis (strain Aoyama B) suspended in 0.05 ml of liquid paraffin was injected subcutaneously in the right hind paw. The injection of mycobacterial adjuvant produced local inflammatory lesions (primary lesion) and then about 10 days later, secondary lesions in both the injected and uninjected paws. The difference in volumes of both paws before and after adjuvant injection was the measure of arthritis. The drug was given orally once a day for 23 consecutive days from day 1. (ii) Test Results : Test compound (Example No.) Dose (mg/kg) Inhibition of secondary lesion (uninjected paw) (%) 4 0.1 87.0 5-2) 10 97.4 28 10 95.6 35 3.2 87.1 47-3) 10 96.9 53 10 88.8 Ibuprofen 100 79.6 [B] ANALGESIC ACTIVITY : Inflammatory hyperalgesia induced by brewer’s yeast in rats : (i) Test Method : Ten male Sprague Dawley rats were used per group. 0.1 ml of 5% brewer’s yeast suspended in 0.5% methylcellulose was injected into the right hind paw. The pain threshold was determined 3 hours after yeast injection, by applying pressure to the foot and reading the pressure at which the rat withdrew the foot.

The drugs were given orally 2 hours after yeast 10 injection. The pain threshold in the treated animals was compared with that in the control animals. (ii) Test Results : Test compound (Example No.) Dose (mg/kg) Relative potency (Control = 1.0) 6 32 1.41 15-24) 32 1.41 18-8) 32 1.32 22-17) 32 1.35 46-2) 32 1.41 62-5) 10 1.50 70-3) 10 1.32 EC] ANTI-RHEUMATIC ACTIVITY : Effect on collagen induced arthritis in mice : (ij Test Method : Eight male DBA/1 mice were used per group. Type II bovine collagen was solublized in 0.1 M acetic acid and 35 emulsified in complete Freund's adjuvant (CFA). Mice were primed with 0.2 mg of Type II collagen in CFA intradermally at the base of the tail. Mice were challenged after 21 day with the same procedure. From 10 day after challenge, drug was administered orally once a day for 3 weeks and mice were inspected weekly for visual signs of arthritis. An arthritis index was used to grade limb 0-3, representing joint swelling and erythema (Grade 1), visible joint disorder (Grade 2) and detectable joint ankylosis (Grade 3). (ii) Test Results : Test compound (Example No.) Dose (mg/kg) Inhibition of arthritis index (%) 4 0.1 56.3 5-2) 10 66.7 53 10 54.8 [D] Effect on Delayed Type Hypersensitivity (DTH) Response to bovine type II collagen (i) Test Method : Seven male DBA/1 mice were used for this test. The mice were sensitized at tail base with 125 pg type II collagen emulsified in complete Freund's adjuvant containing Mycobacterium tuberculosis strain H37Rv (Wako Pure Chemical Industries Ltd., Osaka, Japan). Two weeks' later, a 0.04 ml challenge dose of 2.5 mg/ml type II collagen in phosphate buffered saline (PBS) was injected into the plantar region of the right hind foot and 0.04 ml PBS into the left hind foot to act as a control. Twenty four hours after challenge, the volume of both hind feet were measured with a volume meter (Muromachi MK-550).

The drug was administered orally on consecutive days except holidays starting from the sensitization.

Data was expressed by per cent inhibition compared with vehicle control for each study. (ii) Test Results : Dose (mg/kg) Test Compound — (Example No.) 1.0 10 4 67.7 79.0 For therapeutic purpose, the compound [I] and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external (topical) administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, suppositories, solution, suspension, emulsion, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.

While the dosage of the compound [I] will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, ,250 mg, 500 mg and 1000 mg of the compound [I] may be effective for treating the above-mentioned diseases.

In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.

The following Preparations and Examples are given for the purpose of illustrating this invention.

Preparation 1 A mixture of phosphorus oxychloride (1.6 ml) and Ν,Νdimethylf ormamide (1.8 ml) in dichloroethane (6 ml) was stirred at ambient temperature for 1 hour. Dichloroethane (11 ml) and 4'-fluoro-2-(4-nitrophenyl)acetophenone (3 g) was added, and the mixture was refluxed overnight, washed with water twice, dried and evaporated. The oily residue (4 g) was purified by column chromatography on silica gel (80 g) eluting with toluene to give yellow crystals of 3-chloro-3-(4-fluorophenyl)-2-(4-nitrophenyl)propenal (2.9 g) · IR (Nujol) : 1680, 1600, 1520 cm1 NMR (CDC13, δ) : 6.8-8.4 (8H, m), 9.64 (1H, s) Preparation 2 A mixture of 3,4-difluorophenylacetic acid (10 g), 4-(methylthio)benzaldehyde (8.84 g) and sodium methoxide (3.14 g) in acetic anhydride (30 ml) was refluxed for 20 hours. The solvent was evaporated, and the residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid and water, dried and concentrated to dryness. The obtained solid material was washed with ethanol and dried to give crystals of 2-(3,4-difluorophenyl)-3-[4-(methylthio)phenyl]acrylic acid (12.1 g). mp : 154-158°C IR (Nujol) : 1665, 1585, 1515 cm 1 NMR.. (DMSO-dg, δ) : 2.07 (3H, s), 6.6-7.4 (7H, m) , 7.40 (1H, s), 12.4 (1H, s) Mass (m/z) : 306 (M+), 262 Preparation 3 A mixture of 2-(3,4-difluorophenyl)-3-[4(methylthio)phenyl]acrylic acid (12 g) and phosphorus pentachloride (9.0 g) in dichloromethane (120 ml) was stirred for 1 hour. The solvent was evaporated to give a solid of 2-(3,4-difluorophenyl)-3-[4-(methylthio)phenyl]acryloyl chloride (13 g).

IR (Nujol) : 1740, 1615, 1585, 1515 cm1 A solution of the above acid chloride (13 g) in acetone (50 ml) was added dropwise to an ice-cooled mixture of sodium azide (2.8 g) and sodium bicarbonate (8.2 g) in water (50 ml) and acetone (50 ml). The mixture was stirred for 1 hour at ambient temperature, and acetone was evaporated. The resulting aqueous solution was extracted with toluene. The extract was washed with water, dried and concentrated to give a solid of 2-(3,4-difluoropheny1)-3-(4-(methylthio)phenyl]acryloyl azide.

IR (Nujol) : 2150, 1680, 1590, 1510 cm'1 A mixture of the above acid azide, water (25 ml) and acetic acid (50 ml) was refluxed for 1 hour, and cooled overnight. The precipitates were collected and recrystallized from ethanol to give crystals of 3’,4'-difluoro-2-[4-(methylthio)phenyl]acetophenone (8.3 g) · mp : 123-124°C IR (Nujol) : 1690, 1610, 1515 cm1 NMR (CDC13, δ) : 2.46 (3H, s), 4.19 (2H, s), 7.1-7.9 (7H, m) Mass (m/z) : 278 The following compound (Preparation 4) was obtained according to a similar manner to that of Preparation 3.

Preparation 4 4'-Nitro-2-[4-(methylthio)phenyl]acetophenone mp : 105-107°C IR (Nujol) : 1695, 1600, 1520 cm1 NMR (CDC13, ό) : 2.47 (3H, s), 4.28 (2H, s), 7.1-7.3 (4H, m), 8.13 (2H, d, J=8Hz), 8.27 (2H, d, J=8Hz) Mass (m/z) : 287 (M+) Preparation 5 A mixture of 5-(4-fluorophenyl)-4-(4-nitrophenyl·)thiophene-2-carboxylic acid (7.6 g) and copper powder (1.6 g) in quinoline (12 ml) was stirred and refluxed for 7 hours. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, brine, dilute hydrochloric acid and brine, successively, dried and evaporated. The residue (7.3 g) was purified by column chromatography on silica gel (80 g) eluting with a mixture of hexane and toluene (2:1) to give yellow orange crystals of 2-(4-fluorophenyl)-3-(4-nitrophenyl)thiophene (3.8 g). mp : 108-110’C IR (Nujol) : 1600, 1540, 1510 cm1 The following compounds (Preparation 6-1) to 6-6)) were obtained according to a similar manner to that of Preparation 5.

Preparation 6 1) 2-(4-Fluorophenyl)-3-(4-methoxyphenyl)thiophene IRx(Nujol) : 1605, 1545, 1510, 1500 cm1 2) 2-(4-Chlorophenyl)-3-(4-(methylthio)phenyl]thiophene mp : 133-134°C IR (Nujol) : 1600, 1490 cm’1 3) 3-[4-(Ethylthio)phenyl]-2-(4-fluorophenyl)thiophene IR (Film) : 1605, 1535, 1505 cm1 NMR (CDC13, δ) : 1.31 (3H, t, J=7Hz), 2.92 (2H, q, J=7Hz), 6.7-7.4 (10H, m) 4) 2-(3,4-Difluorophenyl)-3-14-(methylthio)phenyl]thiophene mp : 94-96°C IR (Nujol) : 1600, 1515 cm1 Mass (m/z) : 318 (M+) ) 3-[4-(Methylsulfonyl)pheny11-2-(4-nitrophenyl)thiophene mp : 145-150°C (dec.) IR (Nujol) : 1595, 1510 cm1 NMR (DMSO-dg, δ) : 3.25 (3H, s), 7.39 (1H, d, J=5Hz), 7.4-8.0 (7H, m), 8.21 (2H, d, J=8Hz) Mass (m/z) : 359 (M+) 6) 3-[4-(Methylthio)phenyl]-2-(4-nitrophenyl)thiophene mp : 135-140°C NMR (DMSO-dg, δ) : 2.47 (3H, s), 6.8-8.2 (10H, m) Preparation 7 Bromine (1 ml) was added dropwise to a solution of 2-(4-fluorophenyl)-3-(4-nitrophenyl) thiophene (5.3 g) in acetic acid (53 ml) and dichloromethane (53 ml) at 2°C. The mixture was stirred at 2°C for 45 minutes and concentrated to dryness. The residue was collected and washed with water and ethanol to give dark green crystals of 5-bromo-2-(4-fluorophenyl)-3-(4-nitrophenyl)thiophene (6.5 g). mp : 129-130°C IR (Nujol) : 1605, 1595, 1545, 1510 cm1 NMR (DMSO-dg, δ) : 7.1-7.6 (7H, m), 8.17 (2H, d, J=9Hz) ,E 911942 ' 54 Mass (m/z) : 378 (M+) The following compounds (Preparations8-1) and 8-2)) were obtained according to a similar manner to that of Preparation 7.

Preparation 8 1) 5-Bromo-3-[4-(methylsulfonyl)phenyl]-2-(4nitrophenyl) thiophene mp : 178-180°C (dec.) IR (Nujol) : 1595, 1515 cm NMR (DMSO-dg, δ) : 3.25 (3H, s), 7.4-7.6 (5H, m), 7.90 (2H, d, J=8Hz), 8.20 (2H, d, J=8Hz) Mass (m/z) : 439, 437 2) 5-Bromo-3-[4-(methylthio)phenyl]-2-(4-nitrophenyl)thiophene mp : 2 3 00 C (dec.) IR (Nujol) : 1600, 1515 cm-1 Mass (m/z) : 407, 405 The following compound (Preparation 9) was obtained according to a similar manner to that of Preparation 2.

Preparation 9 2-(4-Nitrophenyl)-3-[4-(methylthio)phenyl]acrylic acid mp : 217-219°C (dec.) IR (Nujol) : 1690, 1670, 1610, 1590, 1515 cm NMR (DMSO-dg, 5) : : 2. 42 (3H, s) , 6.98 (2H, d, J=8Hz), 7.10 (2H, d, J=8Hz) , 7.42 (2H, d, J=8Hz), 7.83 (1H, s) , 8.25 (2H, d, J=8Hz), 12.8 (1H, s) Mass (m/z) : 315 (M+) Preparation 10 A mixture of 3-14-(methylthio)phenyl]-2-(4nitrophenyl)thiophene (0.33 g) and N-chlorosuccinimide (0.15 g) in acetic acid (5 ml) was heated at 80°C for 3 hours. The mixture was poured into an ice-cooled solution of sodium bicarbonate, and the precipitates were collected to give a powder of 5-chloro-3-[4-(methylthio)phenyl]-2(4-nitrophenyl) thiophene (0.31 g). mp : 150-160°C (dec.) IR (Nujol) : 1595, 1515 cm-1 NMR (CDC13, δ) : 2.49 (3H, s), 6.9-8.2 (9H, m) Preparation 11 A mixture of 5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-carboxamide (4.8 g) and methanesulfonyl chloride (8.8 g) in pyridine (25 ml) was stirred at 50°C for 4 hours. The mixture was concentrated and the residue was triturated in dilute hydrochloric acid. The precipitates were collected and recrystallized from ethanol to give crystals of 5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-carbonitrile (3.6 g). mp : 139-140°C IR (Nujol) : 2220, 1600, 1510 cm1 NMR (DMSO-dg, δ) : 3.24 (3H, s), 7.1-7.6 (6H, m), 7.91 (2H, d, J=8Hz), 8.24 (1H, s) MASS (m/z) : 357 (M+) Example 1 A mixture of 3-chloro-3-(4-fluorophenyl)-230 (4-nitrophenyl)propenal (1.5 g), thioglycolic acid (0.36 ml) and'triethylamine (1.5 ml) in pyridine (7.6 ml) was stirred at 70°C for 1 hour and refluxed for 7 hours. Pyridine was evaporated, and the residue was dissolved in ethyl acetate, washed with water and dilute hydrochloric acid, dried and concentrated. The residue (1.6 g) was washed with toluene to give pale brown crystals of 5-(4-fluorophenyl)-4-(4-nitrophenyl)thiophene2-carboxylic acid (1.1 g). mp : 227-229°C IR (Nujol) : 1670, 1600, 1545, 1510 cm1 NMR (DMSO-dg, 6) : 7.2-7.6 (6H, m), 7.91 (1H, s), 8.18 (2H, d, J=9Hz), 13.4 (1H, s) Mass (m/z) : 342, 299 Example 2 A mixture of phosphorus oxychloride (3.2 ml) and Ν,Ν-dimethylformamide (3.4 ml) in dichloroethane (25 ml) was stirred at ambient temperature for 1 hour and 2’,4’-difluoro-2-[4-(methylthio)phenyl]acetophenone (6.2 g) was added thereto. The mixture was refluxed for 8 hours, washed with water twice, dried and evaporated to give 3-chloro-3-(2,4-difluorophenyl)-2-[4(methy1thio)phenyl]propenal as a solid.

A mixture of the above solid, ethyl thioglycolate (3 g) and triethylamine (5 g) in pyridine (35 ml) was stirred and refluxed for 6 hours. Solvent was evaporated, and the residue was dissolved in ethyl acetate, washed with water and dilute hydrochloric acid, dried and concentrated to give an oil of ethyl 5-(2,4-difluorophenyl)-4-[425 (methylthio)phenyl]thiophene-2-carboxylate (9 g).

IR (Film) : 1710, 1600, 1545, 1495 cm1 NMR (CDC13, δ) : 1.39 (3H, t, J=8Hz), 2.41 (3H, s), 4.33 (2H, g, J=8Hz), 6.3-7.9 (8H, m) The following compounds (Examples 3-1) and 3-2)) were obtained- according to a similar manner to that of Example 2.

Example 3 1) Ethyl 5-(3,4-difluorophenyl)-4-[4-(methylthio)35 phenyl]thiophene-2-carboxylate IR (Film) : 1710, 1600, 1540, 1515 cm x NMR (CDC13, δ) : 1.38 (3H, t, J=7Hz), 2.44 (3H, s), 4.33 (2H, q, J=7Hz), 6.9-7.3 (7H, m), 7.69 (1H, s) 2) Ethyl 4-[4-(methylthio)phenyl]-5-(4-nitrophenyl)thiophene-2-carboxylate IR (Film) : 1710, 1600, 1520 cm1 NMR (CDC13, δ) ; 1.30 (3H, t, J=7Hz), 2.48 (3H, s), 4.20 (2H, q, J=7Hz), 7.1-7.3 (4H, m), 7.47 (2H, d, J=8Hz), 7.82 (1H, s), 8.18 (2H, d, J=8Hz) Mass (m/z) : 399 (M+) Example 4 A mixture of 5-bromo-2-(4-fluorophenyl)-3-[4(methylsulfonyl)phenyl]thiophene (7.2 g), sodium trifluoroacetate (9.4 g) and cuprous iodide (6.5 g) in Ν,Ν-dimethylacetamide (109 ml), was stirred and refluxed for 5 hours. Dichloromethane (200 ml), 3N hydrochloric acid (100 ml) and water (100 ml) were added to the reaction mixture. The resulting mixture was filtered, and the filtrate was separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated.

The residue (13.9 g) was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (50:1). The crude product (1.3 g) was recrystallized from ethanol to give pale brown crystal of 2-(4-fluorophenyl) -3-[4-(methylsulfonyl)phenyl] - 5 30 (trifluoromethyl)thiophene (1.04 g). mp :: 145-146°C IR (Nujol) : 1600, 1510 cm1 NMR (DMSO-dc, δ) : 3.20 (3H, s), 7.1-8.0 (9H, m) Mass (m/z) : 400 (M ), 321 The following compounds (Examples 5-1) and 5-2)) were obtained according to a similar manner to that of Example 4.

Example 5 1) 2-(4-Fluorophenyl)-3-(4-nitrophenyl)-5(trifluoromethyl) thiophene mp : 103-107°C IR (Nujol) : 1600, 1560, 1510 cm1 Mass (m/z) : 367 (M+) 2) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl] - 5(pentafluoroethyl) thiophene mp : 183-185°C IR (Nujol) : 1600, 1550, 1510 cm1 NMR (DMSO-d,, δ) : 3.25 (3H, s), 7.1-8.0 (9H, m) 5 + Mass (m/z) : 450 (M ) Example 6 Titanium (IV) chloride (2.7 ml) was added dropwise to a stirred solution of 2-(4-fluorophenyl)-3-(4(methylsulfonyl)phenyl]thiophene (5 g) and acetyl chloride (2.2 ml) in benzene (50 ml) at 5 to 10°C. The mixture was stirred at ambient temperature for 4 hours, poured into ice-water, and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate, dried and concentrated. The residue was recrystallized from a mixture of ethanol and ethyl acetate to give pale brown crystals of 5-acetyl-2-(4-fluorophenyl)-3-(43 0 (methylsulfonyl)phenyl]thiophene (3.7 g). mp:'.: 169-172 °C IR (Nujol) : 1670, 1600, 1510 cm1 NMR (DMSO-d6, δ) : 2.58 (3H, s), 3.21 (3H, s), 7.0-8.0 (8H, m), 8.11 (1H, s) Mass (m/z) : 374 (M+), 359 The following compounds (Examples 7-1) to 7-11)) were obtained according to a similar manner to that of Example ji.

Example 7. 1) 5-Acetyl-2-(4-fluorophenyl)-3-(4-nitrophenyl)thiophene mp : 225-227°C IR (Nujol) : 1660, 1600, 1545, 1510 cm1 NMR (DMSO-dg, δ) : 2.61 (3H, s), 7.2-7.5 (4H, m), 7.56 (2H, d, J=8Hz), 8.20 (1H, s), 8.22 (2H, d, J=8Hz) Mass (m/z) : 341 (M+), 326 2) 5-Acetyl-2-(4-fluorophenyl)-3-(4-methoxyphenyl)thiophene mp : 114-115’C IR (Nujol) : 1650, 1610, 1550, 1510 cm1 NMR (CDC13, δ) : 2.58 (3H, s), 3.82 (3H, s), 6.8-7.4 20 (8H, m), 7.67 (1H, s) Mass (m/z) : 326 (M+) 3) 5-Acetyl-2,3-bis (4-fluorophenyl)thiophene mp : 134-135°C IR (Nujol) : 1645, 1610, 1550, 1510 cm1 NMR (CDC13, δ) : 2.59 (3H, s), 6.9-7.3 (8H, m), 7.67 (1H, s) Mass (m/z) : 314 (M+), 299 4) 5-Acetyl-2-(4-methoxyphenyl)-3-[4-(methylsulfonyl)phenyl]thiophene mp : 141-143’C IR (Nujol) : 1655, 1600, 1540, 1510 cm1 NMR (CDC13, δ) : 2.59 (3H, s), 3.68 (3H, s), 3.83 (3H, s), 6.8-8.0 (9H, m) Mass (m/z) : 386 (M+) ) 2-(4-Methoxyphenyl)-3-(4-(methylthio)phenyl]-5propionylthiophene IR (Film) : 1660, 1605, 1510 cm1 NMR (CDC13, δ) : 1.24 (3H, t, J=7Hz), 2.44 (3H, s), 2.89 (2H, q, J=7Hz), 3.79 (3H, s), 6.4-7.3 (8H, m), 7.58 (1H, s) 6) 5-Acetyl-2-(4-chlorophenyl)-3-(4-(methylthio)phenyl] thiophene IR (Film) : 1660, 1595, 1535, 1490 cm1 NMR (CDC13, δ) : 2.44 (3H, s), 2.53 (3H, s), 7.0-7.6 (9H, m) 7) 5-Acetyl-3-[4-( ethylthio)phenyl]-2-(4-fluorophenyl) thiophene mp : 70-72°C IR (Nujol) : 1670, 1600, 1540, 1510 cm1 Mass (m/z) : 356 (M+) 8) 5-Acetyl-2-(3,4-difluorophenyl)-3-[4-(methylthio)phenyl]thiophene mp : 100-104°C IR (Nujol) : 1675, 1600, 1540, 1515 cm1 Mass (m/z) : 360 (M+) 9) 5-(3,5-Di(t-butyl)-4-hydroxybenzoyl]-2-(4fluorophenyl)-3-(4-(methylsulfonyl)phenyl]thiophene 30 mp : 168-172°C IR/.(Nujol) r 3550, 1625, 1595, 1535, 1510 cm1 NMR (DMSO-dg, δ) : 1.44 (18H, s), 3.22 (3H, s), 7.0-8.0 (12H, m) Mass (m/z) : 564 (M+) ) 5-Acetyl-3-[4-(methylthio)phenyl]-2-(4-nitrophenyl) thiophene IR (Film) : 1660, 1595, 1515 cm1 Mass (m/z) : 369 (M+) 11) 5-Acetyl-2-(4-methoxyphenyl)-3-[4-(methylthio) phenyl]thiophene IR (Film) : 1660, 1610, 1515 cm1 NMR (CDC13, δ) : 2.43 (3H, s), 2.57 (3H, s), 3.80 (3H, s), 6.7-7.3 (8H, m), 7.66 (1H, s) Mass (m/z) : 354 (M+) Example 8 A solution of 2-(4-fluorophenyl)-3-[4-(methylthio)15 phenyl]thiophene (1.0 g) and trifluoroacetic anhydride (2 ml) in dichloroethane (5 ml) was heated in a steel bomb at 120°C overnight. The mixture was washed with an aqueous solution of sodium bicarbonate and water, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and toluene (2:1) to give yellow crystals of 2-(4-fluorophenyl)-3-[4-(methylthio)phenyl]5-(trifluoroacetyl)thiophene (0.87 g).

IR (Film) : 1690, 1600, 1535, 1510 cm1 NMR (CDC13, δ) : 2.52 (3H, s), 6.8-7.5 (8H, m) , 7.95 (1H, s) Mass (m/z) : 396 (M+) Example 9 A mixture of 5-acetyl-2-(4-fluorophenyl)-3-[4(methylsulfonyl)phenyl]thiophene (1 g), thallium(III) nitrate trihydrate (1.4 g) and perchloric acid (70%; 3 ml) in methanol (15 ml) and dioxane (7 ml) was stirred at ambient temperature for 7 hours. The insoluble material was filtered. The filtrate was diluted with water and extracted with chloroform. The extract was dried over magnesium sulfate and concentrated to give an oil of methyl 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-acetate (1.2 g).

IR (Film) : 1740, 1670, 1600, 1510 cm1 NMR (CDC13, δ) : 3.30 (3H, s), 3.81 (3H, s) , 3.91 (2H, s), 6.9-8.0 (9H, m) mass (m/z) : 404 (M+), 345 Example 10 A mixture of methyl 5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-acetate (2 g) and 4N sodium hydroxide solution (3.7 ml) in tetrahydrofuran (20 ml) as stirred at ambient temperature for 1 hour. The mixture was diluted with water and washed with toluene.

The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was recrystallized from a mixture of ethanol and water to give pale orange crystals of 5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-acetic acid (1.6 g). mp : 171-173’C IR (Nujol) : 1700, 1600, 1510 cm1 NMR (DMSO-dg, δ) : 3.24 (3H, s), 3.93 (2H, s), 25 7.1-8.0 (9H, m) Mass (m/z) : 390 (M+), 345 Example 11 A mixture of ethyl 5-(4-fluorophenyl)-43 0 (4-methoxyphenyl) thiophene-2-carboxylate (2.3 g) and potassium hydroxide (640 mg) in methanol (20 ml) was refluxed overnight. The solvent was evaporated, and the residue was dissolved in water, acidified and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated to dryness. The •Ε 911942 residue was washed with ethanol to give crystals of 5-(4-fluorophenyl)-4-(4-methoxyphenyl)thiophene-2carboxylic acid (1.7 g). mp : 204-206°C IR (Nujol) : 1675, 1605, 1545, 1515 cm'1 NMR (DMSO-dg, δ) : 3.75 (3H, s), 6.8-7.5 (8H, m), 7.73 (1H, s), 11.2 (1H, s) Mass (m/z) : 328 (M+) The following compounds (Examples 12-1) to 12-8)) were obtained according to a similar manner to that of Example 11.

Example 12 1) 5-(2,4-Difluorophenyl)-4-[4-(methylthio)phenyl]thiophene-2-carboxylic acid. mp : 193-194’C IR (Nujol) : 1680, 1620, 1595, 1540 cm'1 2) 5-(3,4-Difluorophenyl)-4-[4-(methylthio)phenyl]thiophene-2-carboxylic acid. mp : 148-151°C IR (Nujol) : 2600, 1670, 1600, 1545 cm'1 NMR (DMSO-dg, δ) : 2.47 (3H, s), 7.1-7.6 (7H, m), 7.78 (1H, s), 13.3 (1H, s) Mass (m/z) : 362 (M+) 3) 4,5-Bis(4-fluorophenyl)thiophene-2-carboxylic acid mp : 201-203°C IR (Nujol) : 2600, 1670, 1600, 1550, 1510 cm'1 NMR (DMSO-dg, δ) : 7.1-7.4 (8H, m), 7.78 (1H, s), 13.32 (1H, s) Mass (m/z) : 316 (M+) 4) 4,5-Bis[4-(methylthio)phenyl]thiophene-2-carboxylic acid mp : 224-227°C IR (Nujol) : 2500, 1670, 1590, 1535 cm'1 ) 5-(4-Methoxypheny1)-4-[4-(methylthio)phenyl]5 thiophene-2-carboxylic acid. mp : 225-226°C IR (Nujol) : 1670, 1610, 1540 cm1 6) 4-(4-Fluorophenyl)-5-[4-(methylthio)phenyl]thiophene10 2-carboxylic acid mp : 179-181°C IR (Nujol) : 1665, 1595, 1510 cm1 7) 5-(4-Chlorophenyl)-4-[4-(methylthio)phenyl]thiophene15 2-carboxylic acid mp : 203-20·5°0 IR (Nujol) : 1680, 1535, 1495 cm'1 NMR (DMSO-dg, 5) : 2.49 (3H, s), 7.2-7.5 (8H, m), 7.78 (1H, s) Mass (m/z) : 360 (M+) 8) 4-[4-(Ethylthio)phenyl]-5-(4-fluoropheny1) thiophene-2-carboxylic acid mp : 160-162°C IR (Nujol) : 2600, 1675, 1600, 1540 cm1 NMR (DMSO-dg, δ) : 1.24 (3H, t, J=7Hz), 2.98 (2H, q, J=7Hz), 7.1-7.4 (8H, m), 7.78 (1H, s), 13.27 (1H, s) Mass (m/z) : 358 (M+) Example '.13 A mixture of 5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-acetic acid (4.1 g) and 1,1’-carbonyldiimidazole (1.8 g) in tetrahydrofuran (50 ml) was stirred and refluxed for 1 hour. The mixture was added dropwise to an ice-cooled mixture of ammonia water (28%; 5 ml) and tetrahydrofuran (10 ml). The resulting mixture was stirred overnight, diluted with water, and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate, water, and dilute hydrochloric acid, successively. The organic layer was dried and concentrated, and the residue was recrystallized from a mixture of chloroform, ethyl acetate and ethanol to give crystals of 5-(4-fluorophenyl)-4-[410 (methylsulfonyl)phenyl3thiophene-2-acetaraide (3.2 g). mp : 215-216°C IR (Nujol) : 3450, 3350, 1660, 1510 cm'1 NMR (DMSO-dg, δ) : 3.23 (3H, s), 3.72 (2H, s), 7.0-8.0 (11H, m) Mass (m/z) : 389 (M+), 345 Example 14 A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl )phenyl]thiophene-2-carboxylie acid (7.1 g) and phosphorus pentachloride (4.1 g) in toluene (100 ml) and tetrahydrofuran (25 ml) was stirred at ambient temperature for 1 hour. The mixture was concentrated to dryness to give pale yellow crystals of 5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-carbonyl chloride (8.1 g) .

IR (Film) : 1750, 1600, 1540, 1510 cm1 -(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl]thiophene-2-carbonyl chloride (1.4 g) was added to a stirred mixture of methylamine (25% in water, 2 ml), tetrahydrofuran (15 ml) and water (5 ml) at 5°C. The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with water, and concentrated to dryness. The residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of chloroform and ethyl acetate (1:1). The purified powder (1.1 g) was crystallized from diethyl ether to give colorless crystals of N-methyl-5-(4-fluorophenyl)4-(4-(methylsulfonyl)phenyl]thiophene-2-carboxamide (1.0 g) · mp : 169-170°C IR (Nujol) : 3450, 1650, 1600, 1550, 1510 cm1 NMR (DMSO-dg, δ) : 2.83 (3H, d, J=4Hz), 3.36 (3H, s), 7.2-8.3 (9H, m), 8.4-8.8 (1H, m) Mass (m/z) : 389 (M+), 359 The following compounds (Examples 15-1) to 15-27)) were obtained according to a similar manner to that of Example 14.

Example 15 1) 5-(4-Fluorophenyl)-4-(4-(methylsulfonyl) phenyl]thiophene-2-carboxamide mp : 233-234°C IR (Nujol) : 3480, 3200, 1675, 1600, 1510 cm1 NMR (DMSO-dg, δ) : 3.28 (3H, s), 7.2-8.1 (11H, m), Mass (m/z) : 375 (M+), 357 2) N-Methyl-4,5-bis(4-methoxyphenyl)thiophene-225 carboxamide mp : 161-162°C IR (Nujol) : 3350, 1625, 1560, 1510 cm1 NMR (DMSO-dg, δ) : 2.78 (3H, d, J=4.5Hz), 3.76 (6H, s), 6.8-7.0 (4H, m) , 7.1-7.3 (4H, m), 7.76 (1H, s), 8.47 (1H, q, J=4.5Hz) Maas (m/z) r 353 (M+) 3) N-Methyl-5-(4-fluorophenyl)-4-(4-nitrophenyl)thiophene-2-carboxamide mp : 224-226°C IR (Nujol) : 3440, 1645, 1600, 1550, 1525, 1505 cm NMR (DMSO-dg, 5) : 2.81 (3H, d, J=4.5Hz), 7.1-7.6 (6H, m), 7.94 (1H, s), 8.23 (2H, d, J=9Hz), 8.62 (1H, q, J=4.5Hz) Mass (m/z) : 356 (M+), 326 4) N,N-Dimethyl-5-(4-fluorophenyl)-4-(4-nitrophenyl) thiophene-2-carboxamide IR (Film) : 1620, 1600, 1545, 1505 cm1 ) 5-(4-Fluorophenyl)-4-(4-nitrophenyl)thiophene-2carboxamide mp : 223-225°C IR (Nujol) : 3500, 3400, 1670, 1600, 1550, 1505 cm 6) N,N-Dimethyl-5-(4-fluorophenyl)-4-(4-methoxyphenyl)thiophene-2-carboxamide mp : 95-96°C IR (Nujol) : 1620, 1605, 1550, 1515, 1490 cm1 NMR (DMSO-dg, δ) : 3.16 (6H, s), 3.75 (3H, s), 6.8-7.4 (8H, m), 7.53 (lH, s) Mass (m/z) : 354, 311 7) N-Methyl-5-(4-fluorophenyl)-4-(4-methoxyphenyl)25 thiophene-2-carboxamide mp : 162-163’C IR (Nujol) : 3380, 1620, 1550, 1500 cm1 NMR (CDC13, δ) : 3.0 (3H, d, J=6Hz), 3.75 (3H, s), 6.2 (1H, s), 6.7-7.3 (8H, m), 7.4 (1H, s) Mass (m/z) : 341 (M+) 8) N-Methyl-4,5-bis(4-fluorophenyl)thiophene-2carboxamide mp : 182-183°C IR (Nujol) : 3330, 1615, 1570, 1505 cm1 NMR (CDC13, δ) : 3.01 (3H, d, J=5Hz), 6.12 (1H, q, J=5Hz), 6.9-7.3 (8H, m), 7.49 (1H, s) Mass (m/z) : 329 (M+), 299 9) N,N-Dimethyl-4,5-bis(4-fluorophenyl)thiophene-2carboxamide mp : 119-120°C IR (Nujol) : 1620, 1550, 1510 cm'1 NMR (CDC13, δ) : 3.24 (6H, s), 6.9-7.3 (8H, m) , 7.36 (1H, s) Mass (m/z) : 343 (M+), 299 ) N-Methyl-4,5-bis[4-(methylthio)phenyl]thiophene2-carboxamide mp : 141-142OC IR (Nujol) : 3250, 1630, 1560, 1545 cm'1 NMR (CDC13, δ) : 2.44 (6H, s), 2.97 (3H, d, J=5Hz) 6.19 (1H, q, J=5Hz), 6.9-7.5 (9H, m) Mass (m/z) : 385 (M+) 11) N,N-Dimethyl-4,5-bis[4-(methylthio)phenyl]thiophene 2-carboxamide IR (Film) : 1610, 1535, 1490 cm1 NMR (CDC13, δ) : 2.42 (6H, s), 3.17 (6H, s), 7.0-7.4 (9H, m) 12) N-Methyl-5-(4-methoxyphenyl)-4-[4-(methylthio) phenyl]thiophene-2-carboxamide IR (Film) : 3300, 1630, 1610, 1560, 1510 cm'1 NMR (CDC13, δ) : 2.43 (3H, s), 2.97 (3H, d, J=5Hz) c. 3.76 (3H, s), 6.5-7.3 (9H, m), 7.50 (1H, s) 13) N,N-Dimethyl-5-(4-methoxyphenyl) -4-[4-(methylthio) phenyl]thiophene-2-carboxamide IR (Film) : 1610, 1540, 1500 cm1ιε 911942 NMR (CDC13, δ) : 2.44 (3H, s), 3.19 (6H, s), 3.75 (3H, s), 6.6-7.3 (9H, m) 14) N,N-Dimethyl-5-{2,4-difluorophenyl)-4-[45 (methylthio)phenyl]thiophene-2-carboxamide IR (Film) : 1620, 1545, 1500 cm'1 NMR (CDC13, δ) : 2.44 (3H, s), 3.19 (6H, s), 6.6-7.4 (8H, m) ) N-Methyl-4-(4-fluorophenyl)-5-[4-(methylthio)pheny1]thiophene-2-carboxamide mp : 205-206°C IR (Nujol) : 3340, 1620, 1565, 1550, 1500 cm1 16) N,N-Dimethyl-4-{4-fluorophenyl)-5-[4-(methylthio)phenyl]thiophene-2-carboxamide mp : 121-123’C IR (Nujol) : 1620, 1510 cm'1 Mass (m/z) : 371 (M+) 17) N-Methyl-5-(4-chlorophenyl)-4-[4-(methylthio)phenyl]thiophene-2-carboxamide mp : 168-169°C IR (Nujol) : 3340, 1630, 1560 cm'1 Mass (m/z) : 373 (M+) 18) N,N-Dimethyl-5-(4-chlorophenyl)-4-[4-(methylthio) phenyl]thiophene-2-carboxamide mp : 137-138°C IR (Nujol) : 1620, 1600 cm'1 NMR (DMSO-dg, δ) : 2.45 (3H, s), 3.17 (6H, s), 7.1-7.6 (9H, m) Mass (m/z) : 387 (M+) 19) N-Methyl-4-[4-(ethylthio)phenyl]-5-(4-fluorophenyl) thiophene-2-carboxamide IR (Film) : 3300, 1640, 1625, 1565, 1545, 1500 cm-1 NMR (CDC13, δ) : 1.28 (3H, t, J=7Hz), 2.89 (2H, q, J=7Hz), 2.96 (3H, d, J=6Hz), 6.44 (1H, q, J=6Hz), 6.7-7.3 (8H, m), 7.46 (1H, s) ) N,N-Dimethyl-4-[4-(ethylthio)phenyl]-5-(4fluorophenyl) thiophene-2-carboxamide IR (Film) : 1620, 1540, 1500 cm1 NMR (CDC13, δ) : 1.31 (3H, t, J=7Hz), 2.92 (2H, q, J=7Hz), 3.19 (6H, s), 6.8-7.5 (9H, m) 21) N,N-Dimethyl-5-(3,4-difluorophenyl)-4-(4(methylthio)phenyl]thiophene-2-carboxamide IR (Film) : 1620, 1545, 1500 cm1 2) N-Methy1-5-(4-fluorophenyl)-4-(4-(methylthio)phenyl] thiophene-2-carboxamide mp : 98-100°C IR (Nujol) : 3300, 1630, 1600, 1565, 1505 cm1 NMR (DMSO-dg, δ) : 2.47 (3H, s), 2.79 (1H, d, J=4Hz), 7.1-7.5 (8H, m), 7.83 (1H, s), 8.54 (1H q, J=4Hz) Mass (m/z) : 357 (M+) 23) N-Isopropyl-5-(4-fluorophenyl)-4-(4-(methylsulfonyl) phenyl]thiophene-2-carboxamide mp : 160-164’C IR (Nujol) : 3380, 1645, 1600, 1555, 1510 cm1 NMR (DMSO-dg, δ) : 1.18 (6H, d, J=9Hz), 3.12 (3H, ::. s), 4.0-4.2 (1H, m), 7.1-7.6 (6H, m), 7.90 (2H, d, J=8Hz), 8.02 (1H, s) , 8.36 (1H, d, J=9Hz) Mass (m/z) : 417 (M+) 24) N-Hydroxy-N-methyl-5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-carboxamide mp : 95-98°C IR (Nujol) : 1600, 1540, 1510 cm1 NMR (DMSO-dg, δ) : 3.24 (3H, s), 3.32 (3H, s), 7.2-8.0 (9H, m), 10.78 (1H, s) Mass (m/z) : 405 (M+) ) N-{5-(4-Fluorophenyl)-4-[4-(methylsulfonyl) phenyl]2-thenoyl}-N-methylglycine ethyl ester mp : 148-151’C IR (Nujol) : 1750, 1630 cm-1 NMR (DMSO-dg, δ) : 1.21 (3H, t, J=7Hz), 3.24 (3H, s), 3.40 (3H, s), 4.16 (2H, q, J=7Hz), 4.27 (2H, s), 7.1-8.0 (9H, m) 26) N-Hydroxy-N-methyl-5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-acetamide mp : 99-103°C IR (Nujol) : 1630, 1600, 1510 cm1 NMR (DMSO-dg, δ) : 3.15 (3H, s), 3.22 (3H, s), 4.00 (2H, s), 7.1-8.0 (9H, m), 10.2 (1H, s) Mass (m/z) : 419 (M+) 27) N,N-Dimethyl-5-(2-fluorophenyl)-4-[4-(methylthio)phenyl]thiophene-2-carboxamide IR (Film) : 1620, 1600, 1545, 1500 cm1 Mass (m/z) : 371 (M+) Example 16 A-mixture of 5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-sulfonic acid (10.5 g) and thionyl chloride (20 ml) was refluxed for 1 hour. The mixture was concentrated to dryness. The residue was dissolved in ethyl acetate, washed with ice-water, dried and concentrated to give a brown oil (8.7 g).

A solution of the oil in tetrahydrofuran (45 ml) was added to ammonia water (15 ml) at 5°C. The mixture was stirred for 1 hour and extracted with chloroform. The extract was dried and concentrated. The residual oil was purified by column chromatography on silica gel (120 g) eluting with a mixture of toluene and ethyl acetate (3:1) to give an oil (1.2 g). The purified oil was crystallized from diethyl ether to give pale brown crystals of 5-(4fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2sulfonamide (0.76 g). mp : 195-197°C IR (Nujol) : 3340, 3250, 1600 cm1 NMR (DMSO-dc, δ) : 3.30 (3H, s), 7.0-8.1 (11H, m) Mass (m/z) : 411 (M ) Example 17 A mixture of 5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-carboxylic acid (1.0 g) and 1,1'-carbonyldiimidazole (0.45 g) in tetrahydrofuran (15 ml) was refluxed for 1.5 hours. 5-Aminotetrazole (0.226 g) was added and the mixture was refluxed for 3 hours. The mixture was diluted with water (50 ml), acidified with hydrochloric acid, and cooled in an ice-water bath. The precipitates were collected and recrystallized from ethanol to give colorless crystals of N-(5-tetrazolyl)-5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-carboxamide (0.93 g). mp : 269-271°C (dec.) IR (Nujol) : 3200, 1670, 1600, 1545, 1510 cm-1 NMR (DMSO-dg, δ) : 3.30 (3H, s), 7.1-8.1 (8H, m), 8.56 (IH, s) Mass (m/z) : 443 (M+) The following compounds (Examples 18-1) to 18-9)) were obtained according to a similar manner to that of Example 17.

Example 18 1) N,N-Dimethyl-5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-carboxamide mp : 172-173°C IR (Nujol) : 1605, 1545, 1490 cm1 NMR (DMSO-dg, δ) : 3.21 (3H, s), 3.27 7.0-8.1 (9H, m) Mass (m/z) : 403 (M+), 359 2) N-Pheny1-5-(4-fluoropheny1)-4-[4-{methy1sulfonyl) phenyl]thiophene-2-carboxamide mp : 227-228 °C IR (Nujol) : 1660 , 1595, 1545 cm -1 NMR (DMSO-dg, δ) : 3.28 ( I3H, s), 7 10.35 (1H, s) Mass (m/z) : 450, 359 3) N-(2,2,2-Trifluoroethyl)-5-(4-fluorophenyl)-4-[425 (methylsulfonyl)phenyl]thiophene-2-carboxamide mp : 201-203°C IR (Nujol) : 3400, 1660, 1600, 1555, 1530, 1510 cm NMR (DMSO-dg, δ) : 3.27 (3H, s), 4.0-4.5 (2H, m) , 7.2-8.2 (9H, m), 9.27 (1H, t, J=6Hz) Mass (m/z) : 457 (M+), 359 4) N,N-Dimethy1-5-(4-fluorophenyl)-4-(4-(methylthio) phenyl]thiophene-2-carboxamide IR (Film) : 2920, 1620, 1600, 1530 cm1 NMR (CDC13, δ) : 2.51 (3H, s), 3.28 (6H, s), 6.8-7.5 (9H, m) Mass (m/z) : 371 (M+), 327 ) N,N-Dimethyl-4,5-bis(4-methoxyphenyl)thiophene-2carboxamide mp : 79-81°C IR (Nujol) : 1630, 1610, 1550, 1515 cm'1 NMR (CDC13, δ) ; 3.23 (6H, s), 3.80 (6H, s), 6.7-6.9 (4H, m), 7.1-7.3 (4H, m), 7.35 (1H, s) Mass (m/z) : 367 (M+) 6) N-Ethyl-5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl]thiophene-2-carboxamide mp : 149-151’C IR (Nujol) : 3400, 1640, 1555, 1510 cm1 NMR (DMSO-dg, δ) : 1.14 (3H, t, J=7Hz), 3.25 (3H, s), 3.2-3.4 (2H, m), 7.1-7.6 (6H, m), 7.90 (2H, d, J=8Hz), 7.96 (1H, s), 8.60 (1H, t, J=6Hz) Mass (m/z) : 403 (M+) 7) N- (5-(4-Fluorophenyl)-4-(4-(methylsulfonyl) phenyl]2-thenoyl}morpholine mp : 158-161’C IR (Nujol) : 1620, 1600, 1545, 1510 cm'1 NMR (DMSO-dg, δ) : 3.24 (3H, s), 3.6-3.8 (8H, m), 7.1-8.0 (9H, m) Mass (m/z) : 445 (M+), 359 8) 1-(5-(4-Fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2 thenoyl}-4-methyIpiperazine mp·':: 68-72°C IR (Nujol) : 1610, 1545, 1510 cm'1 NMR (DMSO-dg, δ) : 2.12 (3H, s), 2.37 (4H, broad s) 3.23 (3H, s), 3.72 (4H, broad s), 7.1-8.0 (9H, m) Mass (m/z) : 458 (M+) 9) N-(Ν,Ν-Dimethylaminoethyl)-5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-carboxamide mp : 218-221°C IR (Nujol) : 2600, 2470, 1640, 1595, 1550, 1510 cm1 NMR (DMSO-dg, 5) : 2.83 (6H, s), 3.25 (3H, s), 3.2-3.8 (4H, m), 7.2-8.3 (9H, m), 9.34 (1H, t, J=6Hz) Example 19 To an ice-cooled mixture of 5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl3thiophene-2-acetamide (2.6 g) and diethyl oxalate (0.97 ml) in Ν,Ν-dimethylformamide (18 ml) was added potassium t-butoxide (0.84 g). The mixture was stirred at 0°C for 15 minutes. Potassium t-butoxide (0.87 g) was added to the resulting mixture, and the mixture was stirred at 0°C for 1 hour and at ambient temperature overnight.

The mixture was poured into ice-water (130 ml) and acidified with hydrochloric acid. The precipitates were collected, washed with water, dried, and purified by column chromatography on silica gel (100 g) eluting with a mixture of chloroform and methanol (5:1). The obtained product was dissolved in a mixture of ethanol and ethyl acetate. The solution was filtered and the filtrate was concentrated. The residue was triturated with chloroform to give red brown crystals of 2-{5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]-2-thienyl}-3-hydroxymaleimide potassium salt (1.6 g). mp 305-310°C (dec.) IR (Nujol) : 3400, 1745, 1700, 1610, 1510 cm1 NMR (DMSO-dg, δ) : 3.20 (3H, s), 7.0-7.9 (9H, m), 9.40 (1H, s) Example 20 A mixture of 5-(4-fluorophenyl)-4-[4(methylthio)phenyl]thiophene-2-carboxylic acid (10.8 g) and hydrogen peroxide (30%, 9.3 ml) in acetic acid (108 ml) was stirred at 70°C for 3 hours. The mixture was cooled in an ice-water bath, and the precipitates were collected and washed with ethanol to give pale yellow crystals of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylic acid (8.1 g). mp : 264-264.5°C IR (Nujol) : 1680, 1600, 1545, 1510 cm1 NMR (DMSO-dg, 5) : 3.28 (3H, s), 7.1-8.1 (9H, m) Mass (m/z) : 376 (M+) Example 21 A mixture of 2-(4-fluorophenyl)-3-[4-(methylthio)phenyl]-5-(trifluoroacetyl) thiophene (0.79 g) and m-chloroperbenzoic acid (1 g) in dichloromethane (13 ml) was stirred overnight at room temperature. The insoluble was filtered, and the filtrate was washed with an aqueous solution of sodium bicarbonate, dried and concentrated.

The residue (0.91 g) was recrystallized from ethanol to give pale brown crystals of 2-(4-fluorophenyl)-3-[4(methylsulfonyl)phenyl]-5-(trifluoroacetyl)thiophene (0.73 g). mp : 199-201°C IR (Nujol) : 1685, 1600, 1510 cm1 NMR (DMSO-dc, δ) : 3.22 (3H, s), 7.1-8.3 (9H, m) Mass (m/z) : 428 (M ), 359 The following compounds (Examples 22-1) to 22-19)) were obtained according to a similar manner to that of Example 21.

Example 22 1) N-Methyl-4,5-bis(4-(methylsulfonyl)phenyl]thiophene 2-carboxamide mp : 234-236°C IR (Nujol) : 3400, 1650, 1595, 1500, 1525 cm-1 NMR (DMSO-dg, δ) : 2.81 (3H, d, J=5Hz), 3.26 (3H, s), 7.5-8.0 (9H, m), 8.65 (1H, q, J=5Hz) Mass (m/z) : 449 (M+) X0 2) N,N-Dimethyl-4,5-bis(4-(methylsulfonyl)phenyl]thiophene-2-carboxamide mp : 245-247°C IR (Nujol) : 1620, 1590, 1500 cm-1 NMR (DMSO-dg, δ) : 3.26 (12H, s), 7.5-8.0 (9H, m) Mass (m/z) : 463 (M+), 419 3) N-Methyl-5-(4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxamide mp : 150-151’C IR (Nujol) : 3430, 1640, 1560, 1510 cm1 NMR (CDC13, δ) : 3.0 (3H, d, J=5Hz), 3.03 (3H, s), 3.75 (3H, s), 6.33 (1H, q, J=5Hz), 6.7-7.8 (9H, m) Mass (m/z) : 401 (M+) 4) N,N-Dimethyl-5-(4-methoxyphenyl)-4-(4(methylsulfonyl)phenyl]thiophene-2-carboxamide mp : 168-169°C IR (Nujol) : 1615, 1545, 1510 cm-1 NMR (DMSO-dg, δ) : 3.17 (6H, s), 3.24 (3H, s), 3.77 (3H, s), 6.9-7.9 (9H, m) Mass (m/z) : 415 (M+), 371 ) 2-(4-Methoxyphenyl)-3-(4-(methylsulfonyl) phenyl]-535 propionylthiophene mp : 154-155°C IR (Nujol) : 1655, 1605, 1510 cm1 NMR (CDC13, δ) : 1.28 (3H, t, J=7Hz), 2.97 (2H, q, J=7Hz), 3.07 (3H, s), 3.83 (3H, s), 6.7-8.0 5 (9H, m) Mass (m/z) : 400 (M+), 371 6) N-Methyl-5-(4-chlorophenyl)-4-(4-(methylsulf onyl) phenyl]thiophene-2-carboxamide mp : 196-197°C IR (Nujol) : 3400, 1650, 1635, 1550 cm1 NMR (CDC13, δ) : 3.03 (3H, d, J=5Hz), 3.08 (3H, s), 6.18 (1H, q, J=5Hz), 7.1-7.9 (9H, m) Mass (m/z) : 405 (M+) 7) N,N-Dimethyl-5-(4-chlorophenyl)-4-(4(methylsulfonyl)phenyl]thiophene-2-carboxamide mp : 165-166°C IR (Nujol) : 1620, 1540, 1500 cm1 NMR (CDC13, δ) : 3.0 (3H, s), 3.25 (6H, s), 7.1-8.0 (9H, m) Mass (m/z) : 419 (M+) 8) 5-Acetyl-2-(4-chlorophenyl)-3-(4-(methylsulfonyl)2 5 phenyl) thiophene mp : 159-160’C IR (Nujol) : 1675, 1595, 1540 cm1 NMR (DMSO-dg, δ) : 2.61 (3H, s), 3.25 (3H, s), 7.3-8.0 (8H, m), 8.18 (1H, s) Mass (m/z) : 390 (M+) 9) N-Methyl-4-(4-(ethylsulfonyl)phenyl]-5-(4fluorophenyl) thiophene-2-carboxamide mp : 181-183°C IR (Nujol) : 3400, 1650, 1600, 1555, 1510 cm1 NMR (DMSO-dg, δ) : 1.11 (3H, t, J=7Hz), 2.80 (3H, d, J=5Hz), 3.31 (2H, q, J=7Hz), 7.1-8.0 (9H, m), 8.58 (IH, q, J=5Hz) Mass (m/z) : 4.03 (M+) ) N,N-Dimethyl-4-[4-(ethylsulfonyl)phenyl]-5-(4fluorophenyl)thiophene-2-carboxamide mp : 104-105°C IR (Nujol) : 1620, 1600, 1545, 1500 cm1 NMR (CDC13, δ) : 1.30 (3H, t, J=7Hz), 3.10 (2H, q, J=7Hz), 3.23 (6H, s), 6.8-7.9 (9H, m) Mass (m/z) : 417 (M+) 11) 5-Acetyl-3-[4-(ethylsulfonyl)phenyl]2-(415 fluorophenyl) thiophene mp : 128-129°C IR (Nujol) : 1670, 1600, 1510 cm1 NMR (CDC13, δ) : 1.30 (3H, t, J=7Hz), 2.60 (3H, s), 3.14 (2H, q, J=7Hz), 6.9-7.9 (9H, m) Mass (m/z) : 388 (M+) 12) N,N-Dimethyl-5-(3,4-difluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-carboxamide mp : 112-113°C IR (Nujol) : 1620, 1600, 1545, 1500 cm1 NMR (CDC13, δ) : 3.03 (3H, s), 3.20 (6H, s), 6.9-8.0 (8H, m) Mass (m/z) : 421 (M+) 13) 5-Acetyl-2-(3,4-difluorophenyl)-3-[4(methylsulfonyl)phenyl]thiophene mp : 150-151’C IR (Nujol) : 1675, 1600, 1535, 1510 cm1 NMR (CDC13, δ) : 2.61 (3H, s), 3.09 (3H, s), 7.0-8.0 (8H, m) Mass (m/z) : 392 (M+) 14) N,N-Diethyl-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thenylamine mp : 98-102°C IR (Nujol) : 1600, 1510 cm-1 NMR (DMSO-dg, δ) : 1.20 (6H, t, J=7Hz), 3.0-3.3 (4H, m), 3.23 (3H, s), 4.52 (2H, s), 7.1-7.9 (9H, m) Mass (m/z) : 417 (M+), 345 ) N-Methyl-N-propyl-5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]-2-thenylaraine mp : 128-130°C IR (Nujol) : 1600, 1510 cm-1 NMR (DMSO-dg, δ) : 0.88 (3H, t, J=7Hz), 1.6-2.0 (2H, m), 2.96 (3H, s), 3.0-3.3 (2H, m), 3.23 (3H, s), 4.59 (2H, ABq, J=13Hz), 7.1-7.9 (9H, m) Mass (m/z) : 417 (M+), 345 16) N-Methyl-4-(4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]thiophene-2-carboxamide mp : 280-281°C IR (Nujol) : 3400, 1630, 1560, 1505 cm'1 NMR (CDC13, δ) : 3.04 (3H, d, J=5Hz), 3.07 (3H, s), 6.0 (1H, m), 6.9-7.9 (9H, m) Mass (m/z) : 389 (M+), 359 17) N,N-Dimethyl-4-(4-fluorophenyl)-5-[430 (methylsulfonyl)phenyl]thiophene-2-carboxamide mp-; 192-193°C IR (Nujol) : 1610, 1545, 1510 cm'1 NMR (CDC13, δ) : 3.07 (3H, s), 3.25 (6H, s), 6.9-7.9 (9H, m) Mass (m/z) : 403 (M+), 359 18) Ethyl 4-[4-(methylsulfonylJphenyl]-5-(4-nitrophenyl)thiophene-2-carboxylate mp : 158-160°C IR (Nujol) : 1705, 1595, 1515 cm'1 NMR (CDC13, δ) : 1.40 (3H, t, J=7Hz), 3.10 (3H, s), 4.38 (2H, q, J=7Hz), 7.4-8.3 (9H, m) Mass (m/z) : 431 (M+) 19) N,N-Dimethyl-5-(2-fluorophenyl)-4-[410 (methylsulfonyl)phenyl]thiophene-2-carboxamide mp : 155-158°C IR (Nujol) : 1620, 1600, 1545 cm 1 NMR (CDC13, δ) : 3.06 (3H, s), 3.26 (6H, s), 6.9-7.9 (9H, m) Mass (m/z) : 403 (M+) Example 23 A mixture of N,N-dimethyl-5-(4-fluorophenyl)-4-[4(methylthio)phenyl]-2-thenylamine (1.4 g) and m-chloroperbenzoic acid (2.6 g) in dichloromethane (25 ml) was stirred overnight. The insoluble was filtered. The filtrate was washed with an aqueous solution of sodium bicarbonate, dried and concentrated. The residue was dissolved in 30% hydrogen chloride in methanol (1 ml) and mehtanol was evaporated. The residue was pulverized with diethyl ether to give a pale yellow powder of N,N-dimethyl-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thenylamine hydrochloride (1.4 g). mp : 192-194°C IR (Nujol) : 3400, 2550, 1600, 1510 cm1 NMR.. (DMSO-dg, δ) : 3.23 (3H, s), 3.55 (6H, s), .25 (2H, s), 7.2-8.1 (9H, m) Mass (m/z) : 389 (M+), 345 The following compounds (Examples 24-1) to 24-7)) were obtained according to a similar manner to that of Example 23.

Example 24 1) N,N-Dimethyl-4,5-bis[4-(methylsulfonyl)phenyl]-2thenylamine hydrochloride mp : 215-217°C (dec.) IR (Nujol) : 2500, 1590, 1535 cm1 NMR (DMSO-dg, 5) : 3.26 (6H, s), 3.53 (6H, s), .23 (2H, s), 7.5-8.0 (9H, m), 13.07 (1H, s) Mass (m/z) : 449 (M+), 405 2) N,N-Dimethyl-5-(4-methoxyphenyl)-4-(4(methylsulfonyl)phenyl]-2-thenylamine hydrochloride 15 mp : 206-208°C (dec.) IR (Nujol) : 2550, 1600, 1535, 1515 cm1 NMR (DMSO-dg, δ) : 3.24 (3H, s), 3.51 (6H, s), 3.77 (3H, s), 5.17 (2H, s), 6.9-8.0 (9H, m) Mass (m/z) : 401 (M+), 357 3) N,N-Dimethyl-5-(3,4-difluorophenyl)-4-(4(methylsulfonyl)phenyl]-2-thenylamine hydrochloride mp : 181-183°C (dec.) IR (Nujol) : 2530, 1600, 1520 cm1 NMR (DMSO-dg, δ) : 3.24 (3H, s), 3.52 (6H, s), .19 (2H, s), 7.1-8.0 (8H, m), 13.0 (1H, s) Mass (m/z) : 407 (M+), 363 4) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl]-5 (1-pyrrolidinylmethyl)thiophene hydrochloride mp,: >250°C IR (Nujol) : 2600, 1600, 1545, 1510 cm1 NMR (DMSO-dg, δ) : 2.17 (4H, s), 3.24 (3H, s), 3.90 (4H, s), 5.33 (2H, s), 7.2-8.0 (9H, m), 12.75 (1H, s) ) N-Ethyl-N-methyl-5-{4-fluorophenyl)-4-[4(methylsulfonyl)phenyl3-2-thenylamine hydrochloride mp : 95-100’C (dec.) IR (Nujol) : 1600, 1510 cm1 NMR (DMSO-dg, δ) : 1.40 (3H, t, J=8Hz), 3.20 (3H, s), 3.37 (3H, s), 3.77 (2H, q, J=8Hz), .15 (2H, s), 7.1-8.0 (9H, m) Mass (m/z) : 403 (M+), 344 6) N,N-Dimethyl-5-(4-chlorophenyl)-4-[4(methylsulfonyl)phenyl3-2-thenylamine hydrochloride mp : 181-183’C IR (Nujol) : 2550, 1600, 1535 cm1 NMR (DMSO-dg, δ) : 3.25 (3H, s), 3.52 (6H, s), .21 (2H, s), 7.2-8.0 (9H, m), 13.06 (1H, s) Mass (m/z) : 405 (M+), 361 7) N,N-Dimethyl-4-[4-(ethylsulfonyl)phenyl]-5{4-fluorophenyl)-2-thenylamine hydrochloride mp : 175-177’C (dec.) IR (Nujol) : 2500, 1600, 1510 cm1 NMR (DMSO-d&, δ) : 1.11 (3H, t, J=7Hz), 3.31 (2H, q, J=7Hz), 3.53 (6H, s), 5.21 (2H, s), 7.1-7.9 (9H, m), 13.04 (1H, s) Mass (m/z) : 403 (M+) Example 25 A mixture of N-(benzyloxycarbonyl)-5(4-fluorophenyl)-4-[4-(methylthio)phenyl]-2-thenylamine (1.3 g) and m-chloroperbenzoic acid (80%; 1.3 g) in dichloromethane (20 ml) was stirred at ambient temperature for 3 hours. The insoluble was filtered. The filtrate was washed with an aqueous solution of sodium bicarbonate, dried and concentrated. The residue (1.4 g) was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (5:1) to give an oil (0.78 g). The oil was dissolved in 30% hydrogen bromide in acetic acid. The solution was stirred at ambient temperature for 1 hour and concentrated in vacuo. The residue was washed with isopropyl ether to give white powder of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)[henyl] 2-thenylamine hydrobromide (0.7 g). mp : >200°C IR (Nujol) : 1600, 1510 cm1 NMR (DMSO-dg, δ) : 3.24 (3H, s), 4.32 (2H, s), 7.1-7.5 (7H, m), 7.80 (2H, d, J=8Hz), 8.37 (2H, broad s) Mass (m/z) : 361 (M+) The following compounds (Examples26-1) and 26-2)) were obtained according to a similar manner to that of Example 25.

Example 26 1) N-Methyl-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thenylamine hydrobromide mp : 100-110°C (dec.) IR (Nujol) : 1600, 1510 cm1 NMR (DMSO-dg, δ) : 2.64 (3H, s), 3.24 (3H, s), 4.44 (2H, s), 7.2-7.6 (7H, m), 7.90 (2H, d, J=8Hz), 9.00 (2H, broad s), Mass (m/z) : 375 (M+) 2) N-Ethyl-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)30 phenyl]-2-thenylamine hydrochloride mpr; 100-105°C IR (Nujol) : 1600, 1510 cm1 NMR (DMSO-dg, δ) : 1.35 (3H, t, J=6Hz), 3.0-3.2 (2H m), 3.45 (3H, s), 4.4-4.7 (2H, m), 7.1-8.0 (9H, m) Mass (m/z) : 389 (M+) Example 27 A mixture of N-methyl-5-(4-fluorophenyl)-4-[45 (methylthio)phenyl]thiophene-2-carboxamide (1.66 g), sodium periodate (1.05 g) and water (1 ml) in methanol (100 ml) was stirred at 0°C for 2 days. The insoluble was filtered and the filtrate was evaporated. The residue was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and concentrated to dryness. The residue was recrystallized from ethanol to give colorless crystals of N-methyl-5-(4-fluorophenyl)4-[4-(methylsulfinyl)phenyl]thiophene-2-carboxamide (1.1 g) · mp : 218-220°C IR (Nujol) : 3300, 1640, 1550, 1500 cm-1 NMR (DMSO-dg, 5) : 2.77 (3H, s), 2.80 (3H, d, J=4Hz), 7.1-7.7 (8H, m), 7.89 (1H, s), 8.56 (1H, q, J=4Hz) Mass (m/z) : 373 (M+), 358 Example 28 A mixture of N,N-dimethyl-5-{4-fluorophenyl)-4-[4(methylthio)phenyl]-2-thenylamine (1 g), sodium periodate (1.07 g) and water (5 ml) in methanol (50 ml) was stirred at ambient temperature for 2 hours. The insoluble was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane, washed with an aqueous solution of sodium bicarbonate and water, dried and concentrated in vacuo. The oily residue (1 g) was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (10:1). The obtained oil (0.9 g) was dissolved in a solution of hydrogen chloride in ethanol (10 ml) and the solution was concentrated. The residue was washed with diethyl ether to give white powder of Ν,Ν-dimethy1-5-(4-fluorophenyl)-4[4-(methylsulfinyl)phenyl]-2-thenylamine hydrochloride (0.76 g). mp : 212-216°C IR (Nujol) : 2520, 2480, 1600, 1510 cm'1 NMR (DMSO-dg, δ) : 2.76 (6H, s), 2.78 (3H, s), 4.54 (2H, s), 7.1-7.7 (9H, m), 11.22 (1H, s) Mass (m/z) : 373 (M+) Example 29 A mixture of 5-(4-fluorophenyl)-4-[4-(methylthio)phenyl]thiophene-2-carbaldehyde (2.2 g) and m-chloroperbenzoic acid (3.62 g) in dichloromethane (32 ml) was stirred for 8 hours at ambient temperature. The insoluble was filtered, and the filtrate was washed with an aqueous solution of sodium bicarbonate, dried and concentrated. The residual oil (2 g) was purified by column chromatography on silica gel (150 g) eluting with a mixture of toluene and ethyl acetate (10:1) to give a pale brown powder of 2-(4-fluorophenyl)-5-hydroxy-3-[4(methylsulfonyl)phenyl]thiophene (1.1 g). mp : 60°C IR (CHC13) : 1675, 1605, 1565, 1510 cm'1 NMR (DMSO-dg, δ) : 3.20 (3H, s), 6.74 (1H, s), 6.9-8.0 (9H, m) Mass (m/z) : 348 (M+) Example 30 A mixture of 5-acetyl-2-(4-fluorophenyl)-3-[430 (methylsulfonyl)phenyl]thiophene (1 g) and sodium borohydride (0.12 g) in methanol (19 ml) was stirred at ambient temperature for 2 hours. Acetic acid (1 ml) was added and the mixture was concentrated. The residue was dissolved in ethyl acetate, washed with water and an aqueous solution of sodium bicarbonate, dried and concentrated. The residue was recrystaliized from a mixture of hexane and ethyl acetate to give crystals of 2-(4-fluorophenyl)-5-(1-hydroxyethy1)-3-(4(methylsulfonyl)phenyl]thiophene (0.7 4 g). mp : 103-105°C IR (Nujol) : 3400, 1600, 1510 cm'1 NMR (CDC13, δ) : 1.65 (3H, d, J=7Hz), 2.10 (1H, d, J=4Hz), 3.0 (3H, s), 5.0-5.3 (1H, m), 6.8-7.9 (9H, m) Mass (m/z) : 376 (M+), 361 Example 31 A mixture of 5-(4-fluorophenyl)-4-(4(methylsulfonyl) phenyl]thiophene-2-carbonyl chloride (1.2 g) and sodium borohydride (0.21 g) in dioxane (15 ml) was stirred at ambient temperature for 2 hours. The mixture was diluted with ethyl acetate, washed with water, dilute hydrochloric acid, an aqueous solution of sodium bicarbonate, successively, dried and concentrated. The residue (1.2 g) was recrystaliized from ethanol to give pale brown crystals of 5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-methanol (0.55 g). mp : 140-142°C IR (Nujol) : 3400, 1600, 1515 cm1 NMR (DMSO-dg, δ): 3.20 (3H, s), 4.65 (2H, d, J=5Hz), .56 (1H, t, J=5Hz), 7.0-7.9 (9H, m) Mass (m/z) : 362 (M+) Example 32 A mixture of methyl 5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-acetate (1.8 g) and lithium aluminum hydride (0.63 g) in diethyl ether (30 ml) was stirred at 0°C for 1 hour. Ethyl acetate and 10% sulfuric acid (50 ml) were added, and the resulting mixture was filtered. The organic layer was separated, washed with water, dried and concentrated under reduced pressure. The residual pale yellow oil (1.6 g) was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (2:1). The obtained oil (1.4 g) was pulverized with hexane to give a yellow powder of 2-(4-fluorophenyl)-5-(2-hydroxyethyl) 3-(4-(methylsulfonyl)phenyl]thiophene. mp : 102-108°C IR (Nujol) : 3500, 1600, 1510 cm1 NMR (DMSO-dg, δ) : 2.97 (2H, t, J=6Hz), 3.22 (3H, s), 3.6-3.8 (2H, m), 4.90 (1H, t, J=5Hz), 7.0-7.9 (9H, m) Mass (m/z) : 376 (M+) Example 33 A mixture of 5-acetyl-2-(4-fluorophenyl)-3[4-(methylsulfonyl)phenyl]thiophene (1.35 g), methoxyaraine hydrochloride (0.45 g) and pyridine (0.44 ml) in dioxane (17 ml) was stirred at ambient temperature for 1 hour.

The mixture was concentrated., and the residue was triturated with water, filtered, washed with water and dried. The crude crystals were recrystallized from ethyl acetate to give pure crystals of 2-(4-flurophenyl)-5-[1(methoxyimino) ethyl]-3-[4-(methylsulfonyl)phenyl]thiophene (0.68 g). mp : 200-203’C IR (Nujol) : 1600, 1550, 1510 cm1 NMR (DMSO-dg, δ) : 2.24 (3H, s), 3.20 (3H, s), 3.90 (3H, s), 7.0-8.0 (9H, ra) Mass (m/z) : 403 (M+) The following compound (Example 34) was obtained according to a similar manner to that of Example 3 3.

Example 34 -[3,5-Di(t-butyl)-4-hydroxy-a-(hydroxyimino)benzyl]2-(4-fluorophenyl)-3-(4-(methylsulfonyl) phenyl]thiophene mp : 235-237’C 5 IR (Nujol) : 3630 , 3400, 1600, 1510 cm1 NMR (DMSO-dg, δ) : 1.42 (18H, S), 3.23 (3H, s), 7.1T8 .0 (12H, m) Mass (m/z) : 563, 548 Example 35 Nitric acid (d=1.42; 1.6 ml) was added dropwise to a stirred solution of 2-(4-fluorophenyl)-3-(4(methylsulfonyl)phenyl]thiophene (6 g) in acetic anhydride (98 ml) at -5 to 0°C. The mixture was stirred for 1 hour at 0°C, treated with sodium bicarbonate (1 g), and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and an aqueous solution of sodium bicarbonate, and concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (20:1) to give yellow crystals of 2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl]-5nitrothiophene (4.4 g). mp : 155-156’C IR (Nujol) : 3100, 1600, 1510 cm'1 NMR (DMSO-dg, δ) : 3.28 (3H, s), 7.1-8.1 (8H, m), 8.42 (1H, s) Mass (m/z) : 377 (M+) The following compound (Example 36) was obtained according to a similar manner to that of Example 3 5.

Example 36 2,3-Bis (4-methoxyphenyl)-5-nitrothiophene IR (Film) : 1610, 1510, 1500 cm-1 Example 37 A mixture of 2-(4-fluorophenyl)-3-[4(methylsulfonyl)phenyl]-5-nitrothiophene (3.6 g), iron powder (3.6 g) and ammonium chloride (0.36 g) in ethanol (58 ml) and water (22 ml) was stirred and refluxed for 1 hour. The insoluble was filtered and washed with N,N-dimethylformamide (40 ml). The filtrate was concentrated. The residue was triturated with water, filtered, and washed with water and ethanol to give a pale yellow powder of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thiophenamine (2.7 g). mp : 207-209°C IR (Nujol) : 3450, 3350, 1600, 1510 cm-1 Mass (m/z) : 347 (M+) The following compounds (Examples 38-1) to 38-12)) were obtained according to a similar manner to that of Example 37.

Example 38 1) 4,5-Bis (4-methoxyphenyl)-2-thiophenamine IR (Film) : 3440, 3370, 1610, 1510 cm-1 2) N,N-Dimethyl-4-(4-aminophenyl)-5-(4-fluorophenyl) 25 thiophene-2-carboxamide IR (Film) : 3470, 3370, 3230, 1610, 1550, 1515, 1490 cm1 NMR (DMSO-dg, δ) : 3.15 (6H, s), 5.20 (2H, s), 6.50 (2H, d, J=8.5Hz), 6.93 (2H, d, J=8.5Hz), 7.1-7.5 (5H, m) Mass (m/z) · 340 (M+) 3) 4-(4-Aminophenyl)-5-(4-fluorophenyl)thiophene-2carboxamide mp : 172-174°C IR (Nujol) : 3350, 3170, 1575, 1600, 1515 cm NMR (DMSO-dg, δ) : 5.24 (2H, s), 6.51 (2H, d, J=8Hz), 6.90 (2H, d, J=8Hz), 7.1-7.5 (5H, m), 7.80 (1H, s), 8.00 (1H, s) Mass (m/z) : 312 (M+) 4) N-Methyl-4-(4-aminophenyl)-5-(4-fluorophenyl)thiophene-2-carboxamide mp : 222-223°C IR (Nujol) : 3450, 3330, 1625, 1570, 1510 cm1 NMR (DMSO-dg, δ) : 2.78 (3H, d, J=4.5Hz), .21 (2H, s), 6.4-7.4 (8H, m), 7.74 (1H, s), 8.48 (1H, q, J=4.5Hz) Mass (m/z) : 326 (M+) ) 3-(4-Aminophenyl)-2-(4-fluorophenyl)-5-(trifluoromethyl ) thiophene mp : 114-116°C IR (Nujol) : 3500, 3400, 1630, 1610, 1520 cm1 Mass (m/z) : 337 (M+) 6) 5-Acetyl-3-(4-aminophenyl)-2-(4-fluorophenyl)thiophene IR (Film) : 3480, 3380, 3230, 1650, 1620, 1550, 1515 cm1 NMR (DMSO-dg, δ) : 2.57 (3H, s), 5.24 (2H, s), 6.51 (2H, d, J=8.5Hz), 6.94 (2H, d, J=8.5Hz), 7.1-7.5 (4H, m), 7.94 (1H, s) 7) Ethyl 5-(4-aminophenyl)-4-[4-(methylsulfonyl)phenyl] thiophene-2-carboxylate mp : 160-165°C (dec.) IR (Nujol) : 3475, 3400, 3200, 1700, 1610, 1550 cm NMR (DMSO-dg, δ) : 1.25 (3H, t, J=7Hz), 3.20 (3H, s), 4.30 (2H, q, J=7Hz), 5.54 (2H, s), 6.4-7.9 (9H, m) Mass (m/z) : 401 (M+) 8) 2-(4-Aminophenyl)-5-bromo-3-[4-(methylsulfonyl) phenyl3thiophene mp : 185-190°C (dec.) IR (Nujol) : 3475, 3400, 1620, 1610, 1600, 1515 cm NMR (DMSO-dg, δ) : 3.22 (3H, s), 5.43 (2H, s), 6.50 (2H, d, J=8Hz), 6.89 (2H, d, J=8Hz), 7.39 (1H, s), 7.51 (2H, d, J=8Hz), 7.84 (2H, d, J=8Hz) Mass (m/z) : 408, 406 9) 2-(4-Aminophenyl)-5-chloro-3- [ 4 - (methylthio)phenyl]thiohene mp : 205-210’C (dec.) IR (Nujol) : 1610, 1515 cm1 ) 2-(4-Aminophenyl)-5-bromo-3-[4-(methylthio)phenyl]thiophene IR (Nujol) : 3400, 1610, 1515 cm1 11) 5-Acetyl-2-(4-aminophenyl)-3-[4-(methylthio)phenyl]thiophene IR (Nujol) : 3500, 3400, 1655, 1610, 1515 cm1 12) Ethyl 5-(4-aminophenyl)-4-[4-(methylthio)phenyl3thiophene-2-carboxylate mp : 155-158’C IR (Nujol) : 3500, 3400, 1685, 1630, 1610 cm1 Mass (m/z) : 369 (M+) Example 39 A mixture of 5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl3-2-thiophenamine (1.0 g) and methanesulfonyl chloride (0.27 ml) in pyridine (10 ml) was stirred overnight. Pyridine was evaporated, and the residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The residue was dissolved in tetrahydrofuran (10 ml) and treated with 4N sodium hydroxide (1.8 ml) for 2 hours. Ethyl acetate and water were added and the mixture was separated. The aqueous layer was acidified and extracted with ethyl acetate. The extract was dried and concentrated to dryness. The residue (1.1 g) was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (3:1) to give a pale brown powder of N-{5-(4fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thienyl}- methanesulfonamide (0.79 g). 15 mp : 87-90°C IR (Nujol) : NMR (DMSO-dg, 3200, 1600, 1510 cm'1 δ) : 3.17 (3H, s), 3.26 (3H, s), 6.98 (1H, s), 7.1-8.0 (8H, m), 10.4 (1H, 20 broad s) Mass (m/z) : 425 (M+), 346 The following compounds (Examples 40-1) to 40-7)) were obtained according to a similar manner to that of Example 39.

Example 40 1) N-[4,5-Bis(4-methoxyphenyl)-2-thienyl]methanesulf onamide IR (Film) : 3250, 1610, 1515 cm1 NMR (CDC13, δ) : 3.12 (3H, s), 3.79 (6H, s), 6.5-7.3 (10H, m) Mass (m/z) : 389 (M+), 310 2) N-Methyl-5-(4-fluorophenyl)-4-[4-(methylsulfonyl3 5 amino)phenyl]thiophene-2-carboxamide mp : 233-235’C IR (Nujol) : 3430, 3270, 1650, 1610, 1555, 1510 cm'1 NMR (DMSO-dg, δ) : 2.73 (3H, d, J=4.5Hz), 3.0 (3H, s), 7.0-7.5 (8H, m), 7.78 (1H, s), 8.47 (1H, q, J=4.5Hz), 9.81 (1H, s) Mass (m/z) : 404 (M+), 325 3) Ν,Ν-Dimethy1-5-(4-fluorophenyl)-4-[4-(methylsulfonylamino)phenyl]thiophene-2-carboxamide mp : 163-165°C IR (Nujol) : 3210, 1615, 1605, 1545, 1510 cm'1 NMR (DMSO-dg, δ) : 3.02 (3H, s), 3.16 (6H, s), 7.1-7.4 (8H, m), 7.55 (1H, s), 9.85 (1H, s) Mass (m/z) : 418 (M+), 339 4) N,N-Dimethyl-5-(4-fluorophenyl)-4-(4(methylsulfonylamino)phenyl]-2-thenylamine mp : 178-180°C IR (Nujol) : 3270, 1605, 1515 cm1 NMR (DMSO-dg, δ) : 2.23 (6H, s), 3.00 (3H, s), 3.61 (2H, s), 7.0-7.4 (9H, m), 9.83 (1H, s) Mass (m/z) : 404 (M+), 360 ) 5-(4-Fluorophenyl)-4-(4-(methylsulfonylamino)phenyl]25 thiophene-2-carboxamide mp : 219-220°C IR (Nujol) : 3450, 3280, 3160, 1660, 1605, 1545, 1510 cm1 NMR (DMSO-dg, δ) : 3.03 (3H, s), 7.1-7.4 (8H, m), 7.50 (1H, s), 7.86 (1H, s), 8.03 (1H, s), .,. 9.87 (1H, s) Mass (m/z) : 390 (M+), 311 6) 4’-(2-(4-Fluorophenyl)-5-(trifluoromethyl)-3thienylImethanesulfonanilide ,E 911942 mp : 150-152°C IR (Nujol) : 3320, 1600, 1560, 1510 cm1 NMR (DMSO-dg, 5) : 3.02 (3H, s), 7.1-7.5 (8H, m), 7.85 (IH, s), 9.90 (IH, s) Mass (m/z) : 415 (M+), 336 7) 4’-[5-Acetyl-2-(4-fluorophenyl)-3-thienyl]methanesulfonanilide mp : 147-149°C IR (Nujol) : 3280, 1670, 1610, 1540, 1510 cm1 NMR (DMSO-dg, δ) : 2.58 (3H, s), 3.03 (3H, s), 7.1-7.5 (8H, m), 8.04 (IH, s), 9.89 (IH, s) Mass (m/z) : 389 (M+), 310 Example 41 A mixture of 5-{4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]-2-thiophenamine (1.2 g) and acetic anhydride (0.36 ml) in dichloromethane (12 ml) was stirred at ambient temperature for 2 hours, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (3:1) to give a brown powder of N-{5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]2-thienyl)acetamide (0.77 g). mp : 80-92°C IR (Nujol) : 3300, 1660, 1575, 1535, 1505 cm1 NMR (CDC13, δ) : 2.27 (3H, s), 3.11 (3H, s), 6.68 (IH, s), 6.8-8.0 (8H, m), 8.77 (IH, s) Mass (m/z) : 389 (M+), 347 Example -42 Methyl chloroformate (0.23 ml) in acetonitrile (1 ml) was added dropwise to a stirred solution of 5-(4fluorophenyl)-4-(4-(methylsulfonyl)phenyl]-2-thiophenamine (1.1 g) and pyridine (0.24 ml) in acetonitrile (8 ml) and tetrahydrofuran (10 ml) at -20°C. The mixture was stirred at 5°C for 1 hour, diluted with ethyl acetate, washed with water, dried, and concentrated. The residue was purified by column chromatography on silica gel (30 g) eluting with a mixture of toluene and ethyl acetate (10:1). The product was recrystaliized from ethanol to give pale red crystals of methyl N-{5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]-2-thienyl}carbamate (0.84 g). mp : 103-108°C (dec.) IR (Nujol) : 3330, 1720, 1600, 1580, 1540 cm1 NMR (DMSO-dg, 6) : 3.28 (3H, s), 3.80 (3H, s), 6.77 (1H, s), 7.2-8.1 (8H, m), 10.94 (1H, s) Mass (m/z) : 405 (M+), 373 The following compounds (Examples 43-1) to 43-7)) were obtained according to a similar manner to that of Example 42.

Example 43 1) N-{5-(4-Fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2thieny1}-5-methyl-4-isoxazolecarboxamide mp : 236-240 °C IR (Nujol) : 3330, 1665, 1610, 1570, 1530 cm1 NMR (DMSO-dg, δ) : 2.74 I [3H, s), 3.24 (3H, s), 25 7.0 (1H, s), 7 .2-8.0 (8H, m), 9.08 (IH, s), 11.42 (1H, s) Mass (m/z) : 456 (M+) 2) Methyl N-[4,^-bis(4-methoxyphenyl)-2-thienyl]30 carbamate mp.:: 109-113 °C IR (Nujol) : 3400, 1695, 1610, 1570, 1535, 1510 cm NMR (CDC13, δ) : 3.79 (6H, s), 3.82 (3H, s), 6.62 (1H, s), 6.7-6.9 (4H, m), 7.0-7.3 (5H, m) 35 Mass (m/z) : 369 (M+), 337 3) N-(Benzyloxycarbonyl)-5-(4-fluorophenyl)-4-(4(methylthio) phenyl]-2-thenylamine NMR (DMSO-dg, 5) : 2.45 (3H, s), 4.39 (2H, d, J=6Hz), 5.14 (2H, s), 6.9-7.5 (14H, m) , 8.00 (1H, t, J=6Hz) Mass (m/z) : 463 (M+) 4) N-(Benzyloxycarbonyl)-N-methyl-5-(4-fluorophenyl)-4 [4-(methylthio)phenyl]-2-thenylamine NMR (DMSO-dg, δ) : 2.45 (3H, s), 2.93 (3H, s), 4.60 (2H, s), 5.14 (2H, s), 7.1-7.4 (14H, m) Mass (m/z) : 477 ) N-{5-(4-Fluorophenyl)-4-(4-(methylsulf onyl) phenyl]15 2-thienyl}-3,5-di (t-butyl)-4-hydroxybenzamide mp : >250°C IR (Nujol) : 3630, 3200, 1630, 1600, 1560, 1530, 1510 cm1 NMR (DMSO-dg, δ) : 1.45 (18H, s), 3.23 (3H, s), 7.0-8.0 (13H, m) Mass (m/z) : 579 (M+) 6) Ethyl N-{5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thienyl}carhamate mp : 70-75°C IR (Nujol) : 3300, 1720, 1580, 1530 cm1 NMR (DMSO-dg, δ) : 1.27 (3H, t, J=7Hz), 3.22 (3H, S), 4.19 (2H, q, J=7Hz), 6.67 (1H, s), 7.1-7.9 (8H, m), 10.91 (1H, s) Mass (m/z) : 419 (M+), 373 7) N-(Benzyloxycarbonyl)-N-ethyl-5-(4-fluorophenyl)-4[4-(methylthio)phenyl3-2-thenylamine IR (Film) : 1700, 1510, 1500 cm1 NMR (CDC13, δ) : 1.1-1.3 (3H, m), 2.47 (3H, s), 3.3-3.5 (2H, π»)/4.60 (2H, s) , 5.20 (2H, s), 6.9-7.4 (14H, m) Example 44 A mixture of 5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]-2-thiophenamine (0.9 g) and methyl isocyanate (1.4 ml) in tetrahydrofuran (20 ml) was stirred and refluxed for 1 hour. The solvent was evaporated and the residue (1.5 g) was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (10:1) to give a brown powder of N- {5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl]-2thienyl)-N’-methylurea (0.77 g). mp : 70-75°C IR (Nujol) : 3300, 1680, 1660, 1560, 1510 cm-1 NMR (DMSO-dg, δ) : 2.66 (3H, d, J=4.5Hz), 3.22 (3H, s), 6.30 (1H, q, J=4.5Hz), 6.57 (1H, s), 7.1-7.3 (4H, ra), 7.45 (2H, d, J=8Hz), 7.84 (2H, d, J=8Hz), 9.77 (1H, s) Mass (m/z) : 404 (M+), 373 Example 45 A solution of N,N-dimethyl-5-(4-fluorophenyl)-4-[4(methylthio)phenyl]thiophene-2-carboxaraide (1.95 g) in benzene (15 ml) was added dropwise to an ice-cooled mixture of lithium aluminum hydride (0.27 g) in diethyl ether (10 ml). The mixture was refluxed for 9 hours. To the mixture was added dropwise 4N sodium hydroxide solution. Ethyl acetate was added, and the mixture was filtered. The filtrate was washed with water, dried and evaporated. The oily residue (2 g) was purified by column chromatography on silica gel (20 g) eluting with a mixture of toluene and ethyl acetate (2:1) to give a yellow oil of N,N-dimethyl-5-(4-fluorophenyl)-4-(4-(methylthio)phenyl]35 2-thenylamine (1.5 g).

IR (Film) : 2770, 1600, 1510 cm x NMR (CDC13, δ) : 2.35 (6H, s), 2.50 (3H, s), 3.35 (2H, s), 6.8-7.5 (9H, m) Mass (m/z) : 357 (M+), 313 The following compounds (Examples 46-1) to 46-9)) were obtained according to a similar manner to that of Example 45.

Example 46 1) N,N-Dimethyl-4-(4-aminophenyl)-5-(4-fluorophenyl)2-thenylamine IR (Film) : 3400, 1620, 1515 cm1 NMR (CDC13, δ) : 2.34 (6H, s), 3.63 (2H, s), 3.66 (2H, s), 6.5-7.4 (9H, m) Mass (m/z) : 326 (M+), 282 2) N,N-Dimethyl-4,5-bis (4-fluorophenyl)-2-thenylamine mp : 93-94°C IR (Nujol) : 1600, 1510 cm-1 NMR (CDC13, δ) : 2.35 (6H, s), 3.64 (2H, s), 6.9-7.3 (9H, m) Mass (m/z) : 329 (M+), 285 3) N,N-Dimethyl-4,5-bis[4-(methylthio)phenyl]-2thenylamine IR (Film) : 1600, 1560, 1495 cm1 4) N,N-Dimethyl-5-(4-methoxyphenyl)-4-[4-(methylthio) 0 phenyl]-2-thenylamine IR,·.(Film) :- 1610, 1575, 1515, 1500 cm1 NMR (CDC13, δ) : 2.33 (6H, s), 2.44 (3H, s), 3.58 (2H, s), 3.78 (3H, s), 6.6-7.3 (9H, m) ) N,N-Dimethyl-5-(2,4-difluorophenyl)-4-[4IE 911942 100 (methylthio)phenyl]-2-thenylamine mp : 95-96°C -1 IR (Nujol) : 1595, 1565, 1515, 1495 cm NMR (CDC13, δ) : 2.35 (6H, s), 2.46 (3H, s) 3.67 (2H, s), 6.7-7.3 (8H, Mass (m/z) : 375 (M+), 331 6) N,N-Dimethyl-5-(4-chlorophenyl)-4-[4-(methylthio) phenyl]-2-thenylamine IR (Film) : 1600, 1565, 1495 cm'1 7) N,N-Dimethyl-4-(4-(ethylthio)phenyl]-5-(4fluorophenyl)-2-thenylamine IR (Film) : 1600, 1510 cm'1 Mass (m/z) : 371 (M+) 8) Ν,Ν-Dimethy1-5-(3,4-difluorophenyl)-4-(4(methylthio)phenyl]-2-thenylamine IR (Film) : 1600, 1515, 1500 cm1 9) N-Methyl-5-(4-fluorophenyl)-4-(4-(methylthio)phenyl] 2-thenylamine The following compounds (Examples 47-1) to 47-3)) were obtained by treating the compound as obtained according to a similar manner to that of Example 45 with solution of hydrogen chloride in ethanol.

Example 47 1) N,N-Dimethyl-4,5-bis(4-methoxyphenyl)thenylamine hydrochloride mp : 191-195’C IR (Nujol) : 3420, 2650, 1610, 1515 cm'1 NMR (DMSO-dg, δ) : 2.76 (6H, s), 3.75 (6H, s), 4.49 (2H, s), 6.8-7.3 (8H, m) , 7.45 (1H, s), 11.2 (1H, s) 101 Mass (m/z) : 353 (M^), 309 2) N,N-Dimethyl-5-(4-fluorophenyl)-4-(4-methoxyphenyl)2-thenylamine hydrochloride mp : 214-215°C IR (Nujol) : 3400, 2460, 2370, 1610, 1560, 1510 cm'1 NMR (D2O, δ) : 3.10 (6H, s), 3.70 (3H, s), 4.70 (2H, s), 6.7-7.4 (8H, m), 7.57 (1H, s) Mass (m/z) : 341 (M+), 297 3) N,N-Dimethyl-5-(4-fluorophenyl)-4-[4-(methylthio)phenyl]-2-thenylamine hydrochloride mp : 160-165°C IR (Nujol) : 3400, 2500, 1600, 1510 cm1 NMR (DMSO-dg, δ) : 2.47 (3H, s), 2.77 (6H, s), 4.52 (2H, s), 7.1-7.4 (8H, m), 7.51 (1H, s), 11.27 (1H, s) Mass (m/z) : 357 (M+) The following compounds (Examples 48-1) to 48-5)) were obtained according to a similar manner to those of Examples 17 and 45.

Example 48 1) 2-(4-Fluorophenyl)-3-[4-(methylthio)phenyl]-5-(1pyrrolidinylmethyl)thiophene IR (Film) : 1600, 1510 cm1 NMR (DMSO-dg, δ) : 1.6-1.8 (4H, m), 2.45 (3H, s), 2.4-2.6 (4H, m), 3.79 (2H, s), 7.0-7.3 (9H, m) 2) N-Ethyl-N-methyl-5-(4-fluorophenyl)-4-[4(methylthio)phenyl]-2-thenylamine IR (Film) : 1600, 1510, 1500 cm1 NMR (DMSO-dg, δ) : 1.03 (3H, t, J=7Hz), 2.21 (3H, s), 2.44 (3H, s), 2.44 (2H, q, J=7Hz), 3.68 (2H, •Ε 911942 102 s), 7.0-7.3 (9H, m) 3) N,N-Diethyl-5-(4-fluoropheny1) - 4 - [ 4 - {methylthio)phenyl]-2-thenylamine IR (Film) : 1600, 1510, 1500 cm’1 NMR (DMSO-dg, δ) : 1.01 (6H, t, J=7Hz), 2.45 (3H, s), 2.54 (4H, q, J=7Hz), 3.76 (2H, s), 7.0-7.3 (9H, m) Mass (m/z) : 385 (M+) 4) N-Methyl-N-propyl-5-(4-fluorophenyl)-4-[4(methylthio)phenyl}-2-thenylamine IR (Film) : 1600, 1510, 1500 cm’1 NMR (DMSO-dg, δ): 0.87 (3H, t, J=7Hz), 1.3-1.6 (2H, m), 2.21 (3H, s), 2.36 (2H, t, J=7Hz), 2.46 (3H, s), 3.68 (2H, s), 7.0-7.4 (9H, m) Mass (m/z) : 385 (M+), 313 ) N-Ethyl-5-(4-fluorophenyl)-4-[4-(methylthio)phenyl]20 2-thenylamine IR (Film) : 1605, 1515 cm1 NMR (CDC13, δ) : 1.17 (3H, t, J=7Hz), 3.47 (3H, s), 2.78 (2H, q, J=7Hz), 4.00 (2H, s), 6.9-7.4 (9H, m) The following compound (Example 49) was obtained according to a similar manner to those of Examples 14 and 45.

Example 49 -H-Fluorophenyl)-4-[4-(methylthio)phenyl]-2thenylamine NMR (DMSO-dg, δ) : 2.45 (3H, s), 3.82 (2H, s), 7.0-7.4 (9H, m) 103 Example 50 n-Butyl lithium (1.6 M) in hexane (36 ml) was added dropwise to a stirred solution of 2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl]thiophene 5 (8.0 g) in tetrahydrofuran (80 ml) at -60°C. The mixture was stirred for 30 minutes, and Ν,Ν-dimethylformamide (3.7 ml) was added dropwise over ten minutes to the mixture.

The mixture was stirred at -70 to -20°C for 2 hours.

IN Hydrochloric acid (70 ml) was added dropwise, and the solution was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated. The residual syrup was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (9:1). The obtained crystals (4.5 g) were recrystallized from ethyl acetate to give pale yellow crystals of 5-{4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl]thiophene-2-carbaldehyde (3.7 g). mp : 165-166°C IR (Nujol) : 1660, 1595, 1510 cm1 NMR (CDC13, δ) : 3.09 (3H, s), 7.0-8.0 (9H, m), 9.94 (1H, S) Mass (m/z) : 360 (M+) The following compound (Example 51) was obtained according to a similar manner to that of Example 50.

Example 51 -(4-Fluorophenyl)-4-[4-(methylthio)phenyl]thiophene-2-carbaldehyde.

IR (Film) : 1670, 1600, 1540, 1510 cm1 NMR (CDC13, δ) : 2.53 (3H, s), 6.9-7.6 (8H, m) , 7.83 (1H, s), 10.0 (1H, s) Mass (m/z) : 328 (M+) 104 Example 52 Chlorosulfonic acid (5 ml) was added dropwise to a stirred powder of 2,3-bis(4-methoxyphenyl)thiophene (2.5 g) at ambient temperature. The mixture was stirred overnight and added to a mixture of ammonia water (31 ml), ethyl acetate and ice. The mixture was separated, and the organic layer was dried and concentrated. The residue was washed with ethanol to give pale brown crystals of 4,5-bis(4-methoxy-3-sulfamoylphenyl)thiophene-210 sulfonamide (0.62 g). mp : 242-244°C IR (Nujol) : 3370, 3260, 1610, 1540, 1500 cm1 NMR (DMSO-dg, δ) : 3.89 (3H, s), 3.91 (3H, s), 7.1-7.9 (13H, m) Mass (m/z) : 533 (M+), 454 Example 53 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl]thiophene (1.1 g) was added portionwise to chlorosulfonic acid (1 ml), and the mixture was stirred at ambient temperature for 1 hour. The mixture was added to a mixture of 25% methylamine aqueous solution (20 ml) and tetrahydrofuran (20 ml), and stirred at 0°C for 1 hour.

The reaction mixture was extracted with ethyl acetate, and the extract was washed with water, dried and concentrated. The oily residue (2.4 g) was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1), and then recrystaliized from ethanol to give colorless crystals of N-methyl-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-sulfonamide (1.1 g). mp : 199-201°C IR (Nujol) : 3300, 1600, 1510 cm1 NMR (DMSO-dg, δ): 2.63 (3H, s), 3.25 (3H, s), 7.2-8.0 (9H, m) 105 Mass (m/z) : 425 (M+) The following compound (Example 54) was obtained according to a similar manner to that of Example 53.

Example 54 N,N-Dimethyl-5-(4-fluorophenyl)-4-[4(methylsulfonyl)phenyl]thiophene-2-sulfonamide mp : 189-19VC IR (Nujol) : 1600, 1535, 1510 cm1 NMR (DMSO-dg, δ) : 2.79 (6H, s), 3.25 (3H, s), 7.2-8.0 (9H, m) Mass (m/z) : 439 (M+) Example 55 A mixture of 5-(bromoacetyl)-2-(4-flurophenyl)-3[4-(methylsulfonyl)phenyl3 thiophene (2 g) and thiourea (0.61 g) in ethanol (80 ml) was refluxed for 30 minutes. The mixture was dissolved in chloroform, washed with an aqueous solution of sodium bicarbonate and water, dried, and concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and acetone (10:1) to give pale yellow crystals to 5-(2-amino-4-thiazolyl)-2-(4-fluorophenyl)-3-[42 5 (methylsulfonyl)phenyl]thiophene (0.6 2 g). mp : 243-245°C IR (Nujol) : 3450, 3300, 3150, 1630, 1600, 1535, 1500 cm1 NMR (DMSO-dg, δ) : 3.20 (3H, s), 6.97 (1H, s), 7.0-7.6 (7H, m), 7.86 (2H, d, J=8Hz) Mass (m/z) :. 430 (M+) The following compound (Example 56) was obtained according to a similar manner to that of Example 55. 106 Example 56 2-(4-Fluorophenyl)-5-(2-(methylamino)-4-thiazolyl]3- (4-(methylsulfonyl) phenyl]thiophene mp : 176-180°C IR (Nujol) : 3250, 1590, 1550, 1500 cm-1 NMR (DMSO-dg, δ) : 2.85 (3H, d, J=6Hz), 3.20 (3H, s), 6.9-8.0 (11H, m) Mass (m/z) : 444 (M+) Example 57 A mixture of 5-acetyl-2-(4-fluorophenyl)-3-[4(methylsulfonyl)phenyl]thiophene (1.8 g) and (triphenylphosphoranylidene)acetonitrile (3.2 g) in toluene (40 ml) was refluxed for 28 hours. The mixture was cooled and filtered. The filtrate was concentrated and the residue (4.2 g) was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (10:1). The obtained crystals (1.8 g) were recrystallized from ethanol to give colorless crystals of 3-{5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl]-2-thienyl}-2-butenenitrile (1.5 g). mp : 150-154’C IR (Nujol) : 2200, 1590, 1545, 1505 cm-1 NMR (DMSO-dg, δ) : 2.45 (3H, s), 3.24 (3H, s), 6.12 (1H, s), 7.2-8.0 (9H, m) Example 58 A mixture of 2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl]thiophene (5 g), acetic anhydride (4.3 ml) and sulfuric acid (0.97 ml) in dichloromethane (47 ml) was stirred..at ambient temperature overnight. The mixture was concentrated to give a crude blue oil of 5-(4-fluorophenyl) 4- (4-(methylsulfonyl)phenyl]thiophene-2-sulfonic acid (10.5 g) · The following compounds (Examples 59-1) to 59-4)) 107 were obtained according to a similar manner to that of Example 10.

Example 59 1) N-{5-(4-Fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2 thenoyl}-N-met hylglycine mp : 78-82°C IR (Nujol) : 1740, 1600, 1545 cm1 NMR (DMSO-dg, δ) : 3.24 (3H, s), 3.38 (3H, s), 4.19 (2H, s), 7.1-8.0 (9H, m), 12.9 (1H, s) Mass (m/z) : 447 (M+), 359 2) 4-[4-(Methylsulfonyl)phenyl]-5-(4-nitrophenyl)thiophene-2-carboxylic acid mp : 188-190°C (dec.) IR (Nujol) : 1710, 1600, 1515 cm1 NMR (DMSO-dg, δ) : 3.25 (3H, s), 7.5-7.7 (4H, m), 7.90 (2H, d, J=8Hz), 7.92 (1H, s), 8.23 (2H, d, J=8Hz) Mass (m/z) : 403 (M+) 3) 4-[4-(Methylthio)phenyl]-5-(4-nitrophenyl)thiophene2-carboxylic acid mp : 190-195°C (dec.) IR (Nujol) : 1690, 1595, 1515 cm-1 NMR (DMSO-dg, δ) : 2.47 (3H, s), 6.6-8.3 (9H, m) Mass (m/z) : 371 (M+) 4) 5-(2-Fluorophenyl)-4-[4-(methylthio)phenyl]thiophene 2-carboxylic acid mp-,-: 160-163°C (dec.) IR (Nujol) : 3400, 1680, 1590 cm1 NMR (DMSO-dg, δ) : 2.45 (3H, s), 7.1-7.6 (8H, m), 7.87 (1H, s), 13.3 (1H, s) Mass (m/z) : 344 (M+) 108 Example 60 A mixture of ethyl 5-[4-(N-formylmethylamino)phenyl]4- [4-(methylsulfonyl)phenyl]thiophene-2-carboxylate (0.34 g) and sodium methoxide (0.13 g) in formamide (2 ml) was stirred at 100°C for 2.5 hours. The mixture was poured into ice-water and the precipitates were collected to give - [4-(N-formylmethylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-3-carboxamide (0.3 g). mp : 227-230°C (dec.) IR (Nujol) : 3450, 3350, 3200, 1660, 1605 cm1 NMR (CDC13, δ) : 3.09 (3H, s), 3.33 (3H, s), .87 (2H, s), 7.1-8.0 (9H, m), 8.60 (1H, s) Mass (m/z) : 414 (M+) The following compounds (Examples 61-1) and 61-2)) were obtained according to a similar manner to that of Example 60.

Example 61 1) 5-[4-(N-Formylmethylamino)phenyl]-4-[4-(methylthio) phenyl]thiophene-2-carboxamide mp : 165-170°C (dec.) IR (Nujol) : 3400, 1680, 1660, 1605 cm1 NMR (CDC13, δ) : 2.49 (3H, s), 3.32 (3H, s), 6.06 (2H, s), 7.0-7.5 (8H, m), 7.53 (1H, s), 8.54 (1H, s) 2) 5-(2-Fluorophenyl)-4-[4-(methylthio)phenyl]thiophene2-carboxamide mp : 135-140°C IRjNujol) ϊ- 3400, 3200, 1660, 1605, 1515 cm'1 NMR (DMSO-dg, δ) : 2.45 (3H, s), 7.1-7.8 (8H, m), 7.98 (1H, s) Mass (m/z) : 343 (M+) 109 The following compounds (Examples62-1) to 62-5)) were obtained according to a similar manner to that of Example 27.

Example 62 1) 5-Chloro-2-[4-(N-formylmethylamino)phenyl3-3-[4(methylsulfinyl)phenyl]thiophene mp : 167-170°C IR (Nujol) : 1675, 1605, 1510 cm 1 2) 5-Bromo-2-[4-(N-formylmethylamino)phenyl]-3-[4(me thylsulf inyl)phenyl3 thiophene mp : 168-170°C IR (Nujol) : 1675, 1605, 1515 cm1 3) 5-Acetyl-2-[4-(N-formylmethylamino)phenyl]-3-[4(methylsulfinyl)phenyl3 thiophene mp : 145-150°C IR (Nujol) : 1680, 1660, 1600 cm1 4) 5-[4-(N-Formylmethylamino)phenyl3 — 4-E 4(methylsulfinyl)phenyl]thiophene-2-carbonitrile mp : 185-190°C (dec.) NMR (CDC13, δ) : 2.77 (3H, s), 3.37 (3H, s), 7.1-7.7 (9H, m), 8.57 (1H, s) ) 5-Acetyl-2-(4-methoxyphenyl)-3-[4-(methylsulf inyl) phenyl3 thiophene mp : 175-178°C (dec.) IR (Nujol) : 1660, 1610, 1515 cm1 NMR (CDC13, δ) : 2.59 (3H, s), 2.76 (3H, s), 3.82 (3H, s), 6.8-7.7 (8H, m), 7.71 (1H, s) Mass (m/z) : 370 (M+), 355 110 Example 63 A mixture of acetic anhydride (1.1 g) and formic acid (0.8 g) was heated at 50°C for 30 minutes. To the mixture was added ethyl 5-(4-aminophenyl)-4-[4-(methylsulfonyl)5 phenyl]thiophene-2-carboxylate (0.5 g). The mixture was stirred at ambient temperature for 4 hours and poured into ice-water. The precipitates were collected, washed with water, and dried in vacuo to give ethyl 5-[4(formylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]10 thiophene-2-carboxylate (0.38 g). mp : 175-180°C (dec.) IR (Nujol) : 3350, 1705, 1690, 1600 cm-1 NMR (DMSO-dg, δ) : 1.30 (3H, t, J=7Hz), 3.25 (3H, s), 4.34 (2H, q, J=7Hz), 7.2-8.0 (9H, m), 8.31 15 (1H, s), 10.4 (1H, s) Mass (m/z) : 429 (M+) The following compounds (Examples 64-1) to 64-5)) were obtained according to a similar manner to that of Example 63.

Example 64 1) 5-Bromo-2-[4-(formylamino)phenyl]-3-[4{methylsulfonyl)phenyl J thiophene mp : 145-150°C (dec.) IR (Nujol) : 3300, 1690, 1600, 1515 cm-1 NMR (CDC13, δ) : 3.08 (3H, s), 7.0-7.9 (9H, m), 8.40 (1H, s) Mass (m/z) : 436 (M+) 2) 5-Ghloro-2-[4-(formylamino)phenyl]-3-[4-(methylthio)phenyl]thiophene IR (Nujol) : 1675, 1600, 1515 cm-1 3) 5-Bromo-2-[4-(formylamino)phenyl]-3-[4-(methylthio)IE 911942 111 phenyl]thiophene mp : 150-160°C (dec.) IR (Nujol) : 1690, 1600 cm’1 Mass (m/z) : 405, 403 4) 5-Acetyl-2-[4-{f ormylamino)phenyl]-3-[4-(methylthio) phenyl]thiophene IR (Film) : 3250, 1695, 1660, 1605, 1515 cm’1 ) Ethyl 5-[4-(formylamino)phenyl]-4-[4-(methylthio)pheny1]thiophene-2-carboxylate NMR (DMSO-dg, <5) : 1.35 (3H, t, J=7Hz), 2.47 (3H, s), 4.33 (2H, q, J=7Hz), 7.1-7.7 (8H, m), 7.82 (IH, s), 8.30 (lH, s), 10.4 (IH, s) Mass (m/z) : 397 (M+) Example 65 Sodium hydride (60%; 40 mg) was added to an ice-cooled solution of ethyl 5-[4-(formylamino)phenyl]-420 [4-(methylsulfonyl)phenyl]thiophene-2-carboxylate (0.35 g) in Ν,Ν-dimethylformamide (10 ml). The mixture was stirred at ambient temperature for 30 minutes, and to the resulting mixture was added methyl iodide (0.23 g) at 5°C. The mixture was stirred at ambient temperature for 1.5 hours and poured into ice-water. The precipitates were collected, washed with water, and dried in vacuo to give ethyl 5-[4-(N-formylmethylamino)phenyl]-4-[4-(methylsulf onyl)phenyl]thiophene-2-carboxylate (0.34 g) . mp : 190-195°C (dec.) IR (Nujol) : 1715, 1680, 1605 cm’1 NMR::(CDC13, &) : 1.42 (3H, t, J=7Hz), 3.09 (3H, s), 3.33 (3H, s), 4.40 (2H, q, J=7Hz), 7.1-8.0 (9H, m), 8.57 (IH, s) Mass (m/z) : 443 (M+) 112 The following compounds (Examples 66-1) to 66-5)) were obtained according to a similar manner to that of Example 65.

Example 66 1) 5-Bromo-2-[4-(N-formylmethylamino)phenyl]-3-[4(methylsulfonyl)phenyl]thiophene mp : 188-191°C (dec.) IR (Nujol) : 1680, 1600, 1510 cm1 NMR (CDC13, δ) : 3.12 (3H, s), 3.32 (3H, s), 7.0-7.5 (7H, m), 7.87 (2H, d, J=8Hz), 8.54 (1H, s) 2) 5-Chloro-2-[4-(N-formylmethylamino)phenyl]-3-[415 (methylthio)phenyl]thiophene mp : 165-170°C (dec.) IR (Nujol) : 1680, 1605, 1510 cm1 3) 5-Bromo-2-[4-(N-formylmethylamino)phenyl]-3-[420 (methylthio)phenyl]thiophene mp : 150-155°C (dec.) IR (Nujol) : 1685, 1600 cm1 Mass (m/z) : 419, 417 4) 5-Acetyl-2-[4-(N-formylmethylamino)phenyl]-3-[4(methylthio)phenyl]thiophene IR (Nujol) : 1695, 1660, 1600, 1540 cm'1 Mass (m/z) : 381 (M+) ) Ethyl 5-[4-(N-formylmethylamino)phenyl]-4-ΚΙ methyl thio) phenyl ]thiophene-2-carboxylate mp : 158-160°C IR (Nujol) : 1680, 1605 cm 1 NMR (CDC13, δ) : 1.41 (3H, t, J=7Hz), 2.48 (3H, s), 3.36 (3H, s), 4.40 (2H, q, J=7Hz), 7.0-7.6 (8H, IE 911942 113 m), 7.81 (1H, s), 8.55 (1H, s) Mass (m/z) : 411 (M+) Example 67 A mixture of 5-(4-(N-formylmethylamino)phenyl]-4-(4(methylsulfonyl)phenyl]thiophene-2-carboxamide (0.3 g) and methanesulfonyl chloride (0.5 g) in pyridine (1.5 ml) was stirred at 50°C for 3 hours. The mixture was poured into dilute hydrochloric acid. The precipitates were collected and washed with water to give 5-( 4-(N-formy lmethylamino) phenyl]-4-(4-(methylsulfonyl)phenyl]thiophene-2carbonitrile (0.25 g). mp : 190-195°C (dec.) IR (Nujol) : 2220, 1675, 1600, 1510 cm1 NMR (CDC13, δ) : 3.10 (3H, s), 3.34 (3H, s), 7.1-8.0 (9H, m), 8.58 (IH, s) Mass (m/z) : 396 (M+) The following compound (Example 68) was obtained according to a similar manner to that of Example 67.

Example 68 -(4-(N-Formylmethylamino)phenyl)-4-(4-(methylthio) phenyl]thiophene-2-carbonitrile mp : 155-160°C (dec.) IR (Nujol) : 2230, 1680, 1605 cm'1 NMR (CDC13, δ) : 2.50 (3H, s), 3.32 (3H, s), 7.0-7.4 (8H, m), 7.62 (IH, s), 8.56 (IH, s) Mass (m/z) : 364 (M+) Examplev69 A mixture of 5-(4-(N-formylmethylamino)phenyl)-4-(4(methylsulfonyl)phenyl)thiophene-2-carbonitrile (2.2 g) and concentrated hydrochloric acid (13 ml) in methanol (60 ml) and tetrahydrofuran (40 ml) was stirred at ambient •Ε 911942 114 temperature for 2.5 hours. The mixture was concentrated and the residue was triturated in a sodium bicarbonate solution to give a powder. The crude powder was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (4:1) to give a yellow powder of 5-[4-(methylamino)phenyl]-4-[4(methylsulfonyl)phenyl]thiophene-2-carbonitrile (1.4 g). mp : 188-190°C IR (Nujol) : 3450, 2220, 1610, 1520 cm1 NMR (CDC13, δ) : 2.86 (3H, s), 3.08 (3H, s), 6.50 (2H, d, J=8Hz), 7.04 (2H, d, J=8Hz), 7.45 (2H, d, J=8Hz), 7.60 (1H, s), 7.87 (2H, d, J=8Hz) Mass (m/z) : 368 (M+) The following compounds (Examples 70-1) to 70-5)) were obtained according to a similar manner to that of Example 69.

Example 70 1) 5-Bromo-2-[4-(methylamino)phenyl]-3-[4-(methylsulfonyl)phenyl]thiophene mp : 180-182’C IR (Nujol) : 3450, 1610, 1595, 1520 cm1 NMR (cdci3 , δ) : 2.84 (3H, s), 3.06 ( 3H, s), 6.49 (2H, d, J=8Hz), 7.04 (2H, d, J=8Hz), 7.14 (1H, s), , 7.42 (2H, d, J=8Hz) / 7.82 (2H, d, J=8Hz) Mass (m/z) J 423, , 421 2) 5-Ghloro-2-[4-(methylamino)phenyl]-3-[4(methylsulf inyl)phenyl]thiophene mp : 150-155°C (dec.) IR (Nujol) : 3350, 1610, 1515 cm1 NMR (CDC13, δ) : 2.75 (3H, s), 2.84 (3H, s), IE 911942 115 6.50 (2H, d, J=8Hz), 7.0-7.6 (7H, m) 3) 5-Bromo-2-(4-(methylamino)phenyl] - 3 - [ 4 (methylsulf inyl)phenyl]thiophene mp : 160-164°C (dec.) Mass (m/z) : 407, 405 4) 5-Acetyl-2-[4-(methylamino)phenyl]-3-[4(methylsulfinyl)phenyl]thiophene mp : 180-185°C (dec.) IR (Nujol) : 3350, 1650, 1610, 1515 cm-1 Mass (m/z) : 369 (M+) ) 5-(4-(Methylamino)phenyl]-4-(4-(methylsulfinyl) 15 phenyl]thiophene-2-carbonitrile mp : 140-143°C IR (Nujol) : 3350, 2225, 1610, 1515 cm-1 NMR (CDC13, δ) : 2.75 (3H, s), 2.85 (3H, s), 4.0 (1H, m), 6.49 (2H, d, J=8Hz), 7.0-7.7 (7H, m) Mass (m/z) : 352 (M+) Example 71 A mixture of 5-(4-fluorophenyl)-4-(4(methylsulfonyl)phenyl]thiophene-2-carbonitrile (3.1 g), sodium azide (1.3 g) and ammonium chloride (1.5 g) in Ν,Ν-dimethylformamide (30 ml) was stirred at 120°C for 24 hours. The mixture was poured into ice-water, and the resulting mixture was acidified. The precipitates were collected and recrystallized from ethanol to give crystals of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(5tetrazalyl) thiophene (0.9 g). mp : 200-205°C (dec.) NMR (DMSO-d6, δ) : 3.27 (3H, s), 7.2-7.6 (6H, m), 7.93 (2H, d, J=8Hz), 7.95 (1H, s) Mass (m/z) : 400 (M+), 372

Claims (9)

1. A compound of the formula .· [I] wherein R 1 is hydrogen; halogen; cyano; lower alkyl substituted with substituent(s) selected from the group consisting of halogen, hydroxy, amino, acylamino, lower alkylamino, lower alkyl(acyl)amino, acyl, aryl optionally substituted with hydroxy, a heterocyclic group, hydroxyimino and lower alkoxyimino; lower alkenyl optionally substituted with cyano; acyl; nitro; amino optionally substituted with substituent (s) selected from the group consisting of acyl and lower alkylsulfonyl; sulfo; sulfamoyl optionally substituted with substituent!s) selected from the group consisting of lower alkyl, halo(lower)alkyl, aryl, hydroxy, lower alkylamino!lower)alkyl, a heterocyclic group and (esterified carboxy) lower alkyl; N-containing -, heterocyclicsulfonyl; hydroxy; or a heterocyclic group optionally substituted with substituent!s) selected from the group consisting of hydroxy, oxo, amino and lower IE 91 1942 117 alkylamino; R is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, 5 lower alkylthio, lower alkylsulfinyl, lower akylsulfonyl, nitro, amino, sulfamoyl and lower alkylsulfonylamino; and R is aryl optionally substituted with 10 substituent (s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro, amino, lower alkylamino, acylamino, lower 15 alkyl(acyl) amino, lower alkylsulfonylamino and sulfamoyl; provided that R 3 is aryl substituted with substituent (s) selected from the group consisting of amino, 20 mono(lower)alkylamino, acylamino, lower alkyl(acyl)amino and sulfamoyl when R 1 is hydrogen, halogen or cyano, and pharmaceutically acceptable salts thereof. 2. A compound according to claim 1, wherein R 1 is lower alkyl substituted with substituent (s) selected from the group consisting of halogen, hydroxy, amino, 30 acylamino, lower alkylamino, lower ... alkyl (acyl) amino, acyl, aryl optionally substituted with hydroxy, a heterocyclic group, hydroxyimino and lower alkoxyimino; lower alkenyl 35 optionally substituted with cyano; 118 acyl; nitro; amino optionally substituted with substituent(s) selected from the group consisting of acyl and lower alkylsulfonyl; sulfamoyl 5 optionally substituted with lower alkyl; hydroxy; or a heterocyclic group optionally substituted with substituent (s) selected from the group consisting of 10 hydroxy, oxo, amino and lower alkylamino; and i s aryl optionally substituted with substituent (s) selected from the group consisting of halogen, lower alkoxy, 15 lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, and sulfamoyl. 3. A compound according to claim 2, wherein R 1 is lower alkyl substituted with 20 substituent(s) selected from the group consisting of halogen, hydroxy, amino, acylamino, lower alkylamino, lower alkyl(acyl)amino, acyl, aryl optionally substituted with hydroxy, a 25 heterocyclic group, hydroxyimino and lower alkoxyimino. 4. A compound according to claim 3, wherein R 1 is lower alkyl substituted with halogen, 30 R is phenyl substituted with lower ,- alkylsulfonyl and 3 R is phenyl substituted with halogen. 5. A compound of claim 4, which is 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-535 - 119 (trifluoromethyl)thiophene. 6. A process for preparing a compound of the formula : [1] wherein R 1 is hydrogen; halogen; cyano; lower alkyl 10 substituted with substituent (s) selected from the group consisting of halogen, hydroxy, amino, acylamino, lower alkylamino, lower alkyl(acyl)amino, acyl, aryl optionally 15 substituted with hydroxy, a heterocyclic group, hydroxyimino and lower alkoxyimino; lower alkenyl optionally substituted with cyano; acyl; nitro; amino 20 optionally substituted with substituent(s) selected from the group consisting of acyl and lower alkylsulfonyl; sulfo; sulfamoyl optionally substituted with 25 substituent(s) selected from the group consisting of lower alkyl, halo(lower)alkyl, aryl, hydroxy, lower alkylamino(lower)alkyl, a heterocyclic group and (esterified carboxy)lower 30 alkyl; N-containing ... heterocyclicsulfonyl; hydroxy; or a heterocyclic group optionally substituted with substituent(s) selected from the group consisting of 35 hydroxy, oxo, amino and lower 120 alkylamino; R is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower akylsulfonyl, nitro, amino, sulfamoyl and lower alkylsulfonylamino; and R is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro, amino, lower alkylamino, acylamino, lower alkyl(acyl)amino, lower alkylsulfonylamino and sulfamoyl; provided that R is aryl substituted with substituent(s) selected from the group consisting of amino, mono(lower)alkylamino, acylamino, lower alkyl( acyl) amino and sulfamoyl when R 1 is hydrogen, halogen or cyano, or pharmaceutically acceptable salts thereof, which comprises, 1) reacting a compound of the formula : CHO 2 i 3 R -C=C-R J [II] X or its salt with a compound of the formula : HSCH--R 1 £ cl [III] 121 or its salt to provide a compound of the formula : [1-1] or its salt, in the above formulas, R 1 is cyano or acyl, 3. X is halogen, and 2 3 R and R are each as defined above, or

2. ) reacting a compound of the formula R 3 S ' X or its salt with a haloalkylating agent to provide a compound of the formula : or its salt, in the above formulas, R? is halo(lower)alkyl, and d 2 3 R , R and X are each as defined above,

3. ) reacting a compound of the formula .3 S [IV] [1-2] or [V] or its salt with an acylating agent 122 to provide a compound of the formula : or its salt, in the above formulas, R 1 is lower alkanoyl optionally substituted with c halogen; or 10 aroyl optionally substituted with hydroxy; and 2 3 R and R are each as defined above, or

4. ) reacting a compound of the formula II LI-4] R 3 S ' (CH 2 ) n CCH 3 or its salt with a compound of the formula : R 4 -OH [VI] to provide a compound of the formula R 3 s HCH 2 ) n+1 COR 4 [1-5] or its salt, in the above formulas, 2 3 R and R are. each as defined above, R is lower alkyl, and n is an integer of 0 to 6, or

5. ) subjecting a compound of the formula 123 [1-6] or its salt to deesterification reaction to provide a compound of the formula : [1-7] or its salt, in the above formulas, R 1 is lower alkyl substituted with esterified carboxy; esterified carboxy; or (esterified carboxy)lower alkylcarbamoyl optionally substituted with lower alkyl; R 1 is lower alkyl substituted with carboxy; carboxy; or carboxy(lower)alkylcarbamoyl optionally substituted with lower alkyl; and 2 3 R and R are each as defined above, or

6. ) reacting a compound of the formula : or its reactive derivative at the carboxy or sulfo group or a salt thereof with an amine, or formamide and alkali metal alkoxide to provide a compound of the formula : [1-9] 124 or its salt, in the above formulas, A is -(CH 2 ) n CO- or -SO 2 ~ ; i s amino optionally substituted with substituent(s) selected from the group consisting of lower alkyl, halo(lower) alkyl, aryl, hydroxy, lower alkylamino(lower)alkyl, a heterocyclic group and (esterified carboxy)lower alkyl; or N-containing heterocyclic group; and 2 3 R , R and n are each as defined above, or 7. ) reacting a compound of the formula [1-101 or its salt with a compound of the formula : CO~R* I 4 co 2 r to provide a compound of the formula [VII] [i-ii] or-its salt, in the above formulas, 2 3 4 R , R and R are each as defined above, 8. ) reacting a compound of the formula : 125 or its salt with an oxidizing agent to provide a compound of the formula : or its salt, in the above formulas, 1 3 R and R are each as defined above, R is lower alkylthio-substituted aryl optionally a substituted with substituent (s) selected from the group consisting of halogen, lower alkoxy, nitro, amino, sulfamoyl and lower alkylsulfonylamino; R b is lower alkylsulfinyl- or lower alkylsulfonyl-substituted aryl optionally substituted with substituent (s) selected from the group consisting of halogen, lower alkoxy, nitro, amino, sulfamoyl and lower alkylsulfonylamino; R is aryl optionally substituted with substituent (s) cL selected from the group consisting of halogen, lower alkoxy, lower alkylsulfinyl, lower alkylsulfonyl, nitro, amino, lower alkylamino, acylamino, lower alkyl(acyl)amino and sulfamoyl; or 9. ) reacting a compound of the formula : 126 [1-14] or its salt with an oxidizing agent to provide a compound of the formula [1-15] or its salt, in the above formulas, R 1 is as defined above, R is aryl optionally substituted with substituent(s) c selected from the group consisting of halogen, lower alkoxy, nitro, amino, sulfamoyl and lower alkylsulfonylamino; R fe is lower alkylthio-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, nitro, amino, lower alkylamino, acylamino, lower alkyl(acyl)amino and sulfamoyl; and R is lower alkylsulfinyl- or lower alkylsulfonyl-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, nitro, amino, lower alkylamino, acylamino, lower alkyl(acyl)amino and sulfamoyl; or 30 10. ) reacting a compound of the formula : 127 or its salt with an oxidizing agent to provide a compound of the formula [1-16] OH or its salt, in the above formulas, R 1 is as defined above, 2 C 10 R^ is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylsulfonyl, nitro, amino, sulfamoyl and lower alkylsulfonylamino, and 15 R d is aryl optionally substituted with substituent (s) selected from the group consisting of halogen, lower alkoxy, lower alkylsulfonyl, nitro, amino, lower alkylamino, acylamino, lower alkyl(acyl)amino and sulfamoyl; or 11. ) reacting a compound of the formula ; [1-17] or its salt with a reducing agent to provide a compound of the formula : g or its salt, in the above formulas, r| is carboxy; esterified carboxy; lower alkyl 128 substituted with carboxy or esterified carboxy; or lower alkanoyl optionally substituted with halogen; R 1 is hydroxyl lower)alkyl optionally substituted with halogen; and 2 3 R and R are each as defined above, or 12. ) reacting a compound of the formula [1-3] or its salt with a compound of the formula : h 2 no-r 6 [VIII] or its salt to provide a compound of the formula : or its salt, in the above formulas, R 1 is lower alkoxyimino(lower) alkyl optionally substituted with halogen; or lower alkyl substituted with hydroxyimino and aryl optionally substituted with hydroxy; g R is hydrogen or lower alkyl; and 12 3 R·,, R and R are each as defined above, 13. ) reacting a compound of the formula : 129 [V] or its salt with a nitrating agent or a sulfonating agent to provide a compound of the formula : [1-20] or its salt, in the above formulas, 2 3 R and R are each as defined above, and R^ is nitro or sulfo, or 14. ) subjecting a compound of the formula 3 Xx R NO. [1-21] or its salt to reduction to provide a compound of the formula : [1-22] or its salt, in the above formulas, 2 3 R and R are each as defined above, or 15. ) subjecting a compound of the formula [1-23] - 130 or its salt to reduction to provide a compound of the formula : or its salt, in the above formulas, is nitro-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl and lower alkylsulfonylamino; r| is amino-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl and lower alkylsulfonylamino; and 1 3 R and R are as defined above, or 16. ) reacting a compound of the formula [1-251 or its salt' with an acylating or sulfonylating agent to provide a compound of the formula : 131 in the above formulas, Rg is aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower 5 alkylsulfinyl, lower alkylsulfonyl, nitro, sulfamoyl and lower alkylsulfonylamino; R 1 is amino substituted with substituent(s) from the group consisting of acyl and alkylsulfonyl; and 10 R^ is as defined above, or selected lower 17. ) reacting a compound of the formula : [1-27] or its salt with a sulfonylating agent to provide a compound of the formula : in the above formulas, R 1 is hydrogen; halogen; cyano; lower alkyl substituted with substituent(s) selected from the group consisting of halogen, acylamino, lower alkyl(acyl)amino, acyl, aryl, a heterocyclic group and lower alkoxyimino; lower alkenyl optionally substituted with cyano; acyl; nitro; amino substituted with substituent(s) selected from the group consisting of acyl and lower alkylsulfonyl; sulfo; sulfamoyl optionally substituted with IE 132 substituent(s) selected from the group consisting of lower alkyl, halo(lower)alkyl, aryl, a heterocyclic group and (esterified carboxy)lower alkyl; N-containing 5 heterocyclicsulfonyl; or a heterocyclic group optionally substituted with oxo; Rh is lower alkylsulfonylamino-substituted aryl optionally substituted with substituent (s) selected from the group consisting of halogen, 10 lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl and sulfamoyl; and 2 3 Rf and R are each as defined above, or 18. ) reacting a compound of the formula [1-29] or its salt with a reducing agent to provide a compound of the formula Τχ [1-30] or its salt, in the above formulas, R 1 is N-containing heterocycliccarbonyl; carbamoyl optionally substituted with lower alkyl; or lower alkyl substituted with carbamoyl optionally substituted with lower alkyl; R 1 is lower alkyl substituted with N-containing m heterocyclic group, amino or lower alkylamino; and 133 and R J are each as defined above, or 19. ) reacting a compound of the formula Xu [V] or its salt with a formylating agent to provide a compound of the formula R 3 s< CHO or its salt, in the above formulas, 2 3 R and R are each as defined above, or 20. ) reacting a compound of the formula : g' ,3' 'S' [Va] with a chlorosulfonylating agent and then reacting the resultant product with an amine to provide a compound of the formula : in the above formulas, R g is aryl optionally substituted with substituent!s) 134 selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro, acylamino, lower alkyl(acyl)amino, lower 5 alkylsulfonylamino and sulfamoyl; R 1 is sulfamoyl optionally substituted with substituent(s) selected from the group consisting of lower alkyl, halo(lower)alkyl, aryl, hydroxy, lower alkylamino(lower)alkyl, a 10 heterocyclic group and (esterified carboxy)lower alkyl; or N-containing heterocyclicsulfonyl; and R is as defined above, or g 15 21. ) reacting a compound of the formula : [1-33] coch 2 x or its salt with thiourea or lower (alkyl) thiourea to provide a compound of the formula : or its salt, in the above formulas, R 1 is thiazolyl substituted with amino or lower alkylamino; and 2 3 R , R and X are each as defined above, or 22. ) reacting a compound of the formula : - 135 [1-35] r; or its salt with a compound of the formula : B - R‘ [IX] to provide a compound of the formula : [1-36] R' or its salt, in the above formulas, R 1 is lower alkanoyl; Pl Rg is lower alkenyl optionally substituted with cyano; B is di-esterified phosphono or substituted phosphonium salt; R is lower alkyl optionally substituted with cyano; and 2 3 R and R are each as defined above, or 23. ) subjecting a compound of the formula [1-37] Rf S R 1 or its salt to reduction to provide a compound of the formula 136 or its salt, in the above formulas, 1 2 R and R are each as defined above, R^ is nitro-substituted aryl optionally substituted with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylamino, acylamino, lower alkyl(acyl)amino and sulfamoyl; and R 3 is amino-substituted aryl optionally substituted g with substituent(s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylamino, acylamino, lower alkyl(acyl)amino and sulfamoyl; or 24. ) reacting a compound of the formula : or its salt with an acylating agent to provide a compound of the formula r: in the above formulas, 12 3 R, , R and R are each as defined above, and kl g g R^ is acylamino-substituted aryl optionally [1-40] 137 substituted with substituent (s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkyl(acyl) amino and 5 sulfamoyl; or 25. ) reacting a compound of the formula [1-40] with an alkylating agent to provide a compound of the formula : 20 in the above formulas, 12 3 r£, R‘ and R^ are each as defined above, and R? is lower alkyl(acyl)amino-substituted aryl optionally substituted with substituent (s) selected from the. group consisting of halogen, 25 lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl and sulfamoyl; or 26. ) reacting a compound of the formula [1-42] 138 or its salt with a dehydrating agent to provide a compound of the formula : [1-43] CN or its salt, in the above formulas, 2 3 R and R are each as defined above, or 27. ) subjecting a compound of the formula : [1-41] to deacylation reaction to provide a compound of the formula [1-44] or its salt, in the above formulas, 12 3 R, , R and R. are each as defined above, and kA g i Rj is mono(lower)alkylamino-substituted aryl optionally substituted with substituent (s) selected from the group consisting of halogen, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl and sulfamoyl, or 28. ) reacting a compound of the formula : 139 R [1-43] or its salt with an azide compound to provide a compound of the formula : H or its salt, in the above formulas, 2 3 R and R are each as defined above.

7. A pharmaceutical composition comprising a compound of claim 1, as an active ingredient, in association with a pharmaceutically acceptable, substantially nontoxic carrier or excipient.

8. A compound of claim 1 for use as a medicament.

9. A method for therapeutic treatment of inflammatory conditions, various pains, collagen diseases, 25 autoimmune diseases or various immunity diseases which comprises administering an effective amount of a compound of claim 1- to human beings or animals. -14010. A compound as claimed in claim 1, substantially as hereinbefore described and exemplified. 11. 12. A process for preparing a compound as claimed in claim 1, substantially as hereinbefore described and exemplified. A compound as claimed in claim 1, whenever prepared by a process claimed in claim 6 or 11. 13. A pharmaceutical composition according to claim 7, substantially as hereinbefore described.