NZ226489A - Benzopyran-4-one derivatives, pharmaceutical compositions containing them, and methods of preparing them - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £26489 AM£NDfcD ur,:icr of the hit-ants Act ',(You/ ,<21 i ASSISTANT COMM If/STQNER OF PATENTS ft* '£$ "A iiv, *il Priority Oats:£}: ^ . AO; S~7.

JrX.S/.?^.- Comji/i 0X0 Spec if;"': en Ftioci: .O. Class: ,p. k>,y^. . ^77.0^/^.7?H-.; f.

Publication Da:e: .. Eg. AUG .1930 P.O. Journal, t!c: .. J.<b2 22 6 4 8 9 Patents Form Mo. 5 NEW ZEALAND PATENTS ACT Cla&s Cont: S-£J J£)1Z.\ . i T/ V?/ &; Dkcft C5?.CX- 1 s| 5 kvSy, COMPLETE SPECIFICATION 4H-.l-Benzopyran-4-ONE DERIVATIVE OR ITS SALT, PROCESS FOR PRODUCING THE SAME AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME AS ACTIVE INGREDIENT "^/We, IDYAMA CHEMICAL CO., LTD., a corporation organized under the laws of Japan, of 2-5, 3-chome, Nishishinjuku, Shinjuku-ku, Tokyo, JAPAN hereby declare the invention, for which )(/we pray that a patent may be granted to rij£/us, and the method by which it is to be performed, to be particularly described in and by the following statement: ££040; 1 This invention relates to a novel 4H-1- "S benzopyran-4-one derivative or a salt thereof, processes for producing the same, a pharmaceutical composition comprising the derivative or a salt thereof as active 5 ingredient and a method of curing inflammation by applying the composition.

Substituted sulfonamide compounds are stated in, for example, Japanese Patent Application Kokai Nos. 4,820/71, 27,961/72, 20,777/80, 136,560/82, 140,712/82, 10 203,079/82, 170,748/83, 31,755/84, 199,394/85 and 190,869/88, Japanese Patent Publication Nos. 50,984/83 and 44,311/84, etc. and are known to have antiphlogistic and analgesic activities. However, no information has been obtained of substituted sulfonamides having a 4H-l-benzopyran-4-15 one skeleton.

Many acidic non-steroidal antiinflammatory agents which are now used have a not so great difference between the dose necessary for curing and the dose at which side effect, particularly ulcerogenic effect 20 appears, namely have a small therapeutic index. Therefore, development of antiinflammatory agents having higher safety has been desired.

Under such circumstances, the present inventors £ £0 q 1 structure and salts thereof can exhibit an excellent therapeutic effect on inflammation and have substantially no ulcerogenic effect and hence have high safety.

An object of this invention is to provide a 5 novel 4H-l-benzopyran-4-one derivative or a salt thereof, which has an antiinflammatory, antipyretic, analgesic, antirheumatic and antiallergic activity.

Another object of this invention is to provide processes for producing a novel 4H-l-benzopyran-4-one 10 derivative or a salt thereof.

A further object of this invention is to provide a pharmaceutical composition comprising the above derivative or a salt thereof as active ingredient.

A still further object of this invention is to 15 provide a method of curing inflammation, pyrexia, pain, rheumatism and allergy by applying the above derivative or a salt thereof.

Other objects and advantages will become apparent from the following description.

In the present specification, unless otherwise specified, the term "alkyl" means an alkyl group having 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like; the term "cycloalkyl" means a cyclo-25 alkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like; the term "lower alkyl" means an alkyl group having l„.to ^ 0il carbon atoms such as methyl, ethyl, n-propyl, isopropyl', <r - 3 - ' ^ 1 ✓ 9 22648? 1 n-butyl, isobutyl, tert-butyl, pentyl and the like; the term "lower alkenyl" means an alkenyl group having 2 to 5 carbon atoms such as vinyl, allyl, 1-propenyl, 1-butenyl and the like; the term "alkoxy" means an -O-alkyl group in which the 5 alkyl is the above-mentioned C^_galkyl; the term "acyl" means a formyl group or an alkanoyl group having 2 to 8 carbon atoms such as acetyl, propionyl, butyryl or the like, an alkoxyoxalyl _ group such as nethoxalyl, ethoxyalyl or the like, a C3_gcycloalkylcarbonyl group such as 10 cyclohexylcarbonyl or the like or an aroyl group such as benzoyl or the like; the term "alkoxycarbonyl" means a -COO-alkyl group in which the alkyl is the above-mentioned C^_galkyl; the term "halogen" means fluorine, chlorine, bromine or iodine; the term "alkylthio" means an -S-alkyl 15 group in which the alkyl is the above-mentioned C^_galkyl group; the term "alkylsulfinyl" means an alkylsulfinyl group having 1 to 4 carbon atoms such as methylsulfinyl, ethylsulfinyl or the like; the term "alkylsulfonyl" means an alkylsulfonyl group having 1 to 4 carbon atoms 20 such as methylsulfonyl, ethylsulfonyl or the like; the term "aryl" means a phenyl or naphthyl group; the term "acylamino" means an -NH-acyl group in which the acyl is the above-mentioned acyl group; the term "alkylamino" means an -NH-alkyl group in which the alkyl is the 25 above-mentioned C^ galkyl group; the term "dialkylamino" means an group in which the alkyl is the above-mentioned C^_galkyl group; the term "haloalkyl" means a halo-C, Qalkyl group such as chloromethyl, ' • \ , * \\V ■ ■ - 4 - o L i. 0 4 ti 1 fluoromethy1, dichloromethy1, trifluoromethyl, dichloro-ethyl, trichloroethyl or the like; the term "alkyl-sulfonyloxy" means an alkylsulfonyl-O- group in which the alkylsulfonyl is the above-mentioned C^_^alkylsulfonyl 5 group; the term "arvlsulEonyloxv" means a phenylsulfonvloxy or p-toluenesulfonyloxy group; the term "lower alkinyl" means an alkinyl group having 2 to 5 carbon atoms such as ethinyl, 2-propinyl or the like; and the term "heterocyclic group" means a 4-, 5- or 6-membered. or 10 fused heterocyclic group containing at least one hetero atom selected from the group consisting of oxygen, nitrogen and sulfur atoms such as thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoly1, imidazolyl, benzimidazolyl, benzthiazolyl, 1,2,3-thiadiazolyl, 15 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, quinolyl, isoquinolyl, pyrimidinyl, piperazinyl, pyrazinyl, pyridazinyl, 1,2,3,4-tetrahydroquinoyl, 1,2,4-triazinyl, imidazo[1,2-b][1,2,4]triazinyl, pyrrolidinyl, morpholinyl, 20 quinuclidinyl or the like.

According to this invention, there is provided a 4H-l-benzopyran-4-one derivative represented by the following formula or a salt thereof: <-""s ^ O i L C k 1 wherein R"*" represents an unsubstituted or halogen-substituted lower alkyl, lower alkenyl or aryl group; 2 R represents a hydrogen atom or an alkyl or acyl group; R^ represents a hydrogen or halogen atom, a cyano, azido, 5 formyl, carboxyl, hydroxyl or alkoxycarbony1 group, or a substituted or unsubstituted alkyl, alkoxy, phenoxy, 4 cycloalkyl, carbamoyl, amino or phenyl group; R represents a hydrogen or halogen atom, a nitro, cyano, carboxyl, acyl, hydroxyl or alkoxycarbonyl group, a substituted 10 or unsubstituted alkyl, alkoxy, alkylthio, phenylthio, lower alkenyl, lower alkinyl, sulfamoyl, alkylsulfinyl, alkylsulfonyl, amidino, phenyl or heterocyclic group or p6 g a group of the formula, -N^* n or -CON (R is a R XR hydrogen atom, a hydroxyl, cyano or alkoxycarbonyl group 15 or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkylsulfonyl, iminomethyl or amidino group, is a hydrogen atom or a substituted or unsubstituted alkyl, alkoxy, phenyl, cycloalkyl or f 7 " heterocyclic group, or R anu R , when taken together with the 20 nitrogen atom to which the two are bonded, form a 3- to 7-membered, substituted or unsubstituted heterocyclic group); R^ represents a substituted or unsubstituted phenyl, thienyl, furyl or pyridyl group; Z represents an oxygen or sulfur atom or an imino group; and the 25 broken line means a single or double bond.

This invention further provides processes for producing the above compound, a pharmaceutical composition^ comprising the compound as active ingredient and a method ~ 6 ~ ^ yj- 226489 L of curing inflammation, pyrexia, pain, rheumatism and allergy by applying the above compound. 6 7 In the formula [IJ, when R and R form a 3- to 7-membered heterocyclic group with the nitrogen 3.toni to which the two cire bonded( the heterocyclic cjroup includes azetidin-l-yl, pyrrolidin-l-yl, piperidin-l-yl, pyrrol-l-yl and the like.

The alkyl, alkoxy, cycloalkyl, phenoxy, amino, 3 carbamoyl and phenyl groups for R , the alkyl, alkoxy, alkylthio, phenylthio, amidino, lower alkenyl, lower alkinyl, sulfamoyl, alkylsulfinyl, alkylsulfonyl, 4 phenyl and heterocyclic groups for R , the alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkylsulfonyl, g iminomethyl and amidino groups for R , the alkyl, alkoxy, cycloalkyl, phenyl and heterocyclic groups for 7 6 R , the 3- to 7-membered heterocyclic groups which R 7 and R form with the nitrogen atom to which the two are bonded and the phenyl, thienyl, furyl and pyridyl groups for R^ may each be substituted by at least one substituent 20 selected from the group consisting of halogen atoms and alkoxy, alkylthio, phenoxy, carboxyl, acyl, alkoxycarbonyl, carbamoyl, sulfamoyl, cyano, alkylsulfonyl, hydroxyl, mercapto, acylamino, alkylamino, dialkylamino, alkyl, cycloalkyl, oxo, nitro, haloalkyl, amino, phenyl, alkoxy-25 carbonylamino, hydroxyimino and heterocyclic groups.

The salt of the 4H-l-benzopyran-4-one derivative of the formula [I] includes pharmacologically acceptable salts, for example, salts with alkali metals, such as 226489 1 sodium, potassium, and the like; salts with alkaline earth metals such as calcium, magnesium and the like; ammonium salt; salts with organic amine such as tri-ethylamine, pyridine, and the like; salts with amino 5 acids such as lysine, arqinine, ornithine, and the like; salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; salts with organic carboxylic acids such as fumaric acid, maleic acid, malic acid, citric acid, and the like; and salts 10 with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, and the like.

The compound of this invention includes further all isomers (including geometrical isomers and optical 15 isomers), hydrates, solvates and crystal forms.

The 4H-l-benzopyran-4-one derivative of the formula [I] or a salt thereof can be produced by, for example, the following processes: Production Process 1 R4a r -z/. COOH R -Z R1-S0,-ir'^v0'^R3 closure Rl_ R [3] Production Process 2 s02- I ID I r5-z R -S02-N ,4a cooh K 3a R2 [7] ring closure R5-Z -> R -SO-,-N 2 I R Production Process 3 R -S02-N R -Z ring-formation i > R-S09-N 2 I R R dehydro- r5-z ^ genation „1 Q 0' -r3 ^ R -so2-N R~ [1-2] R 2 [1-1] reduction -> R -S02-N i Production Process 4 reactive derivative of R1-SO,H [29] £ > R [16] r5-z r -s0--n 2 I r Production Process 5 i—1 o R -S02- R5a-X [30] r5-z r -s02-n R O r5-z r-scu-n I- r"1 r 3b

[27] (1) oxidation (2) ring closure -> R r5-z -so2- R } [I] 0 R 0' " r3 [I] ..OH R3b [1-5] Production Process 7 R [1-6] Production Process 8 R -S02-N R8OH [31] and AgBF4 > Production Process 9 R -S02-N R [1-10] thioetherification 0' ^ R" -7] alkali azide R5_z or ammonium azide r1-so2-n 0 Production Process 10 0 R5"!sfYV"2 R1-S02-N-^^O ^R3 R [1-8] acylation -> or reactive derivative thereof R5-Z R -S02-N 0 10 o NH R3 [1-12] to I R7aX [32] or (R7a0)2S02 [33] Production Process 11 R -S02-N deacylation R ~z 3 R -S02-N [X-14] R -S02-N R11NC0 [34] or —j > M -OCN [35] R -S02-N pj rv> Production Process 12 r5-z 0 r -s02-n r halogenating 3 agent r 2 [1-6] R hn-r [36] Production Process 13 > r1-so2-n r -s02-n ^i ^/SrK.3 r -s02-n r [1-19] hydrogen) R [1-20] halogenating agent r -s02-n [1-22] acylation .1 r -s02-n r3cmx [37] 0s r Production Process 14 r -s02-n o r" R [1-8] Production Process 15 r5-z ? r -s0o-n •<- i nh, r" R [1-8] Production Process 16 r -s02-n- r [1-27] r8-o/

[38] r6ax [39] nitration > r -z r -so^-n R 0 I! n ^R3 [1-2:5] r —z r -so -n £ l r' ^ nhr6a [1-26] > r5-z r -s02-n .no. 0" v0h R [1-28] ro rvo cr> CO CO i Production Process 17 r5-z r -s0o-n 2 i 0 NO, r" reduction R [1-29] Production Process 18 0 r5-z r -s02-n cooh CC r HN-r' [36] R [1-30] or reactive derivative thereof Production Process 19 R -S02-N hydrolysis r [1-32] R [1-8] con-r' R [1-31] r5-z, -so9-n 0 conh. r" [1-33] ro ro CD 4N CD CO 22 6 4 8 9 1 In the above formulas, Z, r\ R^, R^ , R.4, R^, R^, R^ and the broken line have the same meanings as 8 9 defined above; R means a lower alkyl group; R means a substituted or unsubstituted alkyl or phenyl group; R"^ means a hydrogen atom, an alkoxy group or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, acyl or alkoxycarbonyl group; R"^ means a hydrogen atom or a chlorosulfonyl or alkyl group? R"^a means a hydrogen a torn or a substituted or unsubstituted alkyl, cycloalkyl or 3 3 b phenyl group as defined as to R ; R means a substituted 3 3c or unsubstituted phenyl as defined as to R ; R means a hydroxyl, cyano or azido group or a substituted or 3 unsubstituted alkoxy or amino group as defined as to R ; R^a means a hydrogen atom, a cyano, acyl or alkoxycarbonyl 15 group, a substituted or unsubstituted alkyl or phenyl R6 / 6 7 group or a group of the formula, -CON^ 7 (R and R have R 4 the same meanings as defined above) as defined as to R ; 6 sl R means a cyano group or a substituted or unsubstituted g alkyl, cycloalkyl or phenyl group as defined as to R ; 7a R means a substituted or unsubstituted alkyl, cycloalkyl, alkoxy, phenyl or heterocyclic group as defined as to R7; R^a means a substituted or unsubstituted phenyl, thienyl, furyl, pyridyl, diphenyliodonium or 4-pyridyl-pyridinium group; M"*" means a hydrogen atom, an alkali 25 metal such as sodium, potassium or the like, an alkaline earth metal such as magnesium or the like or a transition metal such as copper(monovalent) or the like; X means a 22 6 4 8! 1 halogen atom; Y means a halogen or hydrogen atom and means a (E)isomer, a (Z)isomer or a mixture thereof.

The compounds represented by the formulas [I — 1J to [1-33] may also be obtained in the form of 5 salts, and the definition of the salts of the compound of the formula [I] mentioned above can be applied to these salts.

Each production process is explained in detail below.

Production Process 1 (1) The compound of the formula [1-2] can be obtained by subjecting a compound of the formula [3] to ring closure reac tion.

In this reaction, a solvent may be used, which 15 may be any solvent as far as it dose not adversely affect the reaction, and includes, for example, benzene, xylene and the like; however, this reaction may be conducted in the absence of a solvent.

In this ring closure reaction, a condensing 20 agent is used, which includes phosphorus pentoxide, polyphosphoric acid, zinc chloride, conc. sulfuric acid, halogenosulfonic acids, sulfuric anhydride, conc. sulfuric acid-acetyl chloride and the like. The condensing agent is used in an amount of 1 to 50 moles per mole of the 25 compound of the formula [3].

The ring closure reaction may be carried out at a temperature of 0 to 120°C for a period of 30 minutes 226489 1 to 24 hours.

Also, the ring closure may be conducted by treating the compound of the formula [3] with an acid-halogenating agent such as thionyl chloride, phosphorus 5 pentachloride or the like and then subjecting the product to the Friedel-Crafts reaction with a Lewis acid such as aluminum chloride. by subjecting the compound of the formula [1-2] to 10. dehydrogenation reaction.

The dehydrogenation reaction may be conducted by, for example, the following methods: (i) The compound of the formula [I—1J can be t ' obtained by reacting the compound of the formula [1-2] with a dehydrogenating agent.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction. It includes, for example, water; acetic acid; acetic anhydride; aromatic hydrocarbons 20 such as benzene, toluene, xylene and the like; ethers such as dioxane and the like; etc.

The dehydrogenating agent includes, for example, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), chloranil, trityl perchlorate, trityl fluoroborate, selenium dioxide, palladium-carbon and the like.

In the above reaction, the amount of the dehydrogenating agent used is 0.5 to 5 moles per mole of the ^^ (2) The compound of the formula [1—13 can be obtained compound of the formula [1-2] . 18 'I d. b" 4 8 9 1 The above reaction may be carried out at a temperature of: 0 to 150°C for a period of 30 minutes to 72 hours. (ii) The compound of the formula [1-1] can 5 also be obtained by reacting the compound of the formula [1-2] with a halogenating agent and then treating the halogenated product thus obtained with a base.

A solvent may be used in the halogenation reaction, which may be any solvent as far as it does not 10 adversely affect the reaction. It includes, for example, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform and the like; alcohols such as methanol, ethanol and the like; esters such as ethyl acetate and the like; organic carboxylic acids such 15 as acetic acid, formic acid and the like; etc. These solvents may be used alone or in admixture of two or more.

The halogenating agent used in the above reaction includes, for example, chlorine, bromine, 20 sulfuryl chloride and the like.

The amount of the halogenating agent used is 0.9 to 1.1 moles per mole of the compound of the formula [1-2].

The halogenation reaction may usually be carried 25 out at a temperature of 0 to 100°C, preferably 10 to 40°C, for a period of 30 minutes to 3 hours.

The halogenated product thus obtained may be reacted with a base in a solvent which may be any solvent " D H u g 1 as far as it does not adversely affect the reaction. The solvent includes, for example, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform and the like; alcohols such as methanol, 5 ethanol and the like; amides such as N,N-dimethyIformamide and the like; pyridine; etc. These solvents may be used alone or in admixture of two or more.

The base used in the above reaction includes organic bases such as triethylamine, 1,8-diazabicyclo-10 [5,4,0]undec-7-ene (DBU), pyridine and the like and alkali metal carbonates such as sodium carbonate, potassium carbonate and the like. The amount of the base used is 1 to 10 moles per mole of the compound of the formula [1-2] .

The above reaction may be carried out at a temperature of 0 to 100°C for a period of 30 minutes to 24 hours.

Production Process 2 (1) (i) The compound of the formula [1-3] can be obtained by subjecting a compound of the formula [7] to ring closure reaction.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, aromatic 25 hydrocarbons such as benzene, toluene, xylene and the like and halogenated aromatic hydrocarbons such as chlorobenzene and the like. These solvents may be used 22 6 4 8 1 alone or in admixture of two or more.

A condensing agent is used in this reaction, which includes, for example, halogenosulfonic acids, sulfuric anhydride, phosphorus pentoxide, polyphosphoric 5 acid, zinc chloride, conc. sulfuric acid, conc. sulfuric acid-acetyl chloride and the like. The amount of the condensing agent used is 1 to 50 moles per mole of the compound of the formula [7].

The above reaction may usually be carried out 10 at a temperature of 0 to 120°C for a period of 30 minutes to 24 hours. (ii) The ring closure reaction may also be achieved by reacting the compound of the formula [7] with an acid-halogenating agent such as thionyl chloride, 15 phosphorus pentachloride or the like to form a carboxylic acid halide and then subjecting the carboxylic acid halide to the Friedel-Crafts reaction with a Lewis acid such as aluminum chloride or the like. (2) The compound of the formula [1-4] can be obtained by catalytic hydrogenation of a compound of the formula [1-3].

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, alcohols such 25 as methanol, ethanol and the like; organic carboxylic acids such as acetic acid and the like; esters such as ethyl acetate and the like; ethers such as dioxane and the like; aqueous sodium hydroxide solution; etc. These 226 4 8 9 1 solvents may be used alone or in admixture of two or more.

The catalyst used in this reaction includes, for example, palladium, palladium-carbon, platinum 5 and Raney nickel and the like. The amount of the catalyst used is 0.01 to 0.5 mole per mole of the compound of the formula [1-3] .

The above reaction may usually be carried out at a temperature of 0 to 100°C, preferably 20 to 60°C, for a period of 30 minutes to 24 hours.

Production Process 3 (1) The compound of the formula [1-1] can be obtained by subjecting the compound of the formula [11] to ring-formation reaction.

The ring-formation reaction may be conducted by, for example, the following methods: (i) The compound of the formula [11] is 3 12 reacted with a compound of the formula, R COOR [a] in 3 12 which R has the same meaning as defined above and R means a hydrogen atom or the ester residue in the carboxyl group, for example, a lower alkyl group or the like, in the presence of a base to obtain a B-diketone, which is then subjected to ring closure reaction, thereby obtaining the compound of the formula [1-1] .

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, aromatic ZZ 6 4 8 9 1 hydrocarbons such as benzene, toluene, xylene and the like and alcohols such as methanol, ethanol and the like. These solvents may be used alone or in admixture of two or more. The compound of the formula [a] may also 5 be used as the solvent.

The base used in this reaction includes, for example, metallic alkalis such as metallic sodium, metallic potassium and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; 10 and alkali metal amides such as sodium amide, potassium amide and the like.

The amounts of the base and the compound of the formula [a] used are each 1 to 100 moles per mole of the compound of the formula [11].

The above reaction may usually be carried out at a temperature of -20 to 150°C for a period of 30 minutes to 48 hours.

Also, in the subsequent ring closure reaction, a catalyst may be used, which includes, for example, 20 hydrogen halides such as hydrogen chloride, hydrogen bromide and the like; mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; alkali metal acetates such as sodium acetate, potassium acetate and the like; and alkali metal carbonates such 25 as sodium carbonate, potassium carbonate and the like.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, alcohols such 22 6 A 8 9 1 as methanol, ethanol and the like; organic carboxylic acids such as acetic acid and the like; and water.

These solvents may be used alone or in admixture of two or more.

The amount of the catalyst used is 0.1 to 5 moles per mole of the compound of the formula [11].

The above reaction may usually be carried out at a temperature of 20 to 100°C for a period of 5 minutes to 2 hours.

If necessary, ct-acyl form or ketoester form obtained by the Claisen condensation may be isolated as intermediate. In this case, the objective compound of the formula [I — 1] can be obtained by treating the intermediate with a base or an acid. (ii) The compound of the formula [11] is 3 ci reacted with a compound of the formula [b], (R CO) 20 3 d (R means a substituted or unsubstituted alkyl or phenyl 3 group as defined as to R ) and a compound of the formula [c] , R3c^C00M^ (R3<^ has the same meaning as defined above 2 and M means an alkali metal such as sodium, potassium or the like) to obtain a compound of the formula [1-1] in which R3 is R3(^.

This reaction may be effected according to the Allan-Robinson condensation stated in J. Chem. Soc., 25 vol. 125, p. 2192 (1924) or the like.

The amounts of the compounds of the formulas [b] and [c] used are 1 to 50 moles and 1 to 5 moles, respectively, per mole of the compound of the formula [11] 22643 1 This reaction may usually be effected at a temperature of 0 to 200°C for a period of 30 minutes to 24 hours.

If necessary, a-acyl form obtained by the Claisen condensation may be isolated as intermediate, and in this case, the objective compound of the formula [1-1] can be obtained by treating the intermediate with a base or an acid. (iiiXa) The compound of the formula [11] is reacted with a compound of the formula [d], HXO^ (X has the same meaning as defined above), and a compound of 17 17 the formula [e], HC(0R (R means a lower alkyl group), and the reaction product is then subjected to t * hydrolysis to obtain a compound of the formula [1-1] 3 in which R is a hydrogen atom.

This reaction can be effected according to the method stated in the Journal of Chemical Research (M), pp. 864-872 (1978).

In this reaction, the compound of the formula 20 [e] may also be used as a solvent.

The amounts of the compounds of the formulas [d] and [e] used are 1 to 5 moles and 5 to 100 moles, respectively, per mole of the compound of the formula [11].

The above reaction may usually be carried out 25 at a temperature of 0 to 50°C for a period of 10 minutes to 12 hours. (b) Subsequently, the compound thus obtained is hydrolyzed to obtain a compound of the formula [I — 1 ] -S, 9 9 fi /, o U 1 (J 3 1 in which R is a hydrogen atom. (iv) A compound of the formula [11] in which 4 4b 4b R is -COR (R means a hydrogen atom or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, alkoxy or , - ■ 4. necerocycuc group as aenned as to R ) or a nitro group is reacted with a compound of the formula [f], 17 17 (CH^^NCHfOR )2 has t'"ie same meaning as defined above), to obtain a compound of the formula [1-1] in 4 4b 4b which R is -COR (R has the same meaning as defined above) or a nitro group and R3 is a hydrogen atom.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, amides such as N,N-dimethvlformamide and the like; sulfoxides such as dimethylsulfoxide and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as diethyl ether, dioxane, tetrahydrofuran and the like; etc. These solvents may be used alone or in admixture of two or more. 2 0 The amount of the compound of the formula [f] used is 1 to 5 moles per mole of the compound of the formula [11].

The above reaction may usually be carried out at a temperature of 0 to 100°C for a period of 30 minutes to 24 hours.

Also, the compound of the formula [1-1] in 4 4k 4h which R is -COR (R has the same meaning as defined 3 above) or a nitro group and r is a hydrogen atom can be 22 6 41 1 obtained by reacting the compound of the formula [11] 4 4b 4b in which R is -COR (R has the same meaning as defined above) or a nitro group with the compound of the formula [e] and the compound of the formula [b].

This reaction can be effected according to the method stated in Chem. Pharm. Bull., 22, 3 3 1-336 (1974 ).

The amounts of the compounds of the formulas [e] and [b] used are 1 to 5 moles and 1 to 50 moles, respectively, per mole of the compound of the formula

[11] .

The above reaction may usually be carried out at a temperature of 20 to 150°C for a period of 30 minutes to 24 hours.

Further, the compound of the formula [11] in 4 4b 4b which R is -COR (R has the same meaning as defined above) or a nitro group can be reacted with a compound 17 17 of the formula [g], R COCH (R is the same as defined II II 0 0 2 2 above) and a compound of the formula [h], HCOOM (M is an alkali metal such as sodium, potassium or the like), to obtain the compound of the formula [1-1] 4 4b 4b in which R is -COR (R has the same meaning as 3 defined above) or a nitro group and R is a hydrogen atom.

This reaction can be effected according to the 25 method stated in Chem. Pharm. Bull., 2_2 , 33 1-336 (1974).

The amounts of the compounds of the formulas [g] 22 6 4 8 and [h] used are 1 to 100 moles and 1 to 50 moles, respectively, per mole of the compound of the formula [11] - The above reaction may usually be carried out at a temperature of 0 to 100°C for a period of minutes to 24 hours. (v) A compound of the formula [1—13 in which is a hydroxyl group can be obtained by reacting the compound of the formula [11] with a compound of the 17 17 formula [ij, (R O) 2C<3 ^as same meaning as defined above) in the presence of a base.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; amides such as N,N-dimethylformamide and the like; ethers such as tetrahydrofuran, dioxane and the like; etc. However, the above reaction may also be effected in the absence of a solvent.

The base used in this reaction includes, for example, metallic alkalis such as metallic sodium, metallic potassium and the like; alkali metal amides such as sodium amide, potassium amide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; etc .

The amounts of the base and the compound of the ^ o 4 y: 1 formula [i] used are 1 to 10 moles and 1 to 100 moles, respectively, per mole of the compound of the formula [113 .

The above reaction may usually be carried out 5 at a temperature of 20 to 150°C for a period of 30 minutes to 24 hours. (2) The compound of the formula [1-2] can be obtained by subjecting the compound of the formula [1-13 to reduction reaction.

This reaction can be conducted according to the method stated in Production Process 2(2).

Production Process 4 The compound of the formula [13 can be obtained by reacting a compound of the formula [16] with a reactive 15 derivative of a compound of the formula [29].

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, halogenated hydrocarbons such as methylene chloride, chloroform, 20 1,2-dichloroethane and the like; amides such as N,N- dimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; etc. Also, an organic amine such as pyridine or the like may be used as the solvent.

This reaction may be effected in the presence of a base, which includes alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali 2 2 6 4 R o 1 metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; organic amines such as triethylamine, pyridine and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate 5 and the like; etc.

The reactive derivative of the compound of the formula [29] includes, for example, acid haliaes, acid anhydrides and the like.

The amounts of the base and the reactive 10 derivative of the compound of the formula [29] used are each 1 to 1.5 moles per mole of the compound of the formula [16].

The above reaction may be carried out at a temperature of -30 to 150°C for a period of 30 minutes to 15 24 hours .

Production Process 5 The compound of the formula [I] can be obtained by reacting the compound of the formula [41] with a compound of the formula [30].

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, amides such as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide and the like; ketones such as acetone 25 and the like; alcohols such as methanol, ethanol and the like; collidine; etc. These solvents may be used alone or in admixture of two or more. ^ 22648 1 In this reaction, a base may be used, which includes, for example, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxiae and the like; alkali metal hydrides such as sodium 5 hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; etc.

The amounts of the compound of the formula [30] and the base used are 1 to 5 moles and 1 to 3 moles, 10 respectively, per mole of the compound of the formula [41] .

The above reaction can also be carried out using as a catalyst, copper powder, cuprous oxide, cuprous \ ' chloride, cuprous chloride-8-hydroxyquinoline or the like 15 in a proportion of 0.01 to 2 moles per mole of the compound of the formula [41].

A compound of the formula [I] in which is pyridyl or phenyl can be obtained by reacting a 4-pyridylpyridinium chloride hydrochloride or diphenyliodonium 20 bromide with the compound of the formula [41].

The above reaction may usually be carried out at a temperature of -20 to 160°C for a period of 30 minutes to 24 hours.

Production Process 6 25 The compound of the formula [1-5] can be obtained by reacting the compound of the formula [27] with alkalii)^fC^~l /V hydrogen peroxide. ([**• 226489 1 Incidentally, this reaction can be effected according to the method stated in the Journal of the Pharmaceutical Society of Japan, 7J., 1178-1183 (1951) .

Production Process 7 5 (1) The compound of the formula [1-7] can be obtained by reacting a compound of the formula [1-6] with a halogenating agent.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect 10 the reaction, and includes, for example, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform and the like; alcohols such as methanol, ethanol and the like; esters such as ethyl acetate and the like; organic carboxylic acids such as acetic acid, formic acid 15 and the like; etc. These solvents may be used alone or in admixture of two or more.

The halogenating agent used in the above reaction includes, for example, chlorine, bromine, sulfuryl chloride and the like.

The amount of the halogenating agent used is 0.9 to 1.1 moles per mole of the compound of the formula [1-6] .

The above reaction may usually be carried out at a temperature of 0 to 100°C, preferably 10 to 40°C, 25 for a period of 30 minutes to 3 hours. (2) The compound of the formula [1-8] can be obtained by reacting the compound of the formula [1-7] with an 22 6 4 8 1 alkali metal azide such as sodium azide, potassium azide or the like or ammonium azide.

This reaction can be effected according to the method stated in Chemical Abstracts, vol. 89:43022p.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, water; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfolane; nitriles such as acetonitrile 10 and the like; ketones such as acetone and the like; sulfoxides such as dimethyIsulfoxide and the like; alcohols such as methanol, ethanol and the like; ethers such as tetrahydrofuran, dioxane and the like; etc.

These solvents may be used alone or in admixture of two 15 or more.

The amount of the alkali or ammonium azide used is 1 to 5 moles per mole of the compound of the formula [1-7] .

The above reaction may usually be carried out 20 at a temperature of room temperature to 100°C for a period of 30 minutes to 12 hours.

Production Process 8 The compound of the formula [1-9] can be obtained by reacting the compound of the formula [1-7] with a 25 compound of the formula [31] in the presence of silver tetrafluoroborate.

In this reaction, the compound of the formula 22 6 4 8 1 [31] may be used as a solvent.

The amount of the silver tetrafluoroborate and the compound of the formula [31] used in this reaction are 1 to 5 moles and 10 to 100 moles, respectively, per 5 mole of the compound of the formula [1-7].

The above reaction may usually be carried out at a temperature of 20 to 100°C for a period of 30 minutes to 24 hours.

Production Process 9 10 The compound of the formula [1-11] can be obtained by subjecting a compound of the formula [1-10] to thioetherification in the presence of a base. (i) The compound of the formula [1-11] can be obtained by reacting a compound of the formula [1-10] in which Y is a halogen atom with a compound of the formula 9 9 [j] , R SH (R has the same meaning as defined above) in the presence of a base.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect 20 the reaction, and includes, for example, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform and the like; alcohols such as methanol, ethanol, and the like; amides such as N,N-dimethylformamide and the like; ketones such as acetone and the like; ethers such 25 as dioxane, tetrahydrofuran and the like; etc. These solvents may be used alone or in admixture of two or more.

The base used in the above reaction includes, ;"*"N O 0 / /I r 1 for example, organic bases such as triethylamine, pyridine and the like; metallic alkalis such as metallic sodium, metallic potassium and the like; alkali carbonates such as sodium carbonate, potassium carbonate and the like; alkali alkoxides such as sodium methoxide? sodium ethoxide-potassium tert-butoxide and the .dike; etc The amounts of the base and the compound of the formula [jJ used are 1 to 10 moles and 1 to 5 moles, respectively, per mole of the compound of the formula 10 [1-103.

The above reaction may usually be carried out at a temperature of 0 to 150°C for a period of 30 minutes to 2 4 hours. (ii) The compound of the formula [1-11] can be 15 obtained by reacting a compound of the formula [1—103 in which Y is a hydrogen atom with a base, and then reacting the product with a thioetherifying agent.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely 20 affect the reaction, and includes, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene and the like; hexamethylphosphoric triamide(HMPA); and the like. These solvents may be used alone or in admixture 25 of two or more.

The base used in the above reaction includes organolithium compounds such as butyllithium, phenyllithium, lithiumdiisopropylamine, lithiumhexamethyldisilazane andv WT o, - 35 a 2264 1 the like; etc.

Also, the thioetherifying agent includes disulfides such as dimethyl disulfide, diphenvl, disulfide and the like; thiolsulfonates such as methyl benzenethiol-5 sulfonate- methyl methanethiolsulfonate, and the like; sulfenyl halides such as phenylsulfenyl chloride, methylsulphenyl chloride; etc.

The amounts of the base and the thioetherifying agent used are each 1 to 10 moles per mole of the compound 1"0 of the formula [1-10].

The above reaction may be usually carried out at a temperature of -78 to 0°C for a period of 1 to 24 hours.

\ *' Production Process 10 15 (1) The compound of the formula [1-12] can be obtained by reacting a compound of the formula [1-8] or a reactive derivative thereof with an acylating agent.

This acylation can be conducted by reacting, for example, a compound of the formula [1-8] or a reactive 20 derivative thereof with a compound of the formula [k] , R^COOH (R^ has the same meaning as defined above) or a reactive derivative thereof.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect 25 the reaction, and includes, for example, halogenated hydrocarbons such as methylene chloride, 1,2-dichloro-ethane, chloroform and the like; alcohols such as methanol, , < ~ V - 3 6 - ° 226 1 ethanol and the like; esters such as ethyl acetate and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; nitriles such as acetonitrile and the like; organic carboxylic acids such 5 as acetic acid, formic acid and the like; etc. These solvents may be used alone or in admixture of two or more.

In this reaction, a base may also be used, which includes, for example, organic bases such as triethylamine, 1-0 pyridine; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal hydrogen-carbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate and the like.

The reactive derivative of the compound of the 15 formula [1-8] includes, for example, those activated by a conventionally known organic silylating agent.

The reactive derivative of the compound of the formula [k] includes, for example, those in the carboxyl group such as acid halides, mixed acid anhydrides, 20 acid anhydrides, active esters, active amides and the like; and those obtained by reacting the compound of the formula [k] with a Vilsmeier reagent.

Also, when the compound of the formula [k] or a salt thereof is used, the above acylation reaction can 25 be conducted in the presence of a conventionally known condensing agent such as N,N'-dicyclohexylcarbodimide or the like. _v\T 0 The amount of the compound of the formula [k]^ n o ' : -i 22 6 4 8 1 or a reactive derivative thereof used and the amount of the base used are each 1 to 5 moles per mole of the compound of the formula [1-8] or its reactive derivative.

The above reaction may usually be carried out 5 at a temperature of -20 to 100°C for a period of 30 minutes to 2 4 hours.

In the formylation to obtain a compound of the formula [1-12] in which R"^ is a hydrogen atom, there may be used a conventional formylating agent such as 10 formic acid-acetic anhydride, a formic acid ester or the like. (2) The compound of the formula [1-13] can be obtained by reacting the compound of the formula [1-12] with a compound of the formula [32] or [33]. 15 In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, amides such as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide and the like; alcohols such as 20 methanol, ethanol and the like; ketones such as acetone and the like; etc. These solvents may be used alone or in admixture of two or more.

In this reaction, a base may also be used, which includes, for example, alkali metal alkoxides such as 25 sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; etc . 22 6 4 1 The amounts of the compounds of the formula [32] or [33] and the base used are 1 to 5 moles and 1 to 3 moles, respectively, per mole of the compound of the formula [1-12] .

The above reaction may usually he carried out at a temperature of -20 to 150°C for a period of 30 minutes to 24 hours. (3) The compound of the formula [1-14] can be obtained by subjecting the compound of the formula [1-13] to deacyl-10 ation reaction. The deacylation reaction includes, for example, hydrolysis and the like.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, water; amides 15 such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfolane; nitriles such as acetonitrile and the like; ketones such as acetone and the like; sulfoxides such as dimethylsulfoxide and the like; alcohols such as methanol, ethanol and the like; ethers such as 20 tetrahydrofuran, dioxane and the like; etc. These solvents may be used alone or in admixture of two or more.

This reaction is preferably effected in the presence of an acid, which includes, for example, hydrogen halides such as hydrogen chloride, hydrogen bromide and 25 the like; mineral acids such as hydrochloric acid, hydrobromic acid and the like; organic acids such as p-toluenesulfonic acid, methanesulfonic acid and the like; etc . 22 6 4 8 1 The amount of the acid used is 0.5 to 50 moles per mole of the compound of the formula [1-13].

The above reaction may usually be carried out at a temperature of 0 to 150°C for a period of 30 minutes 5 to 2 4 hours.

By subjecting to reaction a compound of the O Rx8 10 " ' formula [1-13] in which R is -C(CH) COOH (n=l, 2 or 3) r18 I "I O "I p or -(CHJ^COOH (m=2, 3 or 4) wherein nR 's or mR ' s may be the same or different and hydrogen atoms or groups mentioned as substituents for R , according to the method stated in Organic Synthesis Col. vol. V, pp. 944-946, there can be obtained a compound of the formula [I] in 6 7 which R and R form a 3- to 7-membered optionally substituted heterocyclic group with the nitrogen atom to 15 which the two are bonded.

Production Process 11 The compound of the formula [1-16] can be obtained by reacting a compound of the formula [1-15] with a compound of the formula [34] or [35]. 20 In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes water and the solvents mentioned in Production Process 7(1).

The amount of the compound of the formula [34] 25 or [35] used is 1 to 5 moles per mole of the compound of the formula [1-15]. 22 6 4 8 1 The above reaction may usually be carried out at a temperature of -20 to 150°C for a period of 5 minutes to 24 hou r s .

Incidentally, when chlorosulfonyl isocyanate 5 is vised, the compound obtained by the reaction can be treated with a conventional acid to convert it to the objective compound of the formula [1-16].

Production Process 12 (1) The compound of the formula [1-17] can be obtained by reacting a compound of the formula [1-6] with a halogenating agent in an amount of 2 to 2.5 moles per mole of the compound of the formula [1-6].

This reaction can be effected in the same manner as stated in Production Process 7(1). (2) The compound of the formula [1-18] can be obtained by reacting the compound of the formula [1-17] with a base.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect 20 the reaction, and includes, for example, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform and the like; alcohols such as methanol, ethanol and the like; esters such as ethyl acetate and the like; amides such as N,N-dimethylformamide and the 25 like; sulfoxides such as dimethylsulfoxide and the like; pyridine; 2,6-lutidine and the like. These solvents may be used alone or in admixture of two or more. 0 9 /.

L k V T 1 The base used in this reaction includes, for example, organic bases such as triethylamine, pyridine, 2,6-lutidine, DBU; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like.

The amour.t cf the base used is 1 to 5 moles per mole of the compound of the formula [1-17].

The above reaction may usually be carried out at a temperature of 20 to 150°C for a period of 10 minutes to 24 hours. (3) The compound of the formula [1-19] can be obtained by reacting the compound of the formula [1-18] with a compound of the formula [36].

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, alcohols such as methanol, ethanol and the like; ethers such as tetrahydrofuran, diethyl ether, dioxane and the like; amides such as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide and the like; water and the like. These solvents may be used alone or in admixture of two or more.

The amount of the compound of the formula [36] is 1 to 50 moles per mole of the compound of the formula [1-18] .

The above reaction may usually be carried out at a temperature of -20 to 80°C, preferably -10 to 30°C for a period of 30 minutes to 24 hours. (4) The compound of the formula [1-20] can be 22 6 4 1 obtained by acylating the compound of the formula [1-19] g in which R is a hydrogen atom in the same manner as stated in Production Process 10(1).

Production Process 13 5 (1) The compound of the formula [1-22] can be obtained by reacting the compound of the formula [1-21] with a halogenating agent in an amount of 0-9 to 1.5 moles per mole of the compound of the formula [1-21] in the same manner as stated in Production Process 7(1). 10 (2) The compound of the formula [1-23] can be obtained by acylating the compound of the formula [1-22] in the same manner as stated in Production Process 10(1). (3) The compound of the formula [1-24] can be obtained by reacting the compound of the formula [1-23] 15 with a compound of the formula [37] .

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, alcohols such as methanol, ethanol and the like? amides such as N,N-20 dimethylformamide and the like; sulfoxides such a dimethylsulfoxide and the like; ethers such as tetra-hydrofuran, dioxane and the like; water; etc. These solvents may be used alone or in admixture of two or more.

In this reaction, a base may be used, which includes, for example, the organic bases mentioned in Production Process 12(2) . 22 6 48 1 The amounts of the compound of the formula [37] and the base are each 1 to 3 moles per mole of the compound of the formula [1-23].

The above reaction may visually be carried out 5 at a temperature of -20 to 1F>0°C for a period of 30 minutes to 24 hours.

The compound of the formula [37] may be prepared in the reaction system.

Also, the compound of the formula [1-24] in 3c which R is a cyano group can be converted into a compound 3 c of the formula [1-24] in which R is a carbamoyl, carboxyl or alkoxycarbonyl group by a conventionally known hydrolysis, esterification or the like.

The compound of the formula [1-24] in which 3c R is an azido group can be converted into a compound 3 c of the formula [1-24] in which R is an amino group by a catalytic hydrogenation or a conventional reduction with hydrogen sulfide-triethylamine or the like.

Production Process 14 20 The compound of the formula [1-25] can be obtained by reacting a compound of the formula [1-8] with a compound of the formula [38] .

This reaction may be effected by, for example, the method stated in Organic Synthesis Col. vol. V, pp. 25 716-719. 226489 Production Process 15 The compound of the formula [1-26] can be obtained by reacting a compound of the formula [1-8] with a compound of the formula [39].

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, the solvents mentioned in Production Process 7(1); amides such as N,N-dimethy1formamide, N-methylpyrrolidone and the like; sulfoxides such as dimethyIsulfoxide and the like; ethers such as 1,2-diethoxyethane and the like; etc. These solvents may be used alone or in admixture of two or more.

In this reaction, a base may also be used, which includes, for example, organic bases such as triethylamine, pyridine and the like; inorganic bases such as sodium carbonate, potassium carbonate and the like; etc.

The amounts of the compound of the formula [39] and the base used are 1 to 10 moles and 1 to 2 moles, respectively, per mole of the compound of the formula [1-8] .

The above reaction may usually be carried out at a temperature of -20 to 150°C for a period of 30 minutes to 10 hours.

Incidentally, when a compound of the formula 6 a

[39] in which R is a substituted or unsubstituted phenyl group is used, there may further be added alkali o o /> CCD 1 iodies such as sodium iodide, potassium iodide or the like; copper powder; a copper compound such as cuprous oxide, cuprous chloride or the like alone or in admixture of two or more as a reaction-accelerating agent. The 5 amounts thereof are each 0.01 to 2 moles per mole of the compound of the formula [1-8].

The above reaction may usually be carried out at a temperature of 100 to 200°C for a period of 1 to 15 hours.

Production Process 16 The compound of the formula [1-28] can be obtained by subjecting a compound of the formula [1-27] to nitration.

In this reaction, a solvent may be used, which 15 includes, for example, acetic acid, acetic anhydride and the like.

The nitrating agent used in this reaction includes conc. nitric acid, fuming nitric acid and the like, and the amount thereof is 1 to 5 moles per mole of 20 the compound of the formula [1-27].

The above reaction may usually be carried out at a temperature of 0 to 150°C for a period of 10 minutes to 24 hours.

Production Process 17 25 The compound of the formula [1-29] can be converted into a compound of the formula [1-8] by a 22648 1 conventional reduction of nitro group.

Production Process 18 The compound of the formula [1-31] can be otc*i.p*ocl ircdcrtincj £i corn»poi-iric^ of tho foirmulct [ J — 3 0 ] oir 5 a reactive derivative thereof with a compound of the formula [36].

The reactive derivative of the compound of the formula [1-30] includes, for example, acid halides, acid anhydrides, mixed acid anhydrides, active esters, active 10 acid amides and reactive derivatives obtained by reacting the compound of the formula [1-30] with a Vilsmeier reagent.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect 15 the reaction, and includes, for example, water; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform and the like; alcohols such as methanol, ethanol and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, 20 toluene and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; nitriles such as acetonitrile and the like; esters such as ethyl acetate and the like; pyridine; 2,6-lutidine; etc. These solvents may be used alone or in admixture of two or more. 25 In this reaction, a base may be used, which includes, for example, organic bases such as triethylamine, DBU, pyridine and the like; alkali metal hydroxides such 22 6 4 8 1 as sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; etc. Further, the compound of the formula [36] may be used as the base, 5 too.

Also, when the compound of the formula [1-30] is used in the form of a free acid or a salt with a nitrogen-containing organic base, the above reaction may be conducted with an appropriate condensing agent. 10 The condensing agent used includes, for example, N,N1-di-substituted carbodiimides such as N,N'-dicyclo-hexylcarbodiimide and the like.

The amount of the compound of the formula [36] used is 1 to 50 moles per mole of the compound of the 15 formula [1-30] or its reactive derivative.

The above reaction may usually be carried out at a temperature of -20 to 150°C for a period of 30 minutes to 24 hours.

Production Process 19 20 The compound of the formula [1-33] can be obtained by hydrolyzing a compound of the formula [1-32] with an acid.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect 25 the reaction, and includes, for example, water and organic carboxylic acids such as formic acid, acetic acid and the like. These solvents may be used alone or in admixture 22 6 489 1 of two or more.

The acid used in this reaction includes, for example, mineral acids such as hydrochloric acid, sulfuric acid and the like; hydrogen chloride; hydrogen bromide; polvphosphoric acid; formic acid; Lewis acids such as boron trifluoride, titanium tetrachloride and the like; etc.

The amount of the acid used is 5 to 100 moles per mole of the compound of the formula [1-32]. 10 The above reaction may usually be carried out at a temperature of 20 to 150°C for a period of 30 minutes to 24 hours.

The starting compounds and intermediate compounds may be used in the form of salts and the definition of the 15 salt of the compound of the formula [I] mentioned above can also be applied to the salts.

The starting compounds in this invention can be produced by, for example, the following production methods: w o Production Process A R5-Z R 3a R -S02~N R 4a OH XCHCHCOOH [2] -> R [1] Production Process B R5-Z R1-SO 2~N R3aCsCCOOR12 [4 J R5-Z or -> ~1 R' [1] OH 3a 12' R^"-S07-N R C=CCOOR 2 I r R4a (5] 13 R Production Process C R5-Z R -CH2-COX [9] R5-Z R -SO2-N OR I2 w 14 R -SOo-N I R X tj4 a p r o 4 a R- COOR R -Z ^ , C0QH 3a hydr°ly5iS- JULX O rJ 'R^SOj-N^0^*38 [6] r2 I'! O 4 V/R or [103 14 removal of protecting R5-Z group R -SO^-N R X/r4 ^OH

[11] Production Process D R 3a R 4a XCHCHCOOH [2] OH > 2 [12] R5-Z r15n R 4a h. rCOOH ^0 3a ring closure r 2 [13] dehydrogenation R5-Z 0 ■COX U r' -> R N - O R '.2 [15] deacylation hn [16a] Production Process E 0 R ^-so -n /^vs)r16 1 I .2

[17] R R 1) R4bCOOR12 [18] r5~z. 1 « 4. 1. R SO-N 2) removal of protect- 2 | ing group when R^-6 ^2 is protecting group Production process F hz r -so 0-n 2 L r' OR 14 R -CH2-COX [9] >

[20] 0 r -s0o-n 2 I - r' xrr or" [21] removal of protecting group r4 o V-4 r -so -n 2 I- R' ring formation > r1-so2-n hydrolysis 3 > 1 r -s0on £■ I HZ reduction -> i r-s0..-n " I- R' Production process G R5-Z 0 r5-z CH- r -s02-n or R3bCHO [26] r 2 [25] r -s09-n 2 I r XJC^" 3b OH 2 [27] Production Process H r5-z r-so„-n 2 |. r' 0 0, 0"X0H hydrolys [1-28] ) r\3 an 22 6 4 8 1 In the above formulas, Z, r\ R2, r\ R^a, R^*3, ^4 4 a 4b ,5 12 , . ,, R , R , R , R , R , X and have the same meanings as defined above; R^ means a halogen atom or a removable group such as an alkylsulfonyloxy or arylsulfonyloxy 14 grnun nr the like; R means a hydroxyl-protoe ting group; R"^ means an acyl group; and R"^ means a hydrogen atom or a hydroxyl-protec ting group.

The hydroxyl-protecting group includes, for example, lower alkyl groups such as methyl, ethyl and the 10 like and aralkyl groups such as benzyl and the like.

Incidentally, the starting compounds and intermediates in the above reactions may also be used in the form of salts, and the definition of salt of the compound of the formula [Ij mentioned above can also be 15 applied to the salts.

Each production process is explained in detail below.

Production Process A The compound of the formula [3] can be produced 20 by reacting a compound of the formula [1] with a compound of the formula [2] in the presence of a base.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, water, N,N-25 dimethylformamide, N,N-dimethylacetamide, dimethyl- sulfoxide or a mixture of water with an organic solvent (e.g., N,N-dimethylformamide, dioxane, methanol, ethanol 22 6 48 1 or the like).

The base used in the above reaction includes alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like.

A B-propiolactone or its derivative may be substituted for the compound of the formula [2].

The amounts of the base and the corapound of the formula [2] used are 1 to 10 moles and 1 to 5 moles, respectively, per mole of the compound of the formula [1] .

The above reaction may be effected at a tempera- ture of 20 to 100°C for a period of 30 minutes to 24 hours.

The compound of the formula [1] which is the starting material can be obtained by subjecting a 3- ... nitrophenol having a R -Z- group in the 4-position xn which R and Z have the same meanings as defined above (see Japanese Patent Application Kokai No. 203,079/82) to conventional reduction of nitro group and sulfonylation which is mentioned hereinbefore in connection with Production Process 4.

Production Process B (1) The compound of the formula [6] can be obtained by reacting a compound of the formula [1] with a compound 226489 1 of the formula [4] or I5J in the presence of a base.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, amides such as 5 N,N-dimethylformamide and the ]ike; sulfoxides such as dimethylsulfoxide and the like; HMPA; halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform and the like. These solvents may be used alone or in admixture of two or more.

The base used in the above reaction includes metallic alkalis such as metallic sodium, metallic potassium and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal alkoxide such as sodium methoxide, sodium ethoxide, IS potassium tert-butoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; organic amines such as triethylamine, DBU, pyridine and the like; etc.

The amounts of the compounds of the formula 20 [4J or [5] and the base are each 1 to 5 moles per mole of the compound of the formula [1].

The above reaction may be carried out at a temperature of -20 to 150°C for a period of 30 minutes to 24 hours.

The compound of the formula [6] obtained by the above reaction includes cis-form, trans-form and a mixture of the two, and all of the cis-form, trans-form and mixture ^ •' may be used as such in the subsequent reaction. .J v \ ^' Q -> O 2 2 6 1 (2) The compound of the formula [7] can be obtained by hydrolyzing the compound of the formula [6].

A solvent may be used in this reaction, which may be any solvent as far as it does not adversely affect 5 the reaction, and includes, for example, water and mixtures of water with organic solvents such as alcohols, for example, methanol, ethanol and the like and ethers, for example, dioxane, tetrahydrofuran and the like.

This hydrolysis may usually be conducted with 10. an inorganic base such as sodium hydroxide, potassium hydroxide or the like.

The amount of the inorganic base used is 1 to 50 moles per mole of the compound of the formula [6].

The above reaction may usually be carried out 15 at a temperature of 0 to 100°C for a period of 30 minutes to 24 hours. ■4 3 When R is an alkoxycarbonyl group, the compound of the formula [6] may be directly subjected to the same ring closure reaction as stated in Production Process 20 2(1} to obtain a compound of the formula [1-3].

Production Process C The compound of the formula [10] can be obtained by reacting a compound of the formula [8] with a compound of the formula [9] in the presence of a Lewis acid such 25 as aluminum chloride, boron trifluoride or the like.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect ' 22 6 4 8 the reaction, and includes, for example, halogenated hydrocarbons such as methylene chloride, 1,2-dichloro-ethane and the like; organic carboxylic acids such as acetic acid and the like; carbon disulfide; nitrobenzene; etc. These solvents may be used alone or in admixture of two or more.

The amounts of the compound of the formula [9] and the Lewis acid used are 1 to 1.2 moles and 1 to 5 moles, respectively, per mole of the compound of the formula [8].

The above reaction may usually be carried out at a temperature of 0 to 150°C for a period of 30 minutes to 2 4 hours.

Moreover, the compound of the formula [11] can be obtained by subjecting a compound of the formula [10] to conventional removal of protecting group.

The compound of the formula [8] can also be prepared, for example, by subjecting a 3-nitroanisole 5 having a R -Z- group m which R and Z have the same meanings as defined above to conventional reduction of nitro group and then to sulfonylation [refer to J. Chem.

Soc., 581-588 (1960); Helv. Chim. Acta. 6JL, 2452-2462 (1978); J. Chem. Soc., 885-889 (1959); Helv. Chim. Acta. 4 8, 336-347 (1965) and Chemical Abstracts, 4_0, 2806 (3) (1946)] .

Production Process D The compound of the formula [15] can be obtained i A 2Z b 4 a 1 by reacting a compound of the formula (12] with a compound of the formula [2] according to the methods stated in Production Process 1 and Production Process A to obtain a compound of the formula [13], then subjecting the ^ compound or tue Cox.muxS [Ij] to ring closurs and subjecting the compound of the formula [14] thus obtained to dehydrogenation .

The compound of the formula [16a] can be obtained by subjecting the compound of the formula [15] to deacylation 10 reaction in the presence of an acid catalyst.

In this reaction, a solvent may be used, which includes water and mixtures of water with organic solvents such as methanol, ethanol, dioxane, tetrahydrofuran and the like.

The acid catalyst used in this reaction includes mineral acids such as hydrochloric acid, sulfuric acid and the like and organic acids such as paratoluenesulfonic acid and the like.

The amount of the acid catalyst is 0.1 to 50 20 moles per mole of the compound of the formula [15].

The above reaction may usually be carried out at a temperature of 0 to 150°C for a period of 30 minutes to 24 hours.

Production Process E 25 The compound of the formula [19] can be obtained by reacting a compound of the formula [17] with a compound of the formula [18] in the presence of a base. 22 6 4 8 1 In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the 5 like: amides such as N,N-dimethylformamide and the like; alcohols such as methanol, ethanol and the like; etc. The compound of the formula [18] may also be used as the solvent.

The base used in this reaction includes, for 10 example, metallic alkalis such as metallic sodium, metallic potassium and the like; alkali metal amides such as sodium amide, potassium amide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali 15 hydrides such as sodium hydride, potassium hydride and the like; etc.

The amounts of the base and the compound of the formula [18] used are 1 to 10 moles and 1 to 100 moles, respectively, per mole of the compound of the formula 20 [17].

The above reaction may usually be carried out at a temperature of 20 to 150°C for a period of 30 minutes to 24 hours. 1 fi When R is a hydroxyl-protecting group, the 25 compound of the formula [19] can also be produced by reacting the compound of the formula [17] with the compound of the formula [18] in the same manner as mentioned above and then subjecting the reaction product to conventional 22648S 1 removal of protecting group.

The compound of the formula [17] can be obtained by reacting a compound of the formula [IJ with boron trifluoride-acetic acid, aluminum chloride-acetic 5 anhydride or the like.

This reaction is effected by applying the Fries rearrangement reaction according to the method described in, for example, Chem. Ber., vol. 95, p. 1413 (1962), Jean Mathieu, Jean Weill-Raynal, "Formation of C-C Bonds", 10 vol. Ill, pp. 384-453 published by Georg» Thieme Publishers, or the like.

Production Process F r (1) The compound of the formula [21] can be obtained by reacting a compound of the formula [20] with a compound 15 of the formula [9] in the presence of a Lewis acid such as aluminum chloride, boron trifluoride or the like.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, halogenated 20 hydrocarbons such as methylene chloride, 1,2-dichloroethane and the like; carbon disulfide; nitrobenzene; and the like. These solvents may be used alone or in admixture of two or more.

The amounts of the compound of the formula [9J 25 and the Lewis acid are 2 to 10 moles and 2 to 5 moles, respectively, per mole of the compound of the formula [20]. ^ "s 0 'v The above reaction can be carried out at a / i ' O temperature of 0 to 150°C for a period of 30 minutes to 22 6 4 8 1 to 2 4 hours.

Moreover, the compound of the formula [22] can be obtained by subjecting the compound of the formula [21] to conventional removal of protecting group. 5 (2) The compound of the formula [23] can be obtained by subjecting the compound of the formula [22] to the same reaction as in Production Process 3.

Furthermore, the compound of the formula [24] can be obtained by subjecting the compound of the formula 10 [23] to conventional hydrolysis. (3) The compound of the formula [40] can be obtained by subjecting the compound of the formula [24] to the same reaction as in Production Process 2(2).

The compound of the formula [20] can also be 15 obtained by subjecting, for example, 3-nitroanisole having a H-Z- group in which Z has the same meaning as defined above to conventional reduction of nitro group and then to sulfonylation which is mentioned hereinbefore in connection with Production Process 4.

Production Process G (1) The compound of the formula [27] can be obtained by reacting a compound of the formula [25] with a compound of the formula [26] in the presence of a base.

In this reaction, a solvent may be used, which 25 may be any solvent as far as it does not adversely affect the reaction, and includes, for example, water; alcohols such as methanol, ethanol and the like; etc. These solvents may be used alone or in admixture of two or more. 22 6 4 8 The base used in the above reaction includes, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, po tci s s i. um tic it fcox id.£ cincl +1^0 liko* 0tc.

The amounts of the base and the compound of the formula [26] used are 1 to 10 moles and 1 to 100 moles, respectively, per mole of the compound of the formula [25].

The above reaction may usually be carried out at a temperature of 0 to 100°C for a period of 30 minutes to 24 hours.

Production Process H The compound of the formula [28] can be obtained by hydrolyzing the compound of the formula [1-28] with an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or the like.

In this reaction, a solvent may be used, which may be any solvent as far as it does not adversely affect the reaction, and includes, for example, water and alcohols such as methanol, ethanol and the like. These solvents may be used alone or in admixture of two or more.

The amount of the alkali hydroxide used in this reaction is 2 to 50 moles per mole of the compound of the formula [1-28], The above reaction may usually be carried out at a temperature of 0 to 100°C for a period of 30 minutes °2648c 1 to 24 hours.

In addition to the production processes mentioned above, the compound of the formula [I] can be obtained by reacting a compound of the formula [1-8] with (i) an alkyl iminoacetate or iminoacetic acid chloride, (ii) cyanamide or (iii) an alkylisothiourea by the method described in the following three literature references (i) to (iii), respectively: (i) Synthetic Organic Chemistry published by 10 John Wiley & Sons, Inc., 1953, pp. 634-639 (ii) Ann. 4£2, p. 144 (1925) (iii) Organic Synthesis Col., vol. Ill, pp. 440-442. Moreover, the compound of this invention and the starting compounds therefor can be converted to 15 another objective compound and another starting compound, respectively, by subjecting them to appropriate combination of conventional oxidation, reduction, dehydrogenation, hydrolysis, halogenation, alkylation, acylation, amidation, alkylsulfonylation, alkenylsulfonylation, arylsulfonylation, 20 esterification, imination, dealkylation, formation of heterocyclic ring and the like. 3 The compounds of the formula [I] in which R , 4 5 R and R are or have formyl, acyl, cyano, carbamoyl or carboxyl groups can be converted to other objective 2 5 compounds. For example, the compounds of the formula [I] 3 4 5 an which R , R and R are or have formyl groups can be 3 4 converted to other objective compounds in which R , R and S R are or have carboxyl, cyano, halogennitro cr hydroxyl. - 64 - \ 226 1 groups according to the methods described in Tetrahedron Lett., 1187-1190 (1974); Synth. Comm., 10, 889-895 (1980); Tetrahedron, 30_, 3563-3568 (1974); Curr. Sci . , 4_9, 18-19 (1980); Tetrahedron Lett., 1955-1998 (1973); U.S.P. 4,196,128 and 3,906,005, AU. 516,897 and the like.

Also, the compounds of the formula [I] in which 3 4 5 R , R and R are or have acyl groups can be converted to the 3 4 5 compounds in which R , R and R are or have alkenyl groups by, for example, the Witting reaction. This reaction can ID- be effected according to the method stated in Organic Reaction, 14_, 270-490. Alternatively, the acyl group can be converted, to a corresponding alcohol by the Grignard reaction. This reaction can be effected according to r . the method described in Jikken Kagaku Kouza, vol. 18, 15 editted by Japan Chemical Society, Yuuki Kagoubutsu no Hannou (Reaction of Organic Compound),, pp. 363-408 published by Maruzen. 3 4 The compounds of the formula [I] in which R , R and R"* are or have carboxyl groups can be converted to those in which R3, R4 and R5 are or have amino or alkoxycarbonyl- amino groups by the Curtius rearrangement. This reaction can be effected according to the method described in Organic Reaction, 3, 337-449.

When the above-mentioned compounds have hydroxyl, amino or carboxyl groups, these groups may be protected by the protecting groups mentioned in, for example, T. W. Green, Protective Groups in Organic Synthesis (1981) published by John Wiley & Sons, Inc., and if necessary, these protecting groups may be removed by conventional methods. - 65 - 22 6 4 1 The compound of the formula [I] can be administered orally or parenterally in a conventional manner in the form of capsules, powders, granules, pills, tablets, suspensions, emulsions, solutions, cataplasms, 5 ointments, injections, eye drops, liniments, syrups or suppositories. Also, the administration method, dose and number of administration times can be appropriately varied depending upon the age and symptom of a patient. Usually, the compound may be administered in several 10 portions a day in a dose of about 5.0 to about 1,000 mg per adult.

Table 1 were subjected to the following tests to obtain the resuLts shown in each test item.

The compounds of this invention shown in 11 6 4 8 Table 1 » Compound No. ~1 R2 •> i\ _4 K „5 K z 1 ch3- H H H 0 4 ch3- H H ch3s- 0 12 ' ch3- H H H N H 34 ch3- h H hn- 1 CHO <Qh 0 39 ch3- H h hn- 1 CHO 0 40 C1CH2- H h HN- i CHO <2>- 0 46 ch3- H h HN- i CHO , r- CH, 0 61 ch3- H ch3- H _NC- 2 II 0 <o>- 0 88 CH3 ~ H H HN- 1 CHO s 94 ch3- H h h 0 9 ch3- h ch3- h 0 1 I - Cont'd - Table 1 (Cont'd) 96 ch3- ch0c- 31l 0 h h <o>- 0 99 ch3- h h MN- i cho <§>- o 100 ch3- h h ch,n- 3I cho <§>- 0 101 ch3- h h nh- i CH3 <o>- 0 122 ch3- H h h,nc- 1! 0 0 L L 0 4 0 5? 1 1, Anti-inflammatory activity (1) Carrageen in-induced paw edema This inhibotory activity was tested according to the method oil C.A. Winter et al. [Proceedings of the 5 Society for Experimental Biology and Medicine, vol. Ill, p. 54 4 (1962)].

To male rats of Donryu strain (body weight: 90-120 g, 6 to 7 rats per group) which had been fasted overnight was orally administered a test compound sus-10 pended in 0.5% (w/v) aqueous carboxyImethylcellulose solution in a proportion of 1 ml/100 g of body weight. After one hour, 0.1 ml of a 1% carrageenin was injected into the subplantar region of the left hind paw. Three hours after carrageenin injection, the paw volume was 15 measured plethysmographically and the percent swelling was determined from the volume before injection and the inhibitory percentage was calculated according to the following equation: Percent swelling in test inhibition (%) = (1 - corapound-admini stered group v Percent swelling in control group The result is shown in Table 2 in terms of 20 inhibitory effect indicated below based on the inhibition (x%) -: x < 10, ±:10<x<15, +: 15 < x < 20, ++: 20 < x < 30 +++: 30 £ x < 40, ++++: x >40. 22 Table 2 Inhibitory Activity against Carrageenin-Induced Paw 6 A Edema Compound No.

Dose (mg/kg) Inhibitory effect 1 +•(-+ 4 -H- 12 + + + 34 + + + + 39 + + + + 40 + + + + 46 + + + + 61 + 88 + + + 94 + + + 9 + + 96 + + + 99 + + + + 100 + + H—h 101 + + + 122 ! 10 + + IM* (control) 1 io i ! + •+ + + Note: IM* refers to indomethacin. 22643< 1 (2) Adjuvant-induced arthritis This inhibitory activity was tested according to the method of E.M. Glenn [American Journal of Veterinary Research, vol. 27, p. 339 (1966)]. weight: 190-230 a, 5 rats per group) was intradermally injected 0.1 ml of a suspension of heat-killed Mycobacterium tuberculosis in liquid paraffin at a concentration of 6 mg'/ml as the adjuvant into the root of tail. 1"0' Eighteen days after the adjuvant injection, the rats were classified based on the volume of both hind paws, and then a suspension of the test compound in 0.5% (w/v) aqueous carboxymethylcellulose solution was orally administered to the classified rats in a proportion of 1 ml/100 g of body weight once a day for seven continuous days (see Table 3) or four continuous days (see Table 4). On the day following the last administration, the volume of both hind paws was measured, and in the same manner as in (1) above, the inhibitory effect was determined.

Incidentally, the result is shown in Tables 3 and 4 in terms of the inhibitory effect indicated below based on inhibition (x%). iO male rats of Vfisfcar-Lewis strain (body x < 10 +: 10 £ x < 15 +: 15 S x < 20, ++: 20 £ x < 30 +++: 30 £ x < 40, ++++: x 2 40. oN 71 4 8 Table 3 Inhibitory Activity against Adjuvant Arthritis Compound No.

Dose (mg/kg) Inhibitory effect I •i. "4- 4» 94 ++++ 9 ++++ 96 ++++ IM* (control) 1 +++ Note: IM* refers to indomethacin. 2 2 6 226489 Table 4 Inhibitory Activity against Adjuvant Arthritis Compound No.

Dose (nig/kg) Inhibitory effect 4 3 ++ 12 3 ++ + 34 3 ++ + 39 3 ++ 40 3 ++ 46 3 ++ 61 ++4- 88 ++ 99 3 + + 100 + + 101 + + 122 3 + + IM* (control) 3 +++- Note: IM* refers to indomethacin. 22643 1 2. Ulcerogenic Effect To male rats of Wistar strain (body weight: 180-230 g, 7 to 8 rats per group) which had been fasted for 24 hours with free access to water was orally 5 adminstered a test compound suspended in 0.5% (w/v) aqueous carboxymethylcellulose solution in a proportion of 1 ml/100 g of body weight. The rats were allowed to stand under abstinence from food and water for 24 hours, and thereafter, sacrificed by dislocation of cervical 1-0' vertebrae, after which the stomach was removed and fixed in 1% (v/v) formaline solution for 30 minutes. This stomach was split along the greater curvature and the length (mm) of the erosion and ulcer formed on the i' ■ gastric mucosa was measured by a stereomicroscope, and 15 the total sum of the lengths (£. mm) was determined, from which ulcerogenic index was assessed based on the following arbitrary scale: 0: £ < 0.5, 1: 0.5 £ Z < 1, 2: 1 < i < 2, 3: 2 < I < 3, 20 4: 3 < I < 5, 5: 5 S £ < 7, 6: 7 < I < 10, 7: 10 £ I < 15, 8: 15 < £ < 25, 9: 25 £ i < 40, : I > 40.

Subsequently, (mg/kg) which is the dose of the test compound which induces ulcerogenic index 5 was determined on each test compound.

The results obtained are shown in Table G t- / <Y - 74 - . .aVs V"\ q ^ V Si \ON-v <*// 22 Table 5 Ulcerogenic Activity Compound No.

UD50 (mg/kg) 1 * > 3 00 3 4 >500 39 >500 46 >500 9 4* >300 99 >500 IM(control) 4 . 3 Note: *: Rats were allowed to stand for 5 hours under abstinence from food and water and then tested. 1 3. Acute toxicity ICR strain male mice (body weight: 20-25 g, 4 weeks old, 3 mice per group) were tested for oral acute toxicity. A test compound suspended in 0.5% (w/v) aqueous carboxymethylcellulose solution was orally administered to the mice in a proportion of 0.2 ml/10 g of body weight. After the administration, general symptom was observed over one week. With Test Compounds Nos. 1, 34, 39, 46, 94 and 99 no death case was found even at a dose of 500 mg/kg, and no behavioural changes were observed.

LD,_~ values of these test compounds were 5U 9 2 fi 4 R 1^, ftu» V I V >500 mg/kg.

Incidentally, LDrr, value of indomethacin was 50 2 5 mg/kg.

From the above results, it can be seen that the compound of c'nis invention has excellent pharmacological effect and high safety, and has a very broad safety region as compared with indomethacin. Accordingly, it is clear that the compound of this invention has excellent pharmacological effect or high safety.

Next, this invention is illustrated by way of Reference Examples and Examples but is not limited to these Examples.

In the Examples, the mixing ratio of solvent is by volume in all cases, and the carrier in column chromatography is a silica gel produced by Merck Co. (Kieselgel 60, Art. 7734).

Also in the Examples, the following abbreviations are used: Me : Methyl Et : Ethyl i-Pr: Isopropyl Ac : Acetyl IPA : Isopropyl alcohol IPE : Diisopropyl ether Bz : Benzoyl DMF : N,N-Dimethylformamide DMSO: Dimethylsufoxide t-Bu: tert-Butyl 11 6 4 8 ! 1 The substance shown in [ ] shows a recrystal- lization solvent.

Reference Example 1 (1) 120 ml of ethanol and 120 ml of water were added to 23.1 g of 3-nitro-4-phenoxyphenol, and the mixture was made into a solution by heating at 60°C. 2.3 ml of 4N hydrochloric acid was added thereto. While maintaining the reaction temperature at 65-70°C, 16.8 g of an iron powder was added thereto in portions in 20 10 minutes. Stirring was conducted for 30 minutes at the same temperature. The reaction mixture was hot-filtered. 50 ml of water was added to the filtrate and the mixture was allowed to stand. The resulting crystal was collected by filtration to obtain 16.5 g (yield: 82.1%) of 15 3-amino-4-phenoxyphenol having a melting point of 156-157°C.

IR (KBr) cm-1: 3400, 3320, 1590, 1453, 1230 The compounds shown in Table 6 were obtained in the same manner. 22 6 4 8 9 Ta b 1 c 6 R5 z Melting point (°C) IR(KBr) cm-1 0 147.1-1'17. 8 [aqueous ethanol] 3400, 3325, 3080, 1600, 1500, 1460 0 113.5-115 (50% aqueous ethanol] 3390, 3325, 1595, 1490, 1450, 1205 0 130-131 [50% aqueous ethanol] 3390, 3300, 1590, 1500, 1440, 1205 0 154-155 [50% aqueous ethanol] 3390, 3300, 1585, 1495, 1460, 1210 Me 0 138-139 [IPE-n-hexane] 3380, 3300, 1585, 1500, 1480, 1445, 1225, 1205, 1175 ««-Q- 0 160-163 [Benzene] 3380, 3300, 1600, 1490, 1450, 1220, 1200 o s 141-143 3475, 3360, 1610, 1570, 1210 0 Oily (Neat) 3480, 3375, 1620, 1505, 1470, 1230, 1210 cl'0* 0 Oily (Neat) 3480, 3375, 1620 226 1 (2) 20.1 g of 3-amino-4-phenoxyphenol and 23.7 g of pyridine were dissolved in 200 ml of methylene chloride. To the resulting solution being ice-cooled was dropwise added a solution of 12.6 g of methanesulfonyl chloride in 60 ml of methylene chloride, .• in 30 minutes. The mixture was subjected to reaction at the same temperature for 2 hours. 200 ml of water was added thereto and then 4N hydrochloric acid was added to adjust the pH to 3. The organic layer was 1"0" separated, washed with water and a saturated aqueous sodium chloride solution in this order, and then dried with anhydrous magnesium sulfate. Thereafter, the organic layer was subjected to distillation under reduced • pressure to remove the solvent. The resulting crystal 15 was recrystallized from ben2ene to obtain 23.7 g (yield: 84.9%) of 3-methylsulfonylamino-4-phenoxyphenol having a melting point of 138-140°C.

IR (KBr) cm"1: 3440, 3250, 1318, 1215, 1150 The compounds shown in Table 7 were obtained 20 in the same manner. 22 6 48! Table 7 R5 1 Z 1 Melting point (°C) J IR(KBr) cm~l : 1 158.9-159.7 [Benzene] | 3460, 3250, 1600, 14 8 7 _ i <$ |° 131-132 [Benzene] 3450, 3270, 1320, 1200, 1140 F ' ^ i° 118-119 [Benzene] 3440, 3250, 1590, 1310, 1210, 1150 r-Q ! o 159-160 [Benzene] 3460, 3250, 1600, 1487 Me i o;• ] 111-116 [Toluene-n-hexane] 3380, 3200, 1600, 1490, 1300, 1265, 1230, 1195, 1150, 1140, 1110 Me-/ V 0 V,,/ 101-103 [Toluene] 3425, 3250, 1600, 1490, 1390, 1320, 1220, 1150 o Is i 169-170 . 5 3300, 1575, 1445, 1330, 1150 CF3 * oL i Oily (Neat) 3400, 3250, 1500, 1440, 1320, 1275, 1215, 1160 Q- |° 1 1 176-177 [ IPA] 3260, 1470, 1420, 1330, 1245, 1165, 1150 ( t t - Cont'd - 226439 Table 7 (Cont'd) <s 0 118-119 [Ethanol] 3280, 1610, 1500, 1390, 1330, 1220, 1150 f)— "-O- 0 iUO-iU? [Toluene] 3240, 1490, 1475, 1380, 1320, 1215, 1155 * These were obtained in the same manner as in Reference Example 1 (1) and (2). 1 Reference Example 2 .1 g of 3-amino-4-phenoxyphenol was dissolved in 60 ml of acetic acid. 30 ml of- acetic anhydride was \ ' added thereto with ice cooling. Stirring was conducted 5 at 20-25°C for 1 hour. The mixture was subjected to distillation under reduced pressure to remove the solvent. The resulting crystal was recrystallized from toluene to obtain 22.6 g (yield: 93%) of 3-acetylamino-4-phenoxyphenol having a melting point of 151-153°C. 10 IR (KBr) cm"1: 3440, 3190, 1665, 1605, 1540, 1450, 1238, 1215 Reference Example 3 (1) 3-Nitro-4-phenoxyanisole was subjected to the same reaction as in Reference Example 1 (1) to obtain the following compound: ,q* > ' % 3-Amino-4-phenoxyanisole ,/t '' >■ - 81 - 'V r '■ V' 22 6 4 1 Melting point: 111-113°C (recrystallized from 50% aqueous ethanol) IR (KBr) cm"1: 3455, 3350, 1618, 1500, 1475, 1215, 1160 NMR (CDC1^)6 : 3.61 (2H, bs), 3.77 (3H, s), 6.12- 7.45 (8 H, m) (2) 21.5 g of 3-amino-4-phenoxyar: isole and 11.1 g of triethylamine were added to 220 ml of methylene chloride, and the mixture was cooled to -40°C. Thereto was dropwise added a solution of 31.0 g of trifluoro- methanesulfonic anhydride in 60 ml of methylene chloride, in 30 minutes. Then, stirring was conducted at -40°C for 1 hour. 200 ml of water was added thereto and the resulting organic layer was separated. The organic layer 15 was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. Thereafter, the organic layer was subjected to distillation under reduced pressure to remove the solvent. To the resulting crystal was added n-hexane. The mixture was 20 filtered to obtain 25.8 g (yield: 74.4%) of 4-phenoxy-3-trifluoromethylsulfonylaminoanisole.

Melting point: 57-58°C IR (KBr) cm"1: 3260, 1500, 1370, 1235, 1215, 1190, 1128 NMR (CDC13)6 : 3.79 (3H, s), 6.58-7.48 (9H, m) (3) 34.7 g of 4-phenoxy-3-trifluoromethylsulfonyl-aminoanisole and 31 g of ethanethiol were dissolved in 350 ml of methylene chloride. The resulting solution i 2264G 1 was then ice-cooled. Thereto was added 27 g of aluminum chloride at the same temperature in 30 minutes. Stirring was conducted for 30 minutes at 5-10°C. The reaction mixture was poured into 300 ml of ice water and the result-5 ing organic layer was separated. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, dried with anhydrous magnesium sulfate, and subjected to distillation under reduced pressure to remove the solvent. The resulting crystal 10 was recrystallized from toluene to obtain 28.5 g (yield: 85.6%) of 4-phenoxy-3-trifluoromethylsulfonylaminophenol having a melting point of 97-99°C.

IR (KBr) cm"1: 3500, 3150, 1500, 1438, 1360, 1230, 1200, 1135 NMR (CDCl_ +d -DMS0)6: 6.56-7.53 (8H, m), 9.03 J o (1H, bs), 10.3 (1H, bs) The following compound was obtained in the same manner: 4-Phenoxy-3-phenylsulfonylaminophenol 20 Melting point: 182-183°C (recrystallized from isopropyl alcohol) IR (KBr) cm"1: 3425, 3240, 1500, 1480, 1305, 1215, 1160 (4) 10.0 g of 3-amino-4-phenoxyanisole was dissolved in 50 ml of pyridine. Thereto was dropwise 25 added 5.59 g of methanesulfonyl chloride in 10 minutes with ice-cooling. The mixture was stirred for 1 hour at 20-25°C. The reaction mixture was introduced into a mixture of 200 ml of ethyl acetate and 100 ml of water. \\jv C\ 22 fi A R 1 The resulting organic layer was separated and washed with throe 100-ml portions of 2N hydrochloric acid and then with a saturated aqueous sodium chloride solution. The organic layer was separated, dried with anhydrous 5 magnesium sulfate, and subjected to distillation under reduced pressure to remove the solvent. The resulting crystal was recrystallized from isopropyl alcohol to obtain 12.5 g (yield: 91.9%) of 3-methylsulfonylamino-4-phenoxyanisole having a melting point of 109.5-111°C. 10 IR (KBr) cm"1: 3250, 1610, 1585, 1480, 1320, 1220, 1150 NMR (CDC13)6 : 2.94 (3H, s), 3.81 (3H, s), 6.36- 7.43 (9H, m) Reference Example 4 15 (1) 21.4 g of 3-amino-4-phenylaminoanisole was dissolved in 210 ml of pyridine. The solution was then ice-cooled. Thereto was dropwise added 12 g of metha-nesulfonyl chloride in 30 minutes. Stirring was conducted for 2 hours at 5-10°C. The mixture was subjected to 20 distillation under reduced pressure to remove the solvent. To the residue were added 500 ml of water and 300 ml of ethyl acetate. The resulting mixture was adjusted to pH 4 with 4N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride 25 solution in this order, and dried with anhydrous magnesium sulfate. The organic layer was then subjected to distillation under reduced pressure to remove the solvent. Toluene was added to the residue, and the resulting crystal was 22 6 4 8 1 filtered to obtain 23.9 g (yield: 81.8%) of 3-methyl- sulfonylamino-4-phenylaminoanisole having a melting point of 109-111°C.

IR (KBr) cm"1: 3360, 3230, 1600, 1490, 1390, 1330, 5 1290, 1150 (2) 29.2 g of 3-methylsulfonylamino-4-phenylamino- anisole, 18.6 g of ethanethiol and 300 ml of methylene chloride were mixed and then ice-cooled. To the mixture was added 40 g of aluminum chloride in 20 minutes. Stirr-10 ing was conducted for 3 hours at 5-10°C. The reaction mixture was introduced into 500 ml of ice water. The resulting organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order and then dried with anhydrous magnesium sulfate. 15 The solvent was removed by distillation under reduced pressure. Ethanol was added to the residue and the resulting crystal was filtered to obtain 23.9 g (yield: 86%) of 3-methylsulfonylamino-4-phenylaminophenol having a melting point of 184-186°C.

IR (KBr) cm-1: 3425, 3380, 3250, 1600, 1490, 1310, 1150 Reference Example 5 (1) 20 g of 4-methoxy-2-nitrophenol was suspended in 350 ml of ethanol. Thereto was added 550 mg of 5% 25 palladium-carbon. The mixture was subjected to hydrogenation at 20-30°C at atmospheric pressure. After the completion of the reaction, the catalyst was removed 226' 1 by filtration and then the solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from isopropyl alcohol to obtain 15.3 g (yield: 93%) of 2-amino-4-methoxyphenol. (2) IQ g of 2 - a rr. i r. c - 4 - m e t h o x y p h e n c I was dissolved in 100 ml of methylene chloride. 17 ml of pyridine was added thereto and the mixture was cooled to 5°C. Then, 9.1 g of methanesulfonyl chloride was added dropwise in 10 minutes and stirring was conducted for 1 hour at 10 5-10°C. The solvent was removed by distillation under reduced pressure. To the residue were added 100 ml of ethyl acetate and 50 ml of water. The mixture was adjusted to pH 2 with 4N hydrochloric acid. The organic layer was I separated, washed with water and a saturated aqueous 15 sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from isopropyl alcohol to obtain 14.4 g (yield: 92%) of 4-methoxy-2-methylsulfonylamino-20 phenol having a melting point of 135-136°C.

IR (KBr) cm"1: 3275, 1600, 1500, 1405, 1325, 1210, 1150 Reference Example 6 4-(3-Methylphenoxy)-3-nitroanisole was subjec-25 ted to the same procedure as in Reference Example 1 (1) and (2) to obtain 3-methylsulfonylamino-4-(3-methyl-phenoxy)anisole. c C u H Q 1 Molting point: 87-88°C (recrystallized from isopropyl alcohol) IR (KBr) cm"1: 3250, 1480, 1385, 1335, 1250, 1210, 1150, 1105 The compounds shown in Table 8 were obtained in the same manner.

Table 8 R5-Z* Me S 0 _ - N OMe ^ H R5 z Melting point (°C) IR(KBr) cm-1: Me f<3- 0 98-99 [IPE] 3225, 1615, 1585, 1485, 1400, 1330, 1210, 1165 i-Pr o 0 83-84.5 [IPE] 3250, 2950, 1490, 1390, 1330, 1230, 1150, 1100 Me ,Me n 0 108-109 [ IPA] 3300, 1610, 1500, 1380, 1330, 1210, 1150 o- s 68-69 [IPA-IPE] 3290, 1590, 1475, 1320, 1290, 1150 2 2 6 4 8 1 Reference Example 7 (1) There were mixed 20 g of <1 -chloro-3-nitro-anisole, 67 ml of acetic acid and 83 ml of 47% (w/w) hydrobromic acid. Thereto was added 50 ml of acetic anhydride. The was r^f luxod for 8,5 hours.

After the completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was mixed with 300 ml of ethyl acetate and 500 ml of water. The resulting organic layer was separated, 10 washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution in this order, and then dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystal-15 lized from toluene to obtain 15.5 g (yield: 83.6%) of 4-chloro-3-nitrophenol having a melting point of 123.5-125.5°C.

IR (KBr) cm"1: 3400, 1510, 1340, 1280, 1200 (2) 2.0 g of 4-chloro-3-nitrophenol was dissolved 20 in 15 ml of N,N-dimethylformamide. Thereto was added 490 mg of sodium hydride (purity: 60%) in 10 minutes at 5-10°C. Then, 1.53 g of benzyl chloride was added dropwise in 10 minutes. Stirring was conducted for 1 hour at 70°C. The reaction mixture was introduced 25 into a mixture of 50 ml of ice water and 50 ml of ethyl acetate. The resulting organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium c <L O I sulfate. The solvent was removed by distillation under reduced pressure. The residue was washed with n-hexane and then mixed with a mixture of diisopropyl ether and n-hexane. The resulting crystal was collected by filtra-5 tion to obtain 1.8 g (yield: 59.4%) of 4-benzyloxy-2-ni tro-1-chlorobe'nzene having a melting point of 50-50.5°C.

IR (KBr) cm"1: 1520, 1475, 1350, 1300, 1235, 990 (3) 880 mg of 4-methoxyphenol was dissolved in 10 ml of N,N-dimethylformamide. 790 mg of potassium t-butoxide was added thereto. Then, 1.7 g of 4-benzyloxy-2-ni tro-1-chlorobenzene was added thereto. The mixture was stirred for 1 hour at 110-120°C. The reaction mixture was introduced into a mixture of 50 ml of ice \ ' ■ water and 50 ml of ethyl acetate. The organic layer was 25 separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: toluene) to obtain 20 1.92 g of 5-benzyloxy-2-(4-methoxyphenoxy)nitrobenzene.

Melting point: 120-120.5°C (recrystallized from ethanol) IR (KBr) cm"1: 1520, 1485, 1245, 1225, 1210, 1195 The following compound was obtained in the 25 same manner: -Benzyloxy-2-(2-methoxyphenoxy)nitrobenzene Melting point: 80-81°C (recrystallized from ethanol) IR (KBr) cm"1: 1525, 1495, 1350, 1265, 1235, 1215, I.Cf05 'i ~ ~ . •• - 8 9 - \ .> -< '•Vv ~ v., I n 226489 1 (4) 1.8 g of 5-benzyloxy-2-(4-methoxyphenoxy)nitro benzene was dissolved in 40 ml of acetic acid. 200 mg of 5% palladium-carbon was added thereto. The mixture was subjected to hydrogenation at room temperature at atmos-5 pheric pressure. After the completion of the reaction, the catalyst was removed by filtration and the solvent was removed by distillation under reduced pressure. The residue was mixed with 7 ml of methylene chloride and 1.10 ml of pyridine to obtain a solution. Thereto was drop-1-0 wise added 400 mg of methanesulfonyl chloride in 5 minutes at 5-10°C. Stirring was conducted for 1 hour at the same temperature. 20 ml of water and 20 ml of chloroform were added thereto. The resulting organic layer was separated 1 ' and washed with 20 ml of 2N hydrochloric acid and 200 ml 15 of water. The organic layer was mixed with a 5% aqueous sodium hydroxide solution. The aqueous layer was separated and adjusted to pH 2 with 6N hydrochloric acid. 50 ml of ethyl acetate was added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium 20 chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography [eluant: a 10 : 1 mixture of toluene and ethyl acetate] to obtain 1.29 g (yield: 81.6%) 25 of 3-methylsulfonylamino-4-(4-methoxyphenoxy)phenol.

Melting point: 109-110.5°C (recrystallized from toluene) IR (KBr) cm"1: 3470, 1500, 1315, 1220, 1150 VI b A « 1 The following compound was obtained in the same manner: 3-Methylsulfonylamino-4-(2-methoxyphenoxy)phenol Melting point: 114-115°C (recrystallized from 5 toluene) IR (KBr) cm"1: 3480, 3250, 1495, 1305, 1275, 1140 Reference Example 8 (1) In 100 ml of anhydrous methylene chloride were dissolved 10 g of 3-methylsulfonylamino-4-phenoxy-10 anisole and 2.81 g of acetyl chloride. Thereto was added 9.1 g of aluminum chloride in 5 minutes with ice-cooling. The mixture was stirred for 1 hour at 20-25°C. The reaction mixture was introduced into 100 ml of ice water. The resulting organic layer was sepa-25 rated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from isopropyl alcohol to obtain 9.83 g (yield: 20 86%) of methyl 4-methylsulfonylamino-2-methoxy-5- phenoxyphenyl ketone having a melting point of 108.5-110°C.

IR (KBr) cm"1: 3300, 1640, 1600, 1490, 1330, 1210, 1155 The compounds shown in Table 9 were obtaind in the same manner. 22 6 Table 9 0 r5-o- me-so -n-h X r ' O-Me R4 R5 Melting point (°C) IR(KBr) cm"1 : Me a 106-107 3270, 1680, 1640, 1610, 1500, 1420, 1340, 1230 Me "-O- Amorphous powder 3270, 1680, 1640, 1610 Et o- 104.8-105.6 3200, 1660, 1600, 1485, 1410, 1340, 1210, 1160, 1130 1 (2) 10.0 g of methyl 4-methylsulfonylamino-2- methoxy-5-phenoxyphenyl ketone was dissolved in 100 ml of methylene chloride. 3.98 g of aluminum chloride was added thereto in portions in 30 5 minutes with ice-cooling. The mixture was stirred for 1 hour at 20-25°C. The reaction mixture was introduced into 100 ml of ice water. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried 10 with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from iso-prppyl alcohol to obtain 8.8 g (yield: 91.9%) of methyl 2-hydroxy-4-methylsulfonylamino-5-15 phenoxyphenyl ketone having a melting point of o o 6 4 8 151-153°C. *" IR (KBr) cm-1: 3230, 1625, 1590, 1580, 1560, 1485 The compounds shown in Table 10 were obtained in the same manner.

Table 10 R5-0 Me-SO_-N H 9 R OH R4 R5 Melting point (°C) IR (KBr) cm-1: He /C1 o 153-154 [Ethanol] 3230, 1630, 1500, 1370, 1320, 1260, 1230 Me 206-208 [Acetonitrile] 3240, 1620, 1480, 1420, 1330, 1310, 1220, 1155 Et o 151.4-152.4 [IPA] 3220, 1630, 1580, 1485, 1330, 1215, 1190, 1160, 1115 Reference Example 9 60 ml of an acetic acid solution containing 40% of boron trifluoride was added to 29.7 g of 3-methylsulfonylamino-4-phenoxyphenol. The mixture was stirred for 30 minutes at 70-75°C. The reaction mixture was introduced into 500 ml of water. The resulting crystal was collected by filtration. The crystal was recrystallized from isopropyl alcohol to obtain 2.85 g (yield: 88.8%) of methyl 2-hydroxy-4-methylsulfonylamino- 1 5-phenoxypheny1 ketone having a melting point of 151-15 3 °C.

The compounds shown in Table 11 were obtained in the same manner. 22 6 489 Table 11 R1 R5 Melting point (°C) IR {KBr)cm-1 : Me d- 171-172 [IPA] 3250, 1635, 1610, 1500, 1420, 1370, 13 4 0, 1265 1 Me H 148-149 [IPA] 3240, 1630, 1600, 1500, 1420, 1350, 1260, 1140 Me '-O- 174-175 [IPA] 3240, 1625, 1500, 1425, 1340, 1200 Me 179 . 5-180 [IPA] 3275, 1640, 1500, 1420, 1375 Me Me ft 132-134 [IPA] 3225, 1630, 1480, 1420, 1325, 1310, 1220 Me HeO 131-133 [IPA] 3230, 1625, 1500, 1425, 1340, 1200, 1160 o 147-148 [IPA] 3240, 1630, 1490, 1340, 1160 22648' 1 Example 1 (1) A g of sodium hydroxide was, dissolved in 2 50 ml of water. Therein was dissolved 27.9 g of 3-mcthylsulfonylamino-4-phenoxyphenol■ Thereto was added an aqueous solution obtained by dissolving 10.9 g of 3-chloropropionic acid and 4 g of sodium hydroxide in 30 ml of water. The mixture was refluxed for 30 minutes. The reaction mixture was water-cooled and adjusted to pH 8 with 4N hydrochloric acid. 70 ml of ethyl acetate 10 was added thereto. The aqueous layer was separated, adjusted to pH 4 with 4N hydrochloric acid and extracted with 100 ml of ethyl acetate. The resulting extracts were washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous 15 magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was mixed with diethyl ether. The resulting solid was collected by filtration to obtain 8.1 g (yield: 23.1%) of 3 — (3 — methylsulfonylamino-4-phenoxyphenoxy)propionic acid 20 having a melting point of 145-149°C.

IR (KBr) cm"1: 3250, 1705, 1482, 1325, 1210, 1145 (2) There were mixed 3.51 g of 3-(3-methylsulfonyl-amino-4-phenoxyphenoxy)propionic acid and 70 g of poly-phosphoric acid. The mixture was stirred for 1.5 hours at 65-70°C. The reaction mixture was introduced into 300 ml of ice water. The resulting mixture was extracted with two 200-ml portions of ethyl acetate. The resulting extracts were combined, washed with water and a saturated 22 6 1 aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from methanol 5 to obtain 18.7 g (yield; 56.1%) of 2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4 H-l-benzopyran-4-one having a melting point of 143-144°C.

IR (KBr) cm-1: 3120, 1665, 1610, 1485, 1440, 1320, 1265 , 12.15, 1160, 1135 10 MNR (CDC13)<S : 2.74 (2H, t, J=6Hz) , 3.10 (3H, s), 4.53 (2H, t, J=6Hz) , 6.91-7-49 (7H, m), 7.40 (1H, s) (3) To 60 ml of dioxane were added 3.33 g of 2.3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1- benzopyran-4-one and 3.40 g of 2,3-dichloro-5,6-dicyano- 1.4-benzoquinone. The mixture was refluxed for 12 hours. After water cooling, the precipitate was removed by filtration. The filtrate was subjected to distillation under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluant: a 5 : 1 mixture of toluene and ethyl acetate) to obtain 2.68 g (yield: 81%) of 7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one [Compound No. 1].

Melting point: 216.7-217.6°C (recrystallized from 25 acetonitrile) IR (KBr) cm"1: 3110, 1620, 1585, 1560, 1485, 1465, 1440, 1320, 1140 z L 0 H u c 1 NMR (CDC13 +dg-DMSO)6: 3.12 (3H, s), 6.24 (1H, d, J=6Hz) , 6.98-7.53 (6H, in), 7.75 (1H, s) , 7.90 (1H, d, J=6Hz) , 9.20 (1H, bs) Example 2 (1) There were mixed 4.12 g of 3-bromo-2,3- dihydro-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one, 9.37 g of silver tetrafluoroborate and 100 ml of methanol. The mixture was refluxed for 4 hours. The reaction mixture was cooled and filtered to remove the 10 insolubles. The filtrate was subjected to distillation under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluant: a 5 : 1 mixture of toluene and ethyl acetate) to obtain 1.27 g (yield: 35%) of 2,3-dihydro-3-methoxy-7-methyl-15 sulfonylamino-6-phenoxy-4H-l-benzopyran-4-one.

Melting point: 139-141°C (recrystallized from ethanol) IR (KBr) cm-1: 3230, 1680, 1610, 1490, 1450, 1330, 1260, 1210, 1150 20 (2) There were mixed 3.63 g of 2,3-dihydro-3- methoxy-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one, 3.41 g of 2,3-dichloro-5,6-dicyano-l,4-benzo-quinone and 150 ml of dioxane. The mixture was refluxed for 48 hours. The reaction mixture was cooled. The 25 resulting precipitate was removed by filtration. The solvent was removed by distillation under reduced pressure. The residue was purified by a column 22 6 chromatography (eluant: a 3 : 1 mixture of toluene and ethyl acetate) to obtain 1.91 g (yield: 52.9%) of 3-methoxy-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one [Compound No. 2].

Melting point: 164-166°C (recrystallized from ethanol) IR (KBr) cm"1: 1610, 1480, 1460, 1330, 1260, 1215, 1175, 1140 (3) 3-Methoxy-7-methylsulfonylamino-6-phenoxy-4H-1 benzopyran-4-one was treated in the same manner as in Reference Example 4(2) to obtain 3-hydroxy-7-methyl-sulfonylamino-6-phenoxy-4H-l-benzopyran-4-one [Compound No. 3] .

Melting point: 170-173°C (recrystallized from isopropyl alcohol) IR (KBr) cm-1: 1610, 1480, 1470, 1340, 1265, 1210, 1150 Example 3 (1) In 50 ml of methylene chloride were dissolved 2.06 g of 3-bromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one and 480 mg of methylmer-captan. Thereto was added 2.02 g of triethylamine at 0-5°C. The mixture was stirred for 1 hour at room temperature. The reaction mixture was introduced into 30 ml of water. The organic layer was separated, washed with water, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under LL b 4 reduced pressure. The residue was purified by a column chromatography (eluant: a 50 : 1 mixture of toluene and ethyl acetate) to obtain 900 mg (yield: 47.4%) of 2,3-dihydro-7-methy1sulfonylamino-3-methylthio-6-phenoxy-4 H-1-benzopyran-4-one.

Melting point: 126-128°C (recrystallized from e thanol) IR (KBr) cm-1: 3250, 1690, 1610, 1480, 1440, 1340, 1260, 1220, 1160, 1140 (2) 350 mg of 2,3-dihydro-7-methylsulfonylamino-3-methylthio-6-phenoxy-4H-l-benzopyran-4-one and 1.08 g of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone were refluxed in 14 ml of dioxane for 9 hours. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 10 : 1 mixture of toluene and ethyl acetate) to obtain 160 mg (yield: 45.7%) of 7-methylsulfonylamino-3- methy1thio-6-phenoxy-4H-l-benzopyran-4-one [Compound No. 4].

Melting point: 175-176°C (recrystallized from acetonitrile) IR (KBr) cm-1: 3120, 1600, 1480, 1420, 1310, 1210, 1140 (3) 7-Methylsulfonylamino-3-methy1thio-6-phenoxy- 4H-l-benzopyran-4-one was reacted with m-chloroperbenzoic acid in equimolar amounts to obtain 3-methylsulfinyl-7- methy1su1fonylamino-6-phenoxy-4H-1-benzopyran-4-one [Compound No. 5].

Melting point:>250°C (recrystallized from acetonitrile) IR (KBr) cm"1: 3100, 1620, 1490, 1460, 1340, 1280, 1220, 1160, 1060 (4) 1 Mole of 7-methylsulfonylamino-3-methylthio- 6-phenoxy-4H-l-benzopyran-4-one was reacted with 2 mole of m-chloroperbenzoic acid to obtain 7-methylsulfonyl-amino-3-methylsulfonyl-6-phenoxy-4H-l-benzopyran-4-one [Compound No. 6].

Melting point: >250°C (recrystallized from acetonitrile) IR (KBr) cm"1: 3280, 1640, 1620, 1480, 1460, 1340, 1310, 1290, 1220, 1160, 1140 Example 4 The compounds shown in Tables 12 to 20 were obtained in the same manner as in Example 1(3), Example 2(2) or Example 3(2).

R -S09-N H No.

R R~ R" Melting point (°C) IR (KBr) cm -1 NMR 6: Et -CF.

H 0 216-218 [Ethanol] 3070, 1620, 1582, 1490, 1455, 1335, 1200, 1155, 1138, (CDC 13 +d f, -DMSO) 1.37 (3H, t, J=7 3.25 (2H r 6.22 (1H, 7.01-7.47 7.68 (1H, (1H, S), J=6Hz) 2Hz) q, J=7.2Hz) d, J=6Hz), (5H, m), s) , 7.76 7.93 (1H, d, 9.21 (1H, bs) H 0 198-200 [Ethanol] 3075, 1620, 1482, 1382, 1295, 1230, 1200, 1140 (CDCi_+d -DMSO) J c 6.24 (1H, 7.03-7.84 8.02 (1H, d, J=6Hz) (7H, m), d, J=6Hz) Me Me 0 186.5-187 [Ethyl acetate-IPE] 3180, 1630, 1597, 1482, 1452 (d,-DMSO) b 2.38 (3H, s), 3.20 (3H, s), 6.15 (1H, s) 6.90-7.5C {6H, m), 7. 65 (1H, s) , 9 . 85 (1H, bs) - Cont'd - Table 12 (Cont'd) Me H o- s 142-144 [Ethyl acetate-IPE] 3200, 1630, 1610, 1590, 1440 (cdci3) 3.05 (3H, s), 6.26 (IH, a, J=6Hz), 6.90-8.15 (4H, m), 7.22 (IH, s), 7.77 (IH, d, J=6Hz), 8.48 (IH, s), 8.95 (IH, bs) 11 Me a- 0 222.5-223.1 [Ethyl acetate-IPE] 3300, 1620, 1483, 1452, 1408 (dg-DMSO) 3.28 (3H, s), 6.94 (IH, s), 7.05-8.20 (12H, m), 9.90 (IH, bs) 12 Me H n H 190-191 [Ethanol] 3380, 1620, 1610, 1580, 1480, 1450, 1310, 1285, 1155, 1130 13 Me H CF 0 182-183.5 [Ethyl acetate-IPE] 3260, 1660, 1625, 1450, 1325, 1140 O" 14 Me H D- 0 186-187 [IPA] 1650, 1620, 1450, 1325, 1220, 1155, 1140 <y> -S> oo Table 13 0 R5-0 R^-SOp-N ' ° H NO.

R1 R5 Melting point (°C) IR (KBr) cm 1: Me 0:' 174.5-175.5 f Ethanol] 3070, 2825, 1620, 14915, 1460, 1335, 1290, 1150 16 Me 212-213 [Acetonitrile] 3000, 2800, 1620, 1590, 1460, 1440, 1325, 1300, 1140 17 Me 211-213 3000, 2800, 1620, 1590, 1500, 1460, 1325, 1300, 1200, 1140 18 Me o- 151-152 [Ethanol] 3180, 1640, 1620, 1455, 1330, 1295, 1155 19 Me cl\> 185-186 [Acetonitrile] 3070, 1615, 1475, 1450, 1320, 1285, 1205, 1145 - Cont'd - Table 13 (Cont'd) Me ^Me d1 140-141 [Ethanol-IPE] 3100, 1640, 1620, 1480, 1450, 1335, 1290, 1225, 1160 21 Me Me^J- 151-152 [50% aqueous Ethanol] 3050, 1620, 1615, 1490, 1450, 1320, 1285, 1205, 1150 22 u- O- 208-209 [Ethanol] 3080, 2875, 1630, 1470, 1435, 1340, 1290, 1160 rvD ro a> -f-CO CO Table 14 NO.

R1 R3 R5 Melting point («?c) IR (KBr) cm 1: NMR 6: 23 Me H u- 173-174 [Ethyl acetate-IPE] 3440, 3350, 3150, 1610, 1580, 1560, 1490, 1465, 1330, 1260, 1155 (CDC13) 3.14 (3 H, s) , 3.32 (2H, bs), 7.05-7.90 (8H, m) 24 1 Me H Q- 207-208 [Ethanol3 3440, 3340, 3180, 1595, 1580, 1460, 1320, 1260, 1150 (d -DMSO) b 3.18 (3H, s), 5.5-6.8 (2H, br), 6.90-7.68 (4H, m) , 7.46 (IH, s), 7.64 (1H, s), 7.96 (IH, s) Me H '-O 204-206 [Ethanol] 3440, 3340, 3175, 1600, 1585, 1550, 1495, 1465, 1320, 1205, 1150 (CDCl3+d6-DMSO) 3.12 (3H, s) , 3.12 (2H, bs), 7.10-8.20 (8H, m) 26 Me H F f~C^ 202-202.5 [Ethanol] 3440, 3340, 1620, 1605, 1575, 1555 (dc-DMS0) b 3.20 (3H, s), 7.12-7.69 (4H, m), 7.61 (IH, s) , 7.96 (1H, s) - Cont'd - Table 14 (Cont'd) 27 28 Me C1CH2- Me H 176.5-178 [Ethanol] 207-209 [IPA] 3320, 3080, 1615, 1580, 1550, 1480, 1460, 1320, 1260, 1215, 1145, 1120 3450, 3350, 3160, 1600, 1570, 1555, 1480, 1460, 1335, 1200, 1155 {d^-DMSO) 6 2.3 8 (3H, s), 3.15 (3H, s) , 7. 0 4-7 . 58 (7H, m) (dc-DMSO) o .15 (2H, s), 5.5-6.8 (211, br), 7.06-7.61 (5H, m), 7.31 (1H, s), 7.67 (1H, s), 7.96 (IH, s) 29 Et H 208-209 [Ethanol] 3450, 3350, 3020, 1610, 1580, 1555, 1485, 1465 Me H CI 199-200 [Acetonitrile] 3450, 3350, 3100, 1620, 1580, 1470, 1330, 1260, 1150 31 Me H CI 215-217 [Acetonitrile] 3460, 3355, 3260, 1615, 1480, 1470, 1325, 1215, 1160 32 Me H Me 193-194 [Ethyl acetate] 3440, 3350, 3100, 1610, 1580, 1465, 1335, 1260, 1150 ro ro CT> 33 Me H Me- 177-178 [Ethyl acetate] 3460, 3350, 3230, 1615, 1465, 1320, 1210, 1155 NO.

R 1 R" R" R' Melting point (°C) IR (KBr) cm -1 NMR 6: 34 Me H CHO 256-257 [Acetonitrile] 3380, 3300, 1690, 1620, 1605, 1460, 1335, 1145 (d_-DMSO) 6 3.26 (5H, 8.36 (IH, 10.16 (3H, s) , m), 7.73 (IH, s), s), 9.77 (HI, S) 7.10-7.70 (IH, s), 9.28 (IH, s) , Me H CHO 231.5-232.5 [Acetonitrile] 3350, 1670, 1455, 1250, 1120 3250, 1600, 1325, 1145, (dg-DMSO) 3. 23 7. 55 (IH, 8.37 (IH, (3H, s), (4H, m) , s), 7.74 (IH, s), s), 9.80 6.92-7.48 (IH, 9. 29 (IH, s) , s) , lO.Ofi (IH, s) 36 Me H -o CHO 237-238 [Acetonitrile] 3340, 1685, 1600, 1460, 1195, 3265, 1620, 1495, 1330, 1140 (dg-DMSO) 3.24 7. 65 (IH, 9.28 (IH, (3H, s), (5H, m) , s) , 8.35 (IH, s), s), 10.04 7 .10-7.71 (IH, s), 9.77 (IH, s) - Cont'd - Tabl e 15 (Cont'd) 37 38 Me Me Me H cho Ac 205-208 [Ethanol] 254-256 [Acetonitrile] 3300, 3150, 1665, 1630, 1620, 1460, 1350, 1320, 1205, 1155 3295, 1665, 1615, 1610, 1490, 1460, 1340, 1210, 1200, 1160 (d .,-DMSO) D 2. 34 (3H, ( 5h, 7.69 (ih, 9.99 (3H, s) , m) , (ih, s) , (ih, s), 3.21 7.07-7.69 7.28 (ih, s) , 9. 35 s) 8 . 20 (1H, s) s) (d,-DMSO) 6 2.12 (3H, (5H, 7.71 (IH, 9.99 (3H, s) , m) , (ih, s) , (ih, s), 3.22 7.05-7.61 7.35 (ih, s) , 9.18 9.18 (ih, S) s) , s) , 39 Me h / cho 240-241 [Acetonitrile] 3365, 3300, 1685, 1620, 1605, 1525, 1500, 1460 (a,-DMSO) b 3.23 7.67 (ih, 9.28 (ih, (3H, s), (4H, m) , s), 8.35 (ih, s) , s), 10.13 7. 19-7. 72 (ih, s) , 9. 75 (ih, s) 40 cich2- H / cho 239-241 [Acetonitrile] 3350, 1685 , 1600, 1460, 1200, 3270 1615 1480 1340 1160 (d,-DMSO) 6 .22 7. 64 (1h, 8.37 (IH, 10.5 (2H, (5H, s) , (IH, s) , (IH, s) , m) , 7.78 s) , 9.77 bs) 7.12- 7.34 (IH, 9.30 (IH, s) s) - Cont'd - Table 15 (Cont'd) 41 Me H 42 Et H 43 -CF.

H C0- (CH„)„ I ^ Z COOH CHO CHO 253.5-254 226-227 [Acetonitrile] 211-212 [Ethanol] 3350, 3260, 3125, 1725, 1675, 1610, 1590 3275, 1685, 1610, 1530, 1485, 1460 3270, 1680, 1615, 1480, 1455, 1380, 1235, 1200, 1135 (dg-DMSO) 3 . 21 ( 4H, (6H, 9.19 (IH, (3H, s) , m) , (IH, s) , s) , 3.21 7.11-7.49 7.71 (IH, s) , 9.27 10.0 (1H, s) , bs) (d^-DMSO) 6 1.26 (3H, 3.32 (2H, 7.08-7.62 7.38 (IH, (IH, 9.27 (IH, t, J=7Hz) q, J=7Hz) (5H, m), s), 7.71 s), 8.35 (1H, (IH, S), 9.77 s), 10.04 (IH, s) s) (d^-DMSO) 6 6.94-7.55 (5H, m), 7.33 (IH, s), 7.65 (IH, s), 8.34 (IH, 9.23 (IH, s), 10.12 (IH, bs) s) 44 Me H CI CHO 241-242 [Ethanol] 3350, 3270, 1680, 1620, 1600, 1455, 1330, 1150 - Cont'd - ro ro CD OO Table 15 (Cont'd) 45 Me H CHO 254-255 [Acetonitrile] 3275, 1660, 1610, 1480, 1450, 1330, 1210 46 Me H .Me Q- CHO 215-217 [Acetonitrile] 3325, 3280, 1685, 1620, 1485, 1455, 1335, 1260, 1155 47 Me H MeO CHO 244-245 [Acetonitrile] 3290, 1670, 1620, 1485, 1450, 1340, 1215, 1160 rv rs o (X Me-SO~-N H NO. r5 r6 r7 Melting point (°C) IR (KBr) cm"1: NMR 6 : 48 o Me CHO 171-172. 5 [Ethanol] 1660, 1640, 1620, 1490, 1460, 1330, 1270, 1160 (cdc13) 3.18 (6H, s), 7.10-7.70 (5H, m), 7.47 (IH, s), 7.82 (IH, s), 7.94 (1H, s), 8.11 (IH, s) 4 9 Me CHO 184-186 [Ethanol] 1655, 1625, 1610, 1490, 1455, 1330, 1270, 1200, 1155 (cdci3) 3.18 (6H, s), 7.05-7.70 (5H, m) , 7.51 (IH, s) , 7.7EI (IH, s) , 7.94 (IH, s), 8.12 (IH, s) 50 Et CHO 189-190 [Ethanol] 1650, 1620, 1490, 1460, 1320, 1160 (cdci3) 1.11 (3H, t, J=8H5:) , 3.16 (3H, s), 3.73 (2H, q, J=8Hz), 6.80-7.60 (6H, m), 7.57 (IH, s) , 7.80 (IH, s), 7.91 (IH, s) , 8.05 (IH, s) 51 o Me Ac 183-185 [Ethanol] 1650, 1610, 1495, 1455, 1330, 1270, 1155 (cdci3) 1.95 (3H, s) , 3.17 (6H, s) , 6.80-7.70 (6H, m) , 7.59 (1H, s) , 7.80 (IH, s), 8.00 (IH, s) - Cont'd - Table 16 (Cont'd) 52 o- CHn- 1 2 COOMe CHO 182-183 [Ethyl acetate-IPE] 3075, 1745, 1660, 1625, 1480, 1450, 1330, 1190, 1145 (d,-DMSO) 6 3.23 (3H, s), 3.64 (3H, s) , 4.34 (2H, s), 7.07-7.51 (5H, m) , 7.31 (IH, s) , 7.76 (1H, s) , 8.20 (IH, s), 8.58 (IH, s), 10.08 (IH, s) 53 o- CH-- l 2 CH- 1 2 CH- 1 ^ COOEt CHO 142.5-144 [Ethanol] 3240, 1725, 1665, 1640, 1620, 1480, 1450, 1320, 1260, 1150 (CDC13) 1.21 (3H, t, J=8Hz), 1.81 (2H, t, J=8Hz), 2.33 (2H, t, J=8Hz), 3.17 (3H, s), 3.69 (2H, t, J=8Hz), 4.10 (2H, q, J=8Hz), 6. 80-7 . 60 (6H, in), 7.57 (IH, s) , 7.80 (IH, s) , 8.00 (IH, s) , 8.07 (IH, s) 54 o- 0~co" CHO 243-244.5 [Acetonitrile] 3360, 3440, 1658, 1620, 1610, 1520, 1450, 1330, 1210, 1150 (dg-DMSO) 3.24 (3H, s), 7.07-7.65 (8H, m) , 7.37 (IH, s), 7.76 (IH, s), 7.87-8.03 (2H, m), 9.11 (IH, s), 9.3 2 (IH, s), 10.05 (IH, s) 55 o- co- 1 COOEt H 232-233 [Acetonitrile] 3355, 3230, 1755, 1700, 1630, 1605, 1525, 1460, 1335, 1160 (dg-DMSO) 1.30 (3H, t, J=7.2Hz) , 3.24 (3H, s) , 4.31 (2H, q, J=7.2Hz), 7.09-7.51 (5H, m), 7.33 (IH, s), 7.75 (IH, s), 9.13 (IH, s) , 9.63 (IH, bs), 10.09 (1H, s) - Cont'd - Table 16 (Cont'd) 56 Q- Me Me 177-178 [Ethanol] 3230, 1635, 1615, 1485, 1455, 1340, 1280, 1160 (d,-DMSO) o 2.67 (6H, s) , 3.20 (3H, s) , 7.07-7.50 (5H, m), 7.34 (IH, s), 7.64 (1H, s), 7.89 (IH, s) , 10.0 (IH, s) 57 Q~ ^N- 191-192 [Ethyl acetate] 3150, 1620, 1600, 1480, 1420, 1340, 1275, 1210, 1150 (d,-DMSO) D 1.5-2.2 (4H, m), 3.13 (3H, s), 3.0-3.6 (4H, m), 7.07-7.49 (5H, ib) , 7.32 (IH, s) , 7.61 (IH, s), 7.75 (IH, s), 9.87 (IH, s) 58 o- H OH 113-115 [Ethyl acetate-benzene] 3280, 3240, 1620, 1560, 1480, 1460, 1320, 1300, 1215, 1135 (dg-DMSO+CDCl3) 2.97 (3H, s), 6.99-7.44 (5H, m), 7.53 (IH, s), 8.06 (IH, s), 8.14 (IH, s), 9.15 (IH, s), 10.80 (IH, bs) CD Table 17 5_0 r Me-SO-j-N H no.

R3 R4 R5 Melting point CC) IR (KBr) cm 1: 59 H -CHO 234-236 [Ethyl acetate] 3120, 3080, 1690, 1640, 1620, 1490, 1460, 1335, 1305, 1270, 1150 60 H -CHO 247-249 [Acetonitrile] 3080, 1680, 1630, 1610, 1485, 1450, 1330, 1300, .1250, 1200, 1150, 61 Me -conh2 o- 248-249 [Acetic acid] 3310, 3260, 1685, 1620, 1485, 1450, 1380, 1330, 1205, 1155 62 H -CONMe h 255-256 [Ethanol] 3250, 1680, 1610, 1540, 1480, 1450, 1325, 1150 63 H -CON<1 H u- 224-225 [Ethanol] 3250, 1670, 1610, 1485, 1455, 1325, 1150 64 H -CON\ -b O >250 [Acetonitrile] 1675, 1610, 1585, 1485, 1455, 1330, 1150 - Cont'd - Table 17 (Cont'd) 65 H -CONOMe H o- 247.5-248.5 [Ethanol] 3280, 3225, 1685, 1615, 1485, 1445, 1330, 1210, 1155 66 H Me -CONQ xMe o- 213-215 [Ethyl acetate] 3075, 1620, 1480, 1440, 1330, 1300, 1220, 1150 67 H -CO0 u- 204.5-205 [IPA] 1640, 1625, 1610, 1490, 1440, 1300 68 H -cos^D u- 216-218 [Ethanol] 3250, 1620, 1460, 1320, 1270 69 -cf3 H o 216-217 [IPA] 3275, 3050, 1665, 1620, 1490, 1460, 1335, 1220, 1165 70 Et H u- 187.5-188.5 [IPA] 3190, 1625, 1450, 1335, 1150 71 -i-Pr H o- 163-165 [IPA] 3260, 1650, 1630, 1485, 1455, 1330, 1215, 1145 72 -<3 H o 203-204 [Ethanol] 3120, 1620, 1455, 1370, 1330, 1205, 1150 73 H H o~ >250 [IPA] 1635, 1575, 1485, 1420, 1340, 1295 - Cont'd - CjQ Table 17 (Cont'd) 74 H H >250 [Dioxane] 3310, 3070, 1620, 1565, 1460, 1405, 1325, 1295, 1235 75 H H igr 192.5-193.5 [Ethanol] 3450, 1620, 1590, 1460, 1440, 1320, 1300 76 H H ^.COOMe 189-191 [Ethyl acetate] 3075, 1710, 1640, 1595, 1450, 1335, 1290, 1160 77 H H /CONHj Q- >250 [Acetonitrile] 3425, 3200, 1660, 1630, 1460, 1320, 1155 fS5 ro cn 4> oo NO.

R4 R5 z Melting point (°C) IR (KBr) cm 1: 78 H ^i-Pr o- 0 181.5-183.5 [Ethanol] 3250, 1640, 1620, 1480, L450, 1330, 1300, 1220, 11C0 79 H Me Me 0 157-158 [Ethanol] 3150, 1640, 1620, 1450, 1335, 1295, 1160 80 H Me p-Cr 0 160-161 [Ethanol] 3120, 1615, 1610, 1590, 1485, 1450, 1335, 1295, 1155 81 H a s 167.5-169 [2-Methoxyethanol] 3050, 1625, 1605, 1465, 1440, 1335, 1160, 1135 82 "="2^0 o- 0 182-183 [Ethanol] 3125, 1625, 1600, 1485, 1455, 1340, 1160 - Cont'd ■) Table 18 (Cont'd) 83 Et o- 0 120-121 [IPA] 3275, 3120, 1630, 1600, 1480, 1420, 1330, 1210, . 114 5 84 -u a 0 210-211 [Ethanol] 3170, 1610, 1590, 1480, 1420, 1155 85 -i-Pr Q- 0 155-156 [IPA] 3250, 1620, 1480, 1450, 1310, 1140 86 -NCHO H Me. 0 225-226 [Ethanol] 3270, 1620, 1605, 1455, 1325, 1150 87 -NCHO H ^Me 0 235-236 [Acetonitrile] 3250, 1680, 1610, 1480, 1450, 1330, 1180, 1155 88 -NCHO H Q- s >250 [Acetonitrile-DMF] 3270, 1620, 1600, 1440, 1325, 1150 89 -NAC H 0 233-234 [Acetonitrile] 3300, 1675, 1605, 1490, 1455, 1330, 1260, 1200, 1155 90 H -C=NOH o- 0 206-207 [Acetonitrile] 3240, 1620, 1490, 1455, 1335, 1260, 1160 M H vo / % - Cont'd - Table 18 (Cont'd) 91 H -C=NOH 0 226-227 [Acetonitrile] 3260, 3220, 1620, 1615, 1490, 1460, 1340, 1160 92 -CN F . 0 244-246 [Acetonitrile] 3140, 3070, 2240, 1655, 1620, 1490, 1460, 1330, 1320, 1270, 1150 93 -CN -d1 0 247-249 [Acetonitrile] 3120, 3070, 1645, 1620, 1480, 1450, 1330, 1150 i i—■ to Table 19 No.

Objective compound Melt i ng Point (°C) IR (KBr) -1 cm : NMR or 94 MeSO„-N H 0 0 182. 2-182.8 [Ethyl acetate] 3 200/ 3090, 1635, 1500, 1480 (d6-DMSO) 3.26(3H, s), 6,. 28 (IH, d, J = 6 H z ) , 7.18(111, s), 7.71 (1H, s), 7.20-7.66(3H, m), 8 . 25 (IH, d, J=l3Hz) , 10 .09 (1H, bs) 95 MeS09-H H 0 0 Me ^ Me 224 .6-225.6 I Ethyl acetate] 3200, 1625, 1605, 1460, 1355, 1340, 1260, 1220, 1200, 1155 (CDC13) 2.01(3H, s), 2 .39(3H, s), 3-10 ( 3 H , s) . 6.93-7.42 (6H, m) , 7 .67 CLH, s) , 7 - 5 9 (1H , s) 96 o°r MeSO_-N Ac 0 0 ) 166-169 [Ethanol] 1700,1640, 1620, 1480, 1445, 1360 1295, 1155 (cdci3) 2.12(3 H, s), 3 . 40(3H, s), 6. 30 (IH, d, J=i5Hz), 7.11-7.63(7H, in), 7.86(1H, d, J = 6Hz), 97 MeS09-N H 0 j/Me 164-165 [IPA] 1630, 1605, 1485, 1460, 1340, 1160 Table 19 (Cont'd) 98 MeSO,-N H 162-163 [Ethanol] 3440, 3330, 3180, 1600, 1580, 1550, 1480, 1465, 1330, 1205, 1150 (d,-DMSO) 6 3 .19(3 H , s), 5.50-7.00 (2H, br), 7.04-7.49(5H, m), 7.35(1H , s), 7.62(IH, s), 7 . 94(IH, s) 99 MeSO?-N NHCHO 236-238 [Aceto-nitri.le] 3340, 3260, 1680, 1615, 1600, 1485, 1460, 1340, 1210, 1150, (d r-DMSO) 6 3 . 24(3H, s), 7.09-7.62 (5H, m), 7.35{IH, s), 7 . 72 (IH, s), 8.36QH, s), 9.2 8(1H, s), 9 . 79(IH, s), 10 . 0 4(1H, s) 100 MeSO„-N H 185-186 [Aceto-nitrile] 1655, 1625, 1610, 1490, 1330, 1275, 1160 (dr-DMSO) 6 3.04(3H, s), 3.24(3H, s) , 7.09-7.62(5H, m), 7.34(1H, s), 7 . 7 6(1H , s), 8.09(IH, s ) , 8.63(1H, s), 10.07 (IH, s) 101 MeSO -H Z H NHMe 192.5-193 [Ethanol] 3350, 1600, 1560, 1415, 1275, 1200 , 3100, 1585, 1480, 1330, 1210, 1140 (d^-DMSO) 2 . 62(3H, s), 3.20(3H , s), 4.50-5.20(1H, br), 7.07-7.50(5H, m), 7.34(IH, s), 7.63(IH, s), 7 . 6 7(1H, s), 9 . 88(IH, s) if^S ro a> f ; / i ) Table 19 (Cont'd) 102 i/v MeSO_-N H 0 6 ^,NHEt 221-222 [Ethanol] 3340, 3100, 1580, .1555, 1480, 1420, 1215, 1140 (cdci3) 1. 2 9(3 H, t, J = 8Hz), 3.00 (2H, t, J=8Hz), 3.11(3H, s), 6.70-8.00(7H, m), 7.64 (IH, s) , 7.70 (IH, s) 103 u-°r MeSO_-H H 0 0 ^■NCOO Me 233-235 [Aceto-nitrile ] 3390, 3330, 1720, 1620, 1605, 1525, 1455, 1335, 1210, 1160 (d ,-DMSO) O 3 . 23(3H , s), 3.66(3!!, s), 7.09-7.50( 5H, m), 7.34(IH , s), 7 . 72{IH , s), 8.34(IH, s), 8.74(1H, s), .00(1H, s) 104 U"°£ MeSO^-N *" H 0 6 ^Br 215-216 [Acetonitrile J 3100, 3080, 1635, 1620, 1485, 1455, 1335, 1155 (d,-DMSO) 0 3.23(3!!, s), 7.06-7.66 (5H, m), 7.30(IH, s), 7.72 (IH, s), 8.8K1H, s), 10 . 07(IH, s) 105 MeS09-N H 0 6 ^C1 200-201 [Ethyl acetate-IPE ] 3220, 3050, 1645, 1600, 1560, 1480, 1450 F\3 FV> o> CO ! Table 19 (Cont'd) 106 o°r MeSO^-N H 0 e _^NCONH2 >250 [Acetic acid ] 3495, 3340, 3300, 1680, 1620, 1590 (d,-DMSO) 6 3.21{3H, S), 6.34(2H, s) 7.02-7.55(6H/ m), 7.69<1H, s), 8 . 02(IH, s) , 9.09 (IH, s), 9 . 9 0(1H, bs) 107 MeSO?-N H 0 e ^NCONH2 145-145.5 [Ethanol] 3450, 3350, 1640, 1620, 1480, 1450 (dg-DMSO) 2 . 95(3H, s), 3.20(3H, s), 5 . 85(2H, bs), 7.06-7.50 (6H, in), 7 . 70 (1H , s) , 8 . 4 3(1H, s), 10.00(1H, bs) 108 Q~°^c MeS0~-N Ac 0 6 V, 220-221 [Ethyl acetate] 3050, 1780, 1720, 1550, 1620, 1575 (dg-DMSO) 2.13(3H, s), 2.88(4H, s), 3.59(3H, s), 7.17-7.56 (6H, m), 8.27(1H, s), 8.63(IH, s) 109 Ov MeS0?-H H 0 0 NCHO Jch2 COOH 98-100 3220, 1730, 1665, 1610, 1490, 1445, 1335, 1205, 1160 (dg-DHSO) 3.22(3H, s), 4.25(2H, s) 7 .07-7.65(5H, m), 7.32(1H, s) , 7.76(IH, s), 8.19 (IH, s), 8.56UH, s), 10.00(1H, bs) rsj ro <y> 4>* CO Table 19 (Cont'd) 110 MeSO_-N Br H (hydrobromic acid salt form) 165 (dec.) 1620, 1480, 1450, 1350, 1260, 1200, 1150 111 i>°- MeSO--H H 0 Jl NHCHO Oc Br 237-238 [Ethyl acetate-IPE] 3170, 1670, 1635, 1610, 1475, 1440, 1325, 1260, 1200, 1150 (d,-DMSO) b 3.23(3H, s), 7.04-7.63 (5H, m), 7.23(IH, s), 7 . 7 3 (1H , s), 8.2K1H, s), 9.63(1H, s), 10 . .17 (1H, s) 112 U"°>Q MeSO_-N H 0 JL ^NHCHO Oc OMe 188 (dec.) [Aceto-nitr ile] 1675, 1610, 1560, 1450, 1320, 1260, 1205, 1140 (dg-DHSO) 3 . 19(3H, s), 4.17(3H, s), 7.04-7.6K5H, m), 7.29 (IH, s), 7.77(]H, s), 8 .16(1H, s), 9.07(1H, s), 10.06(IH, <;) 113 MeSO -M H ohr OH >250 (dec.) [Ethanol] 3350, 3280, 1695, 1670, 1620, 1565, 1370, 1340, 1145 NI' 1X2 a> CO Table 19 (Cont'd) 114 o-°- MeSO„-N L H 0 6 NHCHO CN 229-230 [Aceto-nitrile] 3260, 2225, 1715, 1610, 1485, 1460, 1330, 1215, 1150 (d6-DMSO) 3.28(3H, s), 7.07-7.62 (5H, m), 7 . 2 7(1H, s), 7 . 76(IH, S), 8.37(IH, d, J=3Hz), 10.22(IH, d, J = 3 H 2), 10.22(IH, s) 115 Q-°^ MeSO -N H 0 A ^0' r=\ f€ 238.5- 24 0 [Ethyl acetate-IPE ] 1640, .1615, 1575, 1475, 1440, 1425, 1410 lie i>0^ MeSO^-N H 0 A ^0 rM»<} 212-213 [Aceto-nitrile] 3240, 1645, 1620, 1580, 1485, 1455, 1340, 1265, 1160 (d ,-DMSO) 0 .3. 22 ( 3H, s), 6.9 2-7.59 (12H, m), 7.76(IH, s), 8. 58 (IH , s), 10.0K1H, bs) 117 o~°^c MeSO--N H 0 6 ^ CHO 210-215 (dec.) [Toluene-ethyl acetate] 3125, 3070, 1685, 1635, 1615, 1485, 1455, 1340, 1305, 1210, 1150 Table 20 No.

Objective compound Melting Point (°C) IR (KBr) cm *: 118 u-°^ MeSO„-N H 0 Jl COOEt u 167-168 [Ethanol] 3200/ 1745, 1620, 1450, 1335, 1310, 1160, 1070 119 0-3 MeS07-N H 0 A ^0' ^ COOH >250 [Acetic acid ] 3200, 1730, 1620, 14.60, 1330, 1.1 50 120 €>°r MeS09-N AC 0 6 .COOEt \ Me 166- 167.5 [IPA] 1730, 1705, 1640, 1615, 1435, 1340, 1230, 1160, 1155 121 {J~°NQ MeSO?-N 1 H 0 6 .COOH Me 238-241 [Acetic acid ] 3250, .1725, 1620, 1480, 1450, 1.375, 1330 ro ro CTi CO / Table 20 (Cont'd) 122 MeSO_-N H 0 A ^0" .c°nh2 >250 [Acetic acid ] 3350, 1620, 14 8 5, 1340, 1705, 158 5, 14 60, 1160 123 ^~°X.1 MeSO,-M H 0 j/ac 175-177 [Ethanol] 3220, 1640, 1485, 1330, 1210, 1680, 1620, 1450, 1295, 1155 124 MeS07-H h 0 0 I COOEt 155-156 [Ethyl acetate-IPE] 3235, 1645, 1485, 1360, 1145 1740, 16 20, 1-450, 1 250, 125 °"°X) MeS09-N H 0 6 Is COOH >250 [Ethanol] 3245, 1625, 1460, 1220, 1 7 30 , 1 590, 1 335, 1160 no r\3 a> Table 20 (Cont'd) 126 MeS0--N H 0 0 C0NH2 >250 [Methanol 3 3425, 1700, 1645, 1625, 1450, 1325, 1210, 1135 127 MeS09-H H 0 d I CH20H 210-215 (dec.) {Ethyl acetate] 3375, 3240, 1630, 1585, 1480, 1455, 1395, 1370, 1325, 1260, 1210 128 ox MeS0?-H H 0 0 \ NCOOEt H 207-209 [Ethanol] 3230, 1740, 1620, 1535, 1480, 1450, 1325, 1210, 1140 129 o-°r MeS0?-N H 0 6 ^NCOOt-Bu H 147-150 [Benzene] 3250, 1745, 1620, 1525, 1490, 1450, 1360, 1330 1230, 1140 ro o> .4>» J-4.-N Table 20 (Cont'd) 130 i>0^ MeSO--H Z H 0 A ^0' I NHCHO 214-216 [Acetonitrile] 3225, 3120, 1710, 1625, 1610, 1555, 1450, 1215, 1150, 1145 131 o-°r MeS0_-H H 0 \ NHAc 236-238 [Ethanol] 3170, 1700, 16 20, 1600, 1525, 1450, 1350, 1250, 1240, 1220, 1145 132 i>°r MeSO--N H I NH2 223-225 [Ethanol] 32 25, 16 60, 1615, 1550, 14 80, 1200, 1145 133 F MeS0--M H 6 I Me 180-181 [IPA] 3100, 1640, 1605, 1500, 1460, 1390, 1360, 1160, 1140 rsi rsa 4>-CO \ Table 20 (Cont'd) 134 MeS0--N H ch2OH 165-166.5 [Ethyl acetate-diethyl ether] 3450, 3250, 16 35, 1605, 1485, 14 60, 1325, 1210, 1150 135 MeS09-N H CH = CH 174-175 [Ethanol] 3400, 1630, 1620, 1480, 1450, 1330, 1200, 1155 136 MeSO?-N H CHCH. 136-138 [Ethyl acetate] 3325, 3225, 1615, 1590, 1480, 1445, 1325, 1205, 1145 137 MeS09-N H CH?NAc H 240-242 [IPA] 3350, 3250, 1680, 1640, 1600 , 14150, 1340, 1215, 1150 fNj r\o cr> Table 20 (Cont'd) 0 138 MeSO^-M * H 0 j/CH2NH2 190-195 (dec.) (Ethyl acetate] 3450, 3070, 1635, 1500, 1480, 1455, 1385, 1320, 1275 139 o-x HeSO--N H 0 0 >250 [Acetonitr ile] 3260, 1635, 1620, 1480, 1450, 1315, 1200, 1150 140 MeSO--M H >250 [Acetonitr ile] 3530, 3400, 3300, 1680, 1620, 1560, 1480, 1330, 1225, 1140 141 O-0r MeS09-N Z H 0 e Me ^N=CHNV ^ Me 103-104 [Diethyl ether] 1630, 1580, 1470, 1430, 1330, 1190, 1140 ro rv> Table 20 (Cont'd) 142 o °v^ MeSO ^ H A NCCHMe fnlll J OOH 219.5-221.5 [Ethanol] 34 50, 3350, 3250, 1680, 1620, 1590, 1520, 1480, 1460, 1380, 1340, 1260, 1220, 1200, 1160 143 MeSO -N H 6 NCCHMe fHlll J ONH2 111-113 (dec.) [Ethanol] 3250, 1680, 1620, 1500, 1350, 1210, 1160 144 i>°v- MeSO 1 H 0 6 NS0oMe 199-200 [Ethanol] 3240, 1640, 1630, 1500, 1340, 1330, 12L0, 1150 145 L A— Owv MeS09-N H 0 ^0^ OH OMe A—OMe 222-223.5 [Acetonitr ile] 3225, 1630, 1490, 1320, 1210, 1160, 1120 ro ro C7> -IS.

} Table 20 (Cont'd) 146 COOH i°V^ MeSO„-N H 6 243-246 [Acetonitrile] 3150, 1720, 1670, 1640, 1605, 1430, 1360, 1330, 1260, 1220, 1160 147 NH HeSO--N H & 238-240 (Acetonitr ile] 3415, 3300, 3200, 1635, 1620, 1455, 1330, 1290, 1155 148 NHAc ^~°1C H 6 130-132 [Ethanol] 3250, 1620, 1480, 14 50, 1325, 1290, 1150 149 NHCHO (fv MeS0?-N'/^^ H 6 203-204 [Acetonitr ile] 3220, 1665, 1620, 1490, 1450, 1320, 1295, 1150 Table 20 (Cont'd) 150 MeS09-N z H MeO 151 MeSO^-N H 152 MeSO--N L H 153 MeSO.-N H 122.5-123.5 [Ethanol-IPE] 122-124 [Ethanol] 183.5-184.5 [Ethanol-DHF] 186.5-187 [IPA] 3220, 1620, 1490, 1450, 1325, 1290, 1150 3080, 1620, 1495, 1455, 1335, 1295, 1200, 1160 3170, 1620, 1455, 1330, 1160, 1140 3250, 1620, 1585, 1480, 1450, 1320, 1290, 1160 1140 ro ro a> JS.

Table 20 (Cont'd) 154 155 156 157 MeS09-N H MeS09-H H MeSO~-N i H MeSO--N 1 H MHCHO CH=NOH CONH. 226.5-227 [Ethyl acetate] 199-200 [Ethanol) 219.5-220.5 [Ethanol] 249-251 [Acetic acid ] 32 80, 16515, 1620, 1600, 1495, 14 00, 1335, 1145 3250 y 1620, 1495, 1330, 1210, 11150 3140, 2240, 1650, 1620, 1485, 1455, 1330, 1155 3330, 3260, 3150, 1695, 1620, 1490, 1455, 1330, 1285, 1155 IN* o> CD Table 20 (Cont'd) U) -J 158 f phU^°Y"~ MeSO.-N^^ h i conh » >250 [Acetic acid] 3380, 334 0, 1720, 1670, 1660, 1620, 1500, 1465, 1335, 1300, 1155 159 O~0V^ MeSO^-N h i c 228-230 (dec.) [Acetonitrile| 3300, 1755, 1740, 1620, 1600, 1535, 1485, 1440, 1390, 1330, 1205, 1145 160 i>0^ MeS09-N h 6 j/n02 225-227 [Acetonitrile] 3170, 3070, 1670, 1620, 1480, 1450, 1330, 1300, 1150 161 , v 0 ch9=chso9-n 0 I H 233-234 [Acetoni tr ile] 3270, 1635, 1620, 1600, 1460, 1340, 1220, 1150 fsS ro 0> -jSs cn / Table 20 (Cont'd) 162 MeSO~-H Ac 176-178 f IPA] 1705, 1640, 1620, 1440, 1335, 1295, 1245, 1165 163 Oy MeSO„-N Ac 0 Jl .NHCHO u 237-239 [Acetonitrile] 3320, 1705, 1685, 1610, 1520, 1435, 1440, 1345, 1240, 1215, 1190, 1160 164 o-°r MeSO.-N"^^ Bz 0 6 164-165.5 {Ethyl acetate] 1685, 1650, 1610, 1475, 1435, 1360, 1285, 1260, 1200, 1160 165 ^°)o5 MeS0--N u Me 187-189 [Ethanol] 1630, 1610, 1480, 1440, 1340, 1150 rsi ro CD Table 20 (Cont'd) 166 167 168 169 MeS0_-H H HeS09-N Z H MeSO.-N H MeSO -N H (CH2)3 N N CONH Jl^N H O-0v-A O- N N , II II CONH N''N H 209-210 [Acetonitrile] 192-193 [Ethanol] >250 [Ethanol] >250 [2-Methoxy-ethanol] 3300 j 324 0, 1680, 1620, 1610, 14(50, 1340, 1160 1680, 1635, 1610, 1435, 1335, 1230, 1160 3350, 1630, 1620, 1580, 1495, 1465, 1310, 1220, 1170 3120, 1630, 1570, 1370, 1200, 1690, 1590, 1450 , 1325, 1140 F^S> ro CD -is Table 20 (Cont'd) 170 MeS0_-N H >250 [Dioxane-IPE] 3370, 3170, 1630, 1480, 1460, 1340, 1295, 1160 171 MeSO9-N H CONH. >250 [Acetonitrile] 3460, 3125, 1570, 1475, 1220, 3380 , 1640 , 1545, 1320, 1150 r\S ro cn «£n CO 0 0 R filNB &WH Example 5 (1) 3 g of 4-( 2 , 4-dif luorophenoxy )-3-rnethylsulfonyl- aminophenol was dissolved In 15 ml of N,N-dimethylformamide, 420 mg of sodium hydride (purity: 60%) was added. The mixture was stirred for 20 minute"? at 2Q-25°C. Then, 0.88 g of methyl propiolate was added dropwise in about 5 minutes so that the reaction temperature was maintained below 40°C. The mixture was stirred for 30 minutes at 30-40°C. After the completion of the reaction, 50 ml of water and 50 ml of ethyl acetate were added thereto. The resulting mixture was adjusted to pH 4 with 4N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (eluant: a 20 : 1 mixture of toluene and ethyl acetate) to obtain 1.2 g (yield: 31.6%) of methyl trans-3-[4-(2,4-di fluorophenoxy)-3-methylsulfonylaminophenoxy]aerylate. Melting point: 98.5-98.9°C (recrystallized from ethyl acetate-diisopropyl ether) IR (KBr) cm-1: 3180, 1700, 1645, 1600, 1485, 1335 NMR (CDC13) 6: 3.07(3H, s), 3.73(3H, s), 5.55(1H, d, J=12Hz), 6.70-7.40(7H, m), 7.70(1H, d, J=12Hz) The compounds shown in Table 21 were obtained in the same manner.

Table 21 Objective compound Melting Point (°C) IR (KBr) cm ^: NMR (CDC13) <5: C/h-0 COOMe MeS09-N 1 H 101-103 [Ethyl aceta te-IPE] 3250, 1700, 1645, 1607, 1490, 1340, 1220, 1163, 1145, 1120 3.0K3H, s), 3 . 7 3 ( 3 H, s), 5 .50(IH, d, J = 12Hz), 6.60-7.40(9H, m), 7.70 (IH, d, J=12Hz) C~\~ 0 MeOOC XU cf-.-so9-n H 140-143 [Ethyl acetate-IPE] 3060, 1695, 1640, 1485, 1378, 1230, 1205, 1190, 1160, 1140 3.3 7(3 H, s), 5.20(IH, d, J = 6H2), 6.72-7.42(10H, m) ,—> COOEt °"°Xk£ MeS09-N Me H 90.5-91.1 [ IPE] 3250, 1700, 1620, 1495, 1405 1.23(3H, t, J=7Hz), 2.46(3H, s), 3.00(3H, s), 4.1K2H, q, J=7Hz), 4.95(IH, s ) , 6.5 5-7.55(9H, m) C )r- S COOMe MeS09-N H 102-103 3250, 1700, 1645, 1585, 1565, 1480, 1330, 1175, 1140, 1120 2 . 98(3H, s), 3 . 7 5(3 H, s), 5.65(IH, d, J=12Kz), 7.80(IHf d, J=12Rz ) , 6 . 20-8 . 50(7H, m), 8 . 58(IH, bs) 22 6 4 (2) 24 ml of a IN aqueous sodium hydroxide solution was added to 1.2 g of methyl trans-3-[4-(2,4-difluoro-phenoxy)-3-methylsulfonylaminophenoxy]acrylate. The mixture was stirred for 1 hour at 20-25°C. 30 m.l o£ ethyl acetate was added thereto. The resulting mixture was adjusted to pH 4 with 4tJ hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 1.0 g (yield: 87.0%) of oily trans-3-[4-(2,4-difluocophenoxy)-3-methylsuIfonylaminophenoxvjacrylic acid .

IR (neat) cm"1: 3250, 1690, 1600, 1485 NMR (CDC13) <5: 3 . 07 ( 3H) , s), 5.52(1H, d, J = 12Hz), 6.70-7.04 (7H, rn), 7.79UH, d, J=12Hz) The compounds shown in Table 22 were obtained in the same manner.

Table 22 h-> & Objective compound Melting Point (°C) IR (KBr) cm ^ : NMR 6: Clh 0 .COOH XX./ meso_-n H 110-111 (dec.) 3250, 1670, 1635, 1600, 1490, 1343, 1190, 1155 (dg-DKSO) 2 . 9 9(3 H, s), 5 . 4 0(IH, d, J = 12 H z ) , 6.84-7.^)6(89, m), 7 . 70(IH, d, J=12Hz), 8.40(1H, bs) rVo, HOOC CF,-SO?-N h 190-193 [Ethyl acetate] 3150, 1680, 1625, 1490 1230, 1210, 1185 (CDC1 -,+dc-DMSO) D .15(1H, d, J = 6H;:), 6.7 5-7. 58(9H, in) meso -n H COOH Ok me 153.6-154.1 [Ethyl acetate-IPE] 1680, 1600, 1490, 1330 (cdc1 -j) 2.47(3H, s), 3.02(3H, s), 4.9 4(1H, s), 6.55-7.55(9H, m) /=N Q-sx MeSO_-H H COOH 174-176 1680, 1650, 1580, 1480, 1320, 1180, 1125 (cdci3) 3. 0 0(3 H, s), 5.60(1H, d, J=12Hz), 7 . 75(1H, d, J=12Hz), 6.70-8.50(7H, in) O 1 2 26435 (3) 30 g of polyphosphoric acid was added to 1.0 g of trans-3-(4-(2,4-difluorophenoxy)-3-methy1sulfonyl-aminophenoxyJacrylic acid. The mixture was stirred for 1 hour at 55-65°C. The reaction mixture was introduced into 200 nl of ice water. 5Q ml of ethyl acetate was added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 5 : 1 mixture of toluene and ethyl acetate) to obtain 0.4 g (yield: 42.0%) of 6-(2,4-di fluorophenoxy)-7-methylsulfonylami no-4H-1-benzopyran-4-one.

Melting point: 182.2-182.8°C (recrystallized from ethyl acetate) IR (KBr) cm"1: 3200, 3090, 1635, 1500, 1480 NMR (dg-DHSO) 5: 3.26(3H, s), 6.28(1H, d, J=6Hz), 7.18(1H, s) , 7.7K1H, s), 7.20-7.66(3H, m), 8.25(1H, d, J=6Hz), .09QH, bs) Example 6 The compounds shown in Table 23 were obtained in the same manner as in Example 5(3).

The physical properties of these compounds were identical with those of the compounds in Examples 1 to 4> o h <■ - 145 - I' Oi '22 6 4 8 Table 23 R1 R2 R3a R4a R5 Z Me H H H O 0 Et H H H o- 0 -CF 3 H H H Q- 0 Me H Me H O- 0 Me H H H Q- 0 Me H -o H O 0 Me H H H O- H N Me ■ H H H CF O- 0 Me H H H 9- 0 Table 23 (Cont'd) He H H H F d- 0 Me H H H f>=v. 0 Me h H H >o 0 Me H H H d-1 0 Me H H H t—\ ci"0~ 0 Me H H H Me d- 0 Me H H H "e-Q- 0 o- H H H o 0 Me H H -CHO & 0 Me H H -CHO F f-Q- 0 Me H Me -conh2 o- 0 Me h H -CONMe n o- 0 Table 23 (Cont'd) "22 6 4 Me h h -con-<] h o- 0 Me h h -COM ~/q) h n. 0 Me h h -COMOMe h Q- 0 Me h h Me -com' Me O- 0 Me h h -c°0 o- 0 Me h h -"--O o 0 Me h -CF ^ 3 h o 0 Me h Et h G- 0 Me h -i-Pr h o- 0 Me h -<] h o- 0 Me h h h O 0 Me h h h 0 Table 23 (Cont'd) 122 6 4 8 He H H H 0 He H Ii H C02Me A. 0 4 Me H H H CONH2 o- 0 He H H H i-Pr 0 He H H H Me Me 0 Me H H H Me F~€5~ 0 Me H H H o- s Me H ' H "CH2-0 o 0 Me H H Et o 0 Me H H -o o- 0 Me H H 1 p-1 i-i o- 0 Me H H -CN d-F 0 Z2 6 4 Table 23 (Cont'd) Me H H -CM 0 Me H MG Me <TV 0 Me Ac H H o- 0 Me H H Me o 0 Me H H -CHO o 0 Me H H -COOEt o- 0 Me H H -COOH o- 0 Me Ac Me -COOEt o 0 Me H Me -COOH o- 0 Me H H -CONH2 o- 0 Me H H Ac o- 0 Me H Me H F 0 ?2 6 4 Table 23 (Cont'd) He h h -ch2oh o 0 Me h h -ch Me 1 oh 0 He h h h cooh d- 0 Me h h h 0 He h h h h NAc d- 0 Me h h h h ncho <3- 0 Me h h h OMe d- 0 Me h h h Me0~O~ 0 Me h h h Me 0- 0 Me h h h 0 Me h h -cn o 0 \\ ,C\' ,Vv Pi " 22 6 4 8 Table 23 (Cont1d) Me h H -COtlH 2 f c5- 0 Me h ri -CONH ^ 0 ch2=ch- h h h o- 0 Me Ac h h K5-p 0 Me Bz h h o 0 Me Me h h o 0 Me h h n-nv -con-< > h h o 0 9 0 c / *- <- W *t 0 1 Example 7 In 70 ml of toluene was suspended 3.4 g o£ methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone. 17 ml o£ ethyl formate was added thereto.

Further, 3.4 a oi: sodium hydride {purity; 60%) was added thereto in portions in 20 minutes. The mixture was refluxed for 5 hours. The reaction mixture was introduced into 300 ml of ice water. The aqueous layer was separated and adjusted to pH 4 with 4N hydrochloric acid. The mixture was then extracted with two 100-ml portions of ethyl acetate. The extracts were combined and subjected to distillation under reduced pressure to remove the solvent. The residue was dissolved in 20 ml of acetic acid. 1 ml of concentrated hydrochloric acid was added.

The mixture was heated for 30 minutes at 50-60°C. 200 ml of water was added thereto. The resulting mixture was extracted with 200 ml of ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from acetonitrile to obtain 2.28 g (yield: 65%) of 7-methylsulf onylamino-6-phenoxy-4H-l-benzopyran-4-one having a melting point of 216 . 7-217.6°C.

IR (KBr) cm"1: 3110, 1620, 1585, 1560, 1485, 1465, 1440, 1320, 1140 22 6 4 8 1 Example 8 There were mixed 3.21 g of methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone, 5.45 g of acetic anhydride and 4..1 g of sodium acetate. The mixture 5 was stirred Cor 1.5 hours at 130-140°C. The reaction mixture was cooled to room temperature. 200 ml of ethyl acetate and 100 ml of water were added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, 10 and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to obtain 860 mg (yield: 25%) of 2-methyl-7-methyl-sulfonylamino-6-phenoxy-4H-l-benzopyran-4-one having a 15 melting point of 186.5-187°C.

Example 9 In 16 ml o£ ethyl orthoformate was suspended 3.21 g of methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone. To the mixture being ice-cooled was 20 dropwise added 2.15 g of a 70% aqueous perchloric acid solution in 10 minutes. Stirring was conducted for 30 minutes at 20-25°C. 50 ml of diethyl ether was added thereto. The resulting crystal was collected by filtration. The crystal was mixed with 50 ml of water, and the 25 mixture was refluxed for 2 minutes and then cooled to room temperature. The resulting crystal was collected by filtration and recrystallized from acetonitrile to obtain 226 Q 1 2.90 g (yield: 87.6%) of 7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one.

The properties (melting point, IR and NMR) of this compound agreed with those of the compound obtained i n P vannl a 1 I 1 \ —• ^ • I V .fc \ W / » Example 10 (1) In 500 ml of toluene were suspended 26.0 g of methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone and 52 ml of ethyl formate. Thereto was added 16.3 10 g of sodium hydride (purity: 60%) in portions in 30 minutes at 50-60°C. The mixture was refluxed for 2 hours. The reaction mixture was introduced into 500 ml of \ ' ice water. The mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer was separated, 15 washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting oily matter was purified by a column chromatography (eluant: a 3 : 1 mixture of 20 toluene and ethyl acetate) to obtain 25 g (yield: 88.7%) of 2-(2-hydroxy-4-methy1su1fonylami no-5-phenoxybenzoyl)-acetaldehyde.

Melting point: 121-123°C (recrystallized from ethyl acetate) (2) 25 g of 2-(2-hydroxy-4-methylsulfonylamino-5- phenoxybenzoyl)acetaldehyde was dissolved in 260 ml qjK"'; benzene and 130 ml of N,N-dimethylformamide. Thereto'was £.2 o 1 added 26 ml of: N ,N-dimethylformamide d imetihylacetal. The mixture was stirred for 8 hours at room temperature. The reaction mixture was introduced into a mixture consisting of 200 ml of ethyl acetate and 200 m.l of water. The 5 organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting oily matter was purified by a column chromato-10 graphy (eluant: a 20 : 1 mixture of toluene and ethyl acetate) to obtain 13 g (yield: 50.4%) of 3-formyl-7-methylsu1fony1amino-6-phenoxy-4 H-l-benzopy ran-4-one.

Melting point: 210-215°C (decomposed) (recrystallized from toluene-ethyl acetate) 15 IR (KBr) cm-1: 3125, 3070, 1685, 1635, 1615, 1485, 1455, 1340, 1305, 1210, 1150 Example 11 (1) 50 g of methyl 2-hydroxy-4-methylsulfonylamino- -phenoxypheny1 ketone was dissolved in 1 liter of 20 H, N -dime thy If o rmami de . Thereto v/as added 13.7 g of sodium hydride (purity: 60%) in portions in 30 minutes at 20-40°C. The mixture was stirred for 1 hour at 30-40°C. Thereto was added 29.3 g of benzyl bromide in portions in 1 hour at 10-15°C. Then, stirring was effected for 1 hour 25 at 20-25°C, The reaction mixture was mixed with 500 ml of ethyl acetate and 500 ml of water. The aqueous layer was separated. It was mixed with 500 ml of ethyl acetate. 1 The mixture was adjusted to pH 2 with concentrated hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium 5 sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from toluene to obtain 32.4 g (yield: 50.7%) of methyl 2-benzyloxy-4-methylsulfonylami no-5-phenoxyphenyl ketone having a melting point of 132-134°c.

IR (KBr) cm"1: 3225, 1660, 1500, 1420, 1335, 1215, 1160 (2) There were mixed 4.11 g of methyl 2-benzyloxy- 4-methylsulfonylamino-5-phenoxyphenyl ketone, 20.6 ml of diethyl carbonate, 20.6 ml of N,N-dimethylformamide and 1.6 r g of sodium hydride (purity: 60%). The mixture was 15 stirred for 30 minutes at 90-100°C. The reaction mixture was introduced into 200 nl of ice water. The resulting mixture was washed with 50 ml of diethyl ether. The aqueous layer was separated, adjusted to pH 5 with 4N hydrochloric acid, and extracted with two 100-ml portions 20 of ethyl acetate. The extracts were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromato-25 graphy (eluant; a 3 : 1 mixture of toluene and ethyl acetate) to obtain 4.35 g (yield: 90%) of ethyl 2-(2-benzyloxy-4-me t hy 1 sul f onylami no-5-phe no xy benzoyl) acetate ^ ^ 1 Melting point: 85-90°C (recrystallized from diisopropyl ether) IR (KBr) cm-1: 3325, 1740, 1655, 1605, 1495, 1425, 1395, 1340, 1200, 1160, 1120 5 (3) In 50 ml o£ ethanol was dissolved 4.63 g of ethyl 2-(2-benzvloxy-4-methylsulfonylami no-5-phenoxy-benzoyl )acetate. Thereto was added 200 mg of 5% palladium-carbon. The mixture was subjected to hydrogenation for 1 hour at 40°C at atmospheric pressure. 1"0 After the completion of the reaction, the catalyst was removed by filtration. The filtrate was subjected to distillation under reduced pressure to remove the solvent. The residue was mixed with diisopropyl ether. t ' The resulting crystal was collected by filtration and 15 recrystallized from a nixed solvent of ethyl acetate and diisopropyl ether to obtain 3.46 g (yield: 88%) of ethyl 2-(2-hydroxy-4-methylsulfonylamino-5-phenoxybenzoyl)-acetate having a melting point of 111.5-112.5°C.

IR (KBr) cm"1: 3330, 1740, 1640, 1490, 1345, 1210, 20 1160, 1120 (4) 3.93 g of ethyl 2-(2-hydroxy-4-methylsulfonyl- amino-5-phenoxybenzoylJacetate was dissolved in 40 ml of N,N-dimethylformamide. Thereto was added 2.60 g of N,N-dimethylformamide dimethylacetal. The mixture was 25 stirred for 1 hour at 20-25°C. The reaction mixture was introduced into 200 ml of water. The resulting mixture was adjusted to pH 5 with 4N hydrochloric acid and then extracted with 100 ml of ethyl acetate. The extract was 22 6 4 1 washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from 5 ethanol to obtain 3.55 q (yield: 88.1%) o£ 3-ethoxv- carbonyl-7-methvlsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one having a melting point of 167-168°C.

IR (KBr) cm"1: 3200, 1745, 1620, 1450, 1335, 1310, 1160, 1070 (5) 80 ml of dioxane and 40 ml of 6N hydrochloric acid were added to 4.03 g of 3-ethoxycarbonyl-7-methyl-sulfonylamino-6-phenoxy-4H-l-benzopyran-4-one. The mixture was refluxed for 30 minutes. The reaction mixture was cooled. 200 ml of water was added thereto. The 15 resulting crystal was collected by filtration, washed with water and recrystallized from acetic acid to obtain 3.41 g (yield: 91%) of 3-carboxy-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one having a melting point of >250°C.

IR (KBr) cm"1: 3200, 1730, 1620, 1460, 1330, 1150 Example 12 (1) 2.55 ml of acetic anhydride was added to 850 mg of ethyl 2-(2-hydroxy-4-methylsulfonylamino-5-phenoxy-benzoyl)acetate and 540 mg of sodium acetate. The mixture was stirred for 10 minutes at 110-120°C. The reaction 25 mixture was introduced into a mixture of 20 ml of ethyl acetate and 20 ml of water. The resulting mixture was o 226 1 adjusted to pH 2 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under rcduced pressure. The residue was purified by a column chromatography (eluant: a 5 : 1 mixture of toluene and ethyl acetate) to obtain 550 mg (yield: 55.6%) of 7-(N-acetyl-N-methylsulfonylamino)-3-ethoxycarbony1-2-methy1-6-phenoxy-4H-l-benzopyran-4-one. 10 Melting point: 166-167.5°C (recrystallized from isopropyl alcohol) IR (KBr) cm"1: 1730, 1705, 1640, 1615, 1435, 1340, 1230, 1160, 1155 \ ' (2) 10 ml of dioxane and 10 ml of 6N hydrochloric acid were added to 500 mg of 7-(N-acetyl-N-methyl- sulfonylami no)-3-ethoxycarbonyl-2-methyl-6-phenoxy-4H-l-benzopyran-4-one. The mixture was refluxed for 20 minutes. The reaction mixture was cooled to 5-10°C. 30 ml of water was added thereto. The resulting crystal was 20 collected by filtration and recrystallized from acetic acid to obtain 400 mg (yield: 95.2%) of 3-carboxy-2-methy1-7-methylsulfonylami no-6-phenoxy-4H-l-benzopyran-4-one having a melting point of 238-241°C.

IR (KBr) cm"1: 3250, 1725, 1620, 1480, 1450, 1375, 1330 Example 13 (1) There were mixed 3.21 g of methyl 2-hydroxy-4- methylsulfonylamino- 5-phenoxypheny1 ketone, 50 ml of ethyl 22 6 4 8 1 acetate and 3.2 g of sodium hydride (purity: 60%). The mixture was refluxed for 4 hours- The reaction mixture was introduced into 200 ml of ice water. The aqueous layer was separated, adjusted to pH 4 with 4tJ hydrochloric 5 acid and extracted with two 50-ml portions of ethyl acetate. The extracts were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced 10 pressure. The residue was mixed with toluene. The resulting crystal was collected by filtration and recrystallized from a mixed solvent of ethyl acetate and diisopropyl ether to obtain 2.65 g (yield: 73%) of 2-(2-hydroxy-4-methylsulfonylamino-5-phenoxybenzoy1)acetone 15 having a melting point of 142-143°C.

IR (KBr) cm-1: 3230, 1620, 1580, 1490, 1345, 1320, 1250, 1220, 1160, 1130 (2) 3.63 g of 2-(2-hydroxy-4-methylsulfonylamino-5- phenoxybenzoyl)acetone was dissolved in 18 ml of 20 N , N-dimethylf o rmamide . Thereto was added 2.62 g of N,N-dimethylformamide dimethylacetal. The mixture was stirred for 1 hour at 20-25°C. The reaction mixture was introduced into 100 ml of water. The resulting mixture was adjusted to pH 5 with 4N hydrochloric acid and then 25 extracted with 100 ml of ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethanol to obtain 2.38 g (yield: 64%) of 3-acetyl-7-methy lsu1fonylamino-6-phenoxy-4H-l-benzopyran-4-one having a melting point of 175-177°C.

IR (KBr) cm-1: 3220, 1680, 1640, 1620, 1485, 1450, 1330, 1295, 1210, 1155 Example 14 .0 g of methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone was suspended in 85 ml of ethanol. Thereto was added 4.5 ml of diethyl oxalate. Further, 3.1 g of sodium hydride (purity: 60%) was added thereto in portions in 10 minutes. The mixture was refluxed for 1.5 hours. The reaction mixture was introduced into 300 ml of ice water. The resulting mixture was adjusted to pH 2 with 4N hydrochloric acid. The resulting crystal was collected by filtration and then suspended in 50 ml of acetic acid. 1 ml of concentrated hydrochloric acid was added thereto. The mixture was stirred for 10 minutes at 80°C. After the completion of the reaction, 200 ml of water and 200 ml of ethyl acetate were added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and diisopropyl ether to obtain 3.5 g (yield: 56%) WO LC U 1 of 2-e thoxyca rbonyl-7-me t hylsu 1 Cony lam in 0-6 -phenoxy-4 H-l -benzopyran-4-one having a melting point of 155-156°C. IR (KBr) cm"1: 3235, 1740, 1645, 1620, 1485, 1450, 1360, 1250, 1145 Example .15 1.06 ml of acetic anhydride was added to 2.0 g of methyl 2-hydroxy-4-methylsulfonylamino-5-(2,4-difluoro-phenoxy)phenyl ketone and 550 mg of sodium acetate. The mixture was refluxed for 1 hour. The reaction mixture was 10 introduced into a mixture of 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated and washed with water. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 20 ml of ethanol. 12 ml of a IN aqueous sodium hydroxide solution 15 was added thereto. The mixture was refluxed for 10 minutes. The reaction mixture was introduced into a mixture of 50 ml of ethyl acetate and 50 ml of water. The resulting mixture was adjusted to pH 2.0 with 4N hydrochloric acid. The organic layer was separated, washed 20 with water, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 10 : 1 mixture of toluene and ethyl acetate) to obtain 300 mg (yield: 14.4%) of 7-methyl-25 sulfonylamino-2-methyl-6-(2,4-di fluorophenoxy) - 4H-1-benzopyran-4-one. 22 6 4 8 9 1 Melting point: 13Q-181°C (recrystalLized from isopropyl alcohol) IR (KBr) cm-1: 3100, 1640, 1605, 1500, 1450, 1390, 1360, 1160, 1140 Example 16 3.93 g of ethyl 2-(2-hydroxy-4-methylsulfonyl-amino-5-phenoxybenzoy1Jacetate was dissolved in 20 ml of II,N-dimethylformamide. Thereto was added 880 mg of sodium hydride (purity: 60%). The mixture was stirred for 30 10 minutes at 25-30°C. The reaction mixture was introduced into 100 ml of ice water. Thereto was added 50 ml of diethyl ether. The aqueous layer was separated, adjusted to pH 5 with 4IJ hydrochloric acid, and extracted with two 50-ml portions of ethyl acetate. The extracts were 15 combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from acetonitrile to obtain 3.05 g (yield: 87.9%) of 20 2-hydroxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of >250°C.

IR (KBr) cm"1: 3530, 3400, 3300, 1680, 1620, 1560, 1480, 1330, 1225, 1140 Example 17 (l) in 25 ml of methanol were suspended 2.0 g of methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl o 226 1 ketone and 1.03 g of 3,4-dimethoxybenzaldehyde. Thereto was added 5 ml of 50% aqueous sodium hydroxide solution. The mixture was stirred for 3 hours at room temperature. The reaction mixture was introduced into a mixture of 20 ml of 5 ethyl acetate and 20 ml of water. The resulting mixture was adjusted to pH 2.0 with 4N hydrochloric acid. The resulting crystal was collected by filtration, washed with water and ethyl acetate in this order# and recrystallized from acetic acid to obtain 2.2 g (yield: 75.6%) of 10 2-(3,4-dimethoxyphenyl)vinyl 2-hydroxy-4-methylsulfonyl-amino-5-phenoxyphenyl ketone.

Melting point: 210-212°C (recrystallized from acetic acid) IR (KBr) cm"1: 3520, 3250, 1625, 1490, 1340, 1155, 1120 I5 (2) 2.0 g of 2-(3,4-dimethoxyphenyl)vinyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone was suspended in 20 ml of methanol. Thereto was added 3.7 ml of a 15% aqueous sodium hydroxide solution to obtain a solution. Thereto was dropwise added 2.5 ml of a 15% aqueous 20 hydrogen peroxide solution in 10 minutes at 0-5°C. The mixture was stirred for 10 hours at the same temperature. The reaction mixture was introduced into a mixture of 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with water, and dried with anhydrous 25 magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by \.X "£' 0 a column chromatography (eluant: a 200 : 1 mixture of chloroform and methanol) to obtain 220 mg (yield: 10.7%-)* I , o 2648 1 of 3-hydroxy-7-methylsulfonylanuno-2-( 3, 4-dimethoxy~ phenyl) -6-phenoxy-4H-l-benzopyran-4-one.

Melting point: 222-223.5°C (recrystallized from acetoni trile) IR (KBr) cm"1: 3225, 1630, 1490, 1320, 1210, 1160, 1120 Example 18 (1) 3.47 g of 2-hydroxy-7-methylsulfonylai7iino-6- phenoxy-4H-l-benzopyran-4-one was suspended in 50 ml of acetic acid. Thereto was added 1.67 ml of concentrated 10 nitric acid (specific gravity: 1.38). The mixture was stirred for 20 minutes at 100-110°C. The reaction mixture was introduced into 300 ml of ice water. The resulting crystal was collected by filtration, washed with water, and recrystallized from acetonitrile to obtain 800 mg 15 (yield: 20.4%) of 2-hydroxy-7-methylsulfonylamino- 3-nitro-6-phenoxy-4H-l-benzopyran-4-one having a melting point of 228-230°C (decomposed).

IR (KBr) cm"1: 3300, 1755, 1740, 1620, 1600, 1535, 1485, 1440, 1390, 1330, 1205, 1145 20 ( 2) 3. 92 g of 2-hydroxy-7-inethylsulfonylamino-3- nitro-6-phenoxy-4H-l-benzopyran-4-one was mixed with 80 ml of a IN aqueous sodium hydroxide solution. The mixture was stirred for 5 hours at 20-25°C. The mixture was adjusted to pH 5 with 4N hydrochloric acid. 50 ml of 25 ethyl acetate was added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with Y J" 22 6 48 1 anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting yellow solid was dissolved in N,N-dimethyIfornamide. 2.62 g of H,N-dimethy 1formamide dimethylacetal was added thereto.

The mixture was stirred for 1 hour at 20-25°C. The reaction mixture was introduced into 300 ml of water. The resulting mixture was adjusted to pH 2 with 4N hydrochloric acid. The precipitate was washed with water and then recrystallized from acetonitrile to obtain 1.54 g 10 (yield: 41%) of 3-nitro-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one having a melting point of 225-227°C.

IR (KBr) cm"1: 3170, 3070, 1670, 1620, 1480, 1450, 1330, 1300, 1150 Example 19 The compounds shown in Table 24 were obtained in the same manner as in Examples 7 to 18.

The physical properties of these compounds were identical with those of the compounds in Examples 1 to 4. o 22 Table 24 R1 R2 R3 R* R5 z Me H H -OMe o- o Me H H -OH 0 Me H H -SMe Q- o Me H H QJ o<-§ 1 O 0 Me H H 0 11 -SMe o- 0 22 6 4ft - •*** Table 24 (Cont'd.) Et H H H o 0 -cf3 H H H O 0 Me H Me H O o Me H H H o~ o Me H -o v. —7 H Q- 0 Me H H H O- H N Me H H H CF3 0 Table 24 (Cont'd.) Me H H H 0 Me H H H d- 0 Me H H H b- 0 Me H H H f"0~ 0 Me H H H c? 0 Me H H H ci^O~ 0 Me H H H .Me £S~ 0 Table 24 (Cont1d.) Me h h h 0 o- h h h o 0 Me h h -nh2 f d- 0 Me h h -nh2 f 0 Me h h -nh2 '-O 0 Me h h -nh2 f "C> 0 Me h Me -nh2 o 0 Table 2 4 (Cont'd.) clch2- h H -nh2 G- 0 Et h h -nh2 Q- 0 Me h h -nh2 0 Me h h -nh2 cl~0 0 Me h h -nh2 Me o- 0 Me h h -nh2 0 Me h h -ncho h & 0 Table 24 (Cont'd.) 2 2 6 4 Me h h -ncho h 0 Me h h -ncho h *o 0 Me h Me -ncho h 0 Me h h -NAc h o 0 Me h h -ncho h f p-Q_ 0 cich2- h h -ncho h 0 Me h h h -nco (ch ) 1 2 2 c02h o 0 ♦ Table 24 (Cont'd.) 2 2 6 4 8 9 Et H H -NCHO H Q- 0 ~CF3 H H -NCHO H O 0 Me H H -NCHO H 0 Me H H -NCHO H 0 Me H H -NCHO H Me C^- 0 Me H H -NCHO H Me-nQ- 0 Me H H Me -NCHO d1 0 0 £ V Table 24 (Cont'd.) Me H H Me -NCHO f-Q- 0 Me H H Et -NCHO Q- 0 Me H H Me -NAc 0 Me H H -NCHO I CH_ 1 2 CO 2Me O 0 Me H H -NCHO 1 (CH ) -1 C02Et o 0 Me H H ° i u 1 1 o- 0 Me H H -NH 1 CO C02Et Q- 0 Table 2 4 (Cont1d.) ft n A . _ cl 6 4 8 9 Me H H Me -N NMe o 0 Me H H o- 0 Me H H -NHOH 0 Me H H -CHO F 0 Me H H -CHO F 0 Me H Me -CONH2 o- o Me H H -CONMe H o 0 Table 24 (Cont'd.) Me H H -CON—<^1 H ^ Q- 0 Me H H -con^O) u~ 0 Me H H -CONOMe H o 0 Me H H ^ Me -CON Me o 0 Me H H -coO o- o Me H H N=\ o- 0 Me H -cf3 H o- 0 o L- Table 24 (Cont* <3 .) Me H Et H o- 0 Me H -i-Pr H o 0 Me H ■< H o- 0 Me H H H o 0 Me H H H «-a- 0 Me H H H o 0 Me H H H CO-Me 0 . >,* *A "~C Table 24 (Cont'd.) 22 6 4 Me h h h conh2 d1 0 Me h h h 0 me h h h Me Me 0 Me h h h 0 Me h h h o s Me h h -CHrO o 0 Me h h Et o 0 Table 24 (Cont* d.) ?? fi /• eL. \) £f Me H H -O O 0 Me H H -i-Pr /=\ v/~ 0 Me H H -NCHO H Me & 0 Me H H -NCHO H >le 0 Me H H -NCHO H o- s Me H H -NAC H o 0 Me H H -C=NOH H C5-' 0 Table 24 (Cont'd.) 9? fi 4 « n Me H H -C=NOH H F^J~ 0 Me H H -CN F d- 0 Me H H -CN F 0 Me H H H F F^C^~ 0 Me Ac H H O- 0 Me H H Me 0 Me H H "NH 2 o 0 Table 24 (Cont'd.) Me H H -NCHO H 0 Me H H Me -NCHO o- 0 Me H K -NMe H o 0 Me H H -NEt H o 0 Me H H -NCO Me H * o- 0 Me H H Br o 0 Me H H CI o 0 9? R / o *- V -T U Table 24 (Cont'd.) Me h h -nconh h o- 0 Me h h Me -nconh 0 Me Ac h 0 Vn -n Q- 0 Me h h -ncho ! ch„ I 2 co2h Q- 0 Me h Br -nh2 (hydrobromic acid salt form) 0 Me h Br -ncho h O- 0 Me h -OMe -ncho h o- 0 Table 24 (Cont'd.) 0 0 C / r\ c. u 4 a Me h -oh -ncho h o- 0 Me h -cn -ncho h o- 0 Me h h -n o- 0 Me h h o- 0 Me h h -c0nh2 0 Me h -cooh h 0 Me h -conh2 h a- 0 Table 24 (Cont'd.) b 4 8 Me h -ch2oh h o 0 Me h -ncooet h h o- 0 Me h -NCOOt-Bu h h o 0 Me h -ncho h h o 0 Me h -nac h h o- 0 Me h -nh2 h iJ~ 0 Me h Me h '<5- 0 o ?2<$48< Table 24 (Cont'd.) Me H H -ch2oh o- 0 Me H H -CH=CH-^y o- 0 Me h h -CHMe 1 oh o- o Me H H -CH2NAc H o- o Me h h -ch2nh2 o o Me H H o o 0 Me H -OH H o 0 n o c Table 24 (Contr a.) Me H H Me -N=CHN^ ^ Mo * * O 0 Me H H -NCCHMe H| n OOH o- 0 Me H H -NCCHMe HII | ONH2 o- 0 Me H H -NSO-Me H o 0 Me H ^OMe —OMe -OH o- 0 Me H H H COOH d- 0 Me H H H NH2 <3- 0 22 fi Table 24 (Cont'd.) Me H H H H NAC d- 0 Me H H H H NCKO o 0 Me H H H .,OMe & 0 Me H H H Me°-0~ 0 Me H H H Me 0 Me H H H OH d- 0 Me H H -NCHO H OMe d- 0 Table 24 (Con t'd.) A 2264! Me h h X 0 z II u X 1 o- 0 Me h h -cn o- 0 Me h h -conh2 d- 0 Me h h -conh2 *-d- 0 Me h -oh -n02 o 0 Me h h -no2 o- 0 ch2=ch- h h h o- 0 Table 2 4 (Cont'd.) 22 6 4 8 Me Ac H H 0 Me Ac H -NCHO II 0 Me Bz H H Q- 0 Me Me H H O- 0 Me H H -NH 1 CO 1 (CH ) i CH2C1 o- 0 Me H H Vi -N o- 0 Me H H N-N -CON-^n> H H o- 0 22 6 4 8 § Table 24 (Cont'd.) Me H N-N -CON-^ > H H h o 0 Me h H N-N < > N h o 0 Me h -nh2 -conh2 o- 0 Me h Me Me o 0 1 Example 20 (1) 8.0 g of sodium hydroxide was dissolved in 240 ml of water. In this solution was dissolved 24.3 g of 3-acetylamino-4-phenoxyphenol. Thereto was added 10.9 g 5 of 3-chloropropionic acid. The mixture was refluxed for 30 minutes. The reaction mixture was water-cooled. The resulting crystal was removed by filtration. The filtrate was adjusted to pH 9 with 4N hydrochloric acid and washed with two 5 0-ml portions of ethyl acetate. The aqueous 10 layer was separated, adjusted to pH 4 with 4N hydrochloric acid, and extracted with 200 ml of ethyl acetate. The extract (the organic layer) was washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was 15 removed by distillation under reduced pressure. The o o /-> CC o 1 resulting crystal was mixed with diethyl ether. The resulting crystal was collected by filtration to obtain 10.0 g (yield: 31.7%) of 3-(3-acetylamino-4-phenoxy-phenoxy)propionic acid having a melting point of 138-140°C 5 IR (KBr) cm"1: ?270; 1730, 1630, 1590, 1540, 1475, 1425, 1220 NMR (dg-DMSO) 5: 2.00 (3H, s), 2.68 (2H, t, J=6Hz), 4.14 (2H, t, J=6Hz), 6.50-7.92 (7H, m), 7.67 (IH, d, J=2.4Hz), 9.22 (IH, bs) 10 (2) The following compound was obtained in the same manner as in Example 1 (2). 7-Acetylamino-2,3-dihydro-6-phenoxv-4H-l-benzopyran-4-one Melting point: 214-215°C (recrystallized from 15 acetonitrile-ethyl acetate) IR (KBr) cm-1: 3305, 1700, 1665, 1615, 1590, 1520, 1438, 1270, 1245, 1220 NMR (CDCl3+d6-DMSO) 6: 2.16 (3H, s), 2.69 (2H, t, J=6Hz), 4.49 (2H, t, J=6Hz), 6.75-7.54 (5H, m), 20 7.19 (IH, s), 8.06 (IH, s), 9.32 (lH, bs) (3) The following compound was obtained in the same manner as in Example 1 (3). 7-Acetylamino-6-phenoxy-4H-l-benzopyran-4-one Melting point: 233-235°C (recrystallized from 25 chloroform-ethanol) IR (KBr) cm"1: 3250, 3060, 1695, 1635, 1510, 1435, 1303, 1245, 1210 22 6 4 8 NMR (d,-DMSO) 6: 2.22 (3K, s), 6.24 (1H, d, J=6Hz), D 7.10-7.63 (6H, m), 8.21 (IH, d, J=6Hz), 8.53 (1H, s), 9.91 (1H, bs) (4) 2.95 g of 7-acetylamino-6-phenoxy-4H-l- benzopyran-4-one was dissolved in 30 ml of N,N-dimethyl-formamide. 440 mg of sodium hydride (purity: 60%) was added thereto with ice-cooling. The mixture was stirred at the same temperature until the generation of hydrogen gas stopped. Then, 1.26 g of methanesulfonyl chloride was added thereto dropwise. The mixture was stirred for 1 hour at 20-25°C. 200 ml of water and 200 ml of ethyl acetate were added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from ethanol to obtain 3.22 g (yield: 86.L%) of 7-(N-acety1-N-methylsulfonylamino)-6-phenoxy-4H-l-benzopyran-4-one having a melting point of 166-169°C. IR (KBr) cm"1: 1700, 1640, 1620, 1480, 1445, 1360, 1295, 1155 NMR (CDC13) 5: 2.12 (3H, s), 3.40 (3H, s), 6.30 (IH, d, J=6Hz) , 7.11-7.63 (7H, m) , 7.86 (IH, d, J=6Hz) Example 21 2.95 g of 7-acetylamino-6-phenoxy-4H-l-benzopyran-4-one was dissolved in 30 ml of N,N-dimethylformamide.

O 226485 1 1.35 g of potassium tert-butoxide was added with ice-cooling. The mixture was stirred for 30 minutes at the same temperature. Then, 1.55 g of ethanesulfonyl chloride was added thereto dropwise. The mixture was 5 stirred for I hour at 20-25=C. 200 ml of water and 200 ml of ethyl acetate were added. The organic layer was separated. The solvent was removed by distillation under reduced pressure. The resulting crystal was mixed with 20 ml of a IN aqueous sodium hydroxide solution and 10 10 ml of ethanol. The mixture was refluxed for 2 hours. 100 ml of water and 100 ml of ethyl acetate were added thereto. The mixture was adjusted to pH 4 with 4N , hydrochloric acid. The organic layer was separated, washed with water and'a saturated aqueous sodium chloride 15 solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a mixture of 5 : 1 toluene and ethyl acetate) to obtain 0.75 g (yield: 21.7%) of 2 0 7-ethy1su1fonylamino-6-phenoxy-4H-l-benzopyran-4-one.

Melting point: 216-218°C (recrystallized from ethanol) IR (KBr) cm"1: 3070, 1620, 1582, 1490, 1455, 1335, 1200, 1155, 1138 25 NMR (CDC l3+dg-DMSO) 6: 1.37 (3H, t, J=7.2Hz), 3.25 (2H, q, J=7.2Hz), 6.22 (IH, d, J=6Hz) , 7.01-7.47 (5H, m) , 7.68 (1H, s)\ ^ v ; \\V' 22 6 4 7.76 (1H, s), 7.93 (1H, d, J=6Hz), 9.21 (IH, bs) Example 22 (1) There were mixed 29.7 a of 7-acetylamino-2,3-dihydro-6-phenoxy-4H-l-benzopyran-4-one, 30 ml of ethanol and 300 ml of 6N hydrochloric acid. The mixture was refluxed for 1 hour. The reaction mixture was introduced into 3 liters of ice water. The resulting crystal was collected by filtration and recrystallized from ethanol to obtain 23.5 g (yield: 92.2%) of 7-amino-2,3-dihvdro- 6-phenoxy-4H-l-benzopyran-4-one having a melting point of 154-155°C.

IR (KBr) cm"1: 3470, 3330, 1655, 1610, 1570, 1500, 1460, 1320, 1300, 1255 (2) In 200 ml of pyridine was dissolved 25.5 g of 7-amino-2,3-dihydro-6-phenoxy-4H-l-benzopyran-4-one.

To the solution being maintained at 20-25°C was dropwise added 12.6 g of methanesulfonyl chloride. The mixture was subjected to reaction for 12 hours at the same temperature. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate. The solution was extracted with two 5 00-ml portions of a In aqueous sodium hydroxide solution. The extracts (the aqueous layers) were combined, adjusted to pH 4 with 4N hydrochloric acid, and extracted with two 300-ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with water and 22 6 1 a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from methanol 5 to obtain 27.0 g (yield: 81.1%) of 2,3-dihydro-7-= methylsulfonylamino-6-phenoxy-4H-l~benzopyran-4-one.

The properties (melting point and IR) of this compound agreed with those of the compound obtained in Example 1 (2) .

The compounds shown in Tables 25 and 26 were obtained in the same manner.

Table 25 i i—1 -J I Note: * 2-Chloroethansulfonyl chloride was used in place of the methansulfonyl chloride. f\3 no cn Rl Melting point (°c) IR (KBr) cm 1: c1ch2- 158-160 [ipa] 3150, 1660, 1610, 1480, 1440, 1255, 1190, 1160, 1140 Et 174-175 [Ethanol] 3020, 1665, 1620, 1500, 1450, .1330, 1270 ch2=ch- 132-136 (dec.) [Ethyl acetate-IPE] 3050, 1660, 1605, 1485, 1325, 1265, 1220, 1135 ) Table 26 R1 R3 R4 Melting point (°C) IR (KBr) cm"1: Me H H u- 131-132 [Ethanol] 3240, 1670, 16 L0, 1490, 1440, 1325, 1255 Me H H 146-147 [Ethanol] 3100, 1670, 1430, 1325, 1270, 1145 Me H H '-Q- 167-168 [Ethanol] 3175, 1670, 16L5, 1490, 1440, 1340, 1260 Me H H o- 143-144 [Methanol] 3120, 1665, 1610, 1485, 1440, 1320, 1265, 1215, 1160, 1135, r\3> ro o> 4N \ ) Table 26 (Cont'd.) -CF 3 H H o 128-130 [IPE] 3140, 1680, 1610, 1480, 1440, 1370, 1260, 1230, 1210, 1200, 1135 Me Me H Q- 144-145 [Ethanol] 1665, 1610, 1495, 1440, 1320, 1260, 1215, 1135 Me H H & 130-131 [Ethanol] 3230, 1680, 1610, 1470, 1440, 1320, 1255, 1160 Me H H ci-Q- 144-146 [Ethanol] 3250, 1670, 1610, 1480, 1440, 1340, 1255, 1160 Me H H , ^ Me 157-159 [Toluene] 3230, 1690, 1610, 1480, 1440, 1340, 1260, 1160 Me H H »-o- 120-121 [Toluene] 3250, 1680, 1615, 1490, 1440, 1340, 1320, 1260, 1135 r\3 ro cn Table 26 (Cont'd.) Me H H F S Y\jt 163 .5-165 [Ethanol] 3220, 1665, 1605, 1575, 1495, 1420 Me H Br G- 137-140 [Toluene] 3250, 1680, 1610, 1485, 1325, 1260, 1205 Me H -OMe O- 139-141 [Ethanol] 3230, 1680, 1610, 1490, 1450, 1330, 1260, 1210, 1150 Me H -SMe 126-128 [Ethanol] 3250, 1690, 1610, 1480, 1440, 1340, 1260, 1220, 1160, 1140 r\* ro CD ~£n o 2264 1 Example 23 The compounds shown in Table 27 were obtained ^ in the same manner as in Example 20, 21 or 22.

The physical properties of these compounds 5 were identical with those of the compounds in Examples 1 to 4. 22 6 4 Table 27 R1 R* R4 R z Me H H H o~ 0 Me H H -OMe o- 0 Me H H -SMe o 0 Me H H 0 -SMe o- 0 Me H H 0 11 -SMe II 0 o- 0 Table 27 (Cont'd.) 22 6 4 8! Et H H H O 0 -rr 3 H 14 k A II YJ- 0 Me H Me H o- 0 Me H H H 0 Me H -o H Q- o Me H H H o- H N Me H H H CF^=, 0 Me H H H o- 0 Me H H H 0 22 6 4 £ Table 27 (Cont'd.) Me H H H F O- 0 Me H H H p-Q- 0 Me K H H 0 Me H H H 0 Me H H H Me <5- 0 Me H H H 0 o H H H O 0 Me H H -NCHO H 0 Me H H -NCHO H 0 Table 27 (Cont'd.) 22 6 4 Me h h -ncho h 0 Me h Me -ncho h o 0 Me h h -NAc h Q- 0 Me h h -ncho h 0 cich2- h h -ncho h Q- 0 Me h h h -nco (Ci:h2) 2 co2h O- 0 Et h h -ncho h o- 0 "cf3 h h -ncho h Q- 0 L L D H O y Table 27 (Cont'd.) Me H H -NCHO H CI d- 0 MG H H -NCHO H o Me H H -NCHO H Me d- 0 Me H H -NCHO H »-o- 0 Me H H Me -NCHO rF i> 0 Me H H Me -NCHO fhO~ 0 Me H H Et -NCHO Q- 0 Me H H Me -NAc 0 Me H H -NCHO 1 CH0 1 & C02Me €> 0 L <L 0 ^ B Table 27 (Cont'd.) Me H H -NCHO (CII2)3 CO,Et iJ- o Me w H -hC°^5) o- o Me K H -NH 1 CO 1 C02Et o 0 Me H H Me -< Me Q- 0 Me H H -N o- 0 Me H H -NHOH o- 0 Me H H -CHO d- 0 Me H H -CHO 0 Me H Me -conh2 o- 0 0 O / C u 4 Table 27 (Cont'd.

Me H H -CONMe H o- 0 Me H H -CON—<^1 H Q- 0 Me H H -CON— H X ' Q- 0 Me H H -CONOMe H O 0 Me H H .Me -CON ^Me Q- 0 Me H H -coO O 0 Me H H 1 n o ffi z 6 Q- 0 Me H -cf3 H O 0 Me H Et H o- 0 226489 Table 27 (Cont'd.) Me H -i-Pr H O 0 Me H H 0 Me H H H o- 0 Me H H H «-o- 0 Me H H H 0 Me H H H a--"- 0 Me H H H CONH „ o- 0 Me H H H i-Pr & 0 Me H H H Mev ^Me o- 0 22 6 Table 27 (Cont'd.) Me H H H _/-Me 0 Me K II H o s Me H H l O K Q- 0 Me H H Et O- 0 Me H H -0 Q- 0 Me H H ! i .

H- 1 •XJ H o- 0 Me H H -NCHO H Me 0 Me H H -NCHO H ^-Me 0 Me H H -NCHO H o- s 2 6 4 8! Table 27 (Cont'd.) Me H H -NAc H F . / o 0 Me H H -CN 0 Me H H -CN F~\J~ 0 Me H H H 0 Me H Me Me o- 0 Me H H -NCHO H o 0 Me H H Me -NCHO o- 0 Me H H -NCO„Me H o- 0 Me H H Br o- 0 22 6 4 Table 27 (Cont'd.) Me H H CI O 0 Me H H -NCONH H z o 0 Me H H Me -NCONH ii1" 0 Me AC H H 0 V-| -N o 0 Me H -NCHO 1 CH„ 1 2 co2h Q- 0 Me H Br -NCHO H G- 0 Me H -OMe -NCHO H 0 Me H -OH -NCHO H O- 0 n n r* CC 0 Table 27 (Cont'd.) Me H -CN -NCHO H O 0 Me H H /==! -N^ o 0 Me H H rO o- 0 Me H H -CHO o- 0 Me H H -COOEt o- 0 Me H H -COOH o 0 Me AC Me -COOEt G- 0 Me H Me -COOH o- 0 Me h h -conh2 Q- 0 Table 27 (Cont'd.) 22 6 i Me h h Ac 0 Me h -COOEt H o 0 Me H -COOH H o 0 Me H -conh2 H o- 0 Me h -ncooet H H o 0 Me H -NCOOt-Bu H H o- 0 Me H -ncho H H 0 Me h -NAc H h o 0 Me h Me H '-tf 0 *i 0 ft /. &. £- V/ "? Table 27 (Cont'd.) Me H H -CH=CH-^~^ o- 0 Me H H -CH _NAc H f ^ \j- 0 Me H H O Q- 0 Me H H .•Me -N=CHN Me Q- 0 Me H H -NS0~Me H kJ~ 0 Me H H H COOH d- 0 Me H H H H x NAc 0- 0 Me H H H H /NCHO 0- 0 Me H H H .OMe <5- 0 9 9 R L Q &. e- \j nr u Table 27 (Cont'.d) Me h h h MeO —^ — 0 Me h h h Me 0 Me h h -ncho h ^.ome 0 Me h h -cn o- 0 Me h h -conh2 0 Me h h -conh2 0 Me h h -no2 o 0 ch2=ch- h h h o- 0 Me AC h h 0 22 6 4 Table 27 (Cont'd.) Me ac h -ncho h 0 Me Bz h h o- 0 Me Me h h o 0 Me h h -nh 1 co (cfh2) 2 ch2c1 o 0 Me h h 0 v, -n 0 Me h h n-n -con-4! > h h o 0 Me h n—n -con— h o- 0 Me h h n-n A > h o- 0 Me h h Me O- 0 ^ <n o £> /, •C C V H 1 Example 24 (1) 6.7 g of 4-methoxy-2-methylsulfonylaminophenol was dissolved in 60 ml of methylene chloride. Thereto was added 7.3 g of acetyl chloride. The mixture was cooled to 5°C. Thereto was added 16.5 g of aluminum chloride in portions in 30 minutes at 5-10°C. The mixture was stirred for 1 hour at 5-10°C and for a further 1 hour at 20-25°C. The reaction mixture was introduced into 200 ml of ice water. The resulting crystal was collected 10 by filtration and then recrystallized from acetonitrile to obtain 3.6 g (yield: 41%) of methyl 5-acetoxy-2-hydroxy-4-methylsulfonylaminophenyl ketone having a melting point of 205-206.5°C.

IR (KBr) cm-1: 3250, 1760, 1635, 1580, 1495, 15 1365, 1320, 1190 (2) 2.0 g of methyl 5-acetoxy-2-hydroxy-4-methyl-sulfonylaminophenyl ketone was suspended in 14 ml of ethyl orthoformate. Thereto was dropwise added 2.0 g of 70% (w/w) perchloric acid in 10 minutes with ice-cooling. 20 The mixture was stirred for 1.5 hours at 20-25°C. The reaction mixture was mixed with 20 ml of diisopropyl ether. The resulting crystal was collected by filtration and mixed with 20 ml of water. The mixture was refluxed for 5 minutes and then cooled. 50 ml of ethyl acetate 25 was added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced ZZ 6 4 8 1 pressure. The residue was dissolved in 14 ml of a IN aqueous sodium hydroxide solution. The mixture was stirred for 30 minutes at 20-25°C. The reaction mixture was adjusted to pH 2 with 6N hydrochloric acid.

The resulting crystal was collected by filtration and recrystallized from a mixed solvent of N,N-dimethylformamide and water to obtain 1.0 g (yield: 59%) of 6-hydroxy-7-methylsulfonylamino-4H-l-benzopyran-4-one having a melting point of > 250°C.

IR (KBr) cm"1: 3300, 3250, 1620, 1595, 1460, 1425, 1400, 1330, 1300, 1255 (3) 200 mg of 6-hydroxy-7-methylsulfonylamino-4H- l-benzopyran-4-one was dissolved in 2 ml of N,N-dimethylformamide. Thereto were added 390 mg of bromo-15 benzene, 113 mg of potassium carbonate and 52 mg of a copper powder. The mixture was stirred for 1.5 hours at 150°C. The reaction mixture was introduced into 10 ml of ice water. The mixture was adjusted to pH 2 with 4N hydrochloric acid. Thereto was added 10 ml of ethyl acetate. 20 The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from acetonitrile to obtain 25 210 mg (yield: 80%) of 7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one. The properties (melting point, IR and NMR) of this compound agreed with those of the compound obtained in Example 1 (3). 22 i 1 Example 25 The compounds shown in Table 28 were obtained in the same manner as in Example 24 (3).

The physical properties of these compounds 5 wptp identical with those of the compounds in Examples 1 to 4 . 2 26 4 8! Table 28 1 R R2 RJ R4 z Me H H -OMe O- 0 Me H H -OH o- 0 Me H H -SMe o- 0 Me H H 0 t -SMe o- 0 Me H H 0 II -SMe II 0 o- o 22 6 4 8] Table 28 (Cont'd.) Et H H H o- 0 ~CF3 H H H o- 0 Me H Me H o 0 Me H H H a 0 Me H -o H o 0 Me H H H O- H N Me H H H CFo b- 0 Me H H K o- 0 Me H H H Ct 0 22 6 4 Table 28 (Cont'd.) Me h H h F ^ ij" 0 Me h H h '-O- 0 Me h H h ^C1 C5-- 0 Me h H h ci-Q~ 0 Me h H h .Me <5- 0 Me h H h "*-i> 0 o h h h o- 0 Me h h -nh2 o- 0 Me h h -nh2 '~o- 0 ZZ 6 4 8 ! Table 28 (Cont'd.) Me h h ~~NH 2 '-o- 0 Me h h -m2 *-d- 0 Me h Me -nh2 o 0 cich2- h h -nh2 o- 0 Et h h -nh2 o 0 Me k h -nh2 r-tc1 iJ~ 0 Me h h -nh2 ci^o~ 0 Me h h -nh2 Me 0 Me h h -nh2 0 22 6 4 8 Table 28 (Cont'd.) Me h h -ncho h 0 Me k h -ncho h "O- 0 Me h h -ncho h K> 0 Me h me -ncho h O 0 Me h h -NAc h O 0 Me h h -ncho h '-c£ 0 cich2- h h -ncho h O- 0 Me k h h -n-co 4h2'2 c02h O- 0 22 6 4 8 Table 28 (Cont'd.) Et H H -NCHO H O 0 -CF3 H H -NCHO H o 0 Me H H -NCHO H 0 Me H H -NCHO H ci-0 0 Me H H -NCHO H Me 0- 0 Me H H -NCHO H o Me H H Me -NCHO F d- o Me H H Me -NCHO 0 Me H H Et -NCHO o- 0 22 6 4 8; Table 28 (Cont'd.) Me H H Me -NAC o 0 Me H H -NCHO 1 CH_ 1 2 CO 2 Me /—Jk i 0 Me H H -NCHO (ch2)3 C02Et KJ~ 0 Me H H -NCO—^0^ H N—7 O 0 Me h H -NH 1 CO 1 C02Et o 0 Me H H Me -N Me o 0 Me H H -G Q- 0 Me i H H -NHOH o 0 A o A . . 2L t> 4 * Table 28 (Cont'd.) Me H H -CHO d- 0 Me H H -CHO 0 Me H Me -conh2 0 Me H H -CONMe H €> 0 Me H H l o o A o 0 Me H H -co»H©> 0 Me H H -CONOMe H kJ~ 0 Me H H .Me -CON ^Me o- 0 Me H H -CO0 o- 0 Table 28 (Cont'd.) £d 6 4 Me H H ---o o- 0 Me H t n UJ H o 0 Me H Et H Q- 0 Me H -i-Pr H o- 0 Me H < H 0 Me H H H o- 0 Me H H H °-o 0 Me H H H (> s 0 Me H H H CO~Me 0 9 9 C /. o C. L. \J •? Q Table 28 (Cont'd.) Me H H H CONH 0 / 2 o 0 Me H H H i-Pr 0- 0 Me H H H Me Me & 0 Me H H H Me '-d- 0 Me H H H o- s Me H H -CH2-^0 o- 0 Me H H Et o 0 Me H H -0 o~ 0 Me H H -i-Pr o- 0 22 6 4 £ Table 28 (Cont'd.) Me H H -NCHO H Me 0 Me H H -NCHO H Me r\j- 0 Me H H -NCHO H o- s Me H H -NAc H 0 Me H H -C=NOH H 0 Me H H -C=NOH H 0 Me H H -CN F €3- 0 Me H H -CN 0 Me H H H 0 22 6 4 Table 28 (Cont'd.) Me H Me Me o- 0 Me AC h H o- 0 Me H H Me Q- 0 Me H H -nh2 Q- 0 Me H h -NCHO H O- 0 Me H H Me -NCHO o- 0 Me H H -NMe H o 0 Me H H -NEt H o 0 Me H H -NCO„Me h o- 0 Table 28 (Cont'd.) 22 6 4 Me h h Br O 0 He h h ci Q- 0 Me h h —nconh-h 0 Me h h Me -nconh2 O 0 Me ac h 0 ^— -N 0 Q- 0 Me h h -tjlcho ch0 1 2 c02h O 0 Me h Br -nh2 (hydrobromic acid salt form) O 0 Me h Br -ncho h o 0 Table 28 (Cont'd.) «Ti rj a , c C D 4 Me H -OMe -NCHO H o- 0 Me H -OH -NCHO H v> 0 Me H -CN -NCHO H o- 0 Me H H F=\ -N N=1 o- 0 Me H H 0 1 z as i a 0 Me H H -CHO o- 0 Me H H -COOEt o 0 Me H H -COOH o 0 Me Ac Me -COOEt o 0 0 9 £> / c. c U 4 Table 28 (Cont'd,) Me H Me -COOH a 0 Me H H -conh2 o 0 Me H H Ac o- 0 Me H -COOEt H o- 0 Me H -COOH H o 0 Me H -conh2 H a 0 Me H -ch2oh H o~ 0 Me H -NCOOEt H H a- 0 Me H -NCOOt-Bu h H o- 0 22648 Table 28 (Cont'd.) Me h -NCHO h H o 0 Me h -NAc H H o- 0 Me H -nh2 h o 0 Me h Me h ~d- 0 Me h h -ch2oh o- 0 Me h h -CH=CH-^~^ o- 0 Me h h -CHMe I OH o- 0 Me h h -CH-NAc H o- 0 Me h h -CH2NH2 o- 0 o Table 28 (Cont'd.) Me H H T) O 0 Me H -OH H o- 0 Me H H ^Me -N=CHN Me o- 0 Me H H -NCCHMe Hfl I OOH o- 0 Me H H -NCCHMe H || 1 onh2 o- 0 Me H H -NSO^Me H o- o Me H OMe —OMe -OH o~ o Me H H H COOH & 0 Me H ■ H H m2 6- 0 4 a*- ^ A ,-p 22 fi l Table 28 (Cont'd.) Me H H H H NAc 0 Me H H H H NCHO 0 Me H H H OMe c5- 0 Me H H H MeO—^ ^— 0 Me H H H Me 0 Me H H H ^ OH O- 0 Me H H -NCHO H OMe <5- 0 Me H H -C=NOH H 0 Me H H -CN o 0 - V. '■') - 22 6 4 8 Table 28 (Cont'd.) Me h h -nh I co (ch-)- 1 2 ch2c1 o 0 Me h h 0 v-1 -n^ o- 0 Me h h n -n -con<n> h h o- 0 Me h n—n -con -^3' H N h h h o- 0 Me h h n-n -<n> h o- 0 Me h -nh2 -conh2 o 0 *5 /> ■ £. C D 4 1 Example 26 (1) 27.6 g of formic acid was added to 30.6 g of acetic anhydride. The mixture was stirred for 1.5 hours at 40-45°C. The reaction mixture was dropwise added 5 to a solution of 34.6 q of 3-amino-7-methylsulfonylaminc~ 6-phenoxy-4H-l-benzopyran-4-one dissolved in 400 ml of methylene chloride. The mixture was stirred for 1 hour at 20-25°C. 400 ml of diisopropyl ether was added thereto. The resulting crystal was collected by filtration and 10 recrystallized from acetonitrile to obtain 27.3 g (yield: 73%) of 3~formylamino-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one having a melting point of 236-238 °C.

IR (KBr) cm"1: 3340, 3260, 1680, 1615, 1600, 1485, 15 1460, 1340, 1210, 1150 NMR (dc-DMSO) 6: 3.24 (3H, s), 7.09-7.62 (5H, m) o 7.35 (IH, s) , 7.72 (IH, s), 8.36 (IH, s) , 9.28 (IH, s) , 9.79 (IH, s), 10.04 (IH, s) (2) 37.4 g of 3-formylamino-7-methylsulfonylamino- 6-phenoxy-4H-l-benzopyran-4-one was dissolved in 370 ml of N,N-dimethylformamide. Thereto was added 8.8 g of sodium hydride (purity: 60%) in 30 minutes, with ice-cooling. After the completion of the addition, the 25 reaction mixture was heated to 45°C and stirred for 10 minutes. To the mixture being maintained at 25-30°C was dropwise added 15.6 g of methyl iodide. Stirring was effected for 30 minutes at the same temperature. The c <L O 1 V 1 reaction mixture was introduced into 2 liters of water. The mixture was washed with 200 ml of diethyl ether, adjusted to pH 4 with 4N hydrochloric acid, and extracted with two 500-ml portions of ethyl acetate. The extracts 5 (the organic layers) were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting crystal was recrystallized 10 from acetonitrile to obtain 29.1 g (yield: 75%) of 7- methylsulfonylamino-3-(N-methyl-N-formylamino)-6-phenoxy-4H-l-benzopyran-4-one having a melting point of 185-186°C.

IR (KBr) cm"1: 1655, 1625, 1610, 1490, 1330, 1275, 1160 NMR (d6-DMS0) 6: 3.04 (3H, s), 3.24 (3H, s), 7.09-7.62 (5H, m) , 7.34 (IH, s) , 7.76 (1H, s) , 8.09 (IH, s), 8.63 (IH, s), 10.07 (IH, s) The compounds shown in Table 29 were obtained 20 in the same manner.

The physical properties of these compounds were identical with those of the compounds in Example 4. , v •':i f f a U \- !■' ' v\Y" , R1 RJ R3 R4 R5 z Me H H Me -NCHO F <5- 0 Me H H Me -NCHO 'O- 0 Me H H Et -NCHO O 0 Me H H Me -NAc o- 0 Me H H -NCHO 1 CH„ 1 2 C02Me Q- 0 Me H H -NCHO (CH2>3 CO,Et O- 0 O 22' 1 (3) 3.88 g of 7-methylsulfonylamino-3-(N-formyl- N-methylamino) -6-phenoxy-4H-l-benzopyran-4-one was suspended in 80 ml of methanol. Thereto was added 40 ml of concentrated hydrochloric acid. The mixture was 5 stirred for 5 hours at 40-45°C. The solvent was removed by distillation under reduced pressure. The residue was mixed with 300 ml of ethyl acetate and 200 ml of water. The mixture was adjusted to pH 4 with a saturated aqueous sodium hydrogencarbonate solution. The organic 10 layer was separated, washed with a saturated aqueous sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under , reduced pressure. The resulting crystal was recrystal- I' lized from ethanol to obtain 3.32 g (yield: 92.2%) of 15 3-methy1amino-7-methyIsulfonylamino-6-phenoxy-4H-l- benzopyran-4-one having a melting point of 192.5-193°C. IR (KBr) cm"1: 3350, 3100, 1600, 1585, 1560, 1480, 1415, 1330, 1275, 1210, 1200, 1140 NMR(dg-DMSO)6: 2.62 (3H, s), 3.20 (3H, s), 4.50-5.20 (IH, 20 br) , 7.07-7.50 (5H, rn) , 7.34 (IH, s) , 7.63 (IH, s), 7.67 (IH, s), 9.88 <1H, s) The following compound was obtained in the same manner: 3-Ethyl amino-7-methylsulfonylamino-6-phenoxy-4H-l-25 benzopyran-4-one.

Melting point: 221-222°C (recrystallized from ethanol) -IK (KBr) cm"1: 3340, 3100, 1580, 1555, 1480, 1420, 1215, 1140 22 6 4 NMR(CDC13)6: 1.29 (311, t, J = 8.0Hz), 3.00 (2H, t, J = 8.0Hz), 3.11 (3H, s) , 6.70-8.00 (7H, rn) , 7.35 (IH, s), 7.64 (IH, s), 7.70 (IH, s) Example 2 7 To 70 ml of methylene chloride was added 3.46 g of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one. Further, 8 70 mg of pyridine was added thereto. The mixture was ice-cooled. To this solution was dropwise added a solution of 1.04 g of methyl chlorocarbonate dissolved in 30 ml of methylene chloride, in 10 minutes. The mixture was then stirred for 30 minutes at 20-25°C. 50 ml of water was added thereto. The resulting mixture was adjusted to pH 4 with 4N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from acetonitrile to obtain 2.95 g (yield: 73%) of 3-methoxycarbonylamino-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one having a melting point of 233-235°C.

IR (KBr) cm"1: 3390, 3330, 1720, 1620, 1605, 1525, 1455, 1335, 1210, 1160 NMR(d,-DMS0)6: 3.23 (3H, s), 3.66 (3H, s), 7.09- D 7.50 (5H, m) , 7.34 (IH, s), 7.72 (IH, s), 8.34 (IH, s), 8.74 (IH, s), .00 (1H, s) Example 28 (1) In 100 ml of chloroform was dissolved 3.46 g of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. Thereto was dropwise added 1.92 g of bromine at 25-30°C. The mixture was stirred for 2 hours at the same temperature. The resulting crystal was collected by filtration to obtain 3.60 g (yield: 71.1%) of 3-amino-2-bromo-7-methylsulfonylamino-6-phenoxy-4 H-l-benzopyran-4-one hydrobromide having a melting point of 165 (decomposed).

IR (KBr) cm-1: 1620, 1480, 1450, 1350, 1260, 1200, 1150 (2) 3.06 g of acetic anhydride and 2.76 g of formic acid were mixed and stirred for 1.5 hours at 40-45°C to prepare a mixed acid anhydride. Separately, 5.06 g of 3-amino-2-bromo-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one hydrobromide was suspended in 100 ml of methylene chloride. To the suspension being ice-cooled was added 1.06 g of triethylamine, and the mixture was stirred for 30 minutes at the same temperature. Thereto was added the above mixed acid anhydride, and the resulting mixture was stirred for 1 hour at 20-25°C. The solvent was removed by distillation under reduced pressure. The residue was mixed with 200 ml of water. The resulting crystal was collected by filtration and recrystallized from ethyl acetate- 22 6 1 diisopropyl ether to obtain 4.15 g (yield: 97.6t) of 2-bromo-3-formy1amino-7-methy 1sulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a molting point of 237- 2 38 °C.

IR (KBr) cm"1: 3170, 1670, 1635, 1610, 1475, 1440, 1325, 1260, 1200, 1150 NMR(d^-DMSO)6: 3.23 (3H, s), 7.04-7.63 (5H, m), D 7.23 (IH, s) , 7.73 (IH, s), 8.21 (IH, s), 9.63 (IH, s), 10.17 (IH, s) 10 (3) 510 mg of metallic sodium was dissolved in 60 ml of methanol. The solution was ice-cooled. Thereto was added 4.25 g of 2-bromo-3-formylamino-7-methylsulfon-ylamino-6-phenoxy-4H-l-benzopyran-4-one. The mixture was stirred for 2 hours at 0-5°C. 600 ml of water was 15 added thereto. The resulting mixture was washed with 200 ml of ethyl acetate, adjusted to pH 4 with 4N hydrochloric acid, and extracted with two 300-ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with a saturated aqueous sodium chloride 20 solution, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from acetonitrile to obtain 2.87 g (yield: 71%) of 3-formylamino-2-methoxy-7-methylsulfonylamino-6-phenoxy-25 4H-l-benzopyran-4-one having a melting point of 188°C (decomposed).

IR (KBr) cm-1: 1675, 1610, 1560, 1450, 1320, 1260, 1205, 1140 O ?264 1 NMR (dg-DMSO)5: 3.19 (3H, s), 4.17 (3H, s), 7.04- 7.61 (5H, m) , 7.29 (1H, s) , 7.77 (IH, s), 8.16 (1H, s) , 9.07 (IH, s), 10.06 (1H, s) (4) 2-Bromo-3-forrnylamino-7-methylsulfonylamino-6- phenoxy-4H-l-benzopyran-4-one was reacted with IN aqueous sodium hydroxide solution to obtain 3-formylamino-2-hydroxy-7-methylsulfonylaminc-6-phenoxy-4H-l-benzopyran-4-one. Melting point: >250°C (decomposed) (recrystallized 10 from ethanol) IR (KBr) cm"1: 3350, 3280, 1695, 1670, 1620, 1565, 1370, 1340, 1145 Example 29 (1) 3-Amino-7-methy1sulfony1 amino-6-phenoxy-4H-l-15 benzopyran-4-one was reacted with N,N-dimethylformamide dimethylacetal to obtain 3-(N,N-dimethylamino)methylene-amino- 7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

Melting point: 103-104°C (recrystallized from diethyl 20 ether) IR (KBr) cm"1: 1630, 1580, 1470, 1430, 1330, 1190, 1140 (2) 3-Amino-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one was reacted with 2-acetoxypropiony1- 2 5 chloride. The reaction product was treated with sodium methoxide in methanol to obtain 3- (2-hydroxypropionyl) - amino-7-methy1sulfonylamino-6-phenoxy-4H-l-ben zopyran-4-o^e.

' A n 226 1 Melting point: 219 . 5-221.5°C (recrystallized from ethanol) IR (KBr) cm"1: 3450, 3350, 3250, 1680, 1620, 1590, 1520, 1480, 1460, 1380, 1340, 1260, 5 1220,1200,2260 (3) 3-Amino-7-methylsulfonylamino-6-phenoxy-4H-1-ben2opyran-4-one was reacted with N-tert-butoxycarbonyl-alanine in the presence of N,N 1 -dicyclchexylcarfcs5diimi.de. The reaction product was treated with trifluoroacetic acid to obtain 3-(2-aminopropionyl)amino-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one.

Melting point: 111-113°C (recrystallized from ethanol) IR (KBr) cm-1: 3250, 1680, 1620, 1500, 1350, 1210, 15 1160 (4) 3-Amino-7-methy1sulfonylamino-6-phenoxy-4H-l-benzopyran-4-one was reacted with methanesulfonyl chloride to obtain 3,7-bis(methylsulfonylamino)-6-phenoxy-4H-l-benzopyran-4-one.

Melting point: 199-200°C (recrystallized from ethanol) IR (KBr) cm"1: 3240, 1640, 1630, 1500, 1340, 1330, 1210, 1150 Example 30 6- (2-Methoxyphenoxy)-7-methylsulfonylamino- 4H-l-benzopyran-4-one was treated in the same manner as in Example 40 (1), Example 40 (2) and Example 26 to e' N>V*' - 24 9 - Ci J 22 6 4 8 9 1 obtain 3-formylamino-6-(2-methoxyphenoxy)-7-methylsulf onylamino-4 H-1-benzopyran-4-one.

Melting point: 226.5-227°C (recrystallized from ethyl acetate) IR (KBr) cm"1: 3280, .1685, 1620, 1600, 1495, 1460, 1335, 1145 Example 31 The compounds shown in Table 30 were obtained in the same manner as in Example 26 (1), 27, 28 (2) or 29. 10 The physical properties of these compounds were identical with those of the compounds in Exmaple 4.

Tabic 3 0 r1 r2 r3 r4 r5 ■ ■ 1 z Me h h -ncho h C5-' 0 Me h h -ncho h b- 0 Me h h -ncho h *o 0 Me h me -ncho h .0 0 Me h h -nac h 0 0 Me h h -ncho h 0 cich2- h h -ncho h 0- 0 Me h h h -n<j:o (ch2)2 co?h Q- 0 Et h h -ncho h Q- 0 "cf3 h h -ncho h O- 0 Me h h -ncho h 0 - Cont'd -- 251 - o o f Table 30 (Cont'd) Me H H -NCHO H ci"0" 0 Me H H -NCHO H 0 Me H H -NCHO H Me-0- 0 Me H H -NCO ^O) o- 0 Me H H -NH i CO CO?Et Q- 0 Me H H -NCHO H 0 Me H H -NCHO H ,Me 0 Me H H -NCHO H o s Me H H -NAC H 0 Me H -CN -NCHO H o- 0 Me Ac H -NCHO H '-0-' 0 Me H H -NH go «?h2)2 ch9ci o- 0 Example 3 2 3.75 g of 3-carboxy-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one was suspended in 75 ml of N,N-dimethylformamide. Thereto was dropwise added 4.6 g of phosphorus oxychloride at -10° to -5°C. The mixture was stirred for 3 hours at the same temperature. The reaction mixture was dropwise added to 4 0 ml of a concentrated aqueous ammonia solution at 10-20°C. The mixture was stirred for 3 0 minutes at the same temperature and then adjusted to pH 4 with 4N hydrochloric acid. The resulting crystal was collected by filtration washed with water and recrystallized from acetic acid to obtain' 2.81 g {yield: 75.1%) of 3-carbamoyl-7-methy1su1fony1amino-6-phenoxy-4H-l-benzopyran-4-one having a melting point of ' >250°C.

IR (KBr) cm"1: 3350, 1705, 1620, 1585, 1485, 1460, 1340, 1160 Example 33 3-Carboxy-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one was reacted with 5-aminotetrazole in the presence of N, N' -dicyc.lo'hexylcarbodiimide to obtain 7 methylsulfonylamino-6-phenoxy-3-[ (1,2,3, 4-tetrazol-5-yl) -aminocarbonylj-4H-l-benzopyran-4-one.

Melting point: >250°C (recrystallized from ethanol) IR (KBr) cm"1: 3350, 1680, 1620, 1580, 1495, 1465, 1310, 1220, 1170 rA M A . . p , ™ Example 34 The compounds shown in Table 31 were obtained in the same manner as in Example 32 or 33.

The physical properties of these compounds were identical with those of the compounds in Example 4.

Table 31 R1 R2 R3 R4 R5 z Me H Me -CONH2 o- 0 Me H H -CONMe H o- 0 Me H H -C0N<1 H o- 0 Me H H I O o o 0 Me H H -CONOMe H o- 0 Me H H /Me -CON ^Me o- 0 - Cont'd - Table 31 (Cont1d) 22 6 41 Me h h -coO Q- 0 Me h h o- 0 Me h h -conh2 o-f 0 Me h h -conh2 ^-o-f 0 Me h -nh2 -conh2 o- 0 Me h n — n Ii 11 ■con"*^- n H N h h h <o>- 0 0 22648 1 Example 35 ml of concentrated hydrochloric acid and 60 ml of acetic acid were added to 3.74 g of 3-cyano-6-(2-fluorophenoxy)-7-methylsulfonylamino-4H-l-benzopyran- 4-one. The mixture was refluxed for 30 minutes. After the completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was washed with water and then recrystallized from acetic acid to obtain 1.65g (yield: 42.1%) of 3-carbamoyl-6-10 (2-fluorophenoxy)-7-methylsulfonylamino-4H-l-benzopyran-4-one having a melting point of 249-251°C.

IR (KBr) cm"1: 3330, 3260, 3150, 1695, 1620, 1490, 1455, 1330, 1285, 1155 r Example 36 3.73 g of 3-cyano-6-(2-fluorophenoxy)-7- methylsulfonylamino-4H-l-benzopyran-4-one was dissolved in 100 ml of formic acid saturated with hydrogen chloride. The mixture was stirred for 24 hours at 25-30°C. The solvent was removed by distillation under reduced 20 pressure. The residue was mixed with 100 ml of water. The resulting crystal was collected by filtration and recrystallized from acetic acid to obtain 2.54 g (yield: 65%) of 3-carbamoyl-6-(2-fluorophenoxy)-7-methylsulfonyl-amino-4H-l-benzopyran-4-one. The properties (melting 25 point and IR) of this compound agreed with those of the compound obtained in Example 4. ; . <*\ V ' oo ^ £» Cm Q 1 Example 37 The compounds shown in Table 32 were obtained in the same manner as in Example 35 or 36.

The physical properties of these compounds were 5 identical with those of the compounds in Example 4. o 226 Table 32 r1 r2 r3 & r* r5 "z Me h Me -conh2 o 0 Me h h -conh2 o- 0 Me h h -conh2 f ~c^~ 0 Me h -nh2 -conh2 a- 0 22 64 8 1 Example 38 3.67 g of 6-(2,4-difluorophenoxy)-7-methyl-sulfonylamino-4H-l-benzo^yran-4-one was suspended in 60 ml of acetic acid. Thereto was added 400 mg of 5% 5 palladium-carbon. The mixture was subjected to hydrogenation at 40-50°C at atmospheric pressure. After the completion of the reaction, the catalyst was removed by filtration. The filtrate was concentrated. The resulting crystal was recrystallized from ethanol to obtain 10 3.16 g (yield: 85.6%) of 6-(2,4-difluorophenoxy)-2,3-dihydro-7-methy1sulfonylamino-4H-l-benzopyran-4-one having a melting point of 163.5-165°C.

IR (KBr) cm"1: 3220, 1665, 1605, 1575, 1495, 1420 The compounds shown in Table 33 were obtained 15 in the same manner. o 2264 Table 33 Rl R3 R5 Melting point (°C) IR (KBr) cm"1: Me H CJ-' 131 - 132 [EthanolJ 324 0, 1670, 1610, 1490, 1440, 1325, 1255 Me H 146 - 147 [Ethanol] 3100, 1670, 1490, 1325, 1270, 1145 Me H -€> 167 - 168 [Ethanol] 3175, 1670, 1615, 1490, 1440, 1340, 1260 Me H o- 143 - 144 [Methanol] 3120, 1665, 1610, 1485, 1440, 1320, 1265, 1215, 1160, 1135 "CF3 H o 128 - 130 [IPE] 3140, 1680, 1610, 1480, 1440, 1370, 1260, 1230, 1210, 1200, 1135 Me Me 144 - 145 [Ethanol] 1665, 1610, 1495, 1440, 1320, 1260, 1215, 1135 Me H .CI o 130 - 131 [Ethanol] 3230, 1680, 1610, 1470, 1440, 1320, 1255, 1160 Me H ci~0~ 144 - 146 [Ethanol] 3250, 1670, 1610, 1480, 1440, 1340, 1255, 1160 Me H Me <5- 157 - 159 [Toluene] 3230, 1690, 1610, 14 8 0, 1440, 1340, 1260, 1160 Me H 120 - 121 [Toluene] 3250, 1680, 1615, 1490, 1440, 1340, 1320, 1260, 1135' / 9 9 ft /. o c- «- u -f o 1 Example 39 (1) 6.5 g of 3- ( 3-methy 1sulfonylamino-4-phenoxy-phenoxy)-3-methylacrylic acid was suspended in 200 ml of ethanol. Thereto was added 1.3 g of 10% palladium- c carbon. The mixture was subjected to hydroqenation at 40-50°C at atmospheric pressure. After the completion of the reaction, the catalyst was removed by filtration and the solvent was removed by distillation under reduced pressure. The resulting crystal was recrystal-10 lized from toluene to obtain 5.69 g (yield: 87%) of 3-(3-methylsulfonylamino-4-phenoxyphenoxy)-3-methyl-propionic acid having a melting point of 121-124°C.

IR (KBr) cm"1: 3350, 1710, 1500, 1335, 1215, 1155 (2) 100 g of polyphosphoric acid -was added to 5.69 g of 3-(3-methylsulfonylamino-4-phenoxyphenoxy)-3-methylpropionic acid. The mixture was stirred for 1 hour at 65°C. The reaction mixture was introduced into 400 ml of ice water, and 150 ml of ethyl acetate was added thereto. The organic layer was separated and 20 the solvent was removed by distillation under reduced pressure. The residue was dissolved in 150 ml of IN aqueous sodium hydroxide solution. The solution was washed with diethyl ether and adjusted to pH 4 with 4N hydrochloric acid. 150 ml of ethyl acetate was added 25 thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced 22 6. 1 pressure. The residue was purified by a column chromatography (eluant: a 25 : 1 mixture of toluene and ethyl acetate) and recrystallized from ethanol to obtain 2.16 g (yield: 40%) of 2,3-dihydro-2-methyl-7~methyl-5 sulfonylamino-6-phenoxy-4H-l-benzopyran-4-one.

The properties (melting point and IR) of this compound agreed with those of the compound obtained in Example 22.

Example 4 0 (1) In 300 ml of chloroform was dissolved 33.3 g of 2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one. To this solution being maintained at 25-30°C was dropwise added 16.3 g of bromine in 30 minutes. After the completion of the dropwise addition, 15 the mixture was stirred for 30 minutes at 25-30°C. 100 ml of water was added thereto. The organic layer was separated, washed with a 5% aqueous sodium thiosulfate solution, water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. 20 The solvent was removed by distillation under reduced pressure to obtain 40.1 g (yield: 97.3%) of 3-bromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

Melting point: 137-140°C (recrystallized from toluene) 25 IR (KBr) cm"1: 3250, 1680, 1610, 1435, 1325, 1260, 1205 t <L t> 4 8 NMR (CDC 13) 6 : 3.14 (311, s), 4.54-4.70 (3H, m) , 6.91-7.38 (811, ra) (2) In 280 ml of N,N-dimethylformamide was dissolved 40.1 g of 3-bromo-2,3-dihydro-7-methylsulfonyl-amino-6-phenoxy~4H-l~benzopyran-4-one. Thereto was added 13.9 g of sodium azide. The mixture was stirred for 1 hour at 70-75°C. The reaction mixture was introduced into a mixed solvent consisting of 1.5 liters of water and 300 ml of ethyl acetate. The mixture was adjusted to pH 0.1 with conc. hydrochloric acid. The aqueous layer was separated, washed with 200 ml of ethyl acetate, adjusted to pH 4.0 with a 10% aqueous sodium hydroxide solution, and extracted with two 500-ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The crystal was recrystallized from ethanol to obtain 2.84 g (yield: 82.1%) of 3-amino-7-methy1sulfonylamino-6-phenoxy-4H-l-benzopyran- 4-one having a melting point of 162-163°C.

IR (KBr) cm"1: 3440, 3330, 3180, 1600, 1580, 1550, 1480, 1465, 1330, 1205, 1150 NMR (d,-DMSO)6: 3.19 (3H, s), 5.50-7.00 (2H, br) , b 7.04-7.49 (5H, m), 7.35 (1H, s), 7.62 (IH, s), 7.94 (IH, s) 22 1 Example 41 The compounds shown in Table 34 were obtained in the same manner as in Example 40 (1) and (2).

The physical properties of the compounds were 5 identical with those of the compounds in Example 4.

R1 R3 R5 Me H ^ F o- Me H Me H Me H Me Me o- C1CH2" H / . \ o Et H Q- Me H &*- Me H 01 Me H /Me u- Me H MeHJ- Example 4 2 (1) In 50 ml of chloroform was dissolved 3.33 g of 2 ,3-dihydro-7-methylsulfony1amino-6-phenoxy-4H-l-benzopyran-4-one. Thereto was dropwise added 3.36 g of bromine at 35-4 0°C in 20 minutes. The mixture was stirred for 30 minutes at the same temperature and then introduced into 50 ml of water. The organic layer was separated, washed with a 5% aqueous sodium thiosulfate solution, water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 4.81 g (yield: 98%) of 3,3-dibromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one.

Melting point: 169-170°C (recrystallized from acetonitrile) IR (KBr) cm-1: 3330, 1690, 1610, 1485, 1325, 1255 NMR(CDC13)<5 : 3.15 (3H, s), 4.70 (2H, s), 6.91-7.57 (6H, m), 7.32 (IH, s), 7.40 (IH, s) (2) In 20 ml of pyridine was dissolved 4.81 g of 3,3-dibromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one. The solution was refluxed for 20 minutes. The reaction mixture was introduced into 200 ml of water. The mixture was adjusted to pH 4 with concentrated hydrochloric acid and then extracted with two 100-ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with water and saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from acetonitrile to obtain 3.30 g (yield: 82%) of 3-bromo-7-methylsulfonyl-amino-6-phenoxv-4H-l-benzopyran-4-one having a melting point of 215-216°C.

IR (KBr) cm"1: 3100, 3080, 1635, 1620, 1485, 1455, 1335, 1155 NMR(dr-DMSO)6: 3.23 (3H, s), 7.06-7.66 (5H, m), b 7.30 (IH, s), 7.72 (IH, s), 8.81 (IH, s) , 10 . 07 (IH, s) The following compound was obtained in the same manner as in Example 42 (1) and (2): 3-Chloro-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran- 4-one Melting point: 200-201°C (recrystallized from ethyl acetate-diisopropyl ether) IR (KBr) cm-1: 3220, 3050, 1645, 1600, 1560, 1480, 1450 (3) 50 ml of a 25% aqueous methylamine solution was ice-cooled. Thereto was added 4.1 g of 3-bromo-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one. The mixture was stirred for 2 hours at 0-5°C. 100 ml of water was added thereto. The mixture was adjusted to pH 4 with 4N hydrochloric acid and then extracted with 100 ml of ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was 2Z 6 1 purified by a column chromatography (eluant: a 5 : 1 mixture of toluene and ethyl acetate) and then recrystallized from ethanol to obtain 400 mg (yield: 11.1%) of 3-methylamino-7-me thylsulfonylamino-6-phenoxy-4H-l-5 benzopyran-4-one.

The properties (melting point, IR and NMR) of this compound agreed with those of the compound obtained in Example 4. ' The compounds shown in Table 3 5 were obtained 10 in the same manner.

The physical properties of these compounds were identical with those of the compounds in Example 4.

Table 35 R5 T>6 i \ R7 o Me Me o \ N — j o H OH o H Et c v *i tf t w 1 (4) 34 0 mg of acetic anhydride and 310 mg oC formic acid were mixed. The mixture was stirred for 1.5 hours at 4 0-45°C. Thereto was added 10 ml of methylene chloride. There was further added 4 00 mg 5 of 7-methylsulfonylamino-3-methylamino-6-phenoxy-4H-l-benzopyran-4-one. The resulting mixture was stirred for 1 hour at 25-30°C. 10 ml of diisopropyl ether was added thereto. The resulting crystal was collected by filtration and then recrystallized from acetonitrile 10 to obtain 330 mg (yield: 76.7%) of 7-methy1sulfonylamino-3-(N-formy1-N-methylamino)-6-phenoxy-4H-l-benzopyran-4-one.

The properties (melting point, IR and NMR) of this compound agreed with those of the compound 15 obtained in Example 4.

Example 4 3 500 mg of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one was dissolved in 20 ml of acetic acid and 10 ml of water. The solution was heated 20 to 35°C. Thereto was dropwise added a solution of 190 mg of sodium cyanate dissolved in 5 ml of water, in 5 minutes. The mixture was stirred for 30 minutes at the same temperature. 20 ml of water was added thereto. The resulting crystal was collected by filtration and 25 recrystallized from acetic acid to obtain 350 mg (yield: 62.3%) of 7-methylsulfonylamino-6-phenoxy-3-ureido-4H-1-benzopyran-4-one having a melting point of >250°C. cc o 4 a c IR (KBr) cm 1: 3495, 3340, 3300, 1680, 1620, 1590 NMR(d^-DMSO)6: 3.21 (3H# s), 6.34 (2H, s), 7.02-o 7. 55 (6H, m) , 7 .69 (111, s) , 8.02 (IH, s), 9.09 (IH, s), 9.90 (IH, bs) Example 44 In 10 ml of methylene chloride was dissolved 500 mg of 3-methylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. Thereto was dropwise added 220 mg of chlorosulfonyl isocyanate at 0-5°C. The mixture was stirred for 10 minutes at the same temperature. 20 ml of water was added thereto. The organic layer was separated. The solvent was removed by distillation under reduced pressure. The residue was mixed with 5 ml of methanol and 5 ml of 2N hydrochloric acid. The mixture was stirred for 1 hour at 20-25°C. To the reaction mixture were added 20 ml of methylene chloride and 20 ml of water. The organic layer were separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 1 : 1 mixture of toluene and ethyl acetate) to obtain 220 mg (yield: 35.1%) of 7-methylsulf ony lamino- 3- (1-methylureido)-6-phenoxy-4H-l-benzopyran-4-one.

Melting point: 145-145.5°C (recrystallized from ethanol) 22 6 4 1 IR (KBr) cm"1: 3450, 3350, 1640, 1620, 1480, 1450 NMR(dc-DMSO)6: 2.95 (3H, s), 3.20 (3H, s), 5.85 (2H, bs), 7.06-7.50 (6H, m) , 7.70 (IH, s), 8.43 (IH, s) , 10.00 (IH, bs) Example 4 5 4 ml of acetic anhydride and 200 mg of sodium acetate were added to 4 00 mg of 3-[N-(3-carboxypropionyl)- amino]-7-methy1sulfonylamino-6-phenoxy-4 H-1-benzopyran-4- one. The mixture was stirred for 30 minutes at 90-100°C and then cooled to room temperature. 30 ml of water and ml of ethyl acetate were added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 300 mg (yield: 79%) of 7- (N-acetyl-N-methylsulfonylamino)-6- phenoxy-3- (1-succinimino)-4H-l-benzopyran-4-one having a melting point of 220-221°C.

IR (KBr) cm"1: 3050, 1780, 1720, 1650, 1620, 1575 NMR(d -DMSO)6: 2.13 (3H, s), 2.88 (4H, s), 3.59 (3H, b s) , 7.17-7.56 (6H, m) , 8.27 (IH, s) , 8.63 (IH, s) Example 4 6 In 4 5 ml of a IN aqueous sodium hydroxide solution was dissolved 4.46 g of 7-methylsulfonylamino- 22643 1 3-(N-formyl-N-methoxycarbonylmethylamino) -6-phenoxy-4H-l-benzopyran-4-one. The solution was stirred for 1.5 hours at 25-30°C. The solution was then adjusted to pH 3 with 4N hydrochloric acid and extracted with two 50-5 ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The "0 residue was mixed with diethyl ether. The resulting crystal was collected by filtration to obtain 3.57 g (yield: 82.6%) of 7-methylsulfonylamino-3-(N-formyl-N-carboxymethylamino)-6-phenoxy-4H-l-benzopyran-4-one having a melting point of 98-100°C.

IR (KBr) cm"1: 3220, 1730, 1665, 1610, 1490, 1445, 1335, 1205, 1160 NMR (d -DMSO)6: 3.22 (3H, s) , 4.25 (2H, s), 7.07-7.65 6 (5H, in), 7.32 (IH, s) , 7.76 (IH, s), 8.19 (IH, s), 8.56 (IH, s), 10.00 0 (IH, bs) Example 47 4.25 g of 2-bromo-3-formylamino-7-methylsul-fonylamino-6-phenoxy-4H-l-benzopyran-4-one was dissolved in 50 ml of N,N-dimethylformamide. 1.97 g of cuprous 5 cyanide was added thereto, and the resulting mixture was stirred for 2 hours at 85-90°C. The reaction mixture was introduced into 300 ml of water, adjusted to 22 ft ai q i *j 1 pH '1 with 'IN hydrochloric acid, arid extracted with two 200-ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried c with anhydrous sodium sulfatp. The solvent w?s removed by distillation under reduced pressure. The resulting residue was recrystallized from acetonitrile to obtain 2.05 g (yield: 55.3%) of 2-cyano-3-formylamino-7- me t hy 1 su 1 f ony 1 amino-6-phenoxy-*! H-l-ben zopyran-4-one having a melting point of 229-230°C.

IR (KBr) cm"1: 3260, 2225, 1715, 1610, 1485, 1460, 1330, 1215, 1150 NMR(dg-DMSO)6: 3.28 (3H, s), 7.07-7.62 (5H, m) , 7.27 (IH, s), 7.76 (IH, s), 8.37 (IH, d, J=3.0Hz), 10.22 (IH, d, J= 3.0Hz), 10.22 (IH, s) Example 4 8 In 5 ml of acetic acid were dissolved 500 mg of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-l-20 benzopyran-4-one and 250 mg of 2,5-dimethoxytetrahydro-furan. The mixture was stirred for 30 minutes at 70-80°C and then cooled to room temperature. 50 ml of water was added thereto. The resulting crystal was collected by filtration and recrystallized from ethyl 25 acetate-diisopropyl ether to obtain 250 mg (yield: 43.7%) of 7-methylsulfonylamino-6-phenoxy-3-(1-pyrrolyl)-4H-l-benzopyran-4-one having a melting point of 238.5- 1 24 0 °C .

IR (KBr) cm -1 1640, 1615, 1575, 1475, 1440, 1425, 1410 Example 4 9 3.46 g of 3-amino-7-methylsulfonylamino-6- phenoxy-4H-l-benzopyran-4-one was dissolved in 35 ml of N,N-dimethylformamide. Thereto were added 7 ml of bromobenzene, 1.66 g of potassium iodide, 1.38 g of potassium carbonate and 0.64 g of a copper powder. The 10 mixture was refluxed for 6 hours. The reaction mixture was introduced into a mixture consisting of 300 ral of water and 200 ml of ethyl acetate. The insolubles were removed by filtration, and the filtrate was adjusted to pH 4 with 4N hydrochloric acid. The organic layer was 15 separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 20 : 1 20 mixture of toluene and ethyl acetate) and then recrystallized from acetonitrile to obtain 430 mg (yield: 10.2%) of 7-methylsulfonylamino-3-phenylamino-6-phenoxy-4H-l-benzopyran-4-one having a melting point of 212-213°C.

IR (KBr) cm 1: 3240, 1645, 1620, 1580, 1485, 1455, 1340, 1265, 1160 NMR (dg-DMSO) (5: 3.22 (3H, s), 6.92-7.59 (12H, m) , 7.76 (IH, s) , 8.58 (111, s) , 10.01 (IH, bs) 275 Example 50 (1) 3.5 g of 2-ethoxycarbonyl-7-methylsulfonyl-amino-6-phenoxy-4H-l-benzopyran-4-one was suspended in 30 ml of acetic acid. Thereto was added 20 ml of concentrated hydrochloric acid. The mixture was refluxed for 1 hour. To the reaction mixture was added 100 ml of water. The resulting crystal was collected by filtration and then recrystallized from ethanol to obtain 3.0 g (yield: 91%) of 2-carboxy-7-methylsulfonyl-amino-6-phenoxy-4H-l-benzopyran-4-one having a melting point of >250°C.

IR (KBr) cm-1: 3245, 1730, 1625, 1590, 1460, 1335, 1220, 1160 (2) 3.0 g of 2-carboxy-7-methylsulfonylamino-6-phenoxy-4H~l-benzopyran-4-one was suspended in 30 ml of methylene chloride. Thereto were added 3.8 g of thionyl chloride and 0.1 ml of N,N-dimethylformamide. The mixture was refluxed for 1.5 hours. After the completion of the reaction, the solvent was removed by distillation under reduced pressure to obtain 3.1 g (yield: 98.4%) of 7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one-2-carboxylie acid chloride.

IR (neat) cm 1: 1760 (3) 7-Methylsulfonylamino-6-phenoxy-4H-l-benzo-pyran-4-one-2-carboxylic acid chloride was reacted with ammonia to obtain 2-carbamoyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

Melting point: >250°C (recrysta11ised from methanol) — — v r I IR (KBr) cm 1 : 3425, 1700, 1645 , .1625, ] 4 50, 1325, 1210, 1135 (4) 7-Methylsulfonylamino-6-phenoxy-4H-1-benzo-pyran-4-one-2-carboxylic acid chloride was reduced by sodium boron hydride to obtain 2-hydrcxyrnethy1-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

Melting point: 210-215°C (decomposed) (recrystallized from ethyl acetate) IR (KBr) cm-1: 3375, 3240, 1630, 1585, 1480, 1455, 10 1395, 1370, 1325, 1260, 1210 (5) 3.1 g of 7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one-2-carboxylic acid chloride was dissolved in 80 ml of anhydrous tetrahydrofuran. This solution was dropwise added to 10 ml of an aqueous solution containing 1.26 g of sodium azide in 10 minutes at 5-10°C. The mixture was stirred for 1.5 hours at 10-20°C. The resulting crystal was collected by filtration to obtain 1.45 g (yield: 46%) of 7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one-2-carboxylic acid azide having a 20 melting point of 146-149°C (decomposed).

IR (KBr) cm-1: 3200, 2125, 1700, 1640, 1610, 1480, 1440, 1320, 1200, 1130 (6) 7-Methylsulfonylamino-6-phenoxy-4H-i-benzo-pyran-4-one-2-carboxylic acid azide was reacted with ethanol with heating to obtain 2-ethoxycarbonylamino-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one.

Melting point: 207-209°C (recrystallized from ethanol) IR (KBr) cm"1: 3230, 1740, 1620, 1535, 1480, 1450, 22 64 1 13 2 5, 1210, 1140 (7) 7-Methylsulfony1amino-6-phenoxy-4 H-l-benzopyran- 4-one-2-carboxvlic acid azide was reacted with tert-butanol with heating to obtain 2-tert-butoxycarbonyl~ 5 amino-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one .

Melting point: 14 7-150°C (recrystallized from benzene) IR (KBr) cm"1: 3250, 1745, 1620, 1525, 1490, 1450, 1360, 1330, 1230, 1140 10 (8) 7-Methylsulfonylamino-6-phenoxy-4H-l-benzopyran- 4-one-2-carboxylic acid azide was reacted with formic acid with heating to obtain 2-formylamino-7-methyl-sulfonylamino-6-phenoxy-4 H-l-benzopyran-4-one.

Melting point: 214-216°C (recrystallized from 15 acetonitrile) IR (KBr) cm-1: 3225, 3120, 1710, 1625, 1610, 1555, 1450, 1215, 1150, 1145 (9) 7-Methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one-2-carboxylic acid azide was reacted with acetic acid with heating to obtain 2-acetylamino-7-methyl-sulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

Melting point: 236-238°C (recrystallized from ethanol) IR (KBr) cm"1: 3170, 1700, 1620, 1600, 1525, 1450, 25 1350, 1250, 1240, 1220, 1145 (10) 2-tert-Butoxycarbonylamino-7-methylsulfonyl-amino-6-phenoxy-4H-l-benzopyran-4-one was reacted with trifluoroacetic acid to obtain 2-amino-7- o 22648 methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. Melting point: 223-225°C (recrystallized from ethanol) IR (KBr) cm-1: 3225, 1660, 1615, 1550, 1480, 1200, i 1 Example 51 (1) 3-Formyl-7-methylsuIfonylamino-6-phenoxy-4H-l- benzopyran-4-one was reduced by sodium boron hydride to obtain 3-hydroxymethyl-7-methylsulfonylamino-6-phenoxy-10 4H-l-benzopyran-4-one.

Melting point: 165-166.5°C (recrystallized from ethyl acetate-diethyl ether) IR (KBr) cm"1: 3450, 3250, 1635, 1605, 1485, 1460, 1325, 1210, 1150 15 (2) 3-Formyl-7-methylsulfonylamino-6-phenoxy-4H-l- benzopyran-4-one was reacted with sodium hypochlorite to obtain 3-chloro-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one.

The properties (melting point and IR) of this 20 compound agreed with those of the compound obtained in Example 4. (3) 3-Formyl-7-methylsulfonylamino-6-phenoxy-4H-l- benzopyran-4-one was reacted with benzyltriphenylphos-phonium bromide in the presence of potassium, tert-25 butoxide to obtain 3-(2-phenylvinyl)-7-methylsulfonyl-amino-6-phenoxy-4H-l-benzopyran-4-one.

Melting point: 174-175°C (recrystallized from lri 6 4 1 ethanol) IR (KBr) cm-1: 3400, 1630, 1620, 1480, 1450, 1330, 1200, 1155 (4) 3-Formyl-7-methylsulfonylamino-6-phenoxy-4H-1-5 benzopyran-4-one was reacted with methylmagnesium iodide to obtain 3-(1-hydroxyethyl)-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

Melting point: 136-138°C (recrystallized from ethyl ace tate) IR (KBr) cm-1: 3325, 3225, 1615, 1590, 1480, 1445, 1325, 1205, 1145 (5) 3-Formy1-7-methylsulfonylamino-6-phenoxy-4h-1-benzopyran-4-one was reacted with 2,4-dimethoxybenzyl-amine. The reaction product was reduced by sodium boron hydride to obtain 3- (2 ,4-dirnethoxybenzylamino) - methyl-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one.

This compound was then reacted with acetic anhydride in methanol. The reaction product was treated 20 with trifluoroacetic acid to obtain 3-acetylaminomethyl-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one. Melting point: 240-242°C (recrystallized from isopropyl alcohol) IR (KBr) cm"1: 3350, 3250, 1680, 1640, 1600, 1460, 25 1340, 1215, 1150 (6) 3-Acetylaminomethyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was treated with 6N hydrochloric acid to obtain 3-aminomethyl-7- 09 £ 1 methylsulfonylamino-G-phenoxy-4H-l-benzopyran-4-one.

Melting point: 190-195°C (decomposed) (recrystallized from ethyl acetate) IR (KBr) cm"1: 3450, 3070, 1635, 1580, 1480, 1455, 5 1385.. 1320, 1275 Example 52 3-Acetyl-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one was reacted with bromine to obtain 3-(2-bromoacetyl)-7-rnethylsulfonylamino-6-phenoxy-4H-l-10 benzopyran-4-one. It was reacted with thioformamide to obtain 7-methylsulfonylamino-6-phenoxy-3-(thiazol-4-yl)-4H-l-benzopyran-4-one.

Melting point: >250°C (recrystallized from acetonitrile) IR (KBr) cm"1: 3260, 1635, 1620, 1480, 1450, 1315, 1200, 1150 Example 53 (1) 6-(2-Methoxycarbonylphenoxy)-7-methylsulfonyl- amino-4H-l-benzopyran-4-one was treated in the same 20 manner as in Example 5 (2) to obtain 6-(2-carboxy- phenoxy)-7-methylsulfonylamino-4H-1-benzopyran-4-one. Melting point: 243-246°C (recrystallized from acetonitrile) IR (KBr) cm"1: 3150, 1720, 1670, 1640, 1605, 1480, 25 1360, 1330, 1260, 1220, 1160 O 2264 1 (2) 6-(2-Carboxyphenoxy)-7-methylsulfonyl- amino-4H-l-benzopyran-4-one was treated in the same manner as in Example 50 (2), Example 50 (5), Example 50 (7) and Example 50 (10) to obtain 6-(2-aminophenoxy)-5 7-methy1sulfonylamino-4H-l-benzopyran-4-one.

Melting point: 238-240°C (recrystallized from acetonitrile ) IR (KBr) cm-1: 3415, 3300, 3200, 1635, 1620, 1455, 1330, 1290, 1155 10 (3) 6-(2-Aminophenoxy)-7-methylsulfonylamino-4H-l- benzopyran-4-one was treated in the same manner as in Reference Example 2 to obtain 6-(2-acetylaminophenoxy)-7-methylsulfonylamine-4H-l-benzopyran-4-one.

Melting point: 130-132°C (recrystallized from ethanol) 15 IR (KBr) cm"1: 3250, 1620, 1480, 1450, 1325, 1290, 1150 (4) 6-(2-Aminophenoxy)-7-methylsulfonylamino-4H-l- benzopyran-4-one was treated in the same manner as in Example 26 (1) to obtain 6-(2-formylaminophenoxy)-7-20 methylsulfonylamino-4H-l-benzopyran-4-one.

Melting point: 203-204°C (recrystallized from acetonitrile) IR (KBr) cm"1: 3220, 1665, 1620, 1490, 1450, 1320, 1295, 1150 Example 54 >•+ 6-(2-Methoxyphenoxy)-7-methylsulfonylamino- .'i'V t 4H-l-benzopyran-4-one was treated in the same manner as//.[■,? |i 0, in Reference Example 8 (2) to obtain 6-(2-hydroxy- ;\ ■ o '; >. ,<*J phenoxy)-7-methylsulfonylamino-4K-l-benzopyran-4-one. - 2 82 - .r;.

- V T 1 Melting point: 186.5-187°C (recrystallized from isopropyl alcohol) IR (KBr) era"1: 3250, 1620, 1585, 1480, 1450, 1320, 1290, 1160, 1140 Example 55 (1) 4 g of 3-formyl-7-methylsulfonylamino-6- phenoxy-4H-l-benzopyran-4-one was dissolved in 20 ml of N ,N-dimethylformamide, Thereto was added 8 50 mg of hydroxylamine hydrochloride. The mixture was stirred 10 for 1 hour at 20-25°C. The reaction mixture was mixed with 50 ml of ethyl acetate and 100 ml of water. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The 15 solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from ethanol to obtain 3.0 g (yield: 72.3%) of 3-hydroxy-iminomethyl-7-methylsulfonylamino-6-phenoxy-4H-l-berizo-pyran-4-one having a melting point of 199-200°C. 20 IR (KBr) cm"1: 3250, 1620, 1495, 1330, 1210, 1160 The compounds shown in Table 36 were obtained in the same manner.

R5 Mel ting point (°C) IR (KBr) cm-1: o- 206 - 207 [Acetonitrile] 3240, 1620, 1490, 1455, 1335, 1260, 1160 '-d- 226 - 227 [Acetonitrile] 3260, 3220, 1620, 1615, 1490, 1460, 1340, 1160 22 6 4 8 S 1 (2) 3 . 0 g of 3-hydroxyiminoinethyl-7-methylsulfony 1- amino-6-phenoxy-4H-l-benzopyran-4-one was suspended in 30 ml of acetic acid. Thereto was added 900 mg of sodium acetate. The mixture was refluxed for 3 hours.

After the completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was mixed with 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution 10 in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting ci-ystal was recrystallized from a mixed solvent of ethyl acetate and ethanol to obtain 2.4 g (yield: 83.9%) of 3-cyano-7-methylsulfonyl-15 amino-6-phenoxy-4H-l-benzopyran-4-one having a melting point of 219.5-220.5°C.

IR (KBr) cm-1: 3140, 2240, 1650, 1620, 1485, 1445, 1330, 1155 The compounds shown in Table 3 7 were obtained 20 in the same manner. c R5 Melting point (°C) IR (KBr) cm"1: T? 244 - 246 [Acetonitrile] 3140, 3070, 2240, 1655, 1620, 1490, 1460, 1330, 1320, 1270, 1150 /F f~0~ 247 - 249 [Acetonitrile] 3120, 3070, 1645, 1620, 1480, 1450, 1330, 1150 -•286 - 22 6 4 ft ' ^ i 1 Example 56 3-Carbamoy1-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one was reacted with thionyl chloride in NyN-dimethvlformamide to obtain 3-cyano-7-methyl-5 sulfonylamino-6-phenoxy--'lH-l-benzopvran-4-onR. The properties (melting point and IR) of this compound were identical with those of the compound obtained in Example 4 .

Example 57 (1) 6-(2,4-Difluorophenoxy)-7-methylsulfonylamino- 4H-l-benzopyran-4-one was treated in the same manner as in Reference Example 2 to obtain 6- (2,4-difluorophenoxy )-7-(N-acetyl-N-methylsulfonylamino)-4H-l-benzo-pyran-4-one.

Melting point: 176-178°C (recrystallized from iso propyl alcohol) IR (KBr) cm"1: 1705, 1640, 1620, 1440, 1335, 1295, 1245, 1165 The following compound was obtained in the 20 same manner: 6-(2,4-Di fluorophenoxy)-3-formylamino-7-(N-acetyl-N-methylsulfonylamino)-4H-1-benzopyran-4-one Melting point: 237-239°C (recrystallized from acetonitrile) IR (KBr) cm"1: 3320, 1705, 1685, 1610, 1520, 1485, 1440, 1345, 1240, 1215, 1190, 1160 (2) 7-Methylsulfonylamino-6-phenoxy-4H-l-benzo- pyran-4-one was reacted with benzoyl chloride in the •") rl c <LCOl presence of aluminum chloride to obtain 7-(N-benzoyl-N-methylsulfonylamino)-6-phenoxy-4H-l-benzopyran-4-one.

Melting point: 164-165.5°C (recrystallized from ethyl acetate) TR (KBr) cm"1; 1685; 1650, 1610,- 1475, 1435, 1350, 1285, 1260, 1200, 1160 (3) 7-Methylsulfonylamino-6-phenoxy-4H-l-benzopyran- 4-one was reacted with methyl iodide in the presence of sodium hydride to obtain 7-(N-methyl-N--methy lsulfonyl-amino)-6-phenoxy-4H-l-benzopyran-4-one.

Melting point: 187-189°C (recrystallized from ethanol) IR (KBr) cm"1: 1630, 1610, 1480, 1440, 1340, 1150 Example 58 3- (4-Chlorobutyrylamino)-7-methylsulfonylamino- 6-phenoxy-4H-l-benzopyran-4-one was reacted with sodium hydride in N,N-dimethylformamide to obtain 7-methylsul-fonylamino-3-(2-oxopyrrolidin-l-yl)-6-phenoxy-4H-l-benzopyran-4-one.

Melting point: 192-193°C (recrystallized from ethanol) IR (KBr) cm"1: 1680, 1635, 1610, 1485, 1335, 1280, 1160 Example 59 2-Carboxy-7-methylsulfonylamino-6-phenoxy-4H- l-benzopyran-4-one was reacted with 5-aminotetrazole in ■ \ the presence of itf,N' -dicyclohexylcarbodiimide to obtain 7— o 1 ID o I methylsulfonylamino-"6-phenoxy-2-( (1, 2 , 3/4-tetrazol-5-yl) ■ aminocarbony1]-4H-l-benzopyran-4-one.

Melting point: >250°C (recrystallized from ethylene glyco] monomethyl ether) T D I VOv- \ <-m "I •31*50 icon ui n ic;on i i£c;n • ^ A » V / - v ✓ v , a w v | ^ ^ f ^ ^ r w | * 4 ^ w , 1370, 1325, 1200, 1140 Example 60 3-Cyano-7-me thylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one was reacted with sodiujn azide in the 10 presence of aluminuin chloride to obtain 7-methylsulfonyl-amino-6-phenoxy-3- (1,2,3,4-tetrazol-5-yl)-4H-l-benzopyran-4-one.

* * Melting point: >250°C (recrystallized from dioxane- diisopropyl ether) IR (KBr) cm"1: 3370, 3170, 1630, 1480, 1460, 1340, 12 9 5, 1160 Example 61 3.56 g of 3-cyano-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one/ 970 mg of hydroxylamine 20 hydrochloride, 1.5 ml of water, 7 ml of N,N-dimethylformamide and 150 ml of ethanol were mixed, and subjected to refluxing for 3 hours. The reaction mixture was cooled> and thereafter, the precipitated crystals were collected by filtration and then recrystallized from . 0 acetonitrile to obtain 2.8 g (yield: 72%) of 2-amino-3- .-v CI" carbamoyl-7-methylsulfonylamino-6-phenoxy-4H-1-ben zopyrah- .

\V - 289 - ^ - - O 22648 1 4-one having a melting point of >250°C.

IR (KBr) cm"1: 3460, 3380, 3125, 1640, 1570, 1545, 1475, 1320, 1220, 1150 Example 62 In 10 ml of a mixture of anhydrous tetrahydro- furan-hexamethylphosphoric acid triamide (7 : 3) was dissolved l.OO g of 2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-l-benzopyran-4-one. To the resulting solution was added 10 ml of a tetrahydrofuran solution of 1,1,1,3,-10 '3, 3-hexamethyldis"ilazane lithium salt consisting of 1.17 g of 1, 1,1, 3 , 3, 3-hexair.ethyldisilazane and 6.6 millimoles of n-butyllithium at -78°C, and the resulting mixture was \' stirred for 40 minutes, after which 500 mg of methyl methanethiolsulfonate was added at the same temperature 15 and the mixture was stirred for 15 minutes. Subsequently, the temperature of the reaction mixture was elevated to room temperature. The reaction mixture was introduced into 80 ml of 2N hydrochloric acid with ice-cooling and the resulting mixture was extracted with two 40-ml 20 portions of ethyl acetate. The extracts were combined and washed with water and saturated aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the oily 25 product obtained was purified by a column chromatography ' ' r r (eluant: toluene : ethyl acetate =50 : 1) to obtain 480 mg (yield: 39.6%) of 2,3-dihydro-7-methylsulfonylamino- 22 6 4 1 3-methylthio-6-phenoxy-4 H-l-benzopyran-4-one.

The physical properties (IR and melting point) of this product were identical with those of the compound obtained in Example 22 (2).

Preparation Example 1 Hard gelatin capsules were prepared using the following components: 6- (2-Fluorophenoxy)-3-formylamino-7-methylsulfonylamino-4H-l-benzopyran-4-one 50 mg Lactose 114.5 mg Corn starch 2 0 mg Hydroxypropyl cellulose 2 mg Light silicic acid anhydride 1.5 mg Carboxymethy1 cellulose calcium (ECG 5 05) 10 mg Magnesium stearate 2 mg Total 2 00 mg The above components of the above amounts were filled in one hard capsule according to an ordinary 10 method.

Preparation Example 2 Tablets were prepared using the following components: £ £ U Q ; 3-Formylamino-7-methylsulfonylamino- 6-phenoxy-4H-l~benzopyran-4-one 25 mg Lactose 4 9 mg Macrocrystalline cellulose 36 mg Hydroxypropyl cellulose 1 mg Carboxynisthyl cellulose calcium (ECG 505) 6.6 mg Magnesium stearate 1.2 mg Talc 1.2 mg Total 100 mg The above components of the above amounts were made into one tablet according to an ordinary method.

Preparation Example 3 Tablets were prepared using the following 5 components: 3-Formy1amino-7-methylsulfonylamino- 6-phenoxy-4H-l-benzopyran-4-one 50 mg Lactose 7 4 mg Microcrystalline cellulose 55 mg Hydroxypropyl cellulose 2 mg Carboxymethy1 cellulose calcium (ECG 505) 15 mg Magnesium stearate 2 mg Talc 2 mg Total 200 mg The above components of the above amounts were made into one tablet according to an ordinary method.

Claims (59)

1. s'- 2 2 6 4 G 9 1 Preparation Example 4 Tablets were prepared using the following components: 3-Formy1amino-7-methylsulfonylamino- 6-phenoxy-4H-l-benzopyran-4-one 100 mg Lactose 4 9 mg Microcrystalline cellulose 55 rag Hydroxypropyl cellulose 2 mg Carboxymethyl cellulose calium (ECG 505) 15 mg Magnesium stearate 2 mg Talc 2 mg Total 225 mg The above components of the above amounts were \ ' 5■ made into one tablet according to an ordinary method. Preparation Example 5 Tablets were prepared using the following components: 3-Carbamoy1-7-methyl-sulfonylamino-6-phenoxy -4h'-l-benzopyran-4-one 200 mg Microcrystalline cellulose 100 mg Sodium starch glycolate (NF) 30 mg Magnesium stearate 3 mg Total 333 mg The above components of the above amounts were 10 made into one tablet according to an ordinary method. 293 - VJ./I 22643 WHAT pWE CLAIM IS:- «• VTHiAT IE CLAIMED IEi 1. A 4H-l-benzopyran-4-one derivative represented by the following formula or a salt thereof: wherein R1 represents an unsubstituted or halogen-sub- 2 stituted lower alkyl, lower alkenyl or aryl group; R represents a hydrogen atom or an alkyl or acyl group; 3 R represents a hydrogen or halogen atom, a cyano, azido, carboxyl, hydroxyl, formyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, phenoxy, 4 cycloalkyl, carbamoyl, amino or phenyl group; R represents a hydrogen or halogen atom, a nitro, cyano, carboxyl, acyl, hydroxyl or alkoxycarbonyl group, a substituted or unsubstituted alkyl, alkoxy, alkylthio, phenylthio, lower alkynyl, lower alkenyl, sulfamoyl, alkylsulfinyl, alkylsulfonyl, amidino, phenyl or heterocyclic group or /r6 /r6 6 a group of the formula, -Nv 7 or -CON^ 7 (R is a R R hydrogen atom, a hydroxyl, cyano or alkoxycarbonyl group or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkylsulfonyl, imino- 7 methyl or amidino group and R is a hydrogen atom or a substituted or unsubstituted alkyl, alkoxy, phenyl, 6 7 cycloalkyl or heterocyclic group; or R and R , when - 294 - 2264 taken together with the nitrogen atom to which the two are bonded, form a 3- to 7-membered, substituted or 5 unsubstituted heterocyclic group); R represents a substituted or unsubstituted phenyl, thienyl, furyl or pyridyl group; Z represents an oxygen or sulfur atom or an imino group and the broken line means that the bond between the two carbon atoms is a single or double bond.
2. 2. A 4H-l-benzopyran-4-one derivative or a salt thereof according to claim 1, wherein Z represent an oxygen 5 or sulfur atom; R represents a substituted or unsubstituted phenyl or pyridyl group; R1 represents an unsubstituted or 2 halogen-substituted lower allcyl or lower alkenyl group; R 3 4 represents a hydrogen atom or an acyl group; R and R , which may be the same or different, each represent a hydrogen atom, a carbamoyl, a carboxyl, a formyl, a hydroxyl or an alkoxycarbonyl group or substituted or an unsubstituted alkyl, alkoxy, or phenyl group and the broken line means that the bond between the two carbon atoms is a double bond.
3. 3. A 4H-l-benzopyran-4-one derivative or a salt thereof according to Claim 1, wherein R represents a substituted or unsubstituted phenyl or pyridyl group; Z represents an oxygen or sulfur atom; R1 represents an unsubstituted or halogen-substituted lower alkyl or 2 lower alkenyl group; R represents a hydrogen atom or an 4 acyl group; R represents a group of the formula R6 / 6 -v 1 <■ -Nv 7 (R is a hydrogen atom; a hydroxyl, cyano or R alkoxycarbonyl group or a substituted or unsubstituted, -i r\ - 295 - ~ - • - alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, 7 iminomethyl or amidino group and R is a hydrogen atom or a substituted or unsubstituted alkyl or cycloalkyl group, or R^ and R^, when taken together with the nitrogen atom to which the two are bonded, form a 4- to 6-membered, substituted or unsubstituted heterocyclic group); 3 R represents a hydrogen or halogen atom, a cyano, azido, carbamoyl, carboxyl, hydroxyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, amino or phenyl group and the broken line means chat the bond between the two carbon atoms is a double bond.
4. 4. A 4H-l-benzopyran-4-one derivative or a salt thereof according to any one of Claims 1 to 3, wherein Z represents an oxygen atom.
5. 5. A 4H-l-benzopyran-4-one derivative or a salt thereof according to any one of Claims 1 to 4, wherein R1 represents a lower alkyl group.
6. 6. A 4H-l-benzopyran-4-one derivative or a salt thereof according to any one of Claims 1 to 5, wherein 2 R represents a hydrogen atom.
7. 7. A 4H-l-benzopyran-4-one derivative or a salt thereof according to any one of Claims 1 to 6, wherein R^ represents a hydrogen atom or an alkyl group.
8. 8. A 4H-l-benzopyran-4-one derivative or a salt thereof according to Claim 1, wherein R^ represents a substituted or unsubstituted alkylthio, phenylthio, alkylsulfinyl or alkylsulfonyl group or a group of the 1 - 296 - R6 R6 / s* 6 7 formula, -N. 7 or -CON. 7 (R and R have the same R R meanings as defined in claim 1).
9. 9. A 4H-l-benzopyran-4-one derivative or a salt thereof according to any one of claims 1 to 8, wherein represents an alkylthio, formylamino or carbamoyl group.
10. 10. A 4H-l-benzopyran-4-one derivative or a salt thereof according to any one of claims 1 to 9, wherein R^ represent a substituted or unsubstituted phenyl group.
11. 11. A 4H-l-ben2opyran-4-one derivative or a salt 5 thereof according to Claim 10, wherein R represents a phenyl group which may be substituted by at least one substituent selected from the group consisting of halogen atoms, hydroxyl group, amino group, carboxyl group, haloalkyl groups, alkyl groups, alkoxy groups, alkoxycarbonyl groups, acylamino groups and carbamoyl group.
12. 12. A process for producing a 4H-l-benzopyran-4-one derivative represented by the following formula or a salt thereof: O wherein R1 represents an unsubstituted or halogen-substituted lower alkyl, lower alkenyl or aryl group; 2 R represents a hydrogen atom or an alkyl or acyl group; , 3 ; " R represents a hydrogen or halogen atom, a cyano, azido, - 297 - o £ c carboxyl, hydroxyl, formyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, phenoxy, 4 cycloalkyl, carbamoyl, ammo or phenyl group; R represents a hydrogen or halogen atom, a nitro, cyano, carboxyl, acvl. hydroxyl or alkoxycarbonyl group, a substituted or unsubstituted alkvl, alkoxy, alkylthio, phenylthio, lower alkynyl* lower alkenyl, sulfamoyl, alkylsulfinyl, alkylsulfonyl, amidino, phenyl or hetero- X .R6 cyclic group or a group of the formula, ~Nv. 7 or -CON^" R R? (R^ is a hydrogen atom, a hydroxyl, cyano or alkoxycarbonyl group or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkylsulfonyl, iminomethyl or amidino group and R^ is a hydrogen atom or a substituted or unsubstituted alkyl, alkoxy, 6 7 phenyl, cycloalkyl or heterocyclic group; or R and R , when taken together with the nitrogen atom to which the two are bonded, form a 3- to 7-membered, substituted or unsubstituted heterocyclic group); R^ represents a substituted or unsubstituted phenyl, thienyl, furyl or pyridyl group; and Z represents an oxygen or sulfur atom or an imino group, which comprises subjecting a compound represented by the following formula or a salt thereof: - - 29 8 - 'X . % v J 2264G 1 2 3 4 5 wherein R , R , R , R , R and Z have the same meanings as defined above, to dehydrogenation.
13. 13. A process according to Claim 12, wherein the dehydrogenation is conducted with a dehydrogenating agent.
14. 14. A process according to Claim 13, wherein the dehydrogenating agent is 2,3-dichloro-5,6-dicyano-l,4-benzoquinone, chloranil, trityl perchlorate, trityl fluoroborate, selenium dioxide or palladium-carbon.
15. 15. A process according to Claim 12, wherein the dehydrogenation is conducted by reacting the compound with a halogenating agent and then reacting the halogenated product with a base.
16. 16. A process according to Claim 15, wherein the halogenating agent is chlorine, bromine or sulfuryl chloride and the base is triethylamine, 1,8-dizabicyclo-1 5.4.0]undec-7-ene, pyridine, sodium carbonate or potassium carbonate.
17. 17. A process according to any one of Claims 12 to 16, wherein Z represents an oxygen or sulfur atom; 5 R represents a substituted or unsubstituted phenyl or pyridyl group; R1 represents an unsubstituted or halogen- 2 substituted lower alkyl or lower alkenyl group; R 3 represents a hydrogen atom or an acyl group; R and 4 R , which may be the same or different, represent hydrogen atoms, carbamoyl, carboxyl, formyl, hydroxyl or alkoxycarbonyl groups or substituted or unsubstituted alkyl, alkoxy or phenyl groups.
18. 18. A process according to any one of Claims 12 to - 299 - 226439 16, wherein R~* represents a substituted or unsubstituted phenyl or pyridyl group; Z represents an oxygen or sulfur atom; R1 represents an unsubstituted or halogen- 2 substituted lower alkyl or lower alkenyl group; R 4 represents a hydrogen atom or an acyl group; R represents /r6 6 a group of the formula -NT 7 (R is a hydrogen atom, R a hydroxyl, cyano or alkoxycarbonyl group or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, iminomethyl or amidino group and R^ is a hydrogen atom or a substituted or unsubstituted 6 7 alkyl or cycloalkyl group; or R and R , when taken together with the nitrogen atom to which the two are bonded, form a 4- to 6-membered, substituted or un- 3 substituted heterocyclic group) and R represents a hydrogen or halogen atom, a cyano, azido, carbamoyl, carboxyl, hydroxyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, amino or phenyl group.
19. 19. A process according to any one of Claims 12 to 18, wherein Z represents an oxygen atom.
20. 20. A process according to any one of Claims 12 to 19, wherein R1 represents a lower alkyl group.
21. 21. A process according to any one of Claims 12 to 2 20, wherein R represents a hydrogen atom.
22. 22. A process according to any one of Claims 12 to 21, wherein R3 represents a hydrogen atom or an alkyl group. 4
23. 23. A process according to Claim 12, wherein R - 300 - ?26 represents a substituted or unsubstituted alkylthio, phenyl-thio, alkylsulfinyl or alkylsulfonyl group or a group of the /r6 ^-r6 6 7 formula, -Nl 7 or -CON 7 (R and R have the same R R meanings as defined in claim 12). a
24. 24. A process according to Claim 23, wherein R represents an alkylthio, forrnylamino or carbamoyl group.
25. 25. a process according to any one of claims 12 to 24, wherein r^ represents a substituted or unsubstituted phenyl group.
26. 26. A process according to Claim 25, wherein R"* represents a phenyl group which may be substituted by at least one substituent selected from the group consisting of halogen atoms, hydroxyl group, amino group, carboxyl group, haloalkyl groups, alkyl groups, alkoxy groups, alkoxycarbonyl groups, acylamino groups and carbamoyl group.
27. 27. A process for producing a 4H-l-benzopyran-4-one derivative represented by the following formula or a salt thereof: wherein R1 represents an unsubstituted or halogen-sub- 2 stituted lower alkyl, lower alkenyl or aryl group; R represents a hydrogen atom or an alkyl or acyl group; R3a represents a hydrogen atom or a substituted or unsubstituted A a alkyl, cycloalkyl or phenyl group; R represents a hydrogen atom, an alkoxycarbonyl, cyano or acyl >j.-i - 301 — \ j, \" group, a substituted or unsubstituted alkyl or phenyl group /R6 6 or a group of the formula, -CONv 7 (R is a hydrogen atom xr' a hydroxyl, cyano or alkoxycarbonyl group or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkylsulfonyl, iminomethyl or amidino group and 7 R is a hydrogen atom or a substituted or unsubstituted alkyl, alkoxy, phenyl, cycloalkyl or heterocyclic,group, 6 7 or R and R , when taken together with the nitrogen atom to which the two are bonded, form a 3- to 7-membered, substituted or unsubstituted heterocyclic group); R"* represents a substituted or unsubstituted phenyl, thienyl, furyl or pyridyl group; and Z represents an oxygen or sulfur atom or an imino group, which comprises subjecting a compound represented by the following formula or a salt thereof: 1 2 3a 4a 5 wherein R , R , R , R , R and Z have the same meanings as defined above, and means (E)isomer, (Z)isomer or a mixture thereof, to ring closure reaction.
28. 28. A process according to Claim 27, wherein the ring closure reaction is conducted with a condensing agent,
29. 29. A process according to Claim 28, wherein the vv condensing agent is a halogenosulfonic acid, sulfuric 72 fiio >*• s ^ anhydride, phosphorus pentoxi.de, polyphosphoric acid, zinc chloride, conc. sulfuric acid or conc. sulfuric acid-acetyl chloride.
30. 30. A process according to Claim 27, wherein the rinq closure reaction is conducted by reacting the compound with an acid-halogenating agent and then subjecting the product to the Friedel-Crafts reaction.
31. 31. A process according to Claim 30, wherein the acid-halogenating agent is thionvl chloride or phosphorus pentachloride.
32. 32. A process according to any one of Claims 27 to 5 31, wherein Z represents an oxygen or sulfur atom; R represents a substituted or unsubstituted phenyl or pyridyl group; R1 represents an unsubstituted or halogen- 2 substituted lower alkyl or lower alkenyl group; R 3 3 represents a hydrogen atom or an acyl group; R represents a hydrogen atom or a substituted or unsubstituted alkyl 4 a or phenyl group and R represents a hydrogen atom, a carbamoyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl group.
33. 33. A process according to any one of Claims 27 to 32, wherein Z represents an oxygen atom.
34. 34. A process according to any one of Claims 27 to 33, wherein R1 represents a lower alkyl group.
35. 35. A process according to any one of Claism 27 to 2 34, wherea.n R represents a hydrogen atom.
36. 36. A process according to any one of Claims 27 to 3 a 35, wherein R represents a hydrogen atom or an alkyl - 303 - 226485 group.
37. 37. A process according to Claim 27, wherein R4a R6 > 5 7 represents a group of the formula, -CON^" 7 (R and R R have the same meanings as defined in claim 27).
38. 38. A process according to Claim 37, wherein R4a represents a carbamoyl group.
39. 39. A process according to afry one of clsims 27. to 38, wherein R-* represents a substituted or unsubstituted phenyl group.
40. 40. a process according to Claim 39, wherein R5 represents a phenyl group which may be substituted by at least one substituent selected from the group consisting of halogen atoms, hydroxyl group, amino group, carboxyl group, haloalkyl groups, alkyl groups, alkoxy groups, alkoxycarbonyl groups, acylamino groups and carbamoyl group.
41. 41. A process for producing a 4H-l-benzopyran-4-one derivative represented by the following formula or a salt thereof: ,5 „ f? R4 R -Z R1S0_N 2 i R3 R2 wherein R1 represents an unsubstituted or halogen-sub- 2 stituted lower alkyl, lower alkenyl or aryl group; R 3 represents a hydrogen atom or an alkyl or acyl group; R represents a hydrogen or halogen atom, a cyano, azido, - 304 - carboxyl, hydroxyl, formyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, phenoxy, 4 cycloalkyl, carbamoyl, amino or phenyl group; R represents a hydrogen or halogen atom, a nitro, cyano, carboxyl, acyl, hydroxyl or alkoxycarbonyl group, a substituted or unsubstituted alkyl,. alkoxy. alkylthio, phenylthiof lower alkynyl, lower alkenyl, sulfamoyl, alkylsulfinyl, alkylsulfonyl, amidino, phenyl or heterocyclic group or a group of the formula, .r6 ^r6 5 -N^ or -CON. _ (R is a hydrogen atom, a hydroxyl, R R cyano or alkoxycarbonyl group or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, 7 alkylsulfonyl, iminomethyl or amidino group and R is " a hydrogen atom or a substituted or unsub stituted alkyl, alkoxy, phenyl, cycloalkyl or hetero- 6 7 cyclic group, or R and R , when taken together with the nitrogen atom to which the two are bonded, form a 3- to 7-membered, substituted or unsubstituted heterocyclic 5 group); R represents a substituted or unsubstituted phenyl thienyl, furyl or pyridyl group; and Z represents an oxygen or sulfur atom or an imino group, which comprises reacting a compound represented by the following formula or a salt thereof: - 305 - 2264 r5-z X r4 1 / OH R SO,N I2 "*245 wherein Ra, Rz, RH, R and Z have the same meanings as defined above, with a ring-forming agent.
42. 42. A process according to Claim 41, wherein the ring-forming agent is a compound represented by the following formula: 3 12 R COOR 3 12 wherein R has the same meaning as defined in claim 41 and R represents a hydrogen atom or the ester residue in the carboxyl group.
43. 43. A process according to Claim 41, wherein the ring-forming agent is a combination of compounds represented by the following formulas: (R3dC0)20 and R3dCOOM2 3d wherein R represents a substituted or unsubstituted 2 alkyl or phenyl group and M represents an alkali metal.
44. 44. A process according to Claim 41, wherein the ring-forming agent is a combination of compounds represented by the following formulas: HX04 and HC(OR17)3 wherein R17 represents a lower alkyl group and X represents a halogen atom, and the reaction product is further -'306 - ? 9 ft / o «> - - w T O J? subjected to hydrolysis.
45. 45. A process according to Claim 41, wherein the ring-forming agent is a compound represented by the following formula: (CH3)2NCH(OR1')2 17 wherein R' represents a lower alkyl group.
46. 46. A process according to Claim 41, wherein the ring-forming agent is a combination of compounds represented by the following formulas: HC(OR17)3 and (R3dC0)20 3d wherein R represents a substituted or unsubstituted 17 alkyl or phenyl group and R represents a lower alkyl group.
47. 47. A process according to Claim 41, wherein the ring-forming agent is a combination of compounds represented by the following formulas: 0 0 171' " 2 R COCH and HCOOM 17 2 wherein R represents a lower alkyl group and M represents an alkali metal.
48. 48. A process according to Claim 41, wherein the ring-forming agent is a compound represented by the following formula: (R170)2C0 - 307 - 17 wherein R represents a lower alkyl group.
49. 49. A process according to any one of Claims 41 to 48, wherein Z represents an oxygen or sulfur atom; R^ represents a substituted or unsubstituted phenyl or pyridyl group; R1 represents an unsubstituted or halogen-substituted 2 lower alkyl or lower alkenyl group; R represents a 3 4 hydrogen atom or an acyl group and R and R , which may be the same or different, represent hydrogen atoms, carbamoyl, carboxyl, formyl, hydroxyl or alkoxycarbonyl groups or substituted or unsubstituted alkyl, alkoxy or phenyl groups.
50. 50. A process according to any one of Claims 41 to 49, wherein Z represents an oxygen atom.
51. 51. A process according to any one of Claims 41 to 50, wherein R1 represents a lower alkyl group.
52. 52. A process according to any one of Claims 41 to 2 51, wherein R represents a hydrogen atom.
53. 53. A process according to any one of Claims 41 to 3 52, wherein R represents a hydrogen atom or an alkyl group.
54. 54. A process according to Claim 41, wherein R4 represents a substituted or unsubstituted alkylthio, phenylthio, alkylsulfinyl or alkylsulfonyl group or a group of the /R6 r6 6 7 formula, -N^ 7 or -CON. 7 (R and R have the same R R meanings as defined in claim 41^,
55. 55. A process according to Claim 54, wherein R4 represents an alkylthio, formylamino or carbamoyl group. - 308 - 7 2 6 AI
56. 56. A process according to any one of claims 41 to 55, wherein represents a substituted or unsubstituted phenyl group.
57. 57. A process according to Claim 56, wherein R5 represents a phenyl group which may be substituted by at least one substituent selected from the group consisting of halogen atoms, hydroxyl group, amino group, carboxyl group, haloalkyl groups, alkyl groups, alkoxy groups, alkoxycarbonyl groups, acylamino groups and carbamoyl group.
58. 58. A process for producing a 4H-l-benzopyran-4-one derivative represented by the following formula or a salt thereof: wherein R1 represents an unsubstituted or halogen-sub- 2 stituted lower alkyl, lower alkenyl or aryl group; R represents a hydrogen atom or an alkyl or acyl group; R3 represents a hydrogen or halogen atom, a cyano, azido, carboxyl, hydroxyl, formyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, phenoxy, cycloalkyl, carbamoyl, amino or phenyl group; R4 represents a hydrogen or halogen atom, a nitro, cyano, carboxyl, acyl, hydroxyl or alkoxycarbonyl group, a substituted >"'^"1^" /■\v ' ° or unsubstituted alkyl, alkoxy, alkylthio, phenylthio, lower alkynyl, lower alkenyl, sulfamoyl, alkylsulfinyljl^ ,u\ ^ U 9^ - 309 - 22648 alkylsulfonyl, amidino, phenyl or heterocyclic group or a .r6 /R6 6 group of the formula, -N^ 7 or -CON^ ^ (R is a R R hydrogen atom, a hydroxyl, cyano or alkoxycarbonyl group or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkylsulfonyl, imino- 7 methyl or amidino group and R is a hydrogen atom or a substituted or unsubstituted alkyl, alkoxy, phenyl, 6 7 cycloalkyl or heterocyclic group, or R and R , when taken together with the nitrogen atom to which the two are bonded, form a 3- to 7-membered, substituted or unsubstituted 5 heterocyclic group); R represents a substituted or unsubstituted phenyl, thienyl, furyl or pyridyl group; and Z represents an oxygen or sulfur atom or an imino group, which comprises reacting a compound represented by the following formula or a salt thereof: 2 3 4 5 wherein R , R , R , R and Z have the same meanings as defined above, with a reactive derivative of a compound represented by the following formula: r1so3h wherein R1 has the same meaning as defined above.
59. 59. A process according to Claim 58, wherein Z - 310 - o o 264 represents an oxygen or sulfur atom; represents a substituted or unsubstituted phenyl or pyridyl group; R1 represents an unsubstituted or halogen-substituted lower 2 alkyl or lower alkenyl group; R represents a hydrogen atom 3 4 or an acyl group; and R and R , which may be the same or different, represent hydrogen atoms, carbamoyl, carboxyl, formyl, hydroxyl or alkoxycarbonyl groups or substituted or unsubstituted alkyl, alkoxy or phenyl groups.

    60. A process according to Claim 58 or 59, wherein Z represents an oxygen atom.

    61. A process according to any one of Claims 58 to 60, wherein R1 represents a lower alkyl group.

    62. A process according to any one of Claims 58 to 2 61, wherein R represents a hydrogen atom.

    63. A process according to any one of Claims 58 to 3 62, wherein R represents a hydrogen atom or an alkyl group.

    64. A process according to Claim 58, wherein R4 represents a substituted or unsubstituted alkylthio, phenylthio, alkylsulfinyl or alkylsulfonyl group or a group of the .r6 V 6 7 formula, 7 or -CON. 7 (R and R have the same R R meanings as defined in claim 58).

    65. A process according to Claim 64, wherein R4 represents an alkylthio, formylamino or carbamoyl group. A process according to any one of claims 58-to 65, wherein R^ represents a substituted or unsubstituted phenyl group. • 3'' ^

    67. A process according to Claim 66, wherein R"v - 311 - '''<■• f M 226' represents a phenyl group which may be substituted by at least one substituent selected from the group consisting of halogen atoms, hydroxyl group, amino group, carboxyl group, haloalkyl groups, alkyl groups, alkoxy groups, alkoxycarbonyl groups, acylamino groups and carbamoyl group.

    68. A process for producing a 4H-l-benzopyran-4- one derivative represented by the following formula or a salt thereof: 0 1 wherein R represents an unsubstituted or halogen-sub- 2 stituted lower alkyl, lower alkenyl or aryl group; R represents a hydrogen atom or an alkyl or acyl group; 3 R represents a hydrogen or halogen atom, a cyano, azido, carboxyl, hydroxyl, formyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, phenoxy, 4 cycloalkyl, carbamoyl, amino or phenyl group; R represents a hydrogen or halogen atom, a nitro, cyano, carboxyl, acyl, hydroxyl or alkoxycarbonyl group, a substituted or unsubstituted alkyl, alkoxy, alkylthio, phenylthio, lower alkynyl, lower alkenyl, sulfamoyl, alkylsulfinyl, alkylsulfonyl, amidino, phenyl or heterocyclic group or a r6 R6 / J group of the formula, -N^_ 7 or -CON. 7 (R is a /' R R - 312 - ' " " 22 6 4 8 hydrogen atom, a hydroxyl, cyano or alkoxycarbonyl group or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkylsulfonyl, iminomethyl or 7 amidino group and R is a hydrogen atom or a substituted or unsubstituted alkyl, alkoxy, phenyl, cycloalkyl or 6 7 heterocyclic group, or R and R , when taken together•with the nitrogen atom to which the two are bonded, form a 3-to 7-membered, substituted or unsubstituted heterocyclic 5 group); R represents a substituted or unsubstituted phenyl, thienyl, furyl or pyridyl group; and Z represents an oxygen or sulfur atom or an imino group, which comprises reacting a compound represented by the following formula or a salt thereof: 0 12 3 4 wherein R , R , R , R and Z have the same meanings as defined above, with a compound represented by the following formula: R5a - X wherein R^a represents a substituted or unsubstituted phenyl, thienyl, furyl, pyridyl, diphenyliodonium or 4-pyridylpyridinium group and X represents a halogen atom.

    69. A process according to Claim 68, wherein Z - 313 - AS AMENDED represents an oxygen atom.

    70. A process according to Claim 68 or 69, wherein R"1" represents a lower alkyl group.

    71. A process according to any one of Claims 68 to 2 70, wherein R represents a hydrogen atom.

    72. A process according to any one of Claims 68 to 71, wherein R3 represents a hydrogen atom or an alkyl group. A

    73. A process according to _ any one-of claims 68" to' 72, wherein R represents a substituted or unsubstituted alkylthio, phenylthio, alkylsulfinyl or alkylsulfonyl group or a group of the ^R6 ^R6 6 7 formula, -N 7 or -CON. (R and R have the same R R meanings as defined in. claim 68).

    74. A process according to any one of Claims 68 to 4 73, wherein R represents an alkylthio, formylamino or carbamoyl group.

    75. A process according to any one of Claims 68 to 5 74, wherein R represents a substituted or unsubstituted phenyl group.

    76. A process according to : >■ Claim-—= 75, wherein R represents a phenyl group which may be substituted by at least one substituent selected from the group consisting of halogen atoms, hydroxyl group, amino group, carboxyl group, haloalkyl groups, alkyl groups, alkoxy groups, alkoxycarbonyl groups, acylamino groups and carbamoyl group.

    77. A process for producing a 4H-l-benzopvran-4_-jone N.Z. PATENT OFFICE 314 " 31 OCT 1990 226 4 WQW AMENDED represents an oxygen atom. /

    70. A process according to Claim 68 or 69, wherein R^" represents a lower alkyl group. *'

    71. A process according to any one of Claims 68 to 2 70, wherein R represents a hydrogen atom.

    72. A process according to any one of Claims 68 to 71, wherein R3 represents a hydrogen atom or an alk'yl group.

    73. A process according any one of claims 68' td 72, wherein R represents a substituted or unsubstituted alkylthio, phenylthio alkylsulfinyl or alkylsulfonyl group or a group of the x"r6 ■' /r6 6 7 / formula, -N 7 or -CON. 7 (R and R Jiave the same R / R / . / meanings as defined in-claim 68). / / / /

    74. A process according to any/one of Claims 68 to / / 4 / 73, wherein R Represents an alkylthio, formylamino or / ^ carbamoyl group. / / /

    75. A process according to any one of Claims 68 to / 5 /' 74, wherein' R represents a substituted or unsubstituted h ! / phenyl grpup. ^

    76. / A process according to : ■ of Claim—= 75, wherein R^ represents/a phenyl group which may be substituted by at least/one substituent selected from the'group consisting of halogen atoms, hydroxyl group, / / ajnino group, carboxyl group, haloalkyl groups, alkyl ygroups, alkoxy groups, alkoxycarbonyl groups, acylamino groups and carbamoyl group. / ' v ^

    77. A prc^cess for producing a 4H-l-benzopyran-4-one" * i V - - 314 - X\ rt derivative represented by the following formula or a s thereof or a reactive derivative thereof: wherein. R1 represents an unsubstituted or halogen-sub- 2 stituted lower alkyl, lower alkenyl or aryl group; R represents a hydrogen atom or an alkyl or acyl group; R represents a hydrogen or halogen atom, a cyano, azido, carboxyl, hydroxyl, formyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, phenoxy, cycloalkyl, carbamoyl, amino or phenyl group; R^ represents a substituted or unsubstituted phenyl, thienyl, furyl or pyridyl group; R^ represents a hydrogen atom, an alkoxy group or a substituted or unsubstituted alkyl cycloalkyl, acyl, alkoxycarbonyl or phenyl group and Z represents an oxygen or sulfur atom or an imino group, which comprises reacting a compound represented by the following formula or a reactive; derivative thereof: 12 3 5 wherein R , R , R , R and Z have the same meanings as -' 315 - defined above, with a compound represented by the following formula or a reactive derivative thereof: R10COOH wherein R"^ has the same meaning as defined above.

    78. A process according to Claim 77, wherein represents a substituted or unsubstituted phenyl or pyridyl group; Z represents an oxygen or sulfur atom; R1 represents an unsubstituted or halogen-substituted lower alkyl or 2 lower alkenyl group; R represents a hydrogen atom or an acyl group; represents a hydrogen atom, an alkoxy carbonyl group or a substituted or unsubstituted alkyl, 3 cycloalkyl, acyl or phenyl group; and R represents a hydrogen or halogen atom, a cyano, azido, carbamoyl, carboxyl, hydroxyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, amino or phenyl group.

    79. A process according to Claim 77 or 78, wherein Z represents an oxygen atom.

    80. A process according to any one of Claims 77 to 79, wherein R^" represents a lower alkyl group.

    81. A process according to any one of Claims 77 to 2 80, wherein R represents a hydrogen atom.

    82. A process according to any one of Claims 77 to 81, wherein R^ represents a hydrogen atom or an alkyl group.

    83. A process according to any one of Claims 77 to 82, wherein R~* represents a substituted or unsubstituted phenyl group. - 316 -

    84. A process according to claim 83, wherein represents a phenyl group which may be substituted by at least one substituent selected from the group consisting of halogen atoms, hydroxyl group, amino group, carboxyl group, haloalkyl groups, alkyl groups, alkoxy groups, alkoxycarbonyl groups, acylamino groups and carbamoyl group.

    85. A process according to any one of Claims 77 to 84, wherein R*® represents a hydrogen atom.

    86. A process for producing a 4H-l-benzopyran-4-one derivative represented by the following formula or a salt thereof: R6 r5-z con-r7 r1so2n r3 k2 wherein R"*" represents an unsubstituted or halogen-sub- 2 stituted lower alkyl, lower alkenyl or aryl group; R represents a hydrogen atom or an alkyl or acyl group; r3 represents a hydrogen or halogen atom, a cyano, azido, carboxyl, hydroxyl, formyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, phenoxy, 5 cycloalkyl, carbamoyl, ammo or phenyl group; r represents a substituted or unsubstituted phenyl, thienyl, furyl or g pyridyl group; r represents a hydrogen atom, a hydroxyl, i- i - 317 - 22 6 4 8!Q ■*r cyano or alkoxycarbonyl group or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkylsulfonyl, iminomethyl or amidino group; R7 represents a hydrogen atom or a substituted or un- su'uslifcuced alkyl, alkoxy, phenyl, cycloalkyl or hetero- 6 7 cyclic group; or R and R , when taken together with the nitrogen atom to which the two are bonded, form a 3- to 7-membered, substituted or unsubstituted heterocyclic group and Z represents an oxygen or sulfur atom or an imino group, which comprises reacting a compound represented by the following formula or a reactive derivative thereof or a salt thereof: 12 3 5 wherein R , R , R , R and Z have the same meanings as defined above, with a compound represented by the following formula or a salt thereof: R6 HN-R7 6 7 wherein R and R have the same meanings as defined above

    87. A process according to Claim 86, wherein Z represents an oxygen atom.

    88. A process according to Claim 86 or 87, wherein R1 represents a lower alkyl group. - 318 -

    89. A process according to any one of Claims 86 to 2 88, wherein R represents a hydrogen atom.

    90. A process according to any one of Claims 86 to 89, wherein R3 represents a hydrogen atom or an alkyl group.

    91. A process according to any one of Claims 86 to 90, wherein R^ represents a substituted or unsubstituted phenyl group.

    92. A process according to claim 5 91, wherein R represents a phenyl group which may be substituted by at least one substituent selected from the group consisting of halogen atoms, hydroxyl group, amino group, carboxyl group, haloalkyl groups, alkyl groups, alkoxy groups, alkoxycarbonyl groups, acylamino groups and carbamoyl group.

    93. A process according to any one of Claims 86 to 92, wherein either or both of R® and R^ are hydrogen atoms.

    94. A process for producing a 4H-l-benzopyran-4-one derivative represented by the following formula or a salt thereof: wherein R^" represents an unsubstituted or halogen-sub- 2 stituted lower alkyl, lower alkenyl or aryl group; R - 319 - 22 6 4 o « u & represents a hydrogen atom or an alkyl or acyl group; 3 R represents a hydrogen or halogen atom, a cyano, azido, carboxyl, hydroxyl, formyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, phenoxy, cycloalkyl, car bctmuyi, ammo or phenyl group; R~ represents a substituted or unsubstituted phenyl, thienyl, furyl or pyridyl group and Z represents an oxygen or sulfur atom or an imino group, which comprises subjecting a compound represented by the following formula or a salt thereof: 0 R cn R1SOnN R3 1 r2 12 3 5 wherein R , R , R , R and Z have the same meanings as defined above, to hydrolysis.

    95. A process according to Claim 94, wherein Z represents an oxygen atom.

    96. A process according to Claim 94 or 95, wherein R1 represents a lower alkyl group.

    97. A process according to any one of Claims 94 to 2 96, wherein R represents a hydrogen atom.

    98. A process according to any one of Claims 94 to 3 97, wherein R represents a hydrogen atom or an alkyl group.

    99. A process according to any one of Claims 9 4 to 98, wherein R^ represents a substituted or unsubstituted phenyl group. - 320 - 226 H 100- A process according to claim : 5 99, wherein R represents a phenyl group which may be substituted by at least one substituent selected from the group consisting of halogen atoms, hydroxyl group, amino group, carboxyl group, haloalkyl groups, alkyl groups, alkoxy groups, alkoxycarbonyl groups, acylamino groups and carbamoyl group.

    101. A pharmaceutical composition comprising an effective amount of a 4H-l-benzopyran-4-one derivative represented by the following formula or a salt thereof: wherein R1 represents an unsubstituted or halogen-sub-stituted lower alkyl, lower alkenyl or aryl group; R represents a hydrogen atom or an alkyl or acyl group; R represents a hydrogen or halogen atom, a cyano, azido, carboxyl, hydroxyl, formyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, phenoxy, cycloalkyl, carbamoyl, amino or phenyl group; R4 represents a hydrogen or halogen atom, a nitro, cyano, carboxyl, acyl, hydroxyl or alkoxycarbonyl group, a substituted or unsubstituted■alkyl, alkoxy, alkylthio, phenylthio, lower alkvnyl, lower alkenyl, sulfamoyl, alkylsdlfinyl, alkylsulfonyl, amidino, phenyl or heterocyclic group or a group - 321 - R 6 of the formula, -N \ 7 R / or -CON _ (R i. s a hydrogen \r' atom, a hydroxyl, cyano or alkoxycarbonyl group or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkylsulfonyl, iminomethyl or 7 amidino group and R xs a hydrogen atom or a substituted or unsubstituted alkyl, alkoxy, phenyl, cycloalkyl or 6 7 heterocyclic group, or R and R , when taken together with the nitrogen atom to which the two are bonded, form a 3- to 7-membered, substituted or unsubstituted heterocyclic group); represents a substituted or unsubstituted phenyl, thienyl, furyl or pyridyl group; and Z represents an oxygen or sulfur atom or an imino group.

    102. A pharmaceutical composition according to Claim 101, wherein Z represents an oxygen or sulfur atom; represents a substituted or unsubstituted phenyl or pyridyl group; R'*' represents an unsubstituted or halogen- 2 substituted lower alkyl or lower alkenyl group; R 3 represents a hydrogen atom or an acyl group and R and , which may be the same or different, represent hydrogen atoms, carbamoyl, carboxyl, formyl, hydroxyl or alkoxycarbonyl groups or substituted or unsubstituted alkyl, alkoxy or phenyl groups.

    103. A pharmaceutical composition according to Claim 5 101, wherein R represents a substituted or unsubstituted phenyl or pyridyl group; Z represents an oxygen or sulfur atom; R1 represents an unsubstituted or halogen-substituted 2 lower alkyl or lower alkenyl group; R represents a 322 22 6 4 4 hydrogen atom or an acyl group; R represents a group of th X 6 formula ^ (R is a hydrogen atom, a hydroxyl, cyano R or alkoxycarbonyl group or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, . . . 7 iminomethyl or amidino group and R is a hydrogen atom or a substituted or unsubstituted alkyl or cycloalkyl 6 7 group, or R and R , when taken together with the nitrogen atom to which the two are bonded, form a 4- to 6-membered, 3 substituted or unsubstituted heterocyclic group); and R represents a hydrogen or halogen atom, a cyano, azido, carbamoyl, carboxyl, hydroxyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, amino or phenyl group.

    104. A pharmaceutical composition according to any one of Claims 101 to 103, wherein Z represents an oxygen at.om.

    105. A pharmaceutical composition according to any one of Claims 101 to 104, wherein R1 represents a lower alkyl group.

    106. A pharmaceutical composition according to any 2 one of Claims 101 to 105, wherein R represents a hydrogen atom.

    107. A pharmaceutical composition according to any 3 one of Claims 101 to 106, wherein R represents a hydrogen atom or an alkyl group.

    108. A pharmaceutical composition according to Claim 101, wherein R4 represents a substituted or unsubstituted - 323 - alkylthio, phenylthio, alkylsulfinyl or alkylsulfonyl group or ✓R6 /r6 6 7 a group of the formula _n .. or -CON». 7 (R and R XR7 R have the same meanings as defined in claim 101).

    109. A pharmaceutical composition according to any one 4 of claims 101 to 108, wherein R represents an alkylthio, formylamino or carbamoyl group.

    110. A pharmaceutical composition according to any one of claims 101 to 109, wherein R5 represents a substituted or unsubstituted phenyl group.

    111. A pharmaceutical composition according to Claim 5 110, wherein R represents a phenyl group which may be substituted by at least one substituent selected from the group consisting of halogen atoms, hydroxyl group, amino • group, carboxyl group, haloalkyl groups, alkyl groups, alkoxy groups, alkoxycarbonyl groups, acylamino groups and carbamoyl group.

    112. Use of a 4H-l-benzopyran-4-one derivative or a salt thereof as defined in Claim 1 in manufacture of a therapeutic agent for inflammatory, pyretic, analgesic or rheumatic diseases.

    113. A compound as claimed in claim 1 and as specifically identified in this specification with reference to the tables and examples.

    114. A process for producing a compound as claiuned in claim 1 substantially as described in this specification with reference to any one of the examples.

    115. A compound whenever produced by a process according to any one of claims 12 to 100 and 114. t TOYAMA CHEMICAL CO. LTD ■ „ C, J ) ' - 324 - \ \ by thqir attorneys BALDWIN; SON & CAREY