JPH072715B2 - 4-oxo-1,4-dihydronicotinic acid or salt thereof - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention relates to the general formula [1]

[Chemical 2]

"Wherein R ¹ is a hydrogen atom or a carboxyl protecting group; R ² is an aryl group having a substituent or a heterocyclic group with or without a substituent; and R ³ is , Haloalkyl, aminoalkyl, alkenyl or aralkyl, heterocycle-alkyl, cycloalkyl, cycloalkenyl, iminoalkyl or bridged cyclic hydrocarbon groups, with or without substituents, respectively. " 4-oxo-1,4
-Dihydronicotinic acid or salts thereof.

[0003]

2. Description of the Related Art Conventionally, 4-oxo-1,4-dihydronicotinic acid represented by the general formula [1] or a salt thereof has not been known.

[0004]

The object of the present invention is to provide a novel compound [1] which acts effectively against Gram-positive bacteria and Gram-negative bacteria, and particularly shows a strong antibacterial action against antibiotic-resistant bacteria. To provide. Another object of the present invention is to provide a novel compound having high blood concentration and high safety upon oral or parenteral administration.

[0005]

Means for Solving the Problems As a result of intensive studies by the present inventors, 4-oxo-, which is represented by the general formula [1] and has a different chemical structure from various antibacterial agents currently on the market.
It was found that 1,4-dihydronicotinic acid or a salt thereof has the above-mentioned excellent properties, and the present invention has been completed.

The compound of the present invention is described in detail below. In the general formula [1], the carboxyl protecting group for R ¹ is
For example, an ester-forming group capable of leaving by catalytic reduction, chemical reduction or treatment under other mild conditions; an ester-forming group capable of easily leaving in vivo; easily treated by water or alcohol. Examples thereof include an organic silyl group, an organic phosphorus group, or an organic tin group having a property of leaving; or other various known ester-forming groups.

Suitable protecting groups of this kind of protecting group include the following. (B) alkyl; C ₁ ~ ₄ alkyl group. (B) At least one of the substituents is halogen, nitro, acyl, alkoxy, oxo, cyano, hydroxyl, di-
C ₁ ~ ₄ alkyl amino, cycloalkyl, aryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, 5-alkyl-2-oxo-1,3-dioxol-4-yl, 1-indanyl,
2-indanyl, furyl, pyridyl, 4-imidazolyl, phthalimide, succinimide, azetidino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, N-lower alkylpiperazino, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl. , Oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, quinolyl, phenazinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, coumarinyl, 2,5-dimethylpyrrolidino, 1,4,5,6-tetrahydropyrimidinyl , 4-
Methyl piperidino, 2,6-dimethyl piperidino, 4-
(5-methyl-2-pyrrolinyl), 4- (2-pyrrolinyl), N-methylpiperidinyl, 1,3-benzodioxolanyl, alkylamino, dialkylamino, acyloxy, acylthio, acylamino, dialkylaminocarbonyl, Alkoxycarbonylamino, alkenyloxy, aryloxy, aralkyloxy, cycloalkyloxy, cycloalkenyloxy, heterocyclic oxy, alkoxycarbonyloxy, alkenyloxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, heterocyclic oxycarbonyl Oxy, alkenyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, multiple Ring oxycarbonyl, alkyl anilino or halogen, substituted lower alkyl group which is an alkyl anilino group substituted with a lower alkyl or lower alkoxy.

(C) cycloalkyl group; lower alkyl-substituted cycloalkyl or [2,2-di-lower alkyl-1,
3-dioxol-4-yl] methyl group. (D) Alkenyl group. (E) Alkynyl group. (F) a phenyl group or a phenyl group in which at least one phenyl group or substituent is substituted with a substituent arbitrarily selected from the substituents exemplified in the above (b), or a formula

[0009]

[Chemical 3]

"In the formula, -X- is -CH = CH-O-,
-CH = CH-S -, - CH 2 CH 2 S -, - CH = N-
CH = N-, -CH = CH-CH = CH-, -CO-C
H = CH-CO- or -CO-CO-CH = CH-. Or a substituted derivative thereof [the substituent is arbitrarily selected from those exemplified in the above (b)],
Or expression

[0011]

[Chemical 4]

[0012] "In the formula, -Y- is, - (CH _{2) 3} - or - (CH _{2) 4} -. A lower alkylene group such as" group or a substituted derivative thereof [substituent represented by, The above
Selected from those exemplified in (b)].

(G) At least 1 benzyl or a substituent is a substituent arbitrarily selected from the substituents exemplified in the above (b).
Aralkyl groups such as benzyl, which are substituted with one or more. (H) A heterocyclic group or a heterocyclic group in which at least one or more heterocyclic groups or substituents are substituted with a substituent arbitrarily selected from the substituents exemplified in the above (B). (I) Alicyclic indanyl or phthalidyl and substituted derivatives thereof in which the substituent is methyl or halogen, alicyclic tetrahydronaphthyl and substituted derivatives thereof in which the substituent is methyl or halogen, trityl, cholesteryl or bicyclo [4.4.0]. ] Decyl etc. (Nu) An alicyclic phthalidylidene lower alkyl group or a substituted derivative thereof in which the substituent is halogen or a lower alkyl group.

The carboxyl protecting groups exemplified above are representative examples, and the protecting groups described in the following documents can be arbitrarily selected. U.S. Patents 3,499,909, 3,57
3,296 and 3,641,018; West German Patent Publication 2,301,01
Nos. 4, 2,253,287 and 2,337,105.

More preferred carboxyl protecting groups among them are, for example, 5-lower alkyl-2-oxo-1,3-dioxol-4-yl-lower alkyl group, acyloxyalkyl group, acylthioalkyl group,
Examples thereof include a phthalidyl group, an indanyl group, a phenyl group, a phthalidylidene lower alkyl group having or not having a substituent, or a group which is easily eliminated in vivo such as a group represented by the following formula.

[0016]

[Chemical 5]

"Wherein R ⁴ is a hydrogen atom or a linear or branched alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group with or without a known substituent; R 4 ⁵ is a hydrogen atom or an alkyl group; R ⁶ is a linear or branched alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group with or without a known substituent; means (CH _{2) n} COOR ⁴ (provided that, R ⁴ is mentioned above - ⁷ is a hydrogen atom, or or without alkyl having a halogen atom or a known substituent, cycloalkyl, aryl or heterocyclic group, or formula N is a group represented by 0, 1 or 2, and m is 0, 1 or 2
Means "

Specific examples of the above-mentioned preferred carboxyl protecting group include, for example, 5-methyl-2-oxo-
1,3-dioxol-4-yl-methyl, 5-ethyl-2-oxo-1,3-dioxol-4-yl-methyl and 5-propyl-2-oxo-1,3-dioxol-4-yl-methyl groups 5-lower alkyl-2 such as
-Oxo-1,3-dioxol-4-yl-lower alkyl group; acetoxymethyl, pivaloyloxymethyl,
Propionyloxymethyl, n-butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-acetoxy-n-propyl, 1-pivaloyloxyethyl and 1-pivaloyloxy-n-propyl. Acyloxyalkyl groups such as groups; acetylthiomethyl, pivaloylthiomethyl, benzoylthiomethyl, p-chlorobenzoylthiomethyl,
1-acetylthioethyl, 1-pivaloylthioethyl,
Acylthioalkyl groups such as 1-benzoylthioethyl and 1- (p-chlorobenzoylthio) ethyl groups; alkoxymethyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl and n-butoxymethyl groups; methoxycarbonyl Oxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, n-butoxycarbonyloxymethyl, tert-
Alkoxycarbonyloxyalkyl groups such as butoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl and 1-n-butoxycarbonyloxyethyl groups. An alkoxycarbonylalkyl group such as methoxycarbonylmethyl and ethoxycarbonylmethyl; a phthalidyl group; an indanyl group; a phenyl group; 2- (phthalidylidene) -ethyl, 2- (5-fluorophthalidylidene) -ethyl, 2- (6- And phthalidylidene alkyl groups such as chlorophthalidylidene) -ethyl and 2- (6-methoxyphthalidylidene) -ethyl groups.

Examples of the aryl group represented by R ^{2 in} the general formula [1] include groups such as phenyl and naphthyl; examples of the heterocyclic group represented by R ² and R ³ include thienyl, furyl, pyrrolyl, and the like. Imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, flazanil, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thiatriazolyl,
Pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
Piperidinyl, piperazinyl, pyranyl, morpholinyl, pyridin-1-oxide-3 or 4-yl, pyridazin-1-oxide-6-yl, quinolin-1-oxide-6-yl, triazinyl, benzothienyl, naphthothienyl, benzofuryl, 2 , 3-dihydrobenzofuryl, benzothiazolyl, isobenzofuryl, chromenil, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, 1,2,3,4-tetrahydroquinolyl, 1,2-dihydroquinolyl, isoquinolyl, phthalazinyl , Naphthyridinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, benzoxazolyl, beth Zomoruhoriniru, triazolopyridyl pyridyl, tetrazolo pyridazinyl, tetrazolo pyrimidinyl, thiazolo pyridazinyl, such as thiadiazopyridine pyridazinyl and triazolopyrimidine pyridazinyl N, S and O
5-membered, 6-membered and condensed ring type heterocyclic groups having at least one atom selected from

The haloalkyl group for R ³ is, for example, fluoromethyl, chloromethyl, bromomethyl, 1- or 2-fluoroethyl, 1- or 2
- halo -C ₁ ~ ₈ alkyl group such as chloroethyl and 1- or 2-bromoethyl; the aminoalkyl groups, for example, aminomethyl, 1-aminoethyl and 2-amino -C ₁ ~ ₈ alkyl group such as aminoethyl Alkenyl groups include, for example, vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl and 2-
C ₂ ~ ₈ alkenyl groups such as pentenyl; the aralkyl group, e.g., methyl, ethyl, n- propyl,
Isopropyl, n- butyl, isobutyl, sec- butyl, tert- butyl, pentyl, C ₁ ~ ₈ alkyl group such as hexyl and octyl, groups are substituted with the same aryl groups as described above; heterocycle - alkyl group Is, for example, a group in which an alkyl group similar to the above is substituted with a heterocyclic group similar to the above; examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. C ₃ ~ ₈ cycloalkyl group; a cycloalkenyl group, for example, 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl, 1-cyclopentenyl, 3-cyclopentenyl,
4-cyclopentenyl, 1-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, C ₃ ~ ₈ cycloalkenyl group, such as cycloheptenyl and cyclooctenyl; as iminoalkyl groups, for example, iminomethyl, 1-iminoethyl and 2- iminoethyl imino -C ₁ ~ ₈ alkyl group such as; the well crosslinked cyclic hydrocarbon group, such as C ₄ ~ ₁₅ crosslinked cyclic hydrocarbon group such as 3,6-methanolate cyclohexen-4-yl and adamantyl like To be

The substituents for R ² and R ³ are halogen atoms such as fluorine atom, chlorine atom,
Bromine atom, iodine atom and the like; alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl,
Pentyl, hexyl, straight or branched C ₁ ~ ₁₀ alkyl groups, such as heptyl, and octyl; aralkyl group,
For example, benzyl, phenethyl, phenyl -C ₁ ~ ₄ alkyl or naphthyl -C ₁ ~ ₄ alkyl group such as naphthylmethyl and naphthylethyl; hydroxyl group; an alkoxy group, for example, methoxy, ethoxy, n- propoxy, isopropoxy, n -Butoxy, isobutoxy,
sec- butoxy, tert- butoxy, pentyloxy, hexyloxy, C ₁ ~ ₁₀ alkoxy groups such as heptyloxy, and octyloxy; alkylthio, e.g., methylthio, ethylthio, n- propylthio, isopropylthio, n- butylthio, isobutylthio , Sec
C ₁ such as -butylthio, tert-butylthio, pentylthio, hexylthio, heptylthio and octylthio.
~ ₁₀ alkylthio group; nitro group; cyano group; amino group;
Alkylamino groups such as methylamino, ethylamino, n-propylamino, isopropylamino, n-
Butylamino, isobutylamino, sec- butylamino and tert- butyl C ₁ ~ ₈ alkylamino group such as amino; dialkylamino group, for example, dimethylamino,
Diethylamino, di-n-propylamino and di-n
- di -C ₁ ~ ₈ alkylamino group such as butyl amino;
Alkenyl group, e.g., C ₂ ~ ₈ alkenyl amino groups, such as vinyl amino and arylamino; carboxyl

A group; a carbamoyl group; an acyl group, for example, an alkanoyl group such as formyl, acetyl and propionyl, an aroyl group such as benzoyl and p-nitrobenzoyl, a heterocyclic carbonyl group such as thenoyl and furoyl; an acyloxy group such as the above. An acyl-O-group comprising an acyl group similar to the above; an acylalkyl group, for example, an acyl-alkyl group in which the same acyl group as the above is substituted with an alkyl group similar to the above; an acylamino group, for example, an acyl similar to the above An acyl group consisting of
NH- group; an alkoxycarbonyl group, for example, an alkoxycarbonyl group consisting of the same alkoxy groups as above;
Aminoalkyl group, for example, NH ₂ -alkyl group in which an alkyl group similar to the above is substituted with an amino group; alkylaminoalkyl group, for example, alkylamino in which an alkylamino group similar to the above is substituted with an alkyl group similar to the above An alkyl group; a dialkylaminoalkyl group, for example, a dialkylamino-alkyl group in which a dialkylamino group similar to the above is substituted with an alkyl group similar to the above; a hydroxyalkyl group, for example, an alkyl group similar to the above has a hydroxyl group. A substituted HO-alkyl group; a hydroxyiminoalkyl group, for example, a HON = alkyl group in which a hydroxyimino group is substituted for an alkyl group similar to the above; an alkoxyalkyl group, for example, an alkoxy group similar to the above Group-substituted alkoxy-alkyl A carboxyalkyl group, for example, a HOOC-alkyl group in which a carboxyl group is substituted with an alkyl group similar to the above; an alkoxycarbonylalkyl group, for example, an alkoxycarbonyl in which an alkoxycarbonyl group similar to the above is substituted with an alkyl group similar to the above Alkyl group; sulfoalkyl group, for example, sulfo-alkyl group obtained by substituting sulfo group for alkyl group similar to the above; sulfo group; sulfoxy group; sulfamoyl group; sulfamoylalkyl group, for example, alkyl group similar to the above Sulfamoyl-substituted sulfamoyl group-
An alkyl group; a carbamoylalkyl group, for example,

A carbamoyl-alkyl group in which a carbamoyl group is substituted on an alkyl group similar to the above; an aryl group, for example, an aryl group such as phenyl and naphthyl; an arylthio group, for example, an aryl-S- group consisting of the same aryl group as above. A group; an aryloxy group, for example,
Aryl-O- group consisting of an aryl group similar to the above; oxo group; thioxo group; mercapto group; ureido group; hydroxyamino group; hydroxyalkylamino group, for example, HO- consisting of the same hydroxyalkyl group as above.
An alkyl-NH- group; a halogenoalkyl group, for example,
Chloromethyl, bromomethyl, dichloromethyl, dibromomethyl, mono- trifluoromethyl and dichloroethyl -, di -, tri - halogeno -C ₁ ~ ₄ alkyl group; an alkenyl group, e.g., vinyl, allyl, isopropenyl, 1- propenyl, 2-butenyl and 2-pentenyl C ₂ ~ ₈ alkenyl group such as; alkynyl groups such as ethynyl, 1-propynyl and 2-propynyl C ₂ ~ ₈ alkynyl group and the like; alkenyl amino group, for example, as described above alkenyl -NH- group consisting alkenyl group; a cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, C ₃ ~ ₈ cycloalkyl groups such as cyclohexyl and cycloheptyl;
Cycloalkadienyl group, for example, cyclohexadienyl and C ₆ ~ ₈ cycloalkadienyl groups such cycloheptadienyl; alkylenedioxy group,

[0024] For example, methylenedioxy, C ₁ ~ ₄ alkylenedioxy group such as ethylenedioxy and trimethylene dioxy; epoxy group; a heterocyclic group, for example,
Thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, flazanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, tetrazolyl
Pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
Piperidinyl, piperazinyl, pyranyl, morpholinyl, pyridin-1-oxide-2-yl, pyridazine-
1-oxide-6-yl, triazinyl, benzothienyl, naphthothienyl, benzofuryl, 2,3-dihydrobenzofuryl, benzothiazolyl, isobenzofuryl,
Chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydroquinolyl, 1,2-
Dihydroquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, benzoxazolyl, benzomorpholinyl, triazolo. N, such as pyridyl, tetrazolopyridazinyl, tetrazolopyrimidinyl, thiazolopyridazinyl, thiadiazolopyridazinyl and triazolopyridazinyl
5-membered, 6-membered and condensed ring type heterocyclic groups having one or more atoms selected from S and O; and one or more substituents such as 5-nitrofurfurylideneamino group, and particularly, a halogen atom, Alkyl group, hydroxyl group,
Substituents such as amino group, alkoxy group, alkylamino group, dialkylamino group, nitro group, aryl group and heterocyclic group are preferred.

The substituents of R ² and R ³ are further a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, an alkyl group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, an aryl group and an acyl group. (A halogen atom, an alkyl group, an alkoxy group, an alkylamino group, a dialkylamino group, an aryl group, and an acyl group include those similar to the substituents for R ² and R ³ ) and the like. Alternatively, it may be substituted with two or more kinds of substituents.

When R ² and R ³ of the compound of the present invention have a hydroxyl group, an amino group or a carboxyl group, these groups may be protected by a known protecting group.

The protecting group for the hydroxyl group includes all groups which can be usually used as the protecting group for the hydroxyl group, for example, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4 -Methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 4- (4-methoxyphenylazo) benzyloxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, Isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-furfuryloxycarbonyl,
Acyl groups such as 1-adamantyloxycarbonyl, 1-cyclopropylethoxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl and trifluoroacetyl, which are easily eliminated, and benzyl, benzhydryl, trityl, tetrahydrofuryl, tetrahydropyranyl , Methoxymethyl, 2-nitrophenylthio and 2,4-dinitrophenylthio groups.

The amino group-protecting group includes all groups which can be usually used as an amino group-protecting group, for example, 2,2,2-trichloroethoxycarbonyl,
2,2,2-tribromoethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, o-nitrophenylsulfinyl, (mono-, di-, tri-) Chloroacetyl, trifluoroacetyl, formyl, tert-amyloxycarbonyl, te
rt-Butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 4- (4-methoxyphenylazo) benzyloxycarbonyl, pyridine-1-oxide-2 -Yl-methoxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonyl and 8-quinolyl. Acyl groups such as oxycarbonyl which are easily eliminated are mentioned, and further, trityl, 2-nitrophenylthio,
2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2
-Hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2
-Propylidene, 1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1
-Acetyl-2-propylidene, 1-benzoyl-2-
Propylidene, 1- [N- (2-methoxyphenyl) carbamoyl] -2-propylidene, 1- [N- (4-methoxyphenyl) carbamoyl] -2-propylidene,
Releasable groups such as 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxocyclohexylidene and 4-nitrofurfurylidene, and di- And amino-protecting groups such as tri-alkylsilyl.

Further, as the protective group for the carboxyl group,
It includes all groups which can be used as usual protecting groups for carboxyl groups such as methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p. -Methoxybenzyl, benzoylmethyl, acetylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, phthalimidomethyl, 2,2,2-trichloroethyl, 1,1-dimethylpropyl, acetoxymethyl , Propionyloxymethyl, pivaloyloxymethyl,
1,1-dimethyl-2-propenyl, 3-methyl-3-
Butynyl, succinimidomethyl, 1-cyclopropylethyl, methylsulfenylmethyl, phenylthiomethyl, dimethylaminomethyl, quinoline-1-oxide-
When protected with groups such as 2-yl-methyl, pyridin-1-oxide-2-yl-methyl and bis (p-methoxyphenyl) methyl, it is protected with a non-metallic compound such as titanium tetrachloride. In addition, in Japanese Patent Laid-Open No. 46-70
73 and Dutch publication 7,105,259, for example, the case of being protected by a silyl compound such as dimethylchlorosilane.

Examples of the salts of the compound of the general formula [1] include salts of commonly known basic groups such as amino groups and acidic groups such as carboxyl groups.
Examples of the salt in the basic group such as amino group include salts with mineral acids such as hydrochloric acid and sulfuric acid; salts with organic carboxylic acids such as oxalic acid, formic acid, trichloroacetic acid and trifluoroacetic acid; methanesulfonic acid, p A salt with a sulfonic acid such as toluenesulfonic acid and naphthalenesulfonic acid; and a salt with an amino acid such as aspartic acid and glutamic acid, and as a salt in an acidic group such as a carboxyl group, for example, an alkali metal such as sodium and potassium. Salt; a salt with an alkaline earth metal such as calcium and magnesium; an ammonium salt; procaine, dibenzylamine, N-benzyl-β
-Phenethylamine, 1-ephenamine and N, N-
Salts with nitrogen-containing organic bases such as dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N, N-dimethylaniline, N
Mention may be made of salts with other nitrogen-containing organic bases such as -methylpiperidine, N-methylmorpholine, diethylamine and dicyclohexylamine.

In the present invention, when the compound represented by the general formula [1] or a salt thereof has isomers (eg optical isomers, geometric isomers and tautomers), all of them are included. And extends to all crystalline forms and hydrates.

Next, the antibacterial activity and acute toxicity of the representative compounds of the present invention will be shown. 1. Antibacterial test method Japanese Society of Chemotherapy Standard method [CHEMOTHERAP
Y) Volume 23, pages 1-2 (1975)]
Heart Infusionbroth
(Eiken Chemical Co., Ltd.) at 37 ℃ for 20 hours, the bacterial solution was incubated with the drug containing Heart Infusion Agar (Heart Infu
sion agar) medium (manufactured by Eiken Chemical Co., Ltd.), 37 ° C, 20
After culturing for a period of time, the presence or absence of bacterial growth was observed, and the minimum concentration at which bacterial growth was inhibited was defined as MIC (μg / ml). However, the inoculum is 10 ⁴ cells / plate (10 ⁶ cells / m
l). The results are shown in Table 1. * Penicillinase-producing bacteria ** Cephaloporinase-producing bacteria

The test compounds are as follows. 1. 6-cyclohexyl-1- (4-hydroxy-2
-Methylphenyl) -4-oxo-1,4-dihydronicotinic acid 1. 6- (cyclohexen-4-yl) -1- (4-
Hydroxy-2-methylphenyl) -4-oxo-1,
4-dihydronicotinic acid 3. 6- (cyclohexen-4-yl) -1- (2-
Fluoro-4-hydroxyphenyl) -4-oxo-
1,4-dihydronicotinic acid 4. 6- (cyclohexen-4-yl) -1- (4-
Hydroxyphenyl) -4-oxo-1,4-dihydronicotinic acid 5. 6- (3,6-methanocyclohexen-4-yl) -1- (4-hydroxy-2-methylphenyl)-
4-oxo-1,4-dihydronicotinic acid 6. 6-cyclopentyl-1- (4-hydroxy-2
-Methylphenyl) -4-oxo-1,4-dihydronicotinic acid 7. 6- (cyclohexen-1-yl) -1- (4-
Hydroxy-2-methylphenyl) -4-oxo-1,
4-dihydronicotinic acid 8. 6- (cyclopenten-1-yl) -1- (4-
Hydroxy-2-methylphenyl) -4-oxo-1,
4-dihydronicotinic acid 9. 1- (4-hydroxy-2-methylphenyl)-
6 .- (1-Propenyl) -4-oxo-1,4-dihydronicotinic acid 10. 1- (4-hydroxy-2-methylphenyl)-
6-phenethyl-4-oxo-1,4-dihydronicotinic acid 11. 6- (cyclohexen-4-yl) -1- (4-
Fluoro-2-methylphenyl) -4-oxo-1,4
-Dihydronicotinic acid

[0034]

[Table 1]

2. Acute toxicity test Mice (ICR strain, ♂, body weight 18) of the representative compound of the present invention
The LD ₅₀ value after intravenous administration was as follows.

[0036]

[Chemical 6]

[0037]

[Table 2]

Next, a method for producing the compound of the present invention will be described. As a method for producing the compound of the present invention, a method known per se can be mentioned, but a typical production method will be described in detail below.

[0039]

[Chemical 7]

"In the formula, R ² and R ³ have the same meanings as described above, and R ⁸ represents the same carboxyl protecting group as described for R ^1. "

The compound represented by the general formula [2] can be produced by a conventional method, for example, the Wittig reaction using the corresponding R ³ CHO as a raw material. This compound is reacted with N, N-dimethylformamide dimethyl acetal or N, N-dimethylformamide diethyl acetal, and then reacted with an amine represented by R ² NH ₂ to give a compound represented by the general formula [3]. Can lead to. The solvent used in this reaction is not particularly limited as long as it is an inert solvent in the reaction,
For example, aromatic hydrocarbons such as benzene, toluene or xylene; dioxane, tetrahydrofuran,
Ethers such as anisole, diethylene glycol dimethyl ether or dimethyl cellosolve; halogenated hydrocarbons such as methylene chloride, chloroform or dichloroethane; amides such as N, N-dimethylformamide or N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide Is used. The amount of acetal used is preferably equimolar or more, especially 1.0 to 1.2 times the molar amount of the compound represented by the general formula [2]. This reaction is usually carried out at 0 to 80 ° C. for several tens of minutes.
It will be completed in tens of hours. Subsequently, in order to react the amines represented by R ² NH ₂ , the same solvent as above is used, the amines are used in an equimolar amount to the compound represented by the general formula [2], and at 0 to 100 ° C. The reaction may be performed for several dozen minutes to several hours.

Alternatively, the compound represented by the general formula [2] is reacted with ethyl orthoformate or methyl orthoformate in acetic anhydride, and then the amine represented by R ² NH ₂ is reacted. It can be led to a compound represented by the formula [3]. The amount of orthoformate used is
At least equimolar to the compound represented by the general formula [2],
Especially, 1.0 to 1.2 times mol is preferable, and the reaction is usually completed at 20 to 100 ° C. for several minutes to several hours. Then,
In the presence of the same solvent as described above or in the absence of a solvent, an equimolar amount or more, preferably 1.0 to 1.2 times mol of an amine represented by R ² NH ₂ is reacted with the compound represented by the general formula [2]. Thus, the compound represented by the general formula [3] can be obtained.

Next, the compound represented by the general formula [4] can be produced by subjecting the compound represented by the general formula [3] to a ring closure reaction by heating. This reaction is
Amides such as N, N-dimethylformamide or N, N-dimethylacetamide; sulfoxides such as dimethylsulfoxide; or in the presence or absence of a solvent such as phosphoric acid esters such as ethyl polyphosphate, 50- Complete at several hours to several tens of hours at 150 ℃.

Further, the compound represented by the general formula [1b] is produced by reacting the compound represented by the general formula [4] with a dehydrogenating reagent. Examples of the dehydrogenation reagent include those commonly used, and particularly, 2,3
-Dichloro-5,6-dicyano-p-benzoquinone,
It is preferable to use 2,3,5,6-tetrachloro-p-benzoquinone or 3,4,5,6-tetrachloro-o-benzoquinone, which is equimolar or more to the compound represented by the general formula [4]. , Preferably 1.0 to 1.2 times by mole. This reaction is usually carried out in a solvent, and suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; and ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether and dimethyl cellosolve. Is mentioned. This reaction is 0-100 ℃,
It will be completed in a few minutes to tens of hours.

The compound thus obtained is treated in a conventional manner, for example, in the presence of an alkali or an acid, 0-100.
The compound represented by the general formula [1a] can be obtained by hydrolysis at a temperature of several minutes to several tens of hours. When the compound represented by the general formula [1b] or [1a] is produced by the above reaction route, the compound represented by the general formula [3] and / or the compound represented by the general formula [4] Can be subjected to the reaction of.

The compounds represented by the general formulas [2], [3], [4] and [1b] have an active group (for example, a hydroxyl group, an amino group and a carboxyl group) at a site other than the reaction site. In this case, the active group is protected in advance by a conventional method, and after completion of the reaction, the protecting group is eliminated by a conventional method to produce the compound. The compound thus produced is further subjected to a reaction known per se, for example, halogenation, esterification, amidation, ureido, alkylation,
It can be derivatized to other compounds by alkenylation, alkylideneation, acylation, hydroxylation, iminoethylation, and reduction reaction, and it is also used as an intermediate.

When the compound of the present invention is used as a medicine,
Tablets, capsules, powders, syrups, granules,
It is prepared into a suppository, an ointment or an injection. In addition, the administration method, dose and frequency of administration can be appropriately selected according to the symptoms of the patient. Generally, for adults, oral or parenteral (injection administration or administration to the rectal site) administration is performed. Then, 0.1 to 100 mg / kg / day (converted to the compound represented by the general formula [1]) may be divided into 1 to several times for administration.

[0048]

EXAMPLES Next, the present invention will be explained with reference to reference examples and examples, but the present invention is not limited thereto.

Reference Example 1 [2-Methoxy-3- (methoxycarbonyl) allyl]
Triphenylphosphonium bromide 25.7 g methanol 1
It is dissolved in 00 ml, and 10.5 g of 28% sodium methoxide-methanol solution is added dropwise over 10 minutes while stirring at room temperature. Then, 1,2,3,6-tetrahydrobenzaldehyde (5 g) was added at room temperature, and the mixture was reacted at the same temperature for 2 hours, and then the solvent was distilled off under reduced pressure. 50 ml of water is added to the obtained residue, and the mixture is extracted with 50 ml of chloroform. After the extract is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (Wako silica gel C-200; eluent, benzene: n-
Purification with hexane = 3: 1) gives an oil. This is dissolved in 100 ml of dioxane, 100 ml of 0.1N sulfuric acid is added, and the mixture is reacted at 100 ° C. for 1.5 hours. Then, the solvent is distilled off under reduced pressure, 100 ml of chloroform is added to the obtained residue, and then washed with 100 ml of water. The organic layer is separated and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure.
The obtained residue was subjected to column chromatography (Wako Silica Gel C-200; eluent, benzene: n-hexane =
If purified with 3: 1), oily 5- (cyclohexene-
7.5 g of 4-yl) -3-oxo-4-pentenoic acid methyl ester are obtained. IR (neat) cm ^-1 ; ν _{C = O} 1740 In the same manner, the following compound is obtained. R ³ CH = CHCOCH ₂ COOCH ₃

[0050]

[Table 3]

Example 1 (1) 2.0 g of 5- (cyclohexen-4-yl) -3-oxo-4-pentenoic acid methyl ester was dissolved in 20 ml of benzene, and 1.4 g of N, N-dimethylformamide dimethylacetal was added. And react at 70 ° C for 1.5 hours. The reaction mixture was cooled to room temperature and 1.2 g of p-hydroxyaniline
Is added and reacted for 1.5 hours. Then, 50 ml of diisopropyl ether was added, and the precipitated crystals were collected by filtration and washed with 20 ml of diisopropyl ether to give a melting point of 151-153.
5- (cyclohexen-4-yl) -2- (4 which indicates a temperature of
-Hydroxyphenylaminomethylene) -3-oxo-
2.1 g of 4-pentenoic acid methyl ester are obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1710 Similarly, the following compound is obtained.

[0052]

[Chemical 8]

[0053]

[Table 4]

(2) 5- (cyclohexen-4-yl)
-2- (4-hydroxyphenylaminomethylene) -3
2.0 g of -oxo-4-pentenoic acid methyl ester was added to N, N
-Dissolve in 20 ml of dimethylformamide and react at 140 ° C for 4 hours. Then, the solvent was distilled off under reduced pressure, 50 ml of dioxane was added to the obtained residue, and the precipitated crystals were collected by filtration and washed with 30 ml of diethyl ether to give a melting point of 155.
6- (cyclohexen-4-yl) -1 showing ~ 157 ° C
-(4-Hydroxyphenyl) -4-oxo-1,4
1.4 g of 5,6-tetrahydronicotinic acid methyl ester are obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1715 Similarly, the following compound is obtained.

[0055]

[Chemical 9]

[0056]

[Table 5]

(3) 6- (Cyclohexen-4-yl)
-1- (4-hydroxyphenyl) -4-oxo-1,
4,5,6-Tetrahydronicotinic acid methyl ester 1.
0 g is dissolved in 20 ml dioxane and heated to 80 ° C. Then 2,3,5,6-tetrachloro-p-benzoquinone
A solution prepared by dissolving 0.83 g in 20 ml of dioxane was added dropwise at 80 ° C, and then the mixture was reacted at the same temperature for 1 hour. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration and washed with 50 ml of dioxane to give 6- (cyclohexen-4-yl) -1- (4-hydroxyphenyl) -4 having a melting point of 250 ° C or higher.
-Oxo-1,4-dihydronicotinic acid methyl ester
Get 0.7g. IR (KBr) cm ^-1 ; ν _{C = O} 1735,1705

The NMR of this compound is shown in Table 6.

[0059]

[Table 6]

Similarly, the following compound is obtained.

[0061]

[Chemical 10]

[0062]

[Table 7]

(4) 6- (Cyclohexen-4-yl)
-1- (4-hydroxyphenyl) -4-oxo-1,
0.5 g of 4-dihydronicotinic acid methyl ester is dissolved in 5 ml of methanol and 5 ml of a 1N sodium hydroxide aqueous solution and reacted at room temperature for 30 minutes. Then, the reaction mixture was adjusted to pH 5.5 with acetic acid, and the precipitated crystals were collected by filtration and then washed with water (30 m).
If washed with l and dried, 6- (cyclohexen-4-yl) -1- (4-hydroxyphenyl) -4-oxo-1,4-dihydronicotinic acid having a melting point of 250 ° C. or higher 0.35
get g. IR (KBr) cm ^-1 ; ν _{C = O} 1725,1700

The NMR of this compound is shown in Table 8.

[0065]

[Table 8]

In the same manner, the following compound is obtained.

[0067]

[Chemical 11]

[0068]

[Table 9]

Example 2 5- (Cyclohexen-4-yl) -3-oxo-4-
2.0 g of pentenoic acid methyl ester is dissolved in 30 ml of N, N-dimethylformamide, 1.4 g of N, N-dimethylformamide dimethylacetal is added, and the mixture is reacted at 70 ° C. for 1.5 hours. Then, 1.3 g of 4-hydroxy-2-methylaniline is added at the same temperature, and the mixture is reacted at 80 ° C. for 2 hours and further at 140 ° C. for 3 hours. The reaction mixture is cooled to room temperature and the solvent is distilled off under reduced pressure. 20 ml of dioxane obtained
A solution of 2.4 g of 2,3,5,6-tetrachloro-p-benzoquinone dissolved in 15 ml of dioxane was added dropwise at 80 ° C., and the mixture was reacted at the same temperature for 1 hour. Then, the solvent was distilled off under reduced pressure, and the obtained residue was added with 30 ml of chloroform.
And 30 ml of water and pH 7.5 with sodium bicarbonate.
After adjusting to, the organic layer is separated. This organic layer is 10 ml of water
Then, it is washed with 20 ml of saturated saline and successively, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to give a melting point of 25
6- (cyclohexen-4-yl) -1 showing 0 ° C or higher
1.3 g of-(4-hydroxy-2-methylphenyl) -4-oxo-1,4-dihydronicotinic acid methyl ester are obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1735,1705

The NMR of this compound is shown in Table 10.

[0071]

[Table 10]

Similarly, the following compound is obtained.

[0073]

[Chemical 12]

[0074]

[Table 11]

Example 3 2.0 g of 6- (cyclohexen-4-yl) -1- (4-hydroxy-2-methylphenyl) -4-oxo-1,4-dihydronicotinic acid methyl ester was added to 80 ml of chloroform.
Dissolve in ml and cool to 5 ° C. 1.0 g of bromine in this solution
Was added dropwise to chloroform (5 ml) at 5 ° C over 30 minutes, and the mixture was reacted at room temperature for 30 minutes. Then, the solvent was distilled off under reduced pressure, 50 ml of diethyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration and washed with 20 ml of diethyl ether to give a melting point of 197 to 200 ° C. 6- ( 3,4-dibromocyclohexyl) -1- (4-
Hydroxy-2-methylphenyl) -4-oxo-1,
2.5 g of 4-dihydronicotinic acid methyl ester are obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1730,1700

Example 4 The corresponding compound was hydrolyzed in the same manner as in Example 1 (4) to obtain the following compound.

[0077]

[Chemical 13]

[0078]

[Table 12]

Example 5 (1) 0.7 g of 5- (cyclopenten-1-yl) -3-oxo-4-pentenoic acid methyl ester was dissolved in 5 ml of benzene, and 0.6 g of N, N-dimethylformamide dimethyl acetal was added. And react at 70 ° C for 1.5 hours. The reaction mixture is cooled to room temperature, 0.44 g of 4-hydroxy-2-methylaniline is added, and the reaction is carried out for 1.5 hours. Then,
After adding 5 ml of diethyl ether and collecting the precipitated crystals by filtration, washing with 5 ml of diethyl ether gives a melting point of 148-151.
5- (cyclopenten-1-yl) -2- (4) showing a temperature of
-Hydroxy-2-methylphenylaminomethylene)-
0.7 g of 3-oxo-4-pentenoic acid methyl ester is obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1705

Similarly, the following compound is obtained.

[0081]

[Chemical 14]

[0082]

[Table 13]

(2) 5- (cyclopenten-1-yl)
-2- (4-hydroxy-2-methylphenylaminomethylene) -3-oxo-4-pentenoic acid methyl ester
0.7 g was dissolved in 5 ml of N, N-dimethylformamide,
React at 140 ° C for 2 hours. Then, the solvent is distilled off under reduced pressure, and the obtained residue is purified by column chromatography (Wako Silica Gel C-200; eluent: chloroform) to obtain an oily substance. This oily substance is dissolved in 10 ml of dioxane, 0.5 g of 2,3,5,6-tetrachloro-p-benzoquinone is added, and the mixture is reacted at 80 ° C. for 30 minutes. After cooling the reaction mixture to room temperature, the precipitated crystals are collected by filtration and washed with 5 ml of dioxane. 5 ml of this crystal
And dissolve in 5 ml of 1N aqueous sodium hydroxide solution and react at room temperature for 30 minutes. The reaction mixture was adjusted to pH 5.5 with acetic acid, and the precipitated crystals were collected by filtration, washed with water and dried to give 6- (cyclopentene-1-
Yl) -1- (4-hydroxy-2-methylphenyl)
0.3 g of -4-oxo-1,4-dihydronicotinic acid is obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1720,1700

Similarly, the following compound is obtained.

[0085]

[Chemical 15]

[0086]

[Table 14]

Example 6 0.3 g of 5-cyclooctyl-3-oxo-4-pentenoic acid methyl ester was dissolved in 5 ml of benzene, and 0.3 g of N, N-dimethylformamide dimethyl acetal was added.
Incubate at 70 ° C for 1 hour. The reaction mixture is cooled to room temperature, 0.27 g of 4-hydroxy-2-methylaniline is added, and the mixture is reacted at room temperature for 2 hours. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (Wako silica gel C-200; eluent, toluene: ethyl acetate = 50: 1). N, N-
It is dissolved in 5 ml of dimethylformamide and reacted under reflux for 4 hours. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (Wako silica gel C-200;
After purification with an eluent, chloroform: ethanol = 50: 1), the oil obtained was dissolved in 5 ml of dioxane.
0.2 g of 3,5,6-tetrachloro-p-benzoquinone is added and reacted at 80 to 90 ° C for 30 minutes. The reaction mixture is cooled to room temperature, and the precipitated crystals are collected by filtration. The crystals are dissolved in 20 ml of chloroform, the insoluble matter is filtered off, and the solvent is distilled off under reduced pressure. To the obtained residue, 5 ml of a 1N sodium hydroxide aqueous solution and 5 ml of methanol are added, and the mixture is reacted at room temperature for 30 minutes. Methanol is distilled off under reduced pressure, and the obtained residue is adjusted to pH 6.5 with 2N hydrochloric acid. The precipitated crystals are collected by filtration, washed with water and dried to give 6-cyclooctyl-1- (4-hydroxy-2-methylphenyl) -4-oxo-1,4-dihydro having a melting point of 118 to 120 ° C. This gives 0.14 g of nicotinic acid. IR (KBr) cm ^-1 ; ν _{C = O} 1725,1710

Similarly, the following compound is obtained.

[0089]

[Chemical 16]

[0090]

[Table 15]

Example 7 6- (4-benzyloxycarbonylaminocyclohexyl) -1- (4-hydroxy-2-methylphenyl)
0.15 g of -4-oxo-1,4-dihydronicotinic acid is dissolved in 10 ml of dioxane and 5 ml of water, 0.03 g of 5% palladium-carbon is added, and hydrogenation is carried out under normal pressure for 3 hours.
Then the catalyst is filtered off and the solvent is distilled off under reduced pressure. After adding 3 ml of diethyl ether to the obtained residue, the crystals were collected by filtration and washed with 3 ml of diethyl ether to give 6- (4-aminocyclohexyl) -1 having a melting point of 237 to 250 ° C. (decomposition). -(4-Hydroxy-2-methylphenyl) -4-oxo-1,4-dihydronicotinic acid 0.095 g
To get IR (KBr) cm ^-1 ; ν _{C = O} 1715

Similarly, the following compound is obtained.

[0093]

[Chemical 17]

[0094]

[Table 16]

Example 8 6- (4-benzyloxycarbonylaminocyclohexyl) -1- (4-hydroxy-2-methylphenyl)
0.2 g of -4-oxo-1,4-dihydronicotinic acid methyl ester is dissolved in 15 ml of methanol, 0.05 g of 5% palladium-carbon is added, and hydrogenation is carried out at atmospheric pressure for 1.5 hours. Then the catalyst is filtered off and the solvent is distilled off under reduced pressure. To the resulting residue was added 37% formalin 0.4 g and formic acid 0.1 g to give 1
Incubate at 00 ℃ for 7.5 hours. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (Wako Silica Gel C-200; eluent, chloroform: ethanol = 3:
If purified in 1), 0.04 g of 6- (4-dimethylaminocyclohexyl) -1- (4-hydroxy-2-methylphenyl) -4-oxo-1,4-dihydronicotinic acid having a melting point of 207 to 215 ° C. To get IR (KBr) cm ^-1 ; ν _{C = O} 1720

Similarly, the following compound is obtained.

[0097]

[Chemical 18]

[0098]

[Table 17]

Example 9 (1) 1- (4-acetoxy-2-methylphenyl)-
10.5 g of 6-methyl-4-oxo-1,4-dihydronicotinic acid methyl ester was dissolved in 315 ml of dioxane by heating, 4.43 g of selenium dioxide was added, and the mixture was reacted at 100 ° C. for 2 hours. The reaction mixture is cooled at room temperature, selenium is filtered off, and then the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (Wako Silica Gel C-200; eluent, chloroform: ethanol = 25: 1).
7.9 g of 1- (4-acetoxy-2-methylphenyl) -6-formyl-4-oxo-1,4-dihydronicotinic acid methyl ester having a melting point of 216-217 ° C. are obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1760,1730,1700 (sh)

(2) 1- (4-acetoxy-2-methylphenyl) -6-formyl-4-oxo-1,4-dihydronicotinic acid methyl ester (0.95 g) was added with 6N hydrochloric acid (5 ml) at 100 ° C. React for hours. The reaction mixture is cooled to room temperature and adjusted to pH 7.5 with saturated aqueous sodium hydrogen carbonate solution. Then, after adding 100 ml of acetonitrile,
Saturate the aqueous layer with salt. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 6-formyl-1- (4-hydroxy-2) having a melting point of 230 to 250 ° C. -Methylphenyl) -4-
0.6 g of oxo-1,4-dihydronicotinic acid is obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1715

(3) 6-Formyl-1- (4-hydroxy-2-methylphenyl) -4-oxo-1,4-dihydronicotinic acid (0.15 g) was dissolved in methanol (5 ml) to prepare ethoxycarbonylmethylenetriphenylphosphorane. 0.19
g, and react at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure and column chromatography (Wako silica gel C-200; eluent, chloroform: ethanol = 5)
If purified with 0: 1), 6- (2-
0.06 g of ethoxycarbonylethenyl) -1- (4-hydroxy-2-methylphenyl) -4-oxo-1,4-dihydronicotinic acid is obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1720,1705

(4) 6- (2-ethoxycarbonylethenyl) -1- (4-hydroxy-2-methylphenyl)
-4-oxo-1,4-dihydronicotinic acid 6 in 0.09 g
Add 3 ml of N hydrochloric acid and react at 100 ° C. for 1.5 hours. Then, the solvent was distilled off under reduced pressure, 3 ml of diethyl ether was added to the obtained crystals, and the crystals were collected by filtration to give 6- (2-carboxyethenyl) -1- (4-hydroxy) having a melting point of 280 ° C. or higher. This gives 0.08 g of 2-methylphenyl) -4-oxo-1,4-dihydronicotinic acid. IR (KBr) cm ^-1 ; ν _{C = O} 1720

The NMR of this compound is shown in Table 18.

[0104]

[Table 18]

Example 10 6-formyl-1- (4-hydroxy-2-methylphenyl) -4-oxo-1,4-dihydronicotinic acid 0.15
g was dissolved in 5 ml of methanol and N-aminomorpholine was added.
Add 0.056g and react at 65 ° C for 1 hour. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (Wako silica gel C-200; eluent, chloroform) to give a melting point of 267 to 268 ° C. 1- (4
0.06 g of -hydroxy-2-methylphenyl) -6- (morpholinoiminomethyl) -4-oxo-1,4-dihydronicotinic acid is obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1730

Similarly, the following compound is obtained.

[0107]

[Chemical 19]

[0108]

[Table 19]

Example 11 1- (4-benzyloxy-2-methylphenyl) -6
Dissolve 2 g of-(2-chloroethyl) -4-oxo-1,4-dihydronicotinic acid methyl ester in 20 ml of N, N-dimethylformamide, and at 5 ° C 4-ethyl-2,
0.9 g of 3-dioxopiperazine-1-sodium are added over 20 minutes. Then, after reacting for 30 minutes at the same temperature, the solvent is distilled off under reduced pressure, and the obtained residue is dissolved in 20 ml of chloroform. 20 ml of water and saturated saline
It is washed successively with 20 ml, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to give an oil. This oily substance is dissolved in 10 ml of methanol and 10 ml of a 1N sodium hydroxide aqueous solution and reacted at room temperature for 30 minutes. Then,
The reaction mixture was adjusted to pH 6.0 with acetic acid, the precipitated crystals were collected by filtration, washed with water, dissolved in 10 ml of dioxane and 5 ml of water, added with 0.2 g of 5% palladium-carbon, and required 10 hours. Hydrogenate. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a melting point of 182-190 ° C (decomposition) 6-
[2- (4-ethyl-2,3-dioxopiperazine-1
0.8 g of -yl) -ethyl] -1- (4-hydroxy-2-methylphenyl) -4-oxo-1,4-dihydronicotinic acid are obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1730

Example 12 7- (4-benzyloxycarbonyl-piperazine-1
-Yl) -3-oxo-4-heptenoic acid methyl ester
3.0 g was dissolved in 20 ml of benzene, 1.2 g of N, N-dimethylformamide dimethyl acetal was added, and 1.5 g was added at 70 ° C.
React for hours. The reaction mixture is cooled to room temperature, 1.0 g of 4-hydroxy-2-methylaniline is added and reacted for 1.5 hours. Then, the precipitated crystals are collected by filtration, and benzene is added.
After washing with 10 ml, 20 ml of N, N-dimethylformamide
And dissolve at 140 ° C. for 3 hours. The reaction mixture is cooled to room temperature and the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (Wako Silica Gel C-
200; eluent, chloroform) to give an oil. This oil was dissolved in 20 ml of dioxane to give 2,3,3.
Add 0.7 g of 5,6-tetrachloro-p-benzoquinone,
Incubate at 80 ℃ for 30 minutes. The reaction mixture is cooled to room temperature, the precipitated crystals are filtered off and washed with 10 ml of dioxane. The crystals obtained are dissolved in 10 ml of a 1N aqueous sodium hydroxide solution and reacted at room temperature for 30 minutes. The reaction mixture was adjusted to pH 6.0 with acetic acid, the precipitated crystals were collected by filtration, washed with water, dissolved in 10 ml of dioxane and 5 ml of water, added with 0.2 g of 5% palladium-carbon, and required 2 hours. , Hydrogenate. The reaction mixture was added with 5 ml of 2N hydrochloric acid, filtered, and the filtrate was concentrated to give 1- (4-hydroxy-2-methylphenyl) -6- [2- (piperazine-1- 0.4 g of (yl) ethyl] -4-oxo-1,4-dihydronicotinic acid dihydrochloride is obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1720

[0111]

INDUSTRIAL APPLICABILITY The compound of the present invention is effective as an antibacterial agent because it effectively acts against Gram-positive bacteria and Gram-negative bacteria, and particularly exhibits antibacterial action against antibiotic-resistant bacteria.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Junko Nagai 1763 Gofuku, Toyama City, Toyama Prefecture (72) Inventor Yasuo Watanabe 2-4-9 Nishida District Town, Toyama City, Toyama Prefecture (72) Nobuyuki Matsubara Toyama City, Toyama Prefecture Nakagawara Shinmachi 285-4 (72) Inventor Shinzaburo Minami 167 Nakata, Toyama City, Toyama Prefecture (72) Inventor Isamu Saikawa 7-52 Oizumi Nakamachi, Toyama City, Toyama Prefecture Examiner Shoei Hoshino

Claims (1)

[Claims] 1. A general formula: "Wherein R ¹ is a hydrogen atom or a carboxyl protecting group; R ² is an aryl group having a substituent or a heterocyclic group with or without a substituent; and R
³ represents a haloalkyl group, an aminoalkyl group, an alkenyl group or an aralkyl, a heterocycle-alkyl, a cycloalkyl, a cycloalkenyl, an iminoalkyl or a bridged cyclic hydrocarbon group with or without a substituent, respectively. 4-oxo-1,4-dihydronicotinic acid or a salt thereof.