JPS61246163A - Novel heterocyclic compound and salt thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is carboxy or protected carboxy; R<2> is H, halogen or lower alkyl; R<3> is (substituted) phenyl or heterocyclic group substituted by protected amino; R<4> is (substituted) phenyl, (substituted) phenyl (lower) alkyl, heterocyclic group or heterocyclic group (lower) alkyl; Z is N or CH; formula II is single or double bond] and a salt thereof. EXAMPLE:Ethyl 1-[4-(1,3-dioxolan-2-yl)phenyl]-4-oxo-6-(4-dimethylaminophe- nyl)-1,4,5,6-tetrahydronicotinate. USE:A medicine and antimicrobial agent having high antimicrobial activity against many pathogenic germs, e.g. Gram-positive and Gram-negative bacteria. PREPARATION:For example, a novel compound expressed by formula III or a salt thereof is heated in a solvent, e.g. N,N-dimethylformamide, to give the aimed compound expressed by formula I (formula II is single bond).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] This invention relates to a novel heterocyclic compound having antibacterial activity, and is used in the medical field.

[Object of the Invention] The object of the present invention is to provide a novel heterocyclic compound and a salt thereof having high antibacterial activity against a large number of pathogenic bacteria.

[Structure of the invention] The target heterocyclic compound is novel and has the following general formula (
It can be shown as I).

[In the formula, R1 is a carboxy group or a protected carboxy group, R2 is hydrogen, halogen or a lower alkyl group, and R3 is a phenyl group which may be substituted with an appropriate substituent, or a protected amine group] the heterocyclic group, R4 is a phenyl group which may be substituted with an appropriate substituent, a phenyl group which may be substituted with an appropriate substituent (
(lower) alkyl group, heterocyclic group, or heterocyclic (lower) alkyl group, Z is N or CH.

2 means a single bond or a double bond, respectively.

The target compound (I) can be produced by the following method.

[Manufacturing method 1 (I[) or its salt ○ (Ia) or its salt [Manufacturing method 2 or its salt or its salt [Manufacturing method 3] or its salt or its salt [Manufacturing method 4] (Ie) ( If') or its salt
or its salt [Production method 5] (If) or its salt ↓ (Ig) or its salt Production method 6] or its salt or its salt [Production method 7] (Ik) or its salt [Production method 8] (11 ) (Im) or a salt thereof or a salt thereof [wherein R1, R2, R3, R', z and -----
has the same meaning as before, R1 is a protected carboxy group, A is a lower alkylene group, R5 is hydrogen or an organic group which may have an appropriate substituent, R4 is a lower alkoxy group and phenyl substituted with a halogen. group, phenyl group substituted with lower alkoxy group,
Phenyl (lower) substituted with two lower alkoxy groups
Alkyl group, R4 is a phenyl group substituted with a hydroxy group and a halogen, a phenyl group substituted with a hydroxy group, a phenyl (lower) alkyl group substituted with two hydroxy groups, R6 is a lower alkoxy (lower) alkoxy ( The co-raw material compound (n), in which R2 means a lower alkyl group, is a new compound, and can be produced by the same method or similar method to Production Examples 1 to 16 described later.

Suitable salts of the target compound (I) are conventional non-toxic salts,
Alkali metal salts such as sodium salts, potassium salts, alkaline metal salts such as calcium salts and magnesium salts, inorganic salts such as ammonium salts; such as trimethylamine salts, triethylamine salts, pyridine salts, prohydroline salts, picoline salts, dicyclohexylamine salt, N,
N'-dibenzylethylenediamine salt, N-methylcurcamine salt, jetanolamine salt, triethanolamine salt, tris(hydroxymethylamine)methane salt,
Examples include organic salts such as organic amine salts such as phenylethylbenzylamine salt and dibenzylethylenediamine salt.

In the foregoing and following description of this specification, preferred examples and explanations of the various definitions falling within the scope of this invention are set forth in detail below.

"Lower, unless otherwise specified, shall mean groups having from 1 to 6 carbon atoms.

Examples of suitable 1-protected carboxy groups include esterified carboxy groups.

Suitable examples of the ester moiety of the esterified carboxy group include methyl ester, ethyl ester, propyl ester, isopropyl ester, mesyl ester, isobutyl ester, tertiary mesyl ester, pentyl ester, hexyl ester, 1- a suitable substituent such as cyclopropylethyl ester, at least IM
Lower alkyl esters which may have J, such as acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester ,1
(or 2)-acetoxybutyl ester 1 (or 2 or 3)-acetoxypropyl ester, 1 (or 2 or 3 or 4)-acetoxybutyl ester, 1 (or 2)-pro and onyloxyethyl ester, 1 (or 2 or 3)-propionyloxyprobyl ester, 1 (or 2)-butyryloxyethyl ester, 1 (or 2) inbutyryloxyethyl ester, 1 (or 2)-pivaloyloxymethyl ester, 1 (or 2)-hexanoyloxyethyl ester, isopteryloxymethylester, 2-ethylbutyryloxymethylester, 3,3-dimethylbutyryloxymethylester, 1(or 2)-pentanoyloxy Lower alkanoyloxy(lower) alkyl esters such as ethyl ester, e.g. lower alkanesulfonyl(lower) alkyl esters such as 2-mesyl ester, e.g. 2-yokudoethyl ester, 2.2.2
- Mono (or di or tri)-halo (lower) alkyl esters such as trichloroethyl ester, e.g. methoxycarbonyloxymethyl ester L, ethoxycarbonyloxyethyl ester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester Lower alphoxydicarbonyloxy (lower) alkyl esters such as nyloxydiethyl esters & phthalidylidene (
(lower) alkyl ester or e.g. (5-methyl-
2-year-old xo-1,3-dioxo-4-yl) methyl ester, (5-ethyl-2-year-old xo-1,3-dioxo-4-yl) methyl ester, (5-propyl-
(5-lower alkyl-2-oxo-1,3
-Dioxol-4-yl) (lower) alkyl esters; Lower alkenyl esters such as vinyl esters and allyl esters; Lower alkynyl esters such as ethynyl esters and propynyl esters; For example benzyl esters, 4-methoxybenzyl esters, -Nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(
For example, mono( or al(lower) alkyl esters such as di- or tri)-phenyl(lower) alkyl esters; , aryl esters which may have at least one suitable substituent, such as cumenyl esters.

Suitable "halogens" include chlorine, bromine, fluorine and iodine.

Suitable lower alkyl groups include methyl, ethyl,
Examples include propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, hexyl, etc., and preferably one having 1 to 4 carbon atoms.

Preferred substituents for the phenyl group which may be substituted with an appropriate substituent in R3 include di(lower) alkylamino groups and lower alkyl groups in which the lower alkyl moiety is as exemplified above. Examples include a lower alkylthio group, a lower alkanesulfonyl group (eg, methanesulfonyl, propanesulfonyl, butanesulfonyl, etc.), a thenoylamine group, and the like, in which the moiety is as exemplified above.

"Heterocyclic group substituted with a protected amine group.

Suitable protected amine groups include those substituted with conventional protecting groups such as al(lower)alkyl, which may be substituted with at least one suitable substituent, e.g. benzyl, trityl, etc. Examples include amino or acylamino groups.

Suitable acyl moieties for 1 acylamino herein include aliphatic acyl groups and acyl groups containing aromatic rings or heterocycles. Furthermore, suitable examples of said acyl include lower alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalinosuccininopivaloyl, for example methoxycarbonylcarbonylbrobyl ethoxycarbonyl, impropoxycarbonyl, butoxy Lower alkoxycarbonyl such as carbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, lower alkanesulfonyl such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc., such as benzenesulfonyl, tosyl, etc. Arenesulfonyl, e.g. aroyl such as benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, alkanoyl such as phenylacetyl, phenylpropionyl, al(lower) alkanoyl such as benzyloxycarbonyl, phenethyloxycarbonyl, etc.
Examples include alfkidicarbonyl. The above acyl moiety may have at least one suitable substituent such as halogen such as chlorine, bromine, fluorine, iodine and the like.

Preferred heterocyclic moieties in the "1-heterocyclic group" and the "heterocyclic (lower) alkyl group" include saturated groups containing at least one hetero JQ atom such as oxygen, sulfur, nitrogen atoms, etc. or an unsaturated monocyclic or polycyclic heterocyclic group. Particularly preferred heterocyclic groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-M compounds, pyrimidyl, pyrazinyl, pyridazinyl, such as 4H-1 .2.4-Triazolyl, IH
- Triazolyl such as -1.2.3-triazolyl, 2H-1.2.3-triazolyl, e.g. tetrazolyl such as IH-tetrazolyl, 2H-tetrazolyl, e.g. 4.5
-Unsaturated 3- to 8-membered heterostructure containing 1 to 4 nitrogen atoms, such as dihydrotriazinyl, such as dihydro-1.2.4-1-riazinyl, 2.5-dihydro-1.2.4-triazinyl, etc. Monocyclic groups; e.g. pyrrolidinyl, imidazolidinyl,
Saturated 3- to 8-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms such as piperidino, piperazinyl; e.g. indolyl, isoindolyl, intridinyl, benzimidazolyl, quinolyl, isoquinolyl, imidazolyl, benzotriazolyl, tetracylopyridyl, e.g. Tetrashiro [1.5
-b] Unsaturated fused heterocyclic group containing 1 to 5 nitrogen atoms such as tetraclopyridazinyl such as pyridazinyl, dihydrotriazolopyridazinyl; e.g. oxasilyl, inxazolyl, e.g. 1,2.4- Oxadiazolyl, 1
．． 3. Unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as oxadiazolyl such as 4-oxadiazolyl and 1,2.5-oxadiazolyl; for example, oxygen such as morpholinyl Saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 atoms and 1 to 3 nitrogen atoms; for example, benzoxacylyl, benzoxadiazolyl, etc., containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; Containing unsaturated fused heterocyclic group; for example, 1,3-thiazolinyl 1.
2-thiazolyl, thiazolinyl, such as 1.2.4-thiadiazolyl, 1.3.4-thiadiazolyl, 1.2.
1 to 2 sulfur atoms and 1 nitrogen atom in thiadiazolyl such as 5-thiadiazolyl and 1,2.3-thiadiazolyl
an unsaturated 3- to 8-membered heteromonocyclic group containing ~3; for example, 1-2 sulfur atoms and 1 to 2 nitrogen atoms, such as thiazolidinyl;
A saturated 3- to 8-membered heteromonocyclic group containing 3 sulfur atoms; an unsaturated 3- to 8-membered heteromonocyclic group containing 1 sulfur atom such as chenyl; unsaturated fused heterocyclic groups containing 2 nitrogen atoms and 1 to 3 nitrogen atoms.

Preferred substituents for the ``phenyl group optionally substituted with a suitable substituent'' in R4 include halogens such as chlorine, bromine, fluorine, and iodine, hydroxy groups such as methoxy, ethoxy, propoxy, impropoxy, Lower alkoxy groups such as butoxy, imbutoxy, tertiary butoxy, pentyloxy, hexyloxy, lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, invaleryl, and lower alkoxy moieties are as exemplified above. Examples include a group represented by lower alkoxy (lower) alkoxy (in the formula, R5 has the same meaning as above), and a group represented by ξ.

Suitable substituents for the "phenyl (lower) alkyl group which may be substituted with an appropriate substituent" include hydroxy groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, imbutoxy, tertiary butoxy, Examples include lower alkoxy groups such as pendeloxy and hexyloxy.

Suitable primary alkylene groups include methylene, ethylene, trimeprene, tetramethylene, pentamethylene, and the like.

Preferred organic groups which may have a suitable substituent include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl, hexyl, etc. Lower alkyl groups; For example, chloromethyl, dichloromethyl, difluoromethyl, trichloromethyl, bromomethyl, chloroethyl,
dichloroethyl, trichloroethyl, fluoroethyl,
Mono (or di or tri) halo (lower) alkyl groups such as trifluoroethyl; e.g. vinyl, 1-propenyl, 71)) L-,1-methylalino, 1 or 2 or 3-butenyl, 1 or 2 or 3 or Lower alkenyl groups such as 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl; e.g. 1-propynyl, propargyl, 1
- lower alkynyl groups such as methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl; for example phenyl, tri-L, xylyl, cumenyl, Aryl groups such as naphthyl; Examples include alkyl (lower) alkyl groups such as phenyl (lower) alkyl groups such as benzyl, phenethyl, and phenylpropyl.

Suitable primary alkoxy groups, and “lower alkoxy (
Suitable lower alkoxy groups in the (lower) alkyl group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, imbutoxy,
Examples include tertiary butoxy, benzyloxy, hexyloxy, and the like.

Preferred embodiments of the target compound (1) are as follows.

A preferred embodiment of R1 is a carboxy group or an esterified carboxy group (more preferably a lower alkyl dicarbonyl group), and R2 is hydrogen, halogen (more preferably fluorine) or a lower alkyl group (more preferably methyl). R3 is a phenyl group, a phenyl group substituted with a di(lower) alkylamino group, a phenyl group substituted with a lower alkylthio group, a phenyl group substituted with a lower alkanesulfonyl group, a phenyl group substituted with a thenoylamino group a phenyl group or a thiazolyl group substituted with a protected amine group (more preferably a thiazolyl group substituted with an acylamino group, most preferably a thiazolyl group substituted with a lower alkanoylamino group), R4 is a thiazolyl group substituted with a halogen group; phenyl group,
A phenyl group substituted with a hydroxy group, a phenyl group substituted with a lower alkoxy group, a phenyl group substituted with a lower alkanoyl group, a phenyl group substituted with a lower alkoxy (fffi grade) alkoxy (lower) alkoxy group, a phenyl group substituted with a group represented by the formula: −
6=N-OR5 (in the formula, R51 is water IK* or an organic group which may have an appropriate substituent), a phenyl group substituted with a halogen or a lower alkyl group Chipped phenyl group, phenyl group substituted with halogen and hydroxy group, phenyl (lower) alkyl group substituted with two hydroxy groups, phenyl (lower) alkyl group substituted with two lower alkoxy groups, pyridyl (
(lower) alkyl group, thiazolyl group, or benzothiazolyl group, Z is N or CH.

2 is a single bond or a double bond.

Hereinafter, the method for producing the target compound (I) will be explained in detail.

Production method 1 Compound (Ia> or a salt thereof can be produced by heating compound (I[) or a salt thereof.

For suitable salts of compounds (Ia) and (n), reference may be made to those exemplified for compound (I).

This reaction is typically performed using N,N-dimethylformamide, N,
The reaction is carried out in a solvent such as N-dimethylacetamide or dimethyl sulfoxide, but the reaction can be carried out in any other solvent as long as it does not adversely affect the reaction.

Production method 2 Compound (Ib) or a salt thereof can be produced by subjecting compound (Ia) or a salt thereof to a dehydrogenation reaction.

Suitable salts of compound (Ib) include the salts exemplified for compound (I).

Suitable reagents used in this dehydrogenation reaction include, for example, 2,3-dichloro-5,6-dicya-1,4-benzoquinone, tetrachloro-1,2-benzoquinone, and tetrachloro-1,4-benzoquinone. benzoquinone derivatives, manganese dioxide, etc.

This dehydrogenation reaction is usually carried out using water, alcohols such as methanol and ethanol, N,N-dimethylformamide,
The reaction is carried out in a solvent such as benzene, toluene, dioxane, tetrahydrofuran, or a mixture thereof, but the reaction can be carried out in any other solvent that does not adversely affect the reaction.

The reaction temperature is not particularly limited, and the reaction is carried out in a range from cooling to heating.

Production method 3 Compound (Id) or a salt thereof can be produced by subjecting compound (Ic) or a salt thereof to an elimination reaction of a carboxy protecting group.

Suitable salts of compounds (Ic) and (Id) include the salts exemplified for compound (1).

This reaction is carried out according to conventional methods such as hydrolysis, reduction, etc.

When the protecting group is an ester, it can be removed by hydrolysis. The hydrolysis is preferably carried out in the presence of a base or an acid; suitable bases include, for example, alkali metals such as sodium, potassium, alkaline earth metals such as magnesium, calcium, hydroxides or carbonates of these metals. or bicarbonates, such as trialkylamines such as trimethylamine and triethylamine, picoline, 1,5-diazabicyclo[4°3.
0] ] Non-5-ene 1,4-diazabicyclo[2°2.2 cooctane, 1,8-diazabicyclo[5,4,
Inorganic bases or organic bases such as O]undecene-7 and the like can be mentioned. Suitable acids include formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid,
Examples include hydrochloric acid, hydrobromic acid, sulfuric acid, boron trifluoride, and boron tribromide.

The reaction is usually carried out in a solvent such as water, methylene chloride, an alcohol such as methanol or ethanol, or a mixture of solera, but the reaction can be carried out in any other solvent that does not adversely affect the reaction. can. Liquid bases or acids can also be used as solvents.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.

Reduction+t4-nitrobenzyl, 2-iodoethyl, 2.
It is preferably applied to removal of protecting groups such as 2.2-trichloroethyl and the like.

Reduction is carried out by conventional methods including chemical reduction and catalytic reduction.

Suitable reducing agents used for chemical reduction include, for example, tin,
Metals such as zinc and iron or metal compounds such as chromium chloride and chromium acetate, and formic acid, acetic acid, propionic acid,
It is a combination with an organic or inorganic acid such as trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, or hydrobromic acid.

Suitable catalysts used for catalytic reduction are platinum catalysts such as platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, platinum wires, e.g. palladium sponges, palladium black, palladium oxide, palladium-carbon, colloidal palladium. ,
Palladium catalysts such as palladium-barium sulfate, palladium-barium carbonate, nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, cobalt catalysts such as reduced cobalt, Raney cobalt, iron catalysts such as reduced iron, Raney iron, etc. Conventional catalysts such as copper catalysts such as reduced copper, Raney copper, Ullmann copper, etc.

The reduction is usually carried out in a solvent such as water, alcohols such as methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, mixtures thereof, but any solvent that does not adversely affect the reaction may be used. , the reaction can be carried out in any other solvent.

Furthermore, if the acids used in the chemical reduction are liquids, they can also be used as solvents.

The reaction temperature for this reduction is not particularly limited, but the reaction is usually carried out under cooling or heating.

Production method 4 Compound (If> or a salt thereof can be produced by subjecting compound (Ie) or a salt thereof to hydrolysis.

For suitable salts of compound (Is) and compound (If), reference may be made to those exemplified for compound (I).

Hydrolysis is usually carried out in the presence of an acid.

For suitable acids, reference may be made to those exemplified in Section j) Method.

This hydrolysis is usually carried out in a solvent such as water, an alcohol such as methanol or ethanol, acetone, N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof, provided that the solvent does not adversely affect the reaction. The reaction can be carried out in any other solvent. If the acids to be used are liquid, they can also be used as solvents.

The reaction temperature is not particularly limited, and the reaction is carried out in a temperature range from cooling to heating.

Production method 5 Compound (Ig) or a salt thereof can be produced by reacting compound (If) or a salt thereof with compound (I[[) or a salt thereof.

Suitable salts of compound (I[I) include acid addition salts such as hydrochloride, hydrobromide, and the like.

For suitable salts of compound (Ig), reference may be made to those exemplified for compound (I).

When a salt of the compound (I[I>) is used in the reaction, it is preferable to carry out the reaction in the presence of a base as listed above in Production Method 3.

This reaction is usually carried out in a solvent such as water, an alcohol such as methanol or ethanol, N,N-dimethylformamide, tetrahydrofuran, a mixture thereof, or any other solvent that does not adversely affect the reaction. The reaction can also be carried out in a solvent.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.

Production method 6 Compound (Ii) or a salt thereof can be produced by subjecting compound (Ih) or a salt thereof to an elimination reaction of the lower alkyl group of R4.

For suitable salts of compounds (Ih) and (Ii), refer to the salts exemplified for compound (I).

This elimination reaction can be produced by treating compound (Ih) with an acid.

Suitable acids include boron tribromide, hydriodic acid, hydrobromic acid, hydrochloric acid, p-toluenesulfonic acid, and the like.

The reaction is usually carried out in a solvent such as water, methylene chloride, an alcohol such as methanol or ethanol, or a mixture of solera, but the reaction may be carried out in any other solvent that does not adversely affect the reaction. I can do it. Liquid acids can also be used as solvents.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.

Production method 7 Compound (Ik) or a salt thereof can be produced by reacting compound (Ij) or a salt thereof with compound (IV).

For suitable salts of compounds (Ij) and (Ik),
Reference may be made to those exemplified for compound (I).

This reaction can be carried out in the same or similar manner as in Example 17 below.

Production method 8 Compound (1m) or a salt thereof can be produced by subjecting compound (11) or a salt thereof to an alkylation reaction.

For suitable salts of compounds (■1) and (Im),
Reference may be made to those exemplified for compound (I).

This reaction can be carried out in the same or similar manner as in Example 18 below.

The object compound (I) of the present invention and its salts are novel compounds that exhibit high antibacterial properties and inhibit a wide range of pathogenic bacteria, including Durum-positive bacteria and Durum-negative bacteria, and are useful as antibacterial agents.

For therapeutic purposes, the compounds of this invention may be mixed with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for oral, parenteral or topical administration.
It can be used in the form of customary pharmaceutical preparations containing said compounds as active ingredients. Pharmaceutical formulations may be in solid form, such as capsules, tablets, dragees, ointments, or suppositories, or liquid, such as solutions, suspensions, or emulsions. If desired, the above formulation may contain auxiliary agents, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives.

Although the dosage of the compound will vary depending on the age and condition of the patient, the compounds of this invention have an average single dose of about 10+++
g, 50mg, 100mg, 250mg, 500
mg, 1000μ is effective in treating pathogenic bacterial infections.

Generally, amounts between 1 mg and about 6000 mg per day, or more, may be administered.

In order to demonstrate the usefulness of the target compounds, the antibacterial activity of representative compounds of this invention is shown below.

The antibacterial activity in vitro was measured by the agar plate multiple dilution method described below.

The test bacterial strain was cultured overnight in tryptopase soy broth, and one platinum loop (108 viable bacteria/mF) was added to heart infusion agar (HI) containing the test compound at each concentration level.
After inoculating on agar) and culturing at 37°C for 20 hours, the minimum inhibitory concentration (CMIC) was expressed in st/ml.

(B) Test compound 1-(4-hydroxyiminomethylphenyl)-4-year-old xo-6-(4-dimethylaminophenyl)-1,4-
Dihydronicotinic acid.

(C)! The present invention will be explained in more detail below with reference to production examples and examples.

Production example 1 3-methoxy-4-fluoronitrobenzene (4.5g
) methanol-JL, (5Qml) solution, 10%
The reaction mixture was hydrogenated at room temperature and atmospheric pressure in the presence of palladium-carbon for 5 hours, and the filtrate was evaporated to dryness under reduced pressure to give 4-fluoro-3-methoxyaniline (3,
65 g).

IR (Streak 3-L): 3425. 3350.
3230. 1640°LaI3 cm-1 NMR (CDCl3,8)' 3-8 (3H1s
), 5.93-6-47 (2H1m), 6.56-
7.3 (LH,m) Production Example 2 4-Aminobenzaldehyde bulk ethylene acetal (
6,6 g) and triethyleneamine (5,6 g) in tetrahydrofuran (50+111) at 5°C.
A solution of -thenoyl-chloride (9.2 g) in tetrahydrofuran (10 mL) was added, and the mixture was stirred at the same temperature for 1 hour.
Add water and ethyl acetate. The organic layer is separated, washed with brine, dried, and the solvent is distilled off.

The residue is boiled in ethyl acetate and the insoluble matter is filtered off. The filtrate is concentrated to give 4-(2-tenoylamino)benzaldehyde winged ethylene 3-acetal (7.24 g).

NMR (DMSOds, l; )' 3.51 (4
H9m>, 7.28 (LHlm), 7.88-8.
18 (68, m), 9.93 (IH, s).

10.59 (LH, Broad S) Production Example 3 4-(2-Thenoylamino)benzaldehyde-ethylene gourd acetal (24.5g) in acetone (4tomQ
) and water (35 mQ), p-toluenesulfonic acid (1.7 g) was added, and the mixture was stirred at room temperature for 14 hours.
-tenoylamino)benzaldehyde (17,98[)
get.

IR (Sujoor)' 1705. 1640
cm-1HMR (DMSO-da, S)' 7.2
7 (IH, nn), 7.80-8.13 (6H, m
), 9.88 (18,s), 10.52
(18, Broad S) Production Example 4 A solution of ethyl 2-fluoro-2-(jethoxyphosphoryl)acetate (5.70 g) in tetrahydrofuran (50-) in hexane (161Q) was added with butyllithium at 65°C.
C or lower, stirred for 30 minutes at the same temperature, and a solution of benzaldehyde (2,41 nQ ) in tetrahydrofuran was added dropwise at the same temperature. The mixture is stirred for 30 minutes below -65°C and for 3 hours at room temperature, and water (501n9) and ethyl acetate (somu) are added. The organic layer is separated, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. This syrup-like substance was subjected to silica gel (50 g) column chromatography and ethyl acetate-hexane (10:
90) and ethyl 2-fluoro-3-phenylacrylate (mixture of E-form and H-Z form, E: Z->'l
ls:<5) (3,76 g) is obtained.

IR (film): 1740-1730. 1
660 cm-1HMR (CDCl2.8): 1
．． 20 (3H, t, J=7Hz>, 4.21 (2H
, q, J near Hz), 6.86 (1)1. d, J=
22Hz).

7, lr7.5 (5H, m) (E form) 19F-N
MR (CDCl2-FA, δ): -38,31(
d, J-22Hz) (E form) Mass spectrum: 194. 166, 165.
150. 105 pear jI ethyl 2-fluoro-3-phenylacrylate (mixture of E and Z forms, E: Z->95: <5) (
3,65g) (7) Salt # (10ml) and glacial acetic acid (401nQ) solution were heated under reflux for 7 hours and concentrated under reduced pressure to obtain 2-fluoro-3-phenylacrylic acid (mixture of E and Z forms, E: Z-87:13) (3,2
0g).

IR(KBr)' 1715-1640 cm-11
9F-NMR (CDCl2-TFA, δ) Knee 38.7
6 (d, J=22.3Hz) (E body) -48,0
0 (d, J = 34.7Hz) (Z-body) mass spectrum: 166, 149 Deep bleeding example 2i Magnesium shaving! (0,5g) of ethanol (0,5g)
5ffLQ) Carbon tetrachloride (0.05nQ mol) was added to the middle suspension, and after the reaction started, ether (7,51+LQ) was added.
Add. To the mixture, while refluxing, slowly add an ethanol (3 relative) solution of ethyl-1-butyl dew malonate (3.60 g), further add ether (5 precepts), and reflux for 3 hours to obtain a solution (solution A). . 2-fluoro-3-
Phenyl acrylic acid (mixture of E and Z forms, E:Z-
87:13) (3,10g) of benzene C301111
1) Add thionyl chloride (j, 5mQ) to the solution and heat under reflux for 4 hours. The solution is concentrated under reduced pressure and the residue is dissolved in toluene (30 nQ). The solution is concentrated under reduced pressure to obtain a syrup. The ether of this syrup (2,
5mQ) solution to the solution obtained above (solution A).
The mixture was added dropwise at 150° C., stirred at the same temperature for 1 hour, and heated under reflux for 1 hour.

The mixture is cooled, water (31119) is added, the pH is adjusted to 6 with IN hydrochloric acid and ethyl acetate (20 nQ) is added.

The organic layer is separated, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a syrup. This syrup-like substance was subjected to silica gel (100 g) column chromatography and eluted with chloroform to convert ethyl-butyl-2-(2-
fluoro-3-phenylacryloyl) malonor h(3
, 27g).

IR (film): 1760-1730c
m-1 mass spectrum: 335. 292. 2
85. 262. Ethyl! t-
Butyl-2-(2-fluoro-3-phenylacryloyl)malonate (3,22g) in benzene (100II)
IQ) solution, reflux for 3 hours, and then filter. The filtrate is concentrated under reduced pressure to obtain a syrup. This syrup-like substance was subjected to column chromatography on silica gel (100 g) and eluted with a mixture of ethyl acetate and hexane (5:95).
Ethyl pentenoate (1.59 g) is obtained.

IR (F 4 &): 1745. 1715.
1660-1600 am-1 mass spectrum:
236. 207. 191. 163. 149 Production Example 8 4-Methylthiobenzaldehyde (5.0 g), [)
'[2-Ethoxy-3-(ethoxycarbonyl)allylkotriphenylphosphonium winged yossite (19.6g)
Add sodium ethoxide (2.45 g) to a mixture of ethanol (75 nQ) and stir at room temperature for 5 hours. After ethanol is distilled off, chloroform and water are added, and the chloroform layer is separated, washed with water, dried over magnesium sulfate, and concentrated. The oily residue was treated with dioxane (so+nu) and 0. IN sulfuric acid (40 mg) is added, the mixture is heated at 100° C. for 2 hours, and ethyl acetate and water are added. The organic layer is separated, washed with water, dried and evaporated. The resulting oily residue was applied to a silica gel column chromatograph and eluted with a mixture of n-hexane and ethyl acetate to obtain 3-year-old xo-5-
Ethyl (4-methylthiophenyl)-4-pentenoate (
0.40 g) is obtained.

mp: 59-60°C NMR (CDCl2.l; ): C89,1,85
(Total 3 hours.

t, J=7Hz), 2.50 (3H,s), respectively
, 3.67 (LH, s), 4.25 (2H, q,
J=7Hz>, 6.25-7.70 (6H, m) Manufactured by A Wataru In the same manner as in Production Example 8, the following compound is obtained.

(1) Ethyl 3-year-old xo-5-(2-acetylaminothiazol-5-yl)-4-pentenoate mp:
185-188°C IR (Streak 1-L): 1700. 1625
cTll-1HMR(DMSO-ds,S)'
1-18. (3H9t-9J=7)1z).

2.19 (3H,s), 3.75 (2H,s),
4.10 (2H, q.

J=7Hz>, 6.20-6.58 (LH, m)
, 7.35-7.90 (2H, m) (2) 3-year-old xo-5-[4-(2-tenoylamino)
Ethyl phenyl-4-pentenoate mp: 140-
143℃ IR (KBr): 1715.1660 cm-1H
MR (DMSO-d6.δ): 1.21 (3H,
t, J=71(Z).

3.82 (2H,s), 4.11 (7Hz in 2H,q).

6.63-8.08 (9H, m) 3-year-old 5-(4-dimethylaminophenyl)-4
- ethyl pentenoate (1,5 g) and N.

N-dimethylformamide dimethyl acetal (0
, 91 g) of benzene (7,5 relative) is heated to 70° C. for 2 hours. To this solution was added 4-aminobenzaldehyde-containing ethylene acetal (1.14 g) at room temperature, and then the mixture was stirred at the same temperature for 3 hours. ether (3
0ml) is added to the reaction mixture. The precipitate was collected by filtration, washed with ether, and dried to give 2-[4-(1,3-dioxolan-2-yl)phenylcoaminomethylene-3-
Ethyl oxo-5-(4-dimethylaminophenyl)-4-pentenoate (154 g) is obtained as a solid.

fil: >148°C IR (X di*-4): 1700. 1635.
1600. 1585 cTII-INMR (CD
C13, δ): 1.4 (3H, t, J=7Hz>
, 3.07 (6H,s), 4.12 (4H,s)
, 4.36 (2H, q, J=7Hz).

5.83 (LH, s), 6.7 (2H, d, J=
9Hz), 7.1-7.95 (8H, m), 8.6
(LH, d, , C13Hz), 13.3 (LH,
d.

J=13H2) Production example 11 The following compound is obtained in the same manner as in Production Example 10.

(1) 2-(4-hydroxyphenyl)aminomethylene-3-xo-5-(4-methylthiophenyl)-4-
Ethyl pentenoate mp: 175-177°C IR (KBr): 1700.1618.1600,
1230°1065 cm-' (2) 2-(4-hydroxyphenyl)aminomethylene-3-oxo-5-(2-acetylaminothiazole-
Ethyl 5-yl)-4-pentenoate mp: 258-259°C NMR (DMSO-d6.δ): 1.30 (3H
, t, J=7Hz>, 2.18 (3H, s), 4
．． 14 (2H, q, J=7Hz>, 6.78 (
2H,d.

J=8.5Hz), 7.33 (2H,d, J=8
．． 5Hz).

7.65-7.90 (3H, m), 8.38 (
18, d, J=13Hz).

11.23 (LH, d, J=13Hz) (3) 2-(
4-fluorophenyl)aminomethylene-3-year-old xo-5-[4-(2-tenoylamino)phenyl-ethyl 4-pentenoate mp: 159-161°C NMR (DMSO-ds-1; )' 1.34 <
3H, t, J=6Hz>, 4.25 (2H, qJ=6
Hz), 7.07-8.18 (13H, m>, 8
．． 50 (LH, d, J = 13Hz), 10.39 (
LH,s) Production Example 12 Ethyl 4-fluoro-3-xo-5-phenyl-4-pentenoate (1,55 g) and N,N-dimethylformaldehyde-dimethyl acetal (1,20 ml)
) c7) Heat the benzene (10 mm) # solution at 70-75°C for 1.5 hours and concentrate under reduced pressure to obtain a syrup. Add this syrup-like substance to silica gel (100g)
2-dimethylaminomethylene-4-fluoro-3 was subjected to column chromatography and eluted with a mixture of nibble acetate and hexane (alternating at 20:80 and 50:50).
-Ethyl xoxo-5-phenyl-4-pentenoate (13
5g).

IR (Film): 1695. 1630.
1590-1570 cm-1 HMR (CDCl2.
δ): 1.27 (3H, t, J=7
Hz), 3.01 (6H, broads), 4.
19 (2H, q, J=7Hz), 6.43 (I
H, d, J=22Hz), 7.15-7.45
(5H, m>, 7.72 (IH, s) 19F-NMR (CDCl2-rFA, S):
-26,91 (d.

J=22.3Hz) Mass spectrum: 291. 247 Production Example 13 Ethyl 2-dimethylaminomethylene-4-fluoro-3-year-old xo-5-phenyl-4-pentenoate (0.40g
) and 4-fluoroaniline (0.18 g) in benzene (4-) is stirred at room temperature for one day and concentrated under reduced pressure to give a syrup. Add this syrup-like substance to silica gel (
20g) Column chromatography was performed and eluted with acetic acid ether-hexane mixture (5:95) to obtain 4-fluoro-2-
Ethyl (4-fluorophenyl)aminomethylene-3-year-old xo-5-phenyl-4-pentenoate (0.25g
) I asked Lai.

IR (Film)' 1710-1610. 15
90-1570 cm-119F-NMR (CDCl
2-TFA, δ) Knee 27.4-28.2 (IF.

m), -35,5 to -37,5 (IF, m) Mass spectrum: 357. 336. 308. 28
0 Production Example 14 Ethyl 2-dimethylamitsumeprene-4-fluoro-3-year-old xo-5-phenyl-4-pentenoate (0.44 g
) and 4-hydroxyaniline (0.20 g) in benzene (9), stirred at room temperature for 68 hours and concentrated under reduced pressure to give a syrup. This syrup was subjected to column chromatography on silica gel (25 g) and eluted with an ethyl acetate-hexane mixture (5:95 and 10:90 alternately) to obtain 4-fluoro-2-(4-hydroxyphenyl)amino. Ethyl methylene-3-oxo-5-phenyl-4-pentenoate (0.41 g) is obtained.

mp: 128-130℃ IR (KBr): 1670.1625 crrI''
″119F-NMR (CDCl2-TFA, E)
: -27,12 (d, J = 21.1 Hz), and -27,51 (d, J = 22.3 Hz (ratio 82
:1g>Mass spectrum: 355. 334.
309. 278 Production Example 15 Ethyl 2-dimethylaminomethylene-3-oxo-5-phenyl-4-pentenoate (1,80 g) and 4-fluoroaniline (0,95[) in benzene (20 mm
) The solution is stirred at room temperature for 17 hours. The solution was concentrated under reduced pressure and crystallized from ether to give 2-(4-fluorophenyl)amitumeprene-3-oxo-5-phenyl-4.
- Ethyl pentenoate (1.12 g) is obtained.

mp: 114 (15℃ IR (KBr): 1700.1620.1605
cm-1HMR (DMSO-d6.S): 1.
32 (3H, t, J=7Hz), 4.25 (2H, q
, J=7Hz>, 7.0-8.15 (11)1
．． m), 8.50<LH, dJ=13Hz), 1
2.97 (IH, d, J=13Hz) Mass spectrum 7 339. 293. 262. 2161 and five p-methoxyaniline (1.2g), concentrated hydrochloric acid (3mQ)
Sodium nitrite (1 g
) was added dropwise with stirring at 5°C, and at the same temperature it was heated to 0.
．． After stirring for 5 hours, filter. The filtrate was diluted with ethyl 5-(4-di-1-methyl-deaminophenyl)-3-xo-4-pentenoate (2.1 g) and sodium acetate (2 g) in ethanol (10 mm) and tetrahydrofuran (10 mm).
mm) was added dropwise to the mixed solution at 5°C while stirring, and at the same temperature
Stir for an hour. The precipitate is collected by filtration, washed with water, and dried to give 2-
[Ethyl (4-methoxydiphenyl)hydrazonoco-3-xo-5-(4-dimethylaminophenyl)-4-pentenoate (1.6 g) is obtained.

mp: 136-137°C IR: 1695. 1595.
1580. 1500°1480 cm-1 NMR (DMSO-ds, S)' L-2-1,4
(3H1m), 3.00 (6H,s), 3.75
(3H,s), 4. LO-4,45<2H,m
).

6.73 (2H, d, J=9Hz), 6.95 (
2H, d, J: 9Hz).

7.30-7.65 (6H, m) Mass spectrum: 395 2ξfallen-L 2-[4-(1,3-dioxolan-2-yl)phenylcoaminomethylene-3-oxo-5-( Ethyl 4-dimethylaminophenyl)-4-pentenoate (1.5g)
A solution of N,N-dimethylformamide (1 omn) H is heated to 140°C for 4 hours. The mixture is concentrated under reduced pressure to obtain a syrup. Add syrup to silica gel (75g)
) and eluted with an ethyl acetate-n-hexane mixture (4:1, v/v) to give 1-[4-(1,3-dioxolan-2-yl)phenyl] Ethyl -4-year-old xo-6-(4-dimethylaminophenyl)-1,4,5,6-titrahydronicotinate (0.61 g) is obtained.

mp: 74-88℃ IR (KBr): 1720.1670.1610
cm-1HMR (CDC13,8)' 1.3
3 <3)1. tj=7)1z>, 2-5-3,
5 (2H, m), 2.9 (6H, s), 4.04
(4H, s), 4.25 (2H, q, J=7Hz)
, 5.22 (IH, m), 5.75 (
LH,s).

6.43-7.6 (8H, m), 8.58 (LH
, s) Fu and Sei 1 4-Fluoro-2-(4-fluorophenyl)aminomethylene-3-year-old ethyl 5-phenyl-4-pentenoate (1,20 g) in N,N-dimethylacetamide (
12m) solution at 150-155°C for 6 hours.

and concentrate under reduced pressure to obtain a syrup. This syrup-like substance was subjected to silica gel (50 g) column chromatography, and a mixture of ethyl acetate and hexane (50:50) was used.
Elution was carried out to obtain ethyl 5-fluoro-1-(4-fluorophenyl)-4-year-old xo-6-phenyl-1,4,5,6-titrahydronicotinate (0.29 g).

IR()・rum): 1735. 1690
c+n-'NMR (CDC13, δ): 132 (
3H, t, J=7Hz), 4.26(2)1. q, ni7)1z), 5.1-5.7 (2)1. m), 6
．． 8-7.5 (9H, m), 8.55 (LH, s)
Mass spectrum: 357. 265. A solution of ethyl 4-fluoro-2-(4-hydroxyphenyl)aminomethylene-3-year-old xo-5-phenyl-4-pentenoate (0.70 g) in N,N-dimethylformamide (7-) was prepared at 235 Tue Jl. Heat at 140-145°C for 5 hours,
Concentrate under reduced pressure to obtain a syrup. This syrup-like substance was poured onto a silica gel (40 g) column chromatograph, and methanol-chloroform mixtures (1:99 and 2
;98) to elute with 5-fluoro-1-(4-
Hydroquinphenyl)-4-oxo-6-phenyl-1
, ethyl 4,5,6-titrahydronicotinate (0,2
5g).

mp: 126-129℃ IR (KBr): 1715.1580 cTII-
1HMR(DMSO-d8): 1.20<
38. t, C7Hz), 4.126' (2H, qJ=7Hz), 5.4-6.1 (2H,
m), 6.72 (2H.

d, J=7.5Hz), 7.21 (2H, d, J
=7.5Hz), 7.27(5H,s), 8.
43 <LH,s> Mass spectrum: 355.
335. 310. 263. 233. 205 Example 4 The following compound is obtained in the same manner as in Examples 1 to 3.

(1) 1-(4-fluoro-3-methoxyphenyl)-
4-year-old xo6-(4-dimethylaminophenyl)-1
, ethyl 4,5,6-titrahydronicotinate.

IR (film): 3400. 1725
cm-1HMR (CDCI & ): 1.31
(3t(,t,J=7Hz), 2.5-3.53゛(2H,m>, 2.91 (6H,s), 3.78
(3H, s), 4.26 (2H, q, J=7Hz)
, 5.12 (LH, m), 6.3-7.6 (7
H.

m>, 8.5 (IH,s) (2) 1-(4-fluorophenyl)-4-year-old xo6
-Ethyl phenyl-1,4,5,6-titrahydronicotinate LR (7,4 mu)' 1725. 1675.
1580 aTl-1BMR (DMSO-ds, S
): 1.21 (3H, t, J=7Hz), 4
．． 12 (2H, q, J=7Hz), 5.66 (1)
1. dd, J: 3Hz.

6.5Hz), 7.0-7.6 (9H, m), 8.
60 (LH,s) Mass spectrum: 339.
294. 262. 235(3) Ethyl 1-(2-benzothiazolyl)-4-year-old xo-6-(4-dimethylaminophenyl)-1,4,5,6-titrahydronicotinate NMR (CDC13,8>' 1.38 ( 3H1t
, J near Hz), 2.9 (6H, s), 4.3 (
2H, q, J=7Hz>, 5.7~6.0 (1)
1゜m), 6.62 (2H, d, J=9Hz),
7.19 (2H, d.

J=9)! z), 7.0-8.0 (4H, m),
9.18 <IH, 5) (4) Ethyl 1-(2-thiazolyl)-4-year-old xo-6-(4-dimethylaminophenyl)-1,4°5.6-titrahydronicotinate I
R (7, Lum): 1720. 169 (1-1
660. 1580 cm-'NMR (CDC13,
f; ) ' 1.35 (3H1t, J=7
Hz), 2.5-3.5 (2H, m), 2.9
(6H, s), 4.3 (2H, q, J=7Hz)
.

5.45-5.65 (LH, m>, 6.59
(2H, d, J=9Hz).

6.93 (LH, d, J=3Hz), 7.1
(2H, d, J=9Hz).

7.42 (LH, d, J: 3Hz), 9.1
(LH,s) Mass spectrum; 371 (M”
), 325 (M”-46>(5) 1-(4-pyridylmethyl)-4-oxo-6-(4-dimethylaminophenyl)-1°4.5.6-titrahydronicotinic acid ether NMR ( CDCl2.δ): 1.33 (
3H, tJ=7Hz), 2.7-3.1 (2H, m)
, 2.94 (6H,s), 4.3 <2H,q,
J=7Hz).

4.3-4.7 (3H, m), 6.65 (2H,
dJ=9Hz), 6.9 to 7.2 (4)1. m),
8.43 (IH,s), 8.6~8.75 (2
H.

m) (6) Ethyl 1-[2-(3,4-dimethoxyphenyl)ethyl-4-oxo-6-(4-dimethylaminophenyl)-1,4,5,6-titrahydronicotinate IR (film) : H2S, 1660.
1600 cm-1BMR (CDCl2.δ):
13 (3H, t, J=7Hz), 2.5-3.1(
2H, m), 2.93 (6H, s), 3.2
3-3.6 (2B, m).

3.8 (3H, s), 3.83 (3M, s),
4.22 (2H, q.

J=7+(z), 4.3-4.57 (2H, m>
, 6.47-7.13 (7H.

m), 8.11 (IH, 5) (7) Ethyl 1-(4-bitroxyphenyl)-6-(4-methylthiophenyl)-4-oxo-1°4.5.6-titrahydronicotinate mp: 80-90°C NMR (DMSO-ds, 8)' 1.20 (3
H9t-9J=7Hz), 2-43(3H,s),
3.07-3.50 (2H, m), 4.08 (2
H,q.

J=7Hz>, 5.50 (IH, m), 6.70
(2H, d, J=8Hz>.

7.1077.30 (7H, m), 8.27,8.
43 (Total IH.

5 each) (8) 1-(4-hydroxyphenyl)-6-(2-acetylaminothiazol-5-yl)-4-oxo-1
,4,5,6-ethyl titrahydronicotinate IR(xd9-yl)' 3180. 1720.
1625. 1585°1180 cm-1 (9) 1-(4-fluorophenyl)-6-[4-(2
-tenoylamino)phenyl]-4-year-old xo1,4.
5. Ethyl 6-titrahydronicotinate mp: 218-220°C (10) 1-(4-methoxyphenyl)-3-ethoxycarbonyl-4-year-old xo-6-(4-dimethylaminephenyl)-1,4, 5,6-titrahydroviridazine IR (Xdi1-L): 3400. 1730.
1690. 1615 cm-'NMR (DMSO
-d δ): 1.23 (3)1. t, J=7)
1z), 2.806° (6H, s), 3.15-3.55 (2)1. m)
, 3.70 (3H,s).

4.15 (2H, q, J=7Hz), 6.03 (
LH, m), 6.60 (2H, d, J=9Hz),
6.80-7.00 (4H, m), 7.40 (2H
, d, J=9Hz) Base layer ■1 1-[4-(1,3-dioxolan-2-yl)phenyl]-4-year-old xo6-(4-dimethylaminophenyl)-1,4,5,6 -ethyl titrahydronicotinate (
o, ssg) in benzene (10 mQ) solution, 2.3-
dichloro-o-5,6-dicyano 1,4-benzoquinone (
0.31g) of benzene (1QmQ) Nakano suspension
Add dropwise over 5 minutes at ℃. The mixture was stirred at 80° C. for 20 minutes and concentrated under reduced pressure to obtain a syrup. Mix syrup with chloroform (30mfl) and water (30ffl).
Add to the mixture with Q). The mixture is adjusted to pH 7.5 with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to give 1-[4
-(1,3-dioxolan-2-yl)phenyl2-4
-oxo-6-(4-dimethylaminophenyl)-1,
Ethyl 4-dihydronicotinate (0.77 g) is obtained as a solid.

nnp: 190-193℃ (decomposition) IR (X di”-
') ' 1730. 1610 cm-1NM
R(DMSO-9, f; > : 1.23 <3H,
t, J near Hz>, 2.85 (6) 1. s), 3
．． 97 (4H,s), 4.2 <2H,q,
J=7Hz).

5.7 (LH, s), 6.27 (IH, s),
6.52 <2H, d.

J=9Hz), 7.0 (2H, d, J=9Hz),
7.38 (4H, s).

8.21 (LH,s) Example 6 Ethyl 5-fluoro-1-(4-fluorophenyl)-4-year-old xo-6-phenyl-1,4,5,6-titrahydronicotenoate (0.35 g A suspension of 2.3.5.6-tetrachloro-1,4-benzoquinone (1,00g) in dioxane (lsmIl) is added dropwise to a solution of 2.3.5.6-tetrachloro-1,4-benzoquinone (1,00g) in dioxane (lsml) at 100-105°C over 10 minutes. 1 of the mixture
Stir for 1 hour at 00-105°C and concentrate under g pressure to obtain a syrup. This syrup-like substance is mixed with chloroform (
40 dl) and water (40 m+2), and the pH was adjusted to 75 with a saturated aqueous solution of sodium bicarbonate. The organic layer is separated, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a solid.

This solid was subjected to silica gel (50 g) column chromatography, and a methanol-chloroform mixture (2:98) was used.
Elution was carried out to obtain ethyl 5-fluoro-1-(4-fluorophenyl)-4-xo-6-phenyl-1,4-dihydronicotinate (0.22 g).

mp: 288-290℃ IR□CBr)' 1725.1638.1610
a'n-n-1N (DMSO-ds-8)' 1.
26 (3H1t, J=7Hz>, 4.24(2H,q
, J=7Hz), 6.8-7.7 (9H, m),
8.24 (IH, s) 19F-NMR (DMSO-ds-TFA, S)
Knee 33.2-33.6 (IF, m), -66,5
1 (IF, s) mass spectrum: 355. 31
0. 282. 265 Example 7 The following compound is obtained in the same manner as in Examples 5 and 6.

(1) 1-(4-fluoro-3-methoxyphenyl)-
4-year-old xo6-(4-dimethylaminophenyl)-1
, ethyl 4-dihydronicotinate mp: 212-217°C (decomposition) IR<sujimil): 1730. 1640.
1610. 1580 am-INMR (Dt'1
SO-ds, 8) 't, 26 (3H1t, J
=7Hz), 2.9(6H,s), 3.76(
3H, s), 4.22 (2H, q, J=7Hz)
.

6.2 (LH,s), 6.3-7.5 (7)1
．． +n), 8.22 (IH, 5) (2) 1-C
4-(1,3-dioxolan-2-yl)phenyl-4-oxo-6-(4-dimethylaminophenyl)-1
, 4-dihydronicotinic acid IR (sujimil): 1725. 1635.
1610 cm-1(3)1-(4-fluoro-3
-methoxyphenyl)-4-year-old xo6-(4-dimethylaminophenyl)-1,4-dihydronicotinic acid mp
: 170-176℃ IR (Suji Meal): 1730. 1635.
1615 cm-1(4) 1-(4-formylphenyl)-4-year-old xo6-(4-', ;methylaminophenyl)-1,4-dihydronicotinic acid IR (Xdi5-L): 1725 ．． 1705.
1635. 1610 cm-1<5)1-(4-
hydroxyiminomethylphenyl)-4-oxo-6-
(4-Dimethylaminophenyl)-1,4-dihydronicotinic acid IR (sudil): 1730. 1640.
1615 rho1(6)1-(4-fluoro-3-
Hydroxyphenyl)-4-oxo-6-(4-dimethylaminophenyl)-1,4-'; Hydronicotinic acid mp: 250°C IR (Sujol): 1730. 1640.
1610 am-'(7) 5-fluoro-1-(
Ethyl 4-hydroxyphenyl)-4-year-old xo-6-phenyl-1,4-dihydronicotinate mp: 290°C (decomposition) IR (KBr): 1730.1635.1600
cm-'NMR (DMSO-9, S): 1.26
(3H, t, J=7Hz), 4.22 (2H, q,
J=7Hz), 6.59 (2H, d, J=8.7H
z), 7.14 (2H, d, J = 8.7) 1z),
8.29 (51(,s), 8.20(1)!,s) 19F-NMR (DMSO-d6-TFA, δ):
-66,30(s) Mass spectrum: 353.
308. 281. 264(8) 1 = (4-fluorophenyl)-4-year-old xo-6-phenyl-1,4
-Ethyl dihydronicotinate mp: 243-245°C IR (KBr): 1730.1645.1610.
1590 cm''INMR (CF3CO2H-8)
' 1.50 (3H9?-1J near Hz>,
4.68 (2H, q, J=7Hz>, 7.0-7.
6 (9H, m>, 7.58 (LH, s), 9
．． 13 (IH,s) mass spectrum: 337.
293. 265 (9>1-(2-benzothiazolyl)-4-year-old xo-6-(4-dimethylaminophenyl)
Ethyl-1,4-dihydronicotinate NMR (CDC13,S)' 137 (3H1t
, J=71(z>,2.96(6H,s), 4.39
(2H, d, J=7Hz), 6.53 (LH, s
).

6.57 (2H, d, J=9Hz), 7.15 (
2H, d, J = 9Hz>.

6.9-8.2 (4)1. m), 8.88 (IH
, 5) (10) Ethyl 1-[4-(2-methoxyethoxymethoxy)phenyl-4-oxo-6-(4-dimethylaminophenyl)-1,4-dihydronicotinate IR (Xdi1-L) '1715. 1695.
1650. 1600 am-'NMR (CDC1
3,l; ) ' 1.36 (3H1t, J=7Hz
>, 2.92 (6) 1. s), 3.34 (3Ls)
, 3.42-3.62 (2H, m).

3.62-3.9 (2H, m), 4.35 (2H
, q, J=7Hz>.

5.22 (2H,s), 6.46 (2)1. d,
J=9Hz), 6.55<LH,s), 6.92
(2H, d, J=9Hz), 6.99 (4H, s)
.

8.26 (LH,s) Mass spectrum: 466 (M”) (11)1
-[4-(2-methoxyethoxymethoxy)phenyl]
-5-Methyl-4-oxo-6-(4-dimethylaminophenyl)-1°4-dihydronicotinate ethyl IR: 1730. 1690.
1630-1620°1590 country-1 NMR (CDC13,S)' 137 (3H,t
, J=7Hz), 191(3H,s), 2.90
(6H,s), 3.32 (3H,s), 3.4-
3.58 (2)1. m>, 3.63-3.83 (
2H, m), 4.35 (2H, q, J=7Hz),
5.17 (2H,s>, 6.47 (2)
1. d.

J=9Hz), 6.81 (2H, d, J=9Hz)
, 6.89 (2H,s).

6.91 (2H, s), 8.22 (LH, s) Mass spectrum: 480 (M”) (12) 1-
1.29
3H, tJ=7Hz), 2.956' (6H,s), 4.29 (2H,q,J=7H
z), 6.32 (LH,s).

6.68 (2H, dJ=9Hz), 7.14
(2H, d, J=9Hz).

7.74 (2H,s), 8.33 (1)1
．． s), 8.58 (1) 1.5) (13) 1-
Ethyl (4-pyridylmethyl)-4-year-old xo-6-(4-dimethylaminophenyl)-1,4-dihydronicotinate IR (Sujimil)' 1725. 1710.
1690 cm-1 HMR (CDCl2.S)
' 1.35 (3H1t, J near Hz), 2.96<
6H, s), 4.32 (2H, q, J near Hz>,
4.97 (2H, s).

6.37 (LH,s), 6.35-7.1 (6H
, m), 8.1 (IH.

s), 8.3-8.6 (2)1. m) (14) 1-
[2-(3,4-dimethoxyphenyl)ethylco4-
Oxo-6-(4-dimethylaminophenyl)-1,4
-Ethyl dihydronicotinate IR (Film): C730,1635,16
15cTn-1HMR (CDCl2.δ):C38(
38,t, J=7Hz), 2.56-3.2 (2H
, m), 3.02 (6H,s), 3.72 (3
H,s).

3.82 (3H, s), 4.05 (2H, m>,
4.36 (2H, q.

J=7)1z), 62-6.9 (3H, m), 6
．． 38 (LH,s).

6.72 (2H, dJ=9Hz>, 7.09 (2
H, d, J = 9Hz>.

8.08 (LH,5) (15) 1-'(4-hydroxyphenyl)-6-(
Ethyl 4-methylthiophenyl)-4-oxo-1,4-dihydronicotinate mp: 193°C IR (streak, -4): 1698. 1630
am-1HMR (DMSO-ds, l; )' 1
．． 25 (3H9t-1J=7Hz), 2-43 (3H
,s), 4.21 (2t(,q, J near Hz>,
6.23 (IH, s).

6.68 (2H, d, J=8.5Hz), 7.02
-7.30 (6H, m).

8.17 (IH,s), 9.87 (IH,
Broad S) <16) 1-(4-hydroxyphenyl)-6-(2-acetylaminothiazol-5-yl)
-4-year-old xo-1,4-dihydronicotinate ethyl mp; 310-312°C IR (Sugital): 1705. 1625.
1570. 1235 Low INMR (DMSO-
ds, S )' 1.23 (3H1t, J=7Hz
), 2.10<3H,s), 4.22 (2H,qJ
=7Hz), 6.54 <IH,s).

6.82 (2H, dJ=8.5Hz), 7.30
(2)1. d.

J=8.51(z), 7.47(LH,s), 8
．． 26 (IH,5)(17)1-(4-fluorophenyl)-6-[4-(2-tenoylamino)phenyl]
-4-year old Kin-1.4-; Hydronicotinic acid ethinosilicate IR (sujis-ru)' 1735. 1655.
1635 cm-1 HMR (DMSO-ds, 6
)' 1.25 (3H9t, J=7Hz>, 4.
22 (2H, q, J = 71 (z), 6.35 (LH
, s), 7.08-8.00 (11H, m),
8.25 (LH,5)(18)1-(4-fluorophenyl)-6-(4-methanesulfonylphenyl)-4
-Ethyl 1,4-dihydronicotinate alp: 235-240°C IR (suji 1-l): 1725. 1645
am-1HMR (DMSO-da, 8)' 1.
27 (3H1t, J=6-5Hz).

3.22 (3H, s), 4.22 (2H,
q, J=6.5Hz), 6.38(LH,s),
7.04-7.90 (8H, m), 8.28 (L
H,5)(19)1-(4-methoxyphenyl)-3-
Nitoxycarbonyl-4-okine-6-(4-dimethylaminophenyl)-1,4-dihydropyridazine mp: 112-113°C IR (sudital): 3400. 1720.
1680. 1615 cm-INMR (DMSO
-ds, 8)' 1.25 (3H1t, J=7)
1z), 2-83 (68,s), 3.70 (3H
,s), 4.26 (2H, qJ=7Hz).

6.45-7.30 (9H, m) Tue] U1 1-[4-(2-methoxyethoxymethoxy)phenyl]-5-methyl-4-oxo6-(4-dimethylaminophenyl)-1,4 -Ethyl dihydronicotinate (0
, 3g) and anisole (o, z5mx) in trifluoroacetic acid (1) is refluxed for 3 hours and concentrated under reduced pressure. Methanol (3 mQ) and IN aqueous sodium hydroxide solution (3%) were added to the residue, stirred at room temperature for 3 hours, and adjusted to pH 6 with acetic acid. The precipitate was collected by filtration to obtain ni(4-hydroxyphenyl)-5-methyl-4-hydroxy-6-(4-dimethylaminophenyl)-1,4-dihydronicotinic acid (0,104 g).

IR<Stripe 1-L)' 1610 cm-1H
MR (DMSO-da, δ): 1.84 (3H,
s), 2.87 (6H, s), 6.55 (2H,
d, J=9Hz), 6.6 (2H, d.

J=9Hz), 6.96 (2H, dJ=9Hz>,
7.13 (2H, d.

J=9Hz), 8.36 (LH,s) Example 9 1-[4-(1,3-dioxolan-2-yl)phenyl-4-oxo-6-(4-dimethylaminophenyl)-1, Ethyl 4-dihydronicotinate (0.7g)
A mixture of IN* sodium oxide aqueous solution (7 mQ) and methanol (7 mQ) is stirred at room temperature for 3 hours.

Methanol is distilled off to obtain an aqueous solution. This aqueous solution was adjusted to pH 6 with acetic acid to form a precipitate. The precipitate was collected by filtration to give 1-[4-(1,3-dioxolan-2-yl)phenyl 4-year-old xo6-(4-dimethylaminophenyl)-1,4-dihydronicotine ec0.373 g).
is obtained as a solid.

mp: 171-175°C IR (sugital): 1725. 1635.
1610 cm-1Nl-IR (DMSO-da,
ε)' 2.94 (6H, s), 4.05 (4H
,s), 5.76 (1)1. s), 6.45 (
2H, dJ=9Hz).

6.76 (IH,s), 6.90 (2)! ,d
, J=9Hz), 7.13(2H,d, J=9Hz
), 7.46 (2H, d, J=9Hz), 8
．． 56 (IH, s) Mass spectrum: 406 (M”), 36
2 (M''-44) 9 animals per pot The following compound was obtained in the same manner as in Example 9.

(1) 1-(4-fluoro-3-methoxyphenyl)-
4-year-old xo6-(4-dimethylaminephenyl)-1
,4-dihydronicotinic acid mp: 170-176°C IR〈Sva-L): 1730. 1635.
1615 CI'll11-1N (DMSO-d
s. δ>: 2.88 (6H, s), 3.76 (
3H, s), 6.4-7.6 (8H, m), 8.
65 (LH,s) Mass spectrum: 382
(M”), 338 (M”-14) (2) 1-(
4-formylphenyl)-4-dihydronicotinic acid IR<Zdia4)2 1725. 1705. 1
635. 1610 aT+-'<3)1-(4-hydroxyiminomethylphenyl)-4-year-old xo6-(
4-dimethylaminophenyl)-1,4-dihydronicotinic acid IR (Sujor): 1730. 16
40. 1615 cm-1(4) 1-(4-fluoro-3-hydroxyphenyl)-4-year-old xo6-(4
-dimethylaminophenyl)-1,4-dihydronicotinic acid mp: 250°C IR (Xsilol): 1730. 1640.
1610 Cm-'(5)5-fluoro-1-(4-
fluorophenyl)-4-year-old xo-6-phenyl-1,
4-dihydronicotinic acid mp: 188-190°C IR (KBr): 1730.1630 an-' mass spectrum: 327. 310. 299.
283(6) 5-fluoro-1-(4-hydroxyphenyl)-4-year-old xo-6-phenyl-1,4-dihydronicotinic acid mp: >300°C IR (KBr): 1640-1595 c+n-'
Mass spectrum: 325. 308. 281.
214(7) 1-(4-fluorophenyl)-4-year-old xo-6-phenyl-1,4-dihydronicotinic acid mp: 217-218°C IR (KBr): 1710.1630 am-1N
MR(CF3CO2H1S)' 7.0-7.7
(9N1m), 7.66 (IH, s), 9.27
(LH, s) Mass〈Sctor: 310. 29
4. 265. 248(8) 1-(2-benzothiazolyl)-4-year-old xo-6-(4-dimethylaminophenyl)-1,4-dihydronicotinic acid IR (X dial)' 1730. 1630.
1610 cm −1 NMR (DMSOds, 8
)' Z-9 (6H9s), 6.63 (2H1d.

J=9Hz), 6.72 (LH,s), 7.22
(2H, dJ=9Hz).

7.4-7.6 (2H, m), 7.9-8.15
(2H, m), 8.97<IH, s) Mass spectrum: 391 (M”), 34
7 (M”-44) (9) 1-[4-(2-methoxyethoxymethoxy)phenyl]-4-year-old xo6-(4
-dimethylaminophenyl)-1,4-dihydronicotinic acid IR (X”i-l): 1725. 1640.
1615 cm-1 NMR (DMSO-ds, l;
)' 2.87 (6H9s), 3.18 (3H,s
), 3.3-3.55 (2H, m), 3.6-3
．． 8 (2H, m), 5.26 (2H, s), 6.
56 (2H, d, J-9) 1z).

6.75 (1)1. s), 7.02 (2H, d,
J=9Hz>, 7.05 (2H, d, J=9Hz),
7.38 (2H, d, J=9Hz>, 8.49(
LH, 5) (10) 1-(2-thiazolyl)-4-year-old xo 6-(
4-dimethylaminophenyl)-1,4-dihydronicotinic acid mp: 246.5-248.5°C IR(X4; Yol>: 1730. 1640.
1610 CIClTl-1N (DMSO-ds
, δ): 2.92 (6H,s), 6.64 (
2H,d.

J=9)1z), 6.71 (IH,s), 7.1
4 (2H, d, J=9Hz).

7.71 (1)1. d, J: 3Hz>, 7.76
(IH, d, J=3Hz).

8.77 (IH,s) Mass spectrum: 341 (M”), 29
7 (M”-44>(11)1-(4-pyridylmethyl)-4-year-old xo6-(4-dimethylaminophenyl)-1,4-dihydronicotinic acid mp: 219-221°C IR (Z a-L)' 1715. 1630.
1610 cm-1 NMR (DMSO-da, 8
)' 2.92 (6H5s), 5.44<28. s
), 6.6 (IH,s), 6.65 (2H,d
, J=9Hz).

6.87 (2H, dJ=6Hz), 7.14 (2
)! , d, J=9H2).

8.42 (2H, bd, J=6Hz), 8.9 (
IH,s) Mass spectrum: 349 (M”)
, 305 (M"-44) (12) 1- [
2-(3,4-dimethoxyphenyl)ethyl]-4-oxo-6-(4-dimethylaminophenyl)-1,4-
Dihydronicotinic acid IR (suji i4): 1705. 1635.
1610 am-'NMR (DMSO-46,8)
:2.7 (2H, t, J=6Hz>, 3.0<61
．． s), 3.6 (3H, s), 3.7 (3H,
s), 4.28 (2H, t, J=6Hz), 6.3
-6.8 (3H, m>, 6.48 (LH, s),
6.78 (2H, d, J=9Hz), 7.2
4 (2H, d.

J=9Hz), 8.62 (LH,5)(13)1-
(4-Hydroxyphenyl)-6-(4-methylthiophenyl)-4-oxo-1,4-dihydronicotinic acid mp: 210-212°C IR (suji meal): 1690. 1625.
1255 cm-”NMR (DMSO-ds, S)
'2-42 (3H1s), 6.55-6.85<
48. m), 6.95-7.30 (6H, m),
8.45 (LH,s).

9.87 (LH,5) (14>1-(4-hydroxyphenyl)-6-(2-
acetylaminothiazol-5-yl)-4-year-old xo-1,4-dihydronicotinic acid mp: >300°C Engineering'fi (suji 1-4): 1630C
TCTll-1N (DMSO-ds, S)' 2
-13 (3H1s >, 6-85 (2H1d.

J=8Hz), 7.07 (LH,s), 7.35
<2H, dJ=8Hz>.

7.77 (IH,s), 8.43 (IH,s)<
15) 1-(4-fluorophenyl)-6-[4-(2
-tenoylamino)phenyl]-4-oxo1,4-
Dihydronicotinic acid mp: 260-270°C (decomposition) IR (X-di-&)' 1735. 1665.
1635 an-'NMR (DMSO-da, S
) =6-74-8.48 (13H, m)<16>1
-(4-fluorophenyl)-6-(4-methanesulfonylphenyl)-4-oxo-1,4-dihydronicotinic acid mp: 272-274°C IR (KBr): 1720.1635.1150
cm-1NMR (DMSO-9,8): 3.21
(3H, s), 7.02-8.05 (10H, m)
, 8.30 (LH,5)(17)1-(4-methoxyphenyl)-3-carboxy-4-xo6-(4
-dimethylaminophenyl)-1,4-dihydropyridazine mp: 224-225°C (decomposition) IR<sujimir): 2700-2550.
1725. 1600°1520 cm-1 NMR (DMSO-ds, S)' 2.80 (6
H1s), 3.70 (3H,s), 6.50 (
2H, d, C9Hz>, 6.75-7.15 (5H
, m), 7.20 (2H, d, J=9Hz) (1
8) 1-(4-methoxyphenyl)-3-carboxy-
4-year-old xo6-(4-dimethylaminophenyl)-1
, 4,5,6-titrahydroviridazine mp: 140-142°C (decomposition) IR (stinol): 2600-2700.
1730. 1600. 15201500 cm-1 NMR (DMSO-da, δ): 2.83 (6H
,s), 3.15-3.80(2H,m), 2.8
5 (3H, s), 6.09 (LH, d, J=6H
z).

6.55-7.00 (6H, m), 7.45 <2
H, d, J = 9 Hz) Example 11 1-[4-(1,3-dioxolan-2-yl)phenyl-4-oxo-6-(4-dimethylaminophenyl)-1,4-dihydronicotinic acid (0,3 g) in a mixture of noacetone (5 mA), water (Q, 5 mQ) and p-toluenesulfonic acid-hydrate (0,014 g) is refluxed for 4 hours. The mixture is concentrated under reduced pressure to obtain a residue. Wash the residue with water (101111). The precipitate was collected by filtration, washed with water, and dried to give 1-(4-formylphenyl)-4-oxo-
6-(4-dimethylaminophenyl)-1,4-dihydronicotinic acid (0,186 g) is obtained.

mp: 205-208°C IR (streak 1-L): 1725. 1705.
1635. 1610 ClTl'NMR (DMS
O-da, E): 2.86 (6B, s), 6-
52 (2H1d.

J=9Hz), 6.76 (LH,s), 7
．． 02 (2H, d, J=9Hz>.

7.6 (2H, d, J=9)1z), 7.91
(2H, d, J=9Hz).

8.54 (LH,s) Mass spectrum: 362 (M”), 31
8 (M-44) Table fi tsubo 1-(4-formylphenyl)-4-oxo-6-(4
-dimethylaminophenyl)-1,4-dihydronicotinic acid (0,5 g) in sodium hydroxide (0,055 g)
Hydroxylamine hydrochloride (0,096 g) was added to a solution of a mixture of 10 and water (10 relatives) at room temperature, and then the mixture was stirred at the same temperature for 1 hour.

The reaction mixture is adjusted to pH 6 with acetic acid to form a precipitate. The precipitate was collected by filtration and 1-(4-hydroxyiminomethylphenyl)-4-oxo-6-(4-dimethylaminophenyl)-1,4-dihydronicotine # (0.46 g
).

mp: 165-173°C IR (X di9-l)' 1730. 1640.
1615 cm-1HMR (DMSO-ds, S
)' 2.78 (6)1. s), 6.55 (21
(,d.

J=9Hz), 6.75 (LH,s), 7.
05 G2H, d, J=9Hz).

7.4 (2H, dJ=9t(z), 7.62
(2H, d, J=9Hz).

8.13 (LH,s), 8.51 (IH,s
) Mass spectrum: 377 (M”), 3
59 (M-18).

333 (M"-44) Tu"U" 1-(4-fluoro-3-methoxyphenyl)-4=oxo-6-(4-dimethylaminophenyl)-1,4-
dihydronicotinic acid (0.37 g) in methylene chloride (3
, 7ml) solution, boron tribromide (0.97g) (7ml) solution.
) A solution of methylene chloride (3.87 mfl) is added dropwise at 5° C. over 5 minutes. The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure to obtain a residue. Dissolve the residue in ice water and dilute the solution with 4N
11 tL of sodium hydroxide aqueous solution to form a precipitate. The precipitate was collected by filtration and 1-(4-fluoro-3-hydroxyphenyl)-4-
Dimethylaminophenyl)-1,4-dihydronicotine@ (0,345 g) is obtained as a solid.

mp: 250°C IR: 1730. 1640.
1610 crn″″INMR(DMSO-da,
S): 2.89 (6H1s), 6-25-7-7
5 (7H, m>, 8.45 (LH, s), 9.0
7 (LH,s) Mass spectrum: 368 (
M”), 324 (M-44) Example 14 1-[2-(3,4-dimethoxyphenyl)ethyl]-
4-year-old xo6-(4-dimethylaminophenyl)-1
,4-dihydronicotinic acid were reacted in the same manner as in Example 13 to give 1-[2-(3,4-dihydroxyphenyl)ethyl-4-oxo-6-(4-dimethylaminophenyl)-1,4- Dihydronicotinic acid is obtained.

IR (Suji”) ' 1730. 1640. 1
615 cTIl-1HMR (DMSO-d6.δ)
: 2.56 (2H, m), 2.98 (6) (,
s), 4.22 (2H, m), 6.0-6.65
(3H, m).

6.5 (LH,s), 6.78 (2H,d,,C
9) 1z), 7.26 (2H, d, J=9) 1z),
8.61 (IH,s) Mass spectrum: 39
4 (M”), 376 (M”-18).

350 (M”-44) Example 15 1-(4-methoxyphenyl)-3-carboxy-4-
6-(4-dimethylaminophenyl)-1,4
-Dihydropyridazine was reacted in the same manner as in Example 13, and 1-(4-hydroxyphenyl)-3-carboxy-
4-okine-6-(4-dimethylaminophenyl)-1
, 4-dihydropyridazine is obtained.

IR (Suji Meal): 3200-3500.
2500-2600°1610-1600.1590.
1500 cm-1 HMR (DMSO-ds, l;
): 2-90 (6H,s), 6.45-
6.75 (51, m), 6.95 (4H, d, J:
9Hz), 10.05 (IH, Broad S) 1-(4-methoxyphenyl)-3-carboxy-4-
Oxo-6-(4-dimethylaminophenyl)-1,4
,5,6-titrahydropyridazine were reacted in the same manner as in Example 13 to give 1-(4-hydroxyphenyl)-3-
Carboxy-4-year-old xo-6-(4-dimethylaminophenyl)-1,4°5,6-titrahydroviridazine is obtained.

IR (striped seal): 3270. 2600-
2700. 1715. 1630°1600, 152
0.1500 cm-1HMR (DMSO-ds, S)
' 2-83 (6H2s), 3.10-3.50 (
2H, m), 6.0 (LH, d, J: 6Hz),
6.50-6.95 (6H, m), 6.33 (2H
, dJ=9Hz)
Ethyl 4-dimethylaminophenyl)-1,4゜5.6-titrahydronicotinate and sodium hydride (6
A solution of 0% suspension in mineral oil, 0.076 g) in tetrahydrofuran (LQmll) was stirred at 0°C for 1 hour, and 2-
Methoxyethoxymethyl chloride (0.39 g) was added and the mixture was stirred at room temperature overnight and then concentrated under reduced pressure to obtain a syrup. This syrup-like substance was mixed with ethyl acetate (20ml
) and water (20 mQ). The organic layer is separated, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was applied to a silica gel (35 g) column chromatograph and eluted with chloroform to give 1-[4-(2-methoxyethoxymethoxy)phenylcol-oxo-6
-(4-dimethylaminophenyl)-1,4,5,6-
Ethyl titrahydronicotinate (0.59 g) is obtained.

NMR (CDCl2.l; ): 1.33 (3
H, t, J=8Hz), 2.9 (6H, s), 3.
35 <3H,s>, 3.4-4.0 (4H,m)
.

4.27 (21(, q, J: 8Hz), 5.0-5
．． 3 (IH, m), 5.22 (28, s), 6.
58 (28, d, J: 8Hz), 7.02 (4H
,s).

7.03 (2H, d, J-8Hz>, 8.52 (
LH, 5) IR (film): 1720. 1
680-1660. 1615゜1585 cm Mass spectrum: 468 , the mixture is stirred for 30 minutes at the same temperature. 1-[4-(2-methoxyethoxymethoxy)phenylcol-oxo-6-(4-dimethylaminophenyl)-1,4,5,6- A solution of ethyl titrahydronicotinate (1 g) in anhydrous tetrahydrofuran (5 mQ) was added dropwise at -70°C over 10 minutes, and the reaction mixture was stirred at the same temperature for 40 minutes.
, 45 g) was added at -70°C, stirred at the same temperature for 1.5 hours, stirred at room temperature for 2 hours, and then concentrated under reduced pressure to obtain a syrup-like product. This syrup is added to a mixture of ethyl acetate (20 mL) and water (20 mL), and the organic layer is separated, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a syrup. Add this syrup-like substance to silica gel (30g
) on a column chromatograph and eluted with a mixture of ethyl acetate and n-hexane (3:1) to obtain 1-[4-(2-
methoxyethoxymethoxy)phenyl-4-oxo-5-methyl-6-(4-dimethylaminophenyl)-1
, ethyl 4,5,6-titrahydronicotinate (0,2
8g) is obtained.

IR (Stripe a-L): 1725. 1670.
1615 cm-1HMR (CDCl2.δ):
133 (3H, t, J=7Hz), L, 41 (3
)1. s), 2.9 (6H,S), 3.35 (
3H,s), 3.45-3.6 (2H,m),
3.65-3.86 (2H, m), 4.26
(2H, q, J=7Hz), 4.63-4.76
(IH, m>, 5.22(2)1.5), 6.
57 (2H, d, J: 9Hz), 7.0 (2H
,d.

J=9Hz), 7.02 (2H,s), 7.
03 (2H, s).

8.48 (LH, 9)

Claims (1)

[Claims] General formula: ▲Mathematical formula, chemical formula, table, etc.▼ [In the formula, R^1 is a carboxyl group or a protected carboxy group, R^2 is hydrogen, halogen or lower alkyl group, R^ 3
is a phenyl group optionally substituted with an appropriate substituent, or a heterocyclic group substituted with a protected amino group, R^4 is a phenyl group optionally substituted with an appropriate substituent, an appropriate substituent a phenyl (lower) alkyl group, a heterocyclic group, or a heterocyclic (lower) alkyl group that may be substituted with a group, Z is N or CH, and (2) represents a single bond or a double bond, respectively. Novel heterocyclic compounds and their salts.