4-oxo-1,4-dihydronicotinic acid derivatives, salts thereof, and antibacterial agents containing the same

This invention relates to a novel 4-oxo-1,4-dihydronicotinic acid derivative ##STR1## or a salt thereof, wherein R.sup.1 is hydrogen or carboxyl-protecting group; PA1 R.sup.2 is substituted phenyl and naphthyl, or a substituted or unsubstituted heterocyclic group; and PA1 R.sup.3 is haloalkyl, aminoalkyl, or substituted or unsubstituted alkenyl, phenylalkenyl, naphthylalkenyl, phenylalkyl, naphthylalkyl, phenylalkynyl, naphthylalkynyl, heterocyclic alkyl, heterocyclic alkenyl, phenyl, naphthyl, cycloalkyl, cycloalkenyl, carboxylic acyl, iminoalkyl, heterocyclic or bridged hydrocarbon, which has a broad antibacterial spectrum and a low toxicity, and are useful for treatment of diseases of human beings and animals, to a process for producing the same and to an antibacterial agent containing the same.

This invention is further explained in more detail below referring to 
Referential Examples, Examples and Preparation Examples. 
REFERENTIAL EXAMPLE 1 
In 20 ml of methanol were dissolved 1.6 g of benzo[b]thiophene-2-aldehyde 
and 5.1 g of [2-methoxy-3-(methoxycarbonyl)allyl]triphenylphosphonium 
bromide, and to this solution was added dropwise 2.1 g of a 28% by weight 
solution of sodium methoxide in methanol with stirring at room temperature 
over 10 minutes. This mixture was further reacted at the same temperature 
for 20 minutes, and the solvent was then removed by distillation under 
reduced pressure. To the residue was added 20 ml of water, and the 
resulting mixture was extracted with 20 ml of chloroform. The extract was 
dried with anhydrous magnesium sulfate and the solvent was removed by 
distillation under reduced pressure. The residue was purified by a column 
chromatography (Wako Silica Gel C-200; eluent: benzene/n-hexane (3:1 by 
volume) mixture) to obtain an oily substance. This oily substance was 
dissolved in 12 ml of dioxane, and to the resulting solution was added 12 
ml of 0.1N sulfuric acid. The resulting mixture was subjected to reaction 
at 100.degree. C. for 1.5 hours. This reaction mixture was then cooled to 
room temperature and 20 ml of water was added thereto, after which the 
precipitated crystals were collected by filtration. These crystals were 
washed with water and then dried to obtain 1.1 g of methyl 
5-(2-benzo-[b]thienyl)-3-oxo-4-pentenoate having a melting point of 
105.degree.-107.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1625. 
The compounds shown in Table 3 were obtained in the same manner. 
TABLE 3 
__________________________________________________________________________ 
R.sup.3 CHCHCOCH.sub.2 COOCH.sub.3 
R.sup.3 R.sup.3 R.sup.3 
__________________________________________________________________________ 
##STR223## 
##STR224## 
##STR225## 
##STR226## 
##STR227## 
##STR228## 
##STR229## 
##STR230## 
##STR231## 
##STR232## 
##STR233## 
##STR234## 
##STR235## 
##STR236## 
##STR237## 
##STR238## 
##STR239## 
##STR240## 
##STR241## 
##STR242## 
##STR243## 
##STR244## 
##STR245## 
##STR246## 
##STR247## 
##STR248## 
##STR249## 
##STR250## 
##STR251## 
##STR252## 
##STR253## 
##STR254## 
##STR255## 
##STR256## 
##STR257## 
##STR258## 
##STR259## 
##STR260## 
##STR261## 
##STR262## 
##STR263## 
##STR264## 
##STR265## 
##STR266## 
##STR267## 
##STR268## 
##STR269## 
##STR270## 
##STR271## 
##STR272## 
##STR273## 
##STR274## 
##STR275## 
##STR276## 
##STR277## 
##STR278## 
##STR279## 
##STR280## 
##STR281## 
##STR282## 
##STR283## 
##STR284## 
##STR285## 
##STR286## 
##STR287## 
##STR288## 
##STR289## 
##STR290## 
##STR291## 
##STR292## 
##STR293## 
##STR294## 
##STR295## 
##STR296## 
##STR297## 
##STR298## 
##STR299## 
##STR300## 
##STR301## 
##STR302## 
##STR303## 
##STR304## 
##STR305## 
##STR306## 
##STR307## 
##STR308## 
##STR309## 
##STR310## 
##STR311## 
##STR312## 
##STR313## 
##STR314## 
##STR315## 
##STR316## 
##STR317## 
##STR318## 
##STR319## 
##STR320## 
__________________________________________________________________________ 
REFERENTIAL EXAMPLE 2 
In 100 ml of methanol was dissolved 25.7 g of 
[2-methoxy-3-(methoxycarbonyl)allyl]triphenylphosphonium bromide, and to 
this solution was added dropwise 10.5 g of a 28% by weight solution of 
sodium methoxide in methanol with stirring at room temperature over 10 
minutes. To the mixed solution was then further added 5 g of 
1,2,3,6-tetrahydrobenzaldehyde at room temperature and the resulting 
mixture was subjected to reaction at the same temperature for 2 hours. 
After completion of the reaction, the solvent was removed by distillation 
under reduced pressure, and to the residue was added 50 ml of water. The 
resulting mixture was extracted with 50 ml of chloroform. The extract was 
dried with anhydrous magnesium sulfate, and the solvent was then removed 
by distillation under reduced pressure. The residue was purified by a 
column chromatography (Wako Silica Gel C-200; eluent: benzene/n-haxane 
(3:1 by volume) mixture) to obtain an oily substance. This oily substance 
was dissolved in 100 ml of dioxane, and to the solution was then added 100 
ml of 0.1N sulfuric acid. The resulting mixture was subjected to reaction 
at 100.degree. C. for 1.5 hours. The solvent was then removed by 
distillation under reduced pressure, and to the residue was added 100 ml 
of chloroform. The resulting mixture was washed with 100 ml of water. The 
organic layer was separated, and dried with anhydrous magnesium sulfate 
and then the solvent was removed by distillation under reduced pressure. 
The residue was purified by a column chromatography (Wako Silica Gel 
C-200; eluent: benzene/n-hexane (3:1 by volume) mixture) to obtain 7.5 g 
of oily methyl 5-(cyclohexen-4-yl)-3-oxo-4-pentenoate. 
IR (neat) cm.sup.-1 : .nu..sub.C.dbd.O 1740 
The compounds shown in Table 4 were obtained in the same manner. 
TABLE 4 
__________________________________________________________________________ 
R.sup.3 CHCHCOCH.sub.2 COOCH.sub.3 
R.sup.3 R.sup.3 R.sup.3 
__________________________________________________________________________ 
##STR321## 
##STR322## 
##STR323## 
##STR324## 
##STR325## 
##STR326## 
##STR327## H.sub.3 CCHCH(trans) 
##STR328## 
##STR329## 
##STR330## ClCH.sub.2 CH.sub.2 
##STR331## 
##STR332## 
##STR333## 
##STR334## 
##STR335## 
##STR336## 
__________________________________________________________________________ 
EXAMPLE 1 
(1) In 10 ml of benzene was dissolved 2.0 g of methyl 
5-(4-chlorophenyl)-3-oxo-4-pentenoate, and to this solution was added 1.2 
g of N,N-dimethylformamidodimethylacetal. The resulting mixture was 
subjected to reaction at 70.degree. C. for 1.5 hours. The reaction mixture 
was cooled to room temperature, and 1.12 g of p-fluoroaniline was then 
added thereto, after which the resulting mixture was further subjected to 
reaction for 1.5 hours. After completion of the reaction, 10 ml of diethyl 
ether was added to the reaction mixture, and the precipitated crystals 
were collected by filtration, and washed with 10 ml of diethyl ether to 
obtain 2.2 g of methyl 
5-(4-chlorophenyl)-2-(4-fluorophenylaminomethylene)-3-oxo-4-pentenoate 
having a melting point of 166.degree.-168.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1700. 
The compounds shown in Table 5 were obtained in the same manner. 
TABLE 5 
__________________________________________________________________________ 
##STR337## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR338## 
##STR339## 133-136 
1680 
##STR340## 
##STR341## 235-236 
1685 
##STR342## 
##STR343## 214-217 
1705 
##STR344## 
##STR345## 160-165 
1690 
##STR346## 
##STR347## 193-195 
1690 
##STR348## 
##STR349## 185-187 
1690 
##STR350## 
##STR351## 201-203 
1700, 1660 
##STR352## 
##STR353## 194-195 
1685 
##STR354## 
##STR355## 196-197 
1690, 1665 
##STR356## 
##STR357## 170-172 
1690, 1660 
__________________________________________________________________________ 
(2) In 15 ml of N,N-dimethylformamide was dissolved 2.0 g of methyl 
5-(4-chlorophenyl)-2-(4-fluorophenylaminomethylene)-3-oxo-4-pentenoate, 
and they were reacted at 140.degree. C. for 4 hours. After completion of 
the reaction, the solvent was removed by distillation under reduced 
pressure, and the residue was purified by a column chromatography (Wako 
Silica Gel C-200; eluent: benzene/ethyl acetate (3:1 by volume) mixture) 
to obtain 1.1 g of oily methyl 
6-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxo-1,4,5,6-tetrahydronicotinate. 
IR (neat) cm.sup.-1 : .nu..sub.C.dbd.O 1725 
NMR (CDCl.sub.3) .delta. values: 2.5-3.5 (2H, m, C.sub.5 --H), 3.80 (3H, s, 
--COOCH.sub.3), 5.30 (1H, m, C.sub.6 --H), 7.0-7.5 (8H, m, 
##STR358## 
8.65 (1H, s, C.sub.2 --H) 
The compounds shown in Table 6 were obtained in the same manner. 
TABLE 6 
__________________________________________________________________________ 
##STR359## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR360## 
##STR361## 145-148 1720, 1660 
##STR362## 
##STR363## 202-205 1730, 1700 
##STR364## 
##STR365## 210-212 1720 
##STR366## 
##STR367## Oily substance 
1720 [neat] 
##STR368## 
##STR369## -- 1690 
##STR370## 
##STR371## 102-110 (decomp.) 
1725, 1710 
##STR372## 
##STR373## 128-131 1710, 1665 
##STR374## 
##STR375## 128-131 1720, 1710 1660 
##STR376## 
##STR377## -- 1720, 1710 
##STR378## 
##STR379## -- 1715 
__________________________________________________________________________ 
(3) In 20 ml of benzene was dissolved 1.0 g of methyl 
6-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxo-1,4,5,6-tetrahydronicotinate, 
and to the resulting solution was added a mixed solution of 0.7 g of 
2,3-dichloro-5,6-dicyano-p-benzoquinone and 5 ml of benzene at 80.degree. 
C., after which they were reacted at the same temperature for 30 minutes. 
After completion of the reaction, the solvent was removed from the 
reaction mixture by distillation under reduced pressure, and the residue 
was suspended in 30 ml of chloroform and 30 ml of water This suspension 
was adjusted to a pH of 7.5 with sodium hydrogencarbonate, and the organic 
layer was then separated and washed successively with 30 ml of water and 
30 ml of a saturated aqueous solution of sodium chloride, and then dried 
with anhydrous magnesium sulfate. The solvent was removed by distillation 
under reduced pressure to obtain 0.85 g of methyl 
6-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinate having a 
melting point of 250.degree.-254.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1735. 
The compounds shown in Table 7 were obtained in the same manner. 
TABLE 7 
__________________________________________________________________________ 
##STR380## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR381## 
##STR382## 153-155 
1725, 1670 
##STR383## 
##STR384## 192-196 
1730, 1710 
##STR385## 
##STR386## &gt;250 1700 
##STR387## 
##STR388## 108-110 
1730, 1700 
##STR389## 
##STR390## -- 1725, 1700 
##STR391## 
##STR392## &gt;250 1730, 1690 
##STR393## 
##STR394## &gt;250 1710, 1680 
##STR395## 
##STR396## 189-191 
1730, 1700, 1670 
##STR397## 
##STR398## &gt;250 1730, 1700 
##STR399## 
##STR400## &gt;250 1725, 1705 
__________________________________________________________________________ 
(4) In a mixed solvent of 5 ml of methanol and 5 ml of 1N aqueous sodium 
hydroxide solution was dissolved 0.5 g of methyl 
6-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinate, and 
they were reacted at room temperature for 30 minutes. After completion of 
the reaction, the reaction mixture was adjusted to a pH of 5.5 with acetic 
acid, and the precipitated crystals were collected by filtration, washed 
with 10 ml of water and dried to obtain 0.4 g of 
6-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid 
having a melting point of 199.degree.-204.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1725. 
The compounds shown in Table 8 were obtained in the same manner. 
TABLE 8 
__________________________________________________________________________ 
##STR401## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR402## 
##STR403## 278-280 
1720, 1680 1665 
##STR404## 
##STR405## &gt;250 1720 
##STR406## 
##STR407## &gt;250 1750 
##STR408## 
##STR409## 173-180 
1720 
##STR410## 
##STR411## 268-271 
1720, 1700 
##STR412## 
##STR413## &gt;250 1715 
##STR414## 
##STR415## &gt;250 1720 
##STR416## 
##STR417## &gt;250 1720 
__________________________________________________________________________ 
EXAMPLE 2 
(1) In 25 ml of methylene chloride were dissolved 3.1 g of 2-naphthaldehyde 
and 9.4 g of [2-methoxy-3-(methoxycarbonyl)allyl]triphenylphosphonium 
bromide, followed by addition thereto of 19 ml of a 50% by weight aqueous 
sodium hydroxide solution with stirring at room temperature, and the 
mixture was subjected to reaction at the same temperature for 20 minutes. 
After completion of the reaction, the methylene chloride layer was 
separated from the reaction mixture and washed with water. It was then 
dried with anhydrous sodium sulfate, and the solvent was removed by 
distillation under reduced pressure. To the residue was added 30 ml of 
diethyl ether, and the insolubles were removed by filtration, after which 
the filtrate was concentrated to obtain an oily substance. This oily 
substance was dissolved in a mixed solvent of 45 ml of dioxane and 40 ml 
of 0.1N sulfuric acid, and the solution was refluxed for 30 minutes. Then 
the reaction mixture was cooled to room temperature, extracted with 100 ml 
of ethyl acetate and the extract was dried with anhydrous sodium sulfate. 
The solvent was removed by distillation under reduced pressure, and the 
formed crystals were suspended in 50 ml of benzene, and to the suspension 
was added 2.4 g of N,N-dimethylformamidodimethylacetal, and the resulting 
mixture was subjected to reaction at 60.degree. C. for 30 minutes. The 
reaction mixture was cooled to room temperature, and 2.2 g of 
p-aminophenol was added thereto. The mixture was subjected to reaction at 
the same temperature for 2 hours. The precipitated crystals were collected 
by filtration, washed with 5 ml of benzene and dried to obtain 1.7 g of 
methyl 2-(4-hydroxyphenylaminomethylene)-5-(2-naphthyl)-3-oxo-4-pentenoate 
having a melting point of 191.degree.-192.5.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1710. 
The compounds shown in Table 9 were obtained in the same manner. 
TABLE 9 
__________________________________________________________________________ 
##STR418## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR419## 
##STR420## 172-175 
1685 
##STR421## 
##STR422## 153-159 
1720, 1705 
##STR423## 
##STR424## 146-148 
1700 
##STR425## 
##STR426## 157-159 
1700, 1685 
##STR427## 
##STR428## 199-201 
1685 
##STR429## 
##STR430## 195-196 
1700 
##STR431## 
##STR432## 131-133 
1685 
##STR433## 
##STR434## 141-143 
1705 
##STR435## 
##STR436## 141-142 
1690 
##STR437## 
##STR438## 167-168 
1700 
##STR439## 
##STR440## 118- 120 
1690 
##STR441## 
##STR442## 156-158 
1685 
##STR443## 
##STR444## 134-135 
1675 
##STR445## 
##STR446## 173-175 
1705 
##STR447## 
##STR448## 156-158 
1670 
##STR449## 
##STR450## 189-191 
1685 
##STR451## 
##STR452## 153-154 
1695 
##STR453## 
##STR454## 154-156 
1680 
##STR455## 
##STR456## 152-153 
1700 
##STR457## 
##STR458## 154-157 
1690 
##STR459## 
##STR460## 188-190 
1700 
##STR461## 
##STR462## 234-236 
1695 
##STR463## 
##STR464## 166-168 
1710, 1695 
##STR465## 
##STR466## 149-151 
2190(.nu..sub.C.tbd.C), 1705 
##STR467## 
##STR468## 128-131 
1730 
##STR469## 
##STR470## 153-155 
1690 
##STR471## 
##STR472## 220-222 
1710 
##STR473## 
##STR474## 178-182 
3320(.nu..sub.NH), 1710, 1695, 1670 
##STR475## 
##STR476## 212-214 
1690 
##STR477## 
##STR478## 140-143 
2220(.nu..sub.CN), 1685 
##STR479## 
##STR480## 217-222 
1680 
##STR481## 
##STR482## 197-199 
3300(.nu..sub.NH), 1685, 1630 
##STR483## 
##STR484## 192-194 
1665 
##STR485## 
##STR486## 204-205 
1675 
##STR487## 
##STR488## 180-185 
1705, 1675 
##STR489## 
##STR490## 206-207 
1690 
##STR491## 
##STR492## 134-136 
1700, 1685 
##STR493## 
##STR494## 179-182 
1685 
##STR495## 
##STR496## 180-184 
1710 
##STR497## 
##STR498## 151.5-152.5 
1700 
##STR499## 
##STR500## 157-158 
1710 
##STR501## 
##STR502## 154-156 
1700 
##STR503## 
##STR504## 220-223 
1700 
##STR505## 
##STR506## 163-167 
1655 
##STR507## 
##STR508## 231-234 
1695 
##STR509## 
##STR510## 188-191 
1705, 1665 
__________________________________________________________________________ 
(2) In 12 ml of N,N-dimethylformamide was dissolved 1.7 g of methyl 
2-(4-hydroxyphenylaminomethylene)-5-(2-naphthyl)-3-oxo-4-pentenoate, and 
they were reacted at 140.degree. C. for 2 hours. After completion of the 
reaction, the solvent was removed by distillation under reduced pressure, 
and the residue was purified by a column chromatography (Wako Silica Gel 
C-200; eluent: chloroform/methanol (19:1 by volume) mixture). The purified 
oily substance was dissolved in 15 ml of dioxane and the resulting 
solution was heated to 80.degree. C. To this solution was added dropwise 
at 80.degree. C. a solution formed by dissolving 1.1 g of 
2,3,5,6-tetrachloro-p-benzoquinone in 15 ml of dioxane. After this 
addition was completed, the solvent was removed by distillation under 
reduced pressure, and to the residue was added 20 ml of a 
chloroform/methanol (5:1 by volume) mixed solvent. The crystals thus 
formed were collected by filtration, washed with 5 ml of the same mixed 
solvent as mentioned above, and then dried to obtain 0.75 g of methyl 
1-(4-hydroxyphenyl)-6-(2-naphthyl)-4-oxo-1,4-dihydronicotinate having a 
melting point of 280.degree. C. or more. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1730, 1710. 
The compounds shown in Table 10 were obtained in the same manner. 
TABLE 10 
__________________________________________________________________________ 
##STR511## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR512## 
##STR513## &gt;280 1725, 1700 
##STR514## 
##STR515## 205-209 1740, 1720, 1700 
##STR516## 
##STR517## 228-231 1705 
##STR518## 
##STR519## 241-243 1730, 1700 
##STR520## 
##STR521## 272-274 1730, 1700 
##STR522## 
##STR523## 281.5-283.5 
1735, 1700 
##STR524## 
##STR525## 248-249 1730, 1720 
##STR526## 
##STR527## 275-276 1735, 1700 
##STR528## 
##STR529## 216-217 1730, 1700 
##STR530## 
##STR531## 147-148 1725, 1700 
##STR532## 
##STR533## 275-277 1730, 1710 
##STR534## 
##STR535## 168-170 1730, 1700 
##STR536## 
##STR537## 236-238 1730, 1700 
##STR538## 
##STR539## &gt;280 1735 
##STR540## 
##STR541## &gt;280 1725, 1705 
##STR542## 
##STR543## &gt;280 1730, 1700 
##STR544## 
##STR545## 249-250 1730, 1700 
##STR546## 
##STR547## 221-222 1725 
##STR548## 
##STR549## 246-248 1735 
##STR550## 
##STR551## 232-234 1735, 1700 
##STR552## 
##STR553## 228-238 1730, 1700 
##STR554## 
##STR555## &gt;250 1730, 1705 
##STR556## 
##STR557## 
##STR558## 
##STR559## 
##STR560## 
6.76 (1H, s, C.sub.5H), 
8.20 (1H, s, C.sub.2 H) 
##STR561## 
##STR562## 156-160 2220(.nu..sub.C.tbd.C), 1730 
##STR563## 
##STR564## &gt;250 1730 
##STR565## 
##STR566## &gt;260 1735, 1720 
##STR567## 
##STR568## &gt;250 1690 
##STR569## 
##STR570## 226-228 2230(.nu..sub.CN), 1735, 1700 
##STR571## 
##STR572## &gt; 250 1715 
##STR573## 
##STR574## 279-280 1715, 1685 
##STR575## 
##STR576## &gt;280 1725, 1700 
##STR577## 
##STR578## &gt;280 1720, 1700 
##STR579## 
##STR580## 180-181 1730, 1700 
##STR581## 
##STR582## 198-206 1725, 1700 
##STR583## 
##STR584## 213-217 1730, 1700 
##STR585## 
##STR586## &gt;280 1725, 1700 
##STR587## 
##STR588## &gt;280 1725, 1700 
##STR589## 
##STR590## 167-170 1725, 1680 
##STR591## 
##STR592## &gt;280 1735, 1700 
##STR593## 
##STR594## 263-265 1735, 1705 
##STR595## 
##STR596## 205.5-206.5 
1730, 1700 
##STR597## 
##STR598## 233-235 1730, 1700 
##STR599## 
##STR600## &gt;250 1700 
##STR601## 
##STR602## 246-248 1730, 1700 
##STR603## 
##STR604## &gt;250 1730, 1710 
##STR605## 
##STR606## 236-238 1730, 1680 
__________________________________________________________________________ 
EXAMPLE 3 
(1) To 2.5 g of methyl 5-(4-acetaminophenyl)-3-oxo-4-pentenoate were added 
2.0 g of acetic anhydride and 1.4 g of ethyl orthoformate, and they were 
reacted at 80.degree. C. for one hour. The resulting ethyl acetate was 
removed by distillation under reduced pressure, and the residue was 
dissolved in 15 ml of benzene, and to the resulting solution was added 1.1 
g of p-fluoroaniline and they were reacted at room temperature for one 
hour. After completion of the reaction, the precipitated crystals were 
collected by filtration, washed with 10 ml of benzene and then dried to 
obtain 2.9 g of methyl 
2-(4-fluorophenylaminomethylene)-5-(4-acetaminophenyl)-3-oxo-4-pentenoate 
having a melting point of 161.degree.-164.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1705, 1660. 
The compounds shown in Table 11 were obtained in the same manner. 
TABLE 11 
__________________________________________________________________________ 
##STR607## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR608## 
##STR609## 180-181 
1700 
##STR610## 
##STR611## 161-163 
1705 
##STR612## 
##STR613## -- 1725, 1700 
##STR614## 
##STR615## 155-157 
1703 
##STR616## 
##STR617## 178-179.5 
1690 
##STR618## 
##STR619## -- 3300(.sup..nu. NH) 1690, 1660 [neat] 
##STR620## 
##STR621## 180-182 
1625 
##STR622## 
##STR623## 204-206 
1703 
##STR624## 
##STR625## 153-156 
1690 
##STR626## 
##STR627## 197-199 
1700 
##STR628## 
##STR629## 183-186 
1700 
##STR630## 
##STR631## 122-125 
1690 
__________________________________________________________________________ 
(2) In 25 ml of N,N-dimethylformamide was dissolved 2.9 g of methyl 
2-(4-fluorophenylaminomethylene)-5-(4-acetaminophenyl)-3-oxo-4-pentenoate, 
and they are reacted at 140.degree. C. for 2 hours. After completion of 
the reaction, the solvent was removed by distillation under reduced 
pressure and the residue was purified by a column chromatography (Wako 
Silica Gel C-200; eluent: chloroform) to obtain an oily substance. This 
oily sugstance was dissolved in 30 ml of benzene, followed by dropwise 
addition thereto of a solution of 2.06 g of 
2,3,5,6-tetrachloro-p-benzoquinone in 18 ml of benzene at 80.degree. C. 
After completion of this dropwise addition, the reaction mixture was 
cooled to room temperature, and the precipitated crystals were collected 
by filtration and washed with 30 ml of benzene. These crystals were then 
dissolved in a mixed solution of 20 ml of methanol and 20 ml of a 1N 
aqueous sodium hydroxide solution, and they were reacted at room 
temperature for 30 minutes. The reaction solution was adjusted to a pH of 
6.0 with acetic acid and the precipitated crystals were collected by 
filtration, washed with water and dried to obtain 2.3 g of 
6-(4-acetaminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid 
having a melting point of 249.degree.-250.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720. 
The compounds shown in Table 12 were obtained in the same manner. 
TABLE 12 
__________________________________________________________________________ 
##STR632## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR633## 
##STR634## 240-242 
1725, 1710 
##STR635## 
##STR636## 218-221 
1730 
##STR637## 
##STR638## -- 1720, 1700 
##STR639## 
##STR640## 204-206 
1700 
##STR641## 
##STR642## &gt;250 1725, 1705 
##STR643## 
##STR644## 165-168 
1730, 1685 
##STR645## 
##STR646## &gt;250 1720 
##STR647## 
##STR648## &gt;250 1720 
##STR649## 
##STR650## 182-184 
1715 
##STR651## 
##STR652## &gt;250 1720, 1710 
##STR653## 
##STR654## &gt;250 1715 
##STR655## 
##STR656## &gt;250 1720 
__________________________________________________________________________ 
EXAMPLE 4 
In 10 ml of N,N-dimethylformamide was dissolved 2.0 g of methyl 
5-(3-methyl-4-dimethylaminophenyl)-3-oxo-4-pentenoate, and 1.1 g of 
N,N-dimethylformamidodimethylacetal was added to the resulting solution, 
after which they were reacted at 70.degree. C. for 1.5 hours. To the 
reaction mixture was then added 1.0 g of p-fluoroaniline at 70.degree. C., 
and they were reacted at 80.degree. C. for 2 hours and further at 
140.degree. C. for 3 hours. After completion of the reaction, the reaction 
mixture was cooled to room temperature and the solvent was removed by 
distillation under reduced pressure. The residue was purified by a column 
chromatography (Wako Silica Gel C-200; eluent: chloroform) to obtain an 
oily substance. This oily substance was dissolved in 30 ml of dioxane, and 
to this solution was added dropwise a solution of 2.1 g of 
2,3-dichloro-5,6-dicyano-p-benzoquinone in 10 ml of benzene at 80.degree. 
C. Thereafter, the mixture was subjected to reaction at the same 
temperature for 30 minutes and the solvent was removed by distillation 
under reduced pressure. The residue was suspended in 50 ml of chloroform 
and 50 ml of water, and after adjusting this suspension to a pH 7.5 with 
sodium hydrogencarbonate, the organic layer was separated, washed 
successively with 10 ml of water and 20 ml of a saturated aqueous solution 
of sodium chloride and then dried with anhydrous magnesium sulfate. The 
solvent was removed by distillation under reduced pressure to obtain 1.8 g 
of methyl 
1-(4-fluorophenyl)-6-(3-methyl-4-dimethylaminophenyl)-4-oxo-1,4-dihydronic 
otinate having a melting point of 217.degree.-220.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1725, 1705. 
The compounds shown in Table 13 were obtained in the same manner. 
TABLE 13 
__________________________________________________________________________ 
##STR657## 
IR(KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR658## 
##STR659## &gt;260 1735, 1720 
##STR660## 
##STR661## &gt;250 1730 
##STR662## 
##STR663## 195-197 
1720, 1700 
##STR664## 
##STR665## 167-171 
1730, 1680 
##STR666## 
##STR667## 156-166 
1710, 1685 
##STR668## 
##STR669## &gt;250 1690 
##STR670## 
##STR671## &gt;250 1705 
##STR672## 
##STR673## 251-254 
1720, 1700 
##STR674## 
##STR675## 126-129 
1735, 1695, 1675 
##STR676## 
##STR677## &gt;250 1720, 1690 
##STR678## 
##STR679## 266-268 
1725 
##STR680## 
##STR681## &gt;250 1735, 1700 
##STR682## 
##STR683## &gt;250 1730, 1700 
##STR684## 
##STR685## 136-137.5 
1730, 1710, 1695 
##STR686## 
##STR687## 125-127 
1735, 1705, 1695 
##STR688## 
##STR689## -- 1725, 1700 
__________________________________________________________________________ 
EXAMPLE 5 
(1) In the same manner as in Example 1-(4), the corresponding methyl esters 
were hydrolyzed to obtain the compounds shown in Table 14. 
TABLE 14 
__________________________________________________________________________ 
##STR690## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR691## 
##STR692## &gt;280 1725, 1700 
##STR693## 
##STR694## 212-214 
1720, 1700 
##STR695## 
##STR696## 228.5-231 
1710, 1690 
##STR697## 
##STR698## 230-231 
1720, 1700 
##STR699## 
##STR700## 238-240 
1720, 1700 
##STR701## 
##STR702## &gt;280 1725, 1705 
##STR703## 
##STR704## 226-228 
1720, 1700 
##STR705## 
##STR706## 230-231 
1720, 1700 
##STR707## 
##STR708## 243-245 
1720, 1700 
##STR709## 
##STR710## 217-218 
1720, 1700 
##STR711## 
##STR712## 197-199 
1725, 1700 
##STR713## 
##STR714## 255-257 
1720, 1705 
##STR715## 
##STR716## &gt;260 1745, 1715 
##STR717## 
##STR718## 192-195 
1725, 1700 
##STR719## 
##STR720## 166-167 
3420, (.nu..sub.NH), 1725, 1705 
##STR721## 
##STR722## 180-182 
1725, 1700 
##STR723## 
##STR724## 252-255 
1725, 1705 
##STR725## 
##STR726## &gt;290 1725, 1705 
##STR727## 
##STR728## 201-203 
1715 
##STR729## 
##STR730## 181-185.5 
1720, 1700 
##STR731## 
##STR732## &gt;250 1730 
##STR733## 
##STR734## 169-171 
1725, 1700 
##STR735## 
##STR736## 224-225 
1715 
##STR737## 
##STR738## &gt;250 1730, 1710 
##STR739## 
##STR740## &gt;250 1725 
##STR741## 
##STR742## &gt;230 1725, 1705 
##STR743## 
##STR744## &gt;260 1710 
##STR745## 
##STR746## 223-225 
1705 
##STR747## 
##STR748## 242-246 
2220 (.nu..sub.C.tbd.C ), 1710 
##STR749## 
##STR750## 202-203 
1695 
##STR751## 
##STR752## &gt;260 1725, 1700 
##STR753## 
##STR754## 207-209 
1720, 1700 
##STR755## 
##STR756## 273-275 
2225 (.nu..sub.CN), 1725, 1700 
##STR757## 
##STR758## 196-201 
1710 
##STR759## 
##STR760## 272-273 
3270 (.nu. .sub.CN), 1720, 1705, 
1685 
##STR761## 
##STR762## 180-182 
1725, 1700 
##STR763## 
##STR764## &gt;280 1725, 1710 
##STR765## 
##STR766## 255-257 
1720, 1700 
##STR767## 
##STR768## &gt;250 1710 
##STR769## 
##STR770## 274-276 
3250 (.nu..sub.OH), 1740 
##STR771## 
##STR772## &gt; 250 1750 
##STR773## 
##STR774## &gt;260 1710 
##STR775## 
##STR776## 123-129 
1730, 1710, 1690 
##STR777## 
##STR778## 242-250 
1720 
##STR779## 
##STR780## &gt;280 1690 
##STR781## 
##STR782## &gt;280 1725, 1710 
##STR783## 
##STR784## &gt;280 1730, 1700 
##STR785## 
##STR786## &gt;280 1730, 1700 
##STR787## 
##STR788## &gt;250 1720, 1700 
##STR789## 
##STR790## &gt;250 1705 
##STR791## 
##STR792## &gt;280 1725, 1700 
##STR793## 
##STR794## 196-198 
1715, 1700 
##STR795## 
##STR796## 253-255 
1720, 1680 
__________________________________________________________________________ 
(2) Methyl 
1-[4-(3-ethyloxycarbonyl-4-hydroxy)phenyl]-6-{4-(thiophen-2-yl)phenyl}-4-o 
xo-1,4-dihydronicotinate was hydrolyzed in the same manner as in Example 
1-(4) to obtain the compound shown in Table 15. 
TABLE 15 
______________________________________ 
##STR797## 
IR(KBr) 
m.p.cm.sup.-1 : 
R.sup.3 R.sup.2 (.degree.C.).nu..sub.C.dbd.O 
______________________________________ 
##STR798## 
##STR799## &gt;280 1725, 1710 
______________________________________ 
EXAMPLE 6 
In 10 ml of chloroform was dissolved 1 g of 
1-(4-fluorophenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinic 
acid, and to the resulting solution were then added 0.32 g of 
triethylamine and 0.76 g of pivaloyloxyethyl iodide at room temperature, 
after which the resulting mixture was subjected to reaction at the same 
temperature for 2 hours. After completion of the reaction, the reaction 
mixture was washed successively with 20 ml of a 0.1N aqueous sodium 
hydroxide solution and 20 ml of water and dried with anhydrous magnesium 
sulfate. Then, the solvent was removed by distillation under reduced 
pressure, and to the residue was added 20 ml of a diethyl ether/n-hexane 
(1:1 by volume) mixed solvent, after which insolubles were removed by 
filtration to obtain 0.6 g of 1-pivaloyloxyethyl 
1-(4-fluorophenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinate 
having a melting point of 117.degree.-120.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1745, 1720. 
The compounds shown in Table 16 were obtained in the same manner. 
TABLE 16 
__________________________________________________________________________ 
##STR800## 
IR(KBr) 
R.sup.3 R.sup.2 R.sup.1 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR801## 
##STR802## 
##STR803## 
186-188 
1725, 1700 
##STR804## 
##STR805## 
##STR806## 
220-223 
1785, 1730, 1700 
##STR807## 
##STR808## 
CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 
170-174 
1730, 1695 
##STR809## 
##STR810## 
CH.sub.2 CH.sub.2 CH.sub.3 
181-183 
1720, 1700 
##STR811## 
##STR812## 
CH.sub.2 CH.sub.3 
222-225 
1725, 1695 
__________________________________________________________________________ 
EXAMPLE 7 
In a mixed solvent of 2.5 ml of anisole and 2.5 ml of trifluoroacetic acid 
was dissolved 0.25 g of methyl 
6-(4-diphenylmethyloxycarbonylphenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydro 
nicotinate, and they were reacted at room temperature for 1.5 hours. After 
completion of the reaction, the solvent was removed by distillation under 
reduced pressure, and the residue was dissolved in a mixed solvent of 2.5 
ml of ethanol and 2.5 ml of a 1N aqueous sodium hydroxide solution, and 
the resulting solution was subjected to reaction at room temperature for 3 
hours. After completion of the reaction, 20 ml of water and 20 ml of 
benzene were added to the reaction mixture and the aqueous layer was 
separated. The aqueous solution thus obtained was adjusted to a pH of 5.5 
with acetic acid and the precipitated crystals were collected by 
filtration, to obtain 0.10 g of 
6-(4-carboxyphenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid 
having a melting point of 280.degree. C. or more. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720, 1710 
NMR (d.sub.6 -DMSO) .delta. value: 6.97 (1H, s, C.sub.5 --H), 7.34 (2H, d, 
J=8 Hz, 
##STR813## 
7.16-7.79 (4H, m, 
##STR814## 
7.94 (2H, d, J=8 Hz, 
##STR815## 
8.73 (1H, s, C.sub.2 --H) 
EXAMPLE 8 
In a mixed solvent of 3 ml of methanol and 3 ml of 10% by weight aqueous 
sodium hydroxide solution was dissolved 0.5 g of 
6-(4-acetaminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid, 
and the resulting solution was subjected to reaction at 60.degree. C. for 
4 hours. After completion of the reaction, the reaction mixture was cooled 
to room temperature and adjusted to a pH of 6.0 with acetic acid. The 
precipitated crystals were collected by filtration, washed with water and 
dried to obtain 0.36 g of 
6-(4-aminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid 
having a melting point of 262.degree.-266.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1715. 
A corresponding acetamino form was hydrolyzed in the same manner, to obtain 
the compound shown in Table 17. 
TABLE 17 
______________________________________ 
##STR816## 
IR(KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
______________________________________ 
##STR817## 
##STR818## 265 (decomp.) 
1710 
______________________________________ 
EXAMPLE 9 
In 7 ml of 47% by weight hydrobromic acid was suspended 0.2 g of 
1-(4-fluorophenyl)-6-(4-methoxyphenyl)-4-oxo-1,4-dihydronicotinic acid was 
suspended, and the suspension was refluxed for 2 hours. After completion 
of the reaction, the reaction mixture was cooled to room temperature, 
diluted with 10 ml of water, adjusted to a pH of 12 with a 20% by weight 
aqueous sodium hydroxide solution, and washed with 20 ml of chloroform. 
This aqueous solution was then adjusted to a pH of 6.0 with acetic acid 
and the precipitated crystals were collected by filtration, and washed 
with water to obtain 0.15 g of 
1-(4-fluorophenyl)-6-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinic acid 
having a melting point of 185.degree.-193.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1705. 
The compounds shown in Table 18 were obtained in the same manner. 
TABLE 18 
__________________________________________________________________________ 
##STR819## 
IR(KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR820## 
##STR821## 
&gt;200 1730, 1705 
##STR822## 
##STR823## 
&gt;250 1700 
##STR824## 
##STR825## 
&gt;250 1720, 1705 
##STR826## 
##STR827## 
270-271 
1720 
##STR828## 
##STR829## 
&gt; 250 1720, 1700 
##STR830## 
##STR831## 
144-145 
1720 
##STR832## 
##STR833## 
157-160 
1715 
##STR834## 
##STR835## 
173-175 
1730 
##STR836## 
##STR837## 
&gt;250 1710, 1700 
__________________________________________________________________________ 
EXAMPLE 10 
In 10 ml of ethanol were suspended 0.3 g of 
6-(4-aminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid and 
0.15 g of 5-nitrofurfural, and the suspension was subjected to reaction at 
80.degree. C. for 2 hours. After completion of the reaction, the reaction 
mixture was cooled to room temperature and the insolubles were removed by 
filtration. The solvent was removed by distillation under reduced 
pressure. Then, 10 ml of diethyl ether was added to the residue, and the 
insolubles were collected by filtration to obtain 0.13 g of 
1-(4-fluorophenyl)-6-[4-{(5-nitrofurfurylidene)amino}-phenyl]-4-oxo-1,4-di 
hydronicotinic acid having a melting point of 129.degree.-131.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720, .nu..sub.NO.sbsb.2 1350 
EXAMPLE 11 
In 50 ml of methanol was suspended 6.5 g of 
6-(4-aminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid, and 
the suspension was cooled to 5.degree. C., after which 3.9 g of thionyl 
chloride was added dropwise thereto over 10 minutes. After completion of 
the dropwise addition, the resulting mixture was refluxed for 6 hours, and 
then cooled to room temperature, after which the solvent was removed by 
distillation under reduced pressure. To the residue were added 30 ml of 
water and 30 ml of chloroform, and the resulting mixture was adjusted to a 
pH of 7 with sodium hydrogencarbonate, after which the aqueous layer was 
separated, washed with 30 ml of a saturated aqueous solution of sodium 
chloride, and then dried with anhydrous magnesium sulfate. The solvent was 
removed by distillation under reduced pressure. The resulting crystalline 
substance was washed with 50 ml of diethyl ether to obtain 6.7 g of methyl 
6-(4-aminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinate having a 
melting point of 250.degree. C. or more. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720. 
NMR (d-TFA) .delta. values: 3.75 (3H, s, --COOCH.sub.3), 4.15 (2H, bs, 
--NH.sub.2), 6.20-7.61 (9H, m, 
##STR838## 
C.sub.5 --H), 8.35 (1H, s, C.sub.2 --H) 
EXAMPLE 12 
In a mixed solvent of 5 ml of acetic acid and 4 ml of water was dissolved 
0.7 g of methyl 
6-(4-aminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinate, and to 
this solution was added dropwise a solution of 0.3 g of sodium cyanate in 
3 ml of water at room temperature over 5 minutes, after which the mixture 
was subjected to reaction at the same temperature for 2 hours. After 
completion of the reaction, 10 ml of water was added to the reaction 
mixture and the precipitated crystals were collected by filtration. These 
crystals were suspended in a mixed solution of 5 ml of methanol and 5 ml 
of a 1N aqueous sodium hydroxide solution, and the suspension was stirred 
at room temperature for 30 minutes. The homogenized solution was adjusted 
to a pH of 6.0 with acetic acid and the precipitated crystals were 
collected by filtration, washed with water and dried to obtain 0.5 g of 
1-(4-fluorophenyl-4-oxo-6-(4-ureidophenyl)-1,4-dihydronicotinic acid 
having a melting point of 185.degree.-190.degree. C. (decomp.). 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720. 
EXAMPLE 13 
In 5 ml of N,N-dimethylformamide was dissolved 0.35 g of methyl 
6-(4-aminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinate, and 1 g 
of 2-bromoethanol and 0.3 g of triethylamine were added to the solution, 
after which the resulting mixture was refluxed for 2 hours. After 
completion of the reaction, the reaction mixture was cooled to room 
temperature, and 10 ml of water was then added thereto, after which the 
resulting mixture was extracted with 10 ml of chloroform. The extract was 
washed with 10 ml of a saturated aqueous solution of sodium chloride and 
dried with anhydrous magnesium sulfate. Then, the solvent was removed by 
distillation under reduced pressure and the residue was purified by a 
column chormatography (Wako Silica Gel C-200; eluent: chloroform) to 
obtain an oily substance. This oily substance was dissolved in a mixture 
of 2 ml of methanol and 3 ml of a 1N aqueous sodium hydroxide solution, 
and they were reacted at room temperature for 30 minutes. After completion 
of the reaction, the reaction mixture was adjusted to a pH of 6.0 with 
acetic acid, and the precipitated crystals were collected by filtration, 
washed with water and dried to obtain 0.15 g of 
1-(4-fluorophenyl)-6-[4-N-(2-hydroxyethyl)aminophenyl]-4-oxo-1,4-dihydroni 
cotinic acid having a melting point of 226.degree.-228.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720 
EXAMPLE 14 
In 5 ml of N,N-dimethylformamide was dissolved 0.5 g of methyl 
6-(4-aminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinate, and 0.23 
g of allyl chloride and 0.3 g of triethylamine were added thereto, and the 
resulting mixture was refluxed for 3 hours. After completion of the 
reaction, the reaction mixture was cooled, and 10 ml of water was added 
thereto, after which the resulting mixture was extracted with 10 ml of 
chloroform. The extract was washed with 10 ml of a saturated aqueous 
solution of sodium chloride and dried with anhydrous magnesium sulfate. 
The solvent was then removed by distillation under reduced pressure, and 
the residue was purified by a column chromatograpy (Wako Silica Gel C-200; 
eluant: chloroform) to obtain an oily substance. This oily substance was 
dissolved in a mixture of 2 ml of methanol and 3 ml of a 1N aqueous sodium 
hydroxide solution, and they were reacted at room temperature for 30 
minutes. After completion of the reaction, the reaction mixture was 
adjusted to a pH of 6.0 with acetic acid, and the precipitated crystals 
were collected by filtration, washed with water, and dried to obtain 0.32 
g of 
6-(4-N-allylaminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic aci 
d having a melting point of 183.degree.-185.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720. 
EXAMPLE 15 
In 10 ml of 47% by weight hydrobromic acid was suspended 0.3 g of 
1-(2-fluoro-4-methoxyphenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydroni 
cotinic acid, and the suspension was refluxed for 2 hours. After completion 
of the reaction, the reaction mixture was cooled to room temperature and 
diluted with 10 ml of water. The resulting solution was then adjusted to a 
pH of 12 with 20% by weight aqueous sodium hydroxide solution and washed 
with 20 ml of chloroform. The aqueous layer was adjusted to a pH of 6.0 
with acetic acid, and the precipitated crystals were collected by 
filtration, washed with 10 ml of water, and dried to obtain 0.17 g of 
1-(2-fluoro-4-hydroxyphenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydroni 
cotinic acid having a melting point of 250.degree. C. or more. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720. 
NMR (d.sub.6 -DMSO) .delta. values: 2.97 (6H, s, --N(CH.sub.3).sub.2), 
6.52-7.35 (8H, m, 
##STR839## 
C.sub.5 --H), 8.60 (1H, s, C.sub.2 --H), 10.45 (1H, bs, 
##STR840## 
The compounds shown in Table 19 were obtained in the same manner. 
TABLE 19 
______________________________________ 
##STR841## 
IR 
(KBr) 
m.p. cm.sup.-1 : 
R.sup.3 R.sup.2 (.degree.C.) 
.nu..sub.C.dbd.O 
______________________________________ 
##STR842## 
##STR843## 251- 254 
1720, 1700 
##STR844## 
##STR845## &gt;280 1710 
##STR846## 
##STR847## &gt;280 1720 
##STR848## 
##STR849## &gt;250 1720 
______________________________________ 
EXAMPLE 16 
In a mixed solvent of 10 ml of ethanol and 10 ml of a 10% by weight aqueous 
sodium hydroxide solution was dissolved 0.5 g of methyl 
1-(4-acetaminophenyl)-6-(2-naphthyl)-4-oxo-1,4-dihydronicotinate, and the 
solution was refluxed for 3 hours. After completion of the reaction, the 
reaction mixture was cooled to room temperature, and diluted with 20 ml of 
water. This solution was then adjusted to a pH of 5.5 with acetic acid, 
and the precipitated crystals were collected by filtration, washed with 
water, and dried to obtain 0.38 g of 
1-(4-aminophenyl)-6-(2-naphthyl)-4-oxo-1,4-dihydronicotinic acid having a 
melting point of 148.degree.-151.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.NH 3470, 3360; .nu..sub.C.dbd.O 1715, 1700. 
The compounds shown in Table 20 were obtained in the same manner. 
TABLE 20 
______________________________________ 
##STR850## 
IR 
(KBr) 
m.p. cm.sup.-1 : 
R.sup.3 R.sup.2 (.degree.C.) 
.nu..sub.C.dbd.O 
______________________________________ 
##STR851## 
##STR852## &gt;250 1720, 1700 
##STR853## 
##STR854## 237-239 1720, 1700 
##STR855## 
##STR856## 147-151 1710, 1700 
______________________________________ 
EXAMPLE 17 
With 1 g of 
6-(4-dimethylaminophenyl)-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinic 
acid was mixed 10 ml of acetic anhydride and the resulting mixture was 
subjected to reaction at 130.degree. C. for 2 hours. After completion of 
the reaction, the reaction mixture was cooled to room temperature and 
introduced into 150 ml of water. After stirring the mixture for 1 hour, 
150 ml of ethyl acetate was added to the mixture, and the organic layer 
was separated, washed with 100 ml of water and then with 50 ml of a 
saturated aqueous solution of sodium chloride, and dried with anhydrous 
magnesium sulfate. The solvent was removed by distillation under reduced 
pressure, and to the residue was added 20 ml of diethyl ether, and the 
resulting mixture was filtered to obtain 0.75 g of 
1-(4-acetyloxyphenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinic 
acid having a melting point of 128.degree.-131.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1760, 1720, 1700. 
The compounds shown in Table 21 were obtained in the same manner. 
TABLE 21 
__________________________________________________________________________ 
##STR857## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR858## 
##STR859## 231-234 
1760, 1720 
##STR860## 
##STR861## 178-179 
1765, 1730 
##STR862## 
##STR863## 235-237 
1760, 1700 
##STR864## 
##STR865## 205-207 
1760, 1740, 1720 
##STR866## 
##STR867## 194-195 
1760, 1715 
##STR868## 
##STR869## 230.5-233 
1770, 1730 
##STR870## 
##STR871## 229-231 
1760, 1720 
__________________________________________________________________________ 
EXAMPLE 18 
(1) In the same manner as in Example 4, methyl 
1-(4-fluorophenyl)-6-methyl-4-oxo-1,4-dihydronicotinate (m.p. 
190.degree.-195.degree. C.) was prepared from methyl 3-oxo-4-hexenoate and 
4-flouoroaniline, and 0.7 g of this ester was mixed with 0.32 g of 
nicotinaldehyde and 0.58 g of acetic anhydride, and they were refluxed for 
5 hours. After completion of the reaction, the reaction mixture was cooled 
to room temperature, and 20 ml of water was added thereto, after which the 
mixture was successively extracted with three 40-ml portions of 
chloroform. The chloroform layer was washed with 50 ml of a saturated 
aqueous solution of sodium chloride and dried with anhydrous magnesium 
sulfate, and the solvent was removed by distillation under reduced 
pressure. The residue was purified by a column chromatography (Wako Silica 
Gel C-200; eluent: chloroform) to obtain 0.496 g of methyl 
1-(4-fluorophenyl)-6-[2-(pyridin-3-yl)ethenyl]-4-oxo-1,4-dihydronicotinate 
having a melting point of 201.degree.-204.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1725, 1700 
(2) In a mixture of 9 ml of ethanol and 9 ml of a 10% by weight aqueous 
sodium hydroxide solution was suspended 0.45 g of methyl 
1-(4-fluorophenyl)-6-[2-(pyridin-3-yl)ethenyl]-4-oxo-1,4-dihydronicotinate 
and the suspension was subjected to reaction at room temperature for 30 
minutes. After completion of the reaction, the reaction mixture was 
adjusted to a pH of 6.0 with acetic acid, and the precipitated crystals 
were collected by filtration and dried to obtain 0.357 g of 
1-(4-fluorophenyl)-6-[2-(pyridin-3-yl)ethenyl]-4-oxo-1,4-dihydronicotinic 
acid having a melting point of 250.degree. C. or more. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1710. 
NMR (d.sub.6 -DMSO) .delta. values: 6.64 (1H, d, J=16 Hz, 
##STR872## 
7.10-8.00 (8H, m, 
##STR873## 
8.50-8.85 (3H, m, 
##STR874## 
C.sub.2 --H) 
EXAMPLE 19 
To 0.7 g of 1-(4-fluorophenyl)-6-methyl-4-oxo-1,4-dihydronicotinic acid was 
added 0.33 g of isonicotinaldehyde and 0.61 g of acetic anhydride, and 
they were refluxed for 5 hours. After completion of the reaction, 30 ml of 
water was added to the reaction mixture, and the mixture was successively 
extracted with three 30-ml portions of chloroform. The chloroform layer 
was separated, washed with 20 ml of a saturated aqueous solution of sodium 
chloride, and then dried with anhydrous magnesium sulfate. The solvent was 
removed by distillation under reduced pressure to obtain 0.42 g of 
1-(4-fluorophenyl)-6-[2-(pyridin-4-yl)ethenyl]-4-oxo-1,4-dihydronicotinic 
acid having a melting point of 205.degree.-215.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1715, 1690 
The compounds shown in Table 22 were obtained in the same manner. 
TABLE 22 
__________________________________________________________________________ 
##STR875## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR876## 
##STR877## 
213-215 
1720 
##STR878## 
##STR879## 
218-224 
1700 
__________________________________________________________________________ 
EXAMPLE 20 
In 5 ml of benzene was dissolved 1 g of methyl 
3-oxo-5-(pyrrol-2-yl)-4-pentenoate and to this solution was added 0.74 g 
of N,N-dimethylformamidodimethylacetal. They were reacted at 70.degree. C. 
for 1.5 hours. To the reaction mixture was then added 0.56 g of 
4-hydroxyaniline, and they were further reacted at room temperature for 1 
hour. The precipitated crystals were collected by filtration and dissolved 
in 10 ml of N,N-dimethylformamide. They were reacted at 140.degree. C. for 
3 hours. After completion of the reaction, the reaction mixture was cooled 
to room temperature and the solvent was removed by distillation under 
reduced pressure. The residue was purified by a column chromatography 
(Wako Silica Gel C-200; eluent: chloroform) to obtain an oily substance. 
This oily substance was dissolved in 10 ml of dioxane, and to this 
solution was added dropwise a solution of 0.54 g of 
2,3,5,6-tetrachloro-p-benzoquinone in 5 ml of dioxane at 95.degree. C. 
Thereafter, the mixture was subjected to reaction at the same temperature 
for 30 minutes, and the reaction mixture was cooled to room temperature. 
The precipitated crystals were collected by filtration, dissolved in a 
mixture of 5 ml of methanol and 10 ml of a 10% by weight aqueous sodium 
hydroxide solution, and they were reacted at room temperature for 30 
minutes. After completion of the reaction, the reaction mixture was 
adjusted to a pH of 6.0 with acetic acid, and the precipitated crystals 
were collected by filtration, washed with water, and dried to obtain 0.3 g 
of 1-(4-hydroxyphenyl)-4-oxo-6-(pyrrol-2-yl)-1,4-dihydronicotinic acid 
having a melting point of 250.degree. C. or more. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1710. 
NMR (d-TFA) .delta. values: 7.18-7.90 (8H, m, 
##STR880## 
C.sub.5 --H), 9.0 (1H, s, C.sub.2 --H) 
The compounds shown in Table 23 were obtained in the same manner. 
TABLE 23 
__________________________________________________________________________ 
##STR881## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR882## 
##STR883## 202-203.5 
1720, 1700 
##STR884## 
##STR885## 194-197 
1715, 1700 
##STR886## 
##STR887## &gt;250 1720 
##STR888## 
##STR889## &gt;250 1705 
##STR890## 
##STR891## 196-198 
1715, 1700 
##STR892## 
##STR893## &gt;280 1725, 1700 
##STR894## 
##STR895## &gt;250 1730 
##STR896## 
##STR897## &gt;250 1720 
##STR898## 
##STR899## &gt;250 1750 
##STR900## 
##STR901## 218-220 
1715, 1700 
##STR902## 
##STR903## 212-214 
1725 
##STR904## 
##STR905## &gt;250 1725, 1710 
##STR906## 
##STR907## &gt;250 1720, 1700 
##STR908## 
##STR909## 173-176 
1715 
##STR910## 
##STR911## 125-126 
1725 
##STR912## 
##STR913## 267-269 
1730, 1700 
##STR914## 
##STR915## &gt;250 1725, 1700 
##STR916## 
##STR917## &gt;250 1730 
##STR918## 
##STR919## &gt;250 1730 
##STR920## 
##STR921## &gt;280 1720, 1705 
##STR922## 
##STR923## 160-165 
1720 
##STR924## 
##STR925## 277-278 
1725, 1700 
##STR926## 
##STR927## 178-180 
1720 
##STR928## 
##STR929## 208-209 
1725 
##STR930## 
##STR931## &gt;250 1735 
##STR932## 
##STR933## &gt;250 1740 
##STR934## 
##STR935## &gt;250 1750 
##STR936## 
##STR937## &gt;280 1745, 1715 
##STR938## 
##STR939## &gt;280 1725, 1715 
##STR940## 
##STR941## &gt;250 1730 
##STR942## 
##STR943## &gt;250 1735 
##STR944## 
##STR945## 268-271 
1735, 1700 
##STR946## 
##STR947## 282-288 
1730 
##STR948## 
##STR949## 250 (decomp.) 
1725 
##STR950## 
##STR951## 279-282 
1720 
##STR952## 
##STR953## &gt;280 1730, 1710 
##STR954## 
##STR955## 285-288 
1735, 1720 
##STR956## 
##STR957## &gt;250 1750 
##STR958## 
##STR959## &gt;250 1730 
##STR960## 
##STR961## 253-255.5 
1730 
##STR962## 
##STR963## 295-296 
1725 
##STR964## 
##STR965## 261-263 
1720, 1700 
##STR966## 
##STR967## &gt;250 1720 
##STR968## 
##STR969## 220-221 
1730 
##STR970## 
##STR971## 278-282 
1725, 1715 
##STR972## 
##STR973## &gt;250 1720 
##STR974## 
##STR975## &gt;250 1720 
##STR976## 
##STR977## &gt;250 1720 
##STR978## 
##STR979## 245-250 
1720, 1705 
##STR980## 
##STR981## &gt;250 1710, 1690 
##STR982## 
##STR983## &gt;250 1720 
##STR984## 
##STR985## 185-187 
1720 
##STR986## 
##STR987## 281- 283 
1735 
##STR988## 
##STR989## 220-223 
1715 
##STR990## 
##STR991## 195-197 
1720, 1700, 1660 
##STR992## 
##STR993## 182-183 
1715 
##STR994## 
##STR995## 181-183 
1720 
##STR996## 
##STR997## 207-210 
1705 
##STR998## 
##STR999## &gt;250 1730 
##STR1000## 
##STR1001## 
&gt;270 1725 
##STR1002## 
##STR1003## 
122-125 
1720, 1700 
##STR1004## 
##STR1005## 
&gt;250 1725, 1710 
##STR1006## 
##STR1007## 
215-217 
1725, 1705 
##STR1008## 
##STR1009## 
172-174 
1720 
##STR1010## 
##STR1011## 
257-258 
1715 
##STR1012## 
##STR1013## 
&gt;280 1710 
##STR1014## 
##STR1015## 
&gt;280 1725, 1665 
##STR1016## 
##STR1017## 
239-241 
1720, 1700 
##STR1018## 
##STR1019## 
220-223 
1725 
##STR1020## 
##STR1021## 
&gt;250 1725 
##STR1022## 
##STR1023## 
&gt;250 1715, 1705 
##STR1024## 
##STR1025## 
&gt;250 1720, 1710 
##STR1026## 
##STR1027## 
&gt;290 1725, 1710 
##STR1028## 
##STR1029## 
&gt;250 1720, 1700 
##STR1030## 
##STR1031## 
130-133 
1720 
##STR1032## 
##STR1033## 
168-171 
1720 
##STR1034## 
##STR1035## 
&gt;250 1720, 1700 
##STR1036## 
##STR1037## 
247-250 
1720, 1710 
##STR1038## 
##STR1039## 
252-253 
1715 
##STR1040## 
##STR1041## 
193-196 
1720 
##STR1042## 
##STR1043## 
242- 245 
1720, 1710 
##STR1044## 
##STR1045## 
226-230 
1710 
##STR1046## 
##STR1047## 
208-211 
1720 
##STR1048## 
##STR1049## 
227-229 
1725 
##STR1050## 
##STR1051## 
166-167 
1730 
##STR1052## 
##STR1053## 
144-147 
1715 
##STR1054## 
##STR1055## 
205-209 
1715 
##STR1056## 
##STR1057## 
249-251 
1730 
##STR1058## 
##STR1059## 
178-180 
1720 
##STR1060## 
##STR1061## 
234-238 
1670 
##STR1062## 
##STR1063## 
231-233 
1730, 1710 
##STR1064## 
##STR1065## 
220-222 
1730, 1710 
##STR1066## 
##STR1067## 
247-248 
1720 
##STR1068## 
##STR1069## 
140-155 
1725, 1710, 1685 
##STR1070## 
##STR1071## 
&gt;250 1730 
##STR1072## 
##STR1073## 
&gt;250 1725, 1715 
##STR1074## 
##STR1075## 
281-288 
1720, 1700, 1680 
__________________________________________________________________________ 
EXAMPLE 21 
In 10 ml of 47% by weight hydrobromic acid was suspended 0.15 g of 
1-(3,4-methylenedioxyphenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydroni 
cotinic acid, and they were refluxed for 2 hours. After completion of the 
reaction, the reaction mixture was cooled to room temperature, and diluted 
with 10 ml of water. This solution was adjusted to a pH of 12 with a 20% 
weight aqueous sodium hydroxide solution, washed with 20 ml of chloroform, 
and again adjusted to a pH of 6.0 with acetic acid. This solution was 
extracted with 50 ml of chloroform, and the extract was washed with 30 ml 
of a saturated aqueous solution of sodium chloride and dried with 
anhydrous magnesium sulfate. The solvent was removed by distillation under 
reduced pressure, and the residue was purified by a column chromatography 
(Wako Silica Gel C-200; eluent: chloroform/methanol (15:1 by volume) 
mixture) to obtain 0.05 g of 
1-(3,4-dihydroxyphenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotin 
ic acid having a melting point of 223.degree.-227.degree. C. 
IR (KBr) cm.sup.-1 : .nu.C.dbd.O 1720, 1700. 
EXAMPLE 22 
In 3 ml of methanol and 5 ml of 10% by weight aqueous sodium hydroxide 
solution was dissolved 0.5 g of methyl 
6-(4-acetaminophenyl)-1-(3-pyridyl)-4-oxo-1,4-dihydronicotinate, and they 
were reacted at 60.degree. C. for 4 hours. After completion of the 
reaction, the reaction mixture was cooled to room temperature and adjusted 
to a pH of 6.0 with acetic acid, and the precipitated crystals were 
collected by filtration, washed with 10 ml of water, and then dried to 
obtain 0.34 g of 
6-(4-aminophenyl)-1-(3-pyridyl)-4-oxo-1,4-dihydronicotinic acid having a 
melting point of 207.degree.-208.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720, 1700. 
The compounds shown in Table 24 were obtained in the same manner. 
TABLE 24 
__________________________________________________________________________ 
##STR1076## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR1077## 
##STR1078## 
243-250 
1720, 1710 
##STR1079## 
##STR1080## 
&gt;280 1720, 1700 1680 
##STR1081## 
##STR1082## 
&gt;250 1710 
__________________________________________________________________________ 
EXAMPLE 23 
In 18 ml of anhydrous methylene chloride was dissolved 0.36 g of 
1-(4-acetoxyphenyl)-6-(2-benzo[b]thienyl)-4-oxo-1,4-dihydronicotinic acid, 
and to this solution was added 0.137 ml of triethylamine at room 
temperature. The reaction mixture thus obtained was cooled to -40.degree. 
C., and 0.094 ml of ethyl chlorocarbonate was added thereto. The resulting 
mixture was subjected to reaction at the same temperature for 1 hour. This 
reaction mixture was then mixed with 0.14 g of 5-indanol. The mixture was 
subjected to reaction for 1 hour, and elevated to room temperature. After 
completion of the reaction, the reaction mixture was washed successively 
with 15 ml of water and a saturated aqueous solution of sodium chloride, 
and then dried with anhydrous magnesium sulfate. The solvent was removed 
by distillation under reduced pressure, and the residue was purified by a 
column chromatography (Wako Silica Gel C-200; eluent: chloroform) to 
obtain 0.25 g of indanyl 1-(4-acetoxyphenyl)-6-(2-benzo[b]thienyl)-4 
-oxo-1,4-dihydronicotinate having a melting point of 
234.degree.-236.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1760 (Sh), 1745, 1710. 
The compounds shown in Table 25 were obtained in the same manner. 
TABLE 25 
__________________________________________________________________________ 
##STR1083## 
IR (KBr) 
R.sup.3 R.sup.2 R.sup.1 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR1084## 
##STR1085## 
##STR1086## 
234-235 
1745, 1710 
##STR1087## 
##STR1088## 
##STR1089## 
209-211 
1760, 1745 
##STR1090## 
##STR1091## 
CH.sub.2 CH.sub.3 
232-234 
1760, 1725, 1705 
##STR1092## 
##STR1093## 
CH.sub.2 CH.sub.3 
188-190 
1765, 1730, 1690 
##STR1094## 
##STR1095## 
CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 
186-190 
1760, 1730, 1695 
##STR1096## 
##STR1097## 
CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2 
120-123 
1765, 1730 
__________________________________________________________________________ 
EXAMPLE 24 
(1) In 15 ml of N,N-dimethylformamide was dissolved 0.4 g of 
6-(4-dimethylaminophenyl)-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinic 
acid at room temperature, and to this solution was added 0.33 g of 
potassium carbonate. The resulting mixture was heated to 100.degree. C. 
for 1 hour. The reaction mixture thus obtained was cooled to room 
temperature, and 0.2 g of methoxymethyl chloride was added thereto. The 
resulting mixture was subjected to reaction at room temperature for 1 
hour. After completion of this reaction, the solvent was removed by 
distillation under reduced pressure, and the residue was purified by a 
column chromatography (Wako Silica Gel C-200; eluent: chloroform/ethanol 
(30:1 by volume) mixture) to obtain 0.16 g of methoxymethyl 
6-(4-dimethylaminophenyl)-1-(4-methoxymethyloxyphenyl)-4-oxo-1,4-dihydroni 
cotinate having a melting point of 199.degree.-201.degree. C. and 0.13 g of 
methoxymethyl 
6-(4-dimethylaminophenyl)-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinate 
having a melting point of 211.degree.-213.degree. C. 
Methoxymethyl 
6-(4-dimethylaminophenyl)-1-(4-methoxymethyloxyphenyl)-4-oxo-1,4-dihydroni 
cotinate: 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1725, 1695. 
Methoxymethyl 
6-(4-dimethylaminophenyl)-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinate: 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1735, 1700. 
(2) In 1 ml of ethanol was dissolved 0.08 g of methoxymethyl 
6-(4-dimethylaminophenyl)-1-(4-methoxymethyloxyphenyl)-4-oxo-1,4-dihydroni 
cotinate at room temperature, and 1 ml of a 10% by weight aqueous sodium 
carbonate solution was added to the resulting solution. The resulting 
mixture was subjected to reaction at the same temperature for 1 hour. 
After completion of the reaction, the reaction mixture was adjusted to a 
pH of 6.0 with acetic acid, and the precipitated crystals were collected 
by filtration, washed with 5 ml of water, and dried to obtain 0.06 g of 
6-(4-dimethylaminophenyl)-1-(4-methoxymethyloxyphenyl)-4-oxo-1,4-dihydroni 
cotinic acid having a melting point of 150.degree.-152.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720. 
EXAMPLE 25 
In 12 ml of N,N-dimethylformamide was dissolved 0.6 g of methyl 
1-(3-nitro-4-fluorophenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronico 
tinate and to this solution was added 0.2 g of 5% by weight palladium 
carbon, and the above ester was hydrogenated under atmospheric pressure 
for 2 hours. Then, the catalyst was removed by filtration and the solvent 
was removed by distillation under reduced pressure. The resulting residue 
was dissolved in a mixture consisting of 2 ml of ethanol and 2 ml of a 1N 
aqueous sodium hydroxide solution, and the solution was subjected to 
reaction at room temperature for one hour. This reaction mixture was mixed 
with 10 ml of water and 10 ml of chloroform, and the mixture was adjusted 
to a pH of 5.5 with acetic acid. The organic layer was separated, washed 
successively with 10 ml of water and 10 ml of a saturated aqueous solution 
of sodium chloride, and dried with anhydrous magnesium sulfate. Then the 
solvent was removed by distillation under reduced pressure, and the 
residue was purified by a column chromatography (Wako Silica Gel C-200; 
eluent: chloroform/ethanol (100:1 by volume) mixture) to obtain 0.1 g of 
1-(3-amino-4-fluorophenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronico 
tinic acid having a melting point of 198.degree.-201.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720. 
EXAMPLE 26 
To 0.2 g of 5% by weight palladium carbon was added 5 ml of methanol, and 
the resulting mixture was stirred under atmospheric pressure in a hydrogen 
atmosphere for 10 minutes. To this mixture was added a solution prepared 
by dissolving 0.3 of methyl 
6-[4-(p-nitrobenzyl)-2H-3,4-dihydrobenzo-1,4-oxazin-7-yl]-1-(4-fluoropheny 
l)-4-oxo-1,4-dihydronicotinate in 3 ml of methanol. The resulting mixture 
was subjected to hydrogenation at room temperature under 3 atm. for 2 
hours. After completion of the reaction, the catalyst was removed by 
filtration and the solvent was removed by distillation under reduced 
pressure. The residue was purified by a column chromatography (Wako Silica 
Gel C-200; eluent: chloroform/ethanol (25:1 by volume) mixture) and the 
fraction containing the objective substance was concentrated to obtain 
0.17 g of methyl 
6-(2H-3,4-dihydrobenzo-1,4-oxazin-7-yl)-1-(4-fluorophenyl)-4-oxo-1,4-dihyd 
ronicotinate having a melting point of 194.degree.-197.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1725, 1695. 
EXAMPLE 27 
In 10 ml of methanol was dissolved 0.5 g of 
6-(4-hydroxy-3-nitrophenyl)-4-oxo-1-(4-fluorophenyl)-1,4-dihydronicotinic 
acid, and to this solution was added 0.1 g of 5% by weight palladium 
carbon. The said acid was hydrogenated under atmospheric pressure for 2 
hours. After completion of the reaction, the reaction mixture was filtered 
and the filtrate was concentrated under reduced pressure to obtain 0.45 g 
of 
6-(4-hydroxy-3-aminophenyl)-4-oxo-1-(4-fluorophenyl)-1,4-dihydronicotinic 
acid having a melting point of 231.degree.-233.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1730. 
EXAMPLE 28 
In 7 ml of benzene was dissolved 0.6 g of methyl 
5-(4-benzoyl-2H-3,4-dihydrobenzo-1,4-oxazin-6-yl)-3-oxo-4-pentenoate, and 
0.2 g of N,N-dimethylformamidodimethylacetal was added to the solution. 
They were reacted at 60.degree.-70.degree. C. for 2 hours. The reaction 
mixture was cooled to room temperature, and 0.19 g of p-fluoroaniline was 
added thereto. The resulting mixture was subjected to reaction at room 
temperature for 4 hours. After completion of this reaction, the solvent 
was removed by distillation under reduced pressure, and the residue was 
purified by a column chromatography (Wako Silica Gel C-200; eluent: 
toluene/ethyl acetate (20:1 by volume) mixture). The fraction containing 
the objective substance was concentrated and the crystals thus formed were 
dissolved in 5 ml of N,N-dimethylformamide, and they were refluxed for 5 
hours. After completion of the reaction, the solvent was removed by 
distillation under reduced pressure, and the residue was purified by a 
column chromatography (Wako Silica Gel C-200; eluent: chloroform). The 
fraction containing the objective substance was concentrated, and the oily 
substance thus formed was dissolved in 5 ml of toluene, and 0.11 g of 
2,3,5,6-tetrachloro-p-benzoquinone was added to the resulting solution. 
The solution was subjected to reaction at 80.degree.-90.degree. C. for 30 
minutes. After completion of the reaction, the solvent was removed by 
distillation under reduced pressure, and the residue was dissolved in 2 ml 
of chloroform. The insolubles were removed by filtration, and the filtrate 
was purified by a column chromatography (Wako Silica Gel C-200; eluent: 
chloroform). The fraction containing the objective substance was 
concentrated, and to crystals thus formed were added 5 ml of ethanol and 5 
ml of a 1N aqueous sodium hydroxide solution, and they were reacted at 
room temperature for 2 hours. After completion of this reaction, ethanol 
was removed by distillation under reduced pressure, and the residue was 
adjusted to a pH of 6.5 with acetic acid. The precipitated crystals were 
collected by filtration, washed with water, and dried to obtain 0.4 g of 
6-(2H-3,4-dihydrobenzo-1,4-oxazin-6-yl)-1-(4-fluorophenyl)-4-oxo-1,4-dihyd 
ronicotinic acid having a melting point of 155.degree.-167.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720. 
The following compound was obtained in the same manner: 
##STR1098## 
Melting point (.degree.C.): 205-207 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1725. 
EXAMPLE 29 
In 5 ml of benzene was dissolved 0.3 g of methyl 
5-phenyl-3-oxo-4-pentenoate, and 0.2 g of 
N,N-dimethylformamidodimethylacetal was added to the solution. They were 
reacted at 60.degree.-70.degree. C. for 2 hours. The reaction mixture was 
cooled to room temperature, and 0.3 g of 4-(4-acetylpiperazino)-aniline 
was added thereto. The mixture was subjected to reaction at room 
temperature for 4 hours. After completion of the reaction, the solvent was 
removed by distillation under reduced pressure, and the oily substance 
thus obtained was dissolved in 5 ml of N,N-dimethylformamide, and they 
were refluxed for 5 hours. After completion of the reaction, the solvent 
was removed by distillation under reduced pressure, and the residue was 
purified by a column chromatography (Wako Silica Gel C-200; eluent: 
chloroform/ethanol (25:1 by volume) mixture). The fraction containing the 
objective substance was concentrated, and the oily substance thus obtained 
was dissolved in 4 ml of dioxane, and 0.12 g of 
2,3,5,6-tetrachloro-p-benzoquinone was added thereto. They were reacted at 
90.degree.-100.degree. C. for 30 minutes. After completion of the 
reaction, the solvent was removed by distillation under reduced pressure, 
and the residue was purified by a column chromatography (Wako Silica Gel 
C-200; eluent: chloroform/ethanol (100:3 by volume) mixture). The fraction 
containing the objective substance was concentrated, and to the crystals 
thus formed were added 3 ml of 6N hydrochloric acid, and the resulting 
mixture was refluxed for 2 hours. Water was removed by distillation under 
reduced pressure, to obtain 0.12 g of 6-phenyl-1-(4 
-piperazinophenyl)-4-oxo-1,4-dihydronicotinic acid dihydrochloride having 
a melting point of 211.degree.-213.degree. C. (decomp.) 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720, 1695. 
EXAMPLE 30 
5 ml of methanol was carefully added to 0.05 g of 5% by weight palladium 
carbon under ice cooling, and this mixture was stirred under a hydrogen 
atmosphere for 20 minutes, followed by addition of a solution of 0.4 g of 
methyl 
6-(1-benzyloxycarbonyl-3-piperidinyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1 
,4-dihydronicotinate in 2 ml of methanol, and the mixture was subjected to 
hydrogenation under atmospheric pressure for 4 hours. After completion of 
the reaction, the palladium carbon was removed by filtration, and the 
solvent was removed by distillation under reduced pressure. The residue 
was dissolved in 5 ml of methanol, and 1.4 ml of 1N aqueous sodium 
hydroxide was added thereto, and they were reacted at room temperature for 
10 minutes. Thereafter, the solvent was removed by distillation under 
reduced pressure, to obtain 0.15 g of disodium 
6-(3-piperidinyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinate 
having a melting point of 250.degree. C. or more. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1630. 
NMR (d.sub.6 -DMSO-D.sub.2 O) .delta. values: 0.88-3.17 (12H, m, 
##STR1099## 
6.50-7.21 (4H, m, 
##STR1100## 
8.07 (1H, s, 
##STR1101## 
EXAMPLE 31 
(1) 5 ml of methanol was carefully added to 0.06 g of 5% by weight 
palladium carbon under ice cooling, and this mixture was stirred under a 
hydrogen atomosphere at room temperature for 20 minutes, followed by 
addition of a solution of 0.4 g of methyl 
6-(1-benzyloxycarbonyl-4-piperidinyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1 
,4-dihydronicotinate in 2 ml of methanol, and the mixture was subjected to 
hydrogenation under atmospheric pressure for 4 hours. After completion of 
the reaction, the palladium carbon was removed by filtration and the 
solvent was removed by distillation under reduced pressure to obtain 0.24 
g of methyl 
6-(4-piperidinyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinate 
having a melting point of 226.degree.-228.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1730. 
(2) In 4 ml of N,N-dimethylformamide was dissolved 0.24 g of methyl 
6-(4-piperidinyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinate 
, and 0.17 g of isopropyl bromide and 0.06 g of potassium carbonate were 
added to the solution, after which they were reacted at 60.degree. C. for 
6 hours. After completion of the reaction, the solvent was removed by 
distillation under reduced pressure, and the residue was dissolved in a 
mixture of 20 ml of chloroform and 20 ml of water. The organic layer was 
separated, washed twice with 20-ml portions of water, and dried with 
anhydrous sodium sulfate. Then, the solvent was removed by distillation 
under reduced pressure, and the oily substance thus obtained was purified 
by a column chromatography (Wako Silica Gel C-200; eluent: 
chloroform/ethanol (20:1 by volume) mixture). The fraction containing the 
objective substance was concentrated, and to the oily substance thus 
obtained was added 5 ml of 6N hydrochloric acid, and they were refluxed 
for 2 hours. The solvent was removed by distillation under reduced 
pressure to obtain 0.11 g of 
1-(4-hydroxy-2-methylphenyl)-6-(1-isopropyl-4-piperidinyl)-4-oxo-1,4-dihyd 
ronicotinic acid hydrochloride having a melting point of 
195.5.degree.-200.5.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720. 
EXAMPLE 32 
(1) In 20 ml benzene was dissolved 2.0 g of methyl 
5-(cyclohexen-4-yl)-3-oxo-4-pentenoate, and 1.4 g of 
N,N-dimethylformamidodimethylacetal was added thereto. They were reacted 
at 70.degree. C. for 1.5 hours. This reaction mixture was cooled to room 
temperature, and 1.2 g of p-hydroxyaniline was added thereto. They were 
reacted for 1.5 hours. After completion of the reaction, 50 ml of 
diisopropyl ether was added to the reaction mixture and the precipitated 
crystals were collected by filtration and washed with 20 ml of diisopropyl 
ether to obtain 2.1 g of methyl 
5-(cyclohexen-4-yl)-2-(4-hydroxyphenylaminomethylene)-3-oxo-4-pentenoate 
having a melting point of 151.degree.-153.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1710. 
The compounds shown in Table 26 were obtained in the same manner. 
TABLE 26 
__________________________________________________________________________ 
##STR1102## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR1103## 
##STR1104## 
173-175 
1705, 1655 
##STR1105## 
##STR1106## 
142-147 
1700, 1660 
##STR1107## 
##STR1108## 
-- 1700 (neat) 
##STR1109## 
##STR1110## 
167-169 
1700, 1680, 1660 
##STR1111## 
##STR1112## 
167-168 
1720, 1700 
##STR1113## 
##STR1114## 
141-145 
1725, 1695 
##STR1115## 
##STR1116## 
120-130 
1725, 1710 
__________________________________________________________________________ 
(2) In 20 ml of N,N-dimethylformamide was dissolved 2.0 g of methyl 
5-(cyclohexen-4-yl)-2-(4-hydroxyphenylaminomethylene)-3-oxo-4-pentenoate, 
and they were reacted at 140.degree. C. for 4 hours. After completion of 
the reaction, the solvent was removed by distillation under reduced 
pressure, and to the residue was added 50 ml of dioxane, after which the 
precipitated crystals were collected by filtration and washed with 30 ml 
of diethyl ether to obtain 1.4 g of methyl 
6-(cyclohexen-4-yl)-1-(4-hydroxyphenyl)-4-oxo-1,4,5,6-tetrahydronicotinate 
having a melting point of 155.degree.-157.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1715. 
The compounds shown in Table 27 were obtained in the same manner. 
TABLE 27 
__________________________________________________________________________ 
##STR1117## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR1118## 
##STR1119## 
217-219 
1720, 1690 
##STR1120## 
##STR1121## 
154-157 
1720, 1705 
##STR1122## 
##STR1123## 
-- 1720 (neat) 
##STR1124## 
##STR1125## 
201-205 
1720, 1710 
##STR1126## 
##STR1127## 
197-201 
1725, 1710, 1670 
##STR1128## 
##STR1129## 
105-110 
1725, 1710 
##STR1130## 
##STR1131## 
110-120 
1720 
__________________________________________________________________________ 
(3) In 20 ml of dioxane was dissolved 1.0 g of methyl 
6-(cyclohexen-4-yl)-1-(4-hydroxyphenyl)-4-oxo-1,4,5,6-tetrahydronicotinate 
, and the resulting solution was heated to 80.degree. C. To this solution 
was added dropwise a solution of 0.83 g of 
2,3,5,6-tetrachloro-p-benzoquinone in 20 ml of dioxane at 80.degree. C., 
followed by reaction at the same temperature for 1 hour. After completion 
of this reaction, the reaction mixture was cooled to room temperature, and 
the precipitated crystals were collected by filtration and washed with 50 
ml of dioxane to obtain 0.7 g of methyl 
6-(cyclohexene-4-yl)-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinate 
having a melting point of 250.degree. C. or more. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1735, 1705. 
NMR (d.sub.6 -DMSO) .delta. values: 
##STR1132## 
The compounds shown in Table 28 were obtained in the same manner. 
TABLE 28 
__________________________________________________________________________ 
##STR1133## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR1134## 
##STR1135## 
&gt;250 1730 
##STR1136## 
##STR1137## 
&gt;250 1735, 1705 
##STR1138## 
##STR1139## 
247-249 
1725 
##STR1140## 
##STR1141## 
240-243 
1730, 1700 
##STR1142## 
##STR1143## 
254-257 
1725, 1695 
##STR1144## 
##STR1145## 
130-135 
1725, 1710 
##STR1146## 
##STR1147## 
150-158 
1720, 1700 
__________________________________________________________________________ 
(4) In a mixture consisting of 5 ml of methanol and 5 ml of a 1N aqueous 
sodium hydroxide solution was dissolved 0.5 g of methyl 
6-(cyclohexen-4-yl)-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinate, and 
they wre reacted at room temperature for 30 minutes. After completion of 
the reaction, the reaction mixture was adjusted to a pH of 5.5 with acetic 
acid, and the precipitated crystals were collected by filtration, washed 
with 30 ml of water, and dried to obtain 0.35 g of 
6-(cyclohexen-4-yl)-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinic acid 
having a melting point of 250.degree. C. or more. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1725, 1700. 
NMR (D.sub.6 -DMSO) .delta. values: 
##STR1148## 
The compounds shown in Table 29 were obtained in the same manner. 
TABLE 29 
__________________________________________________________________________ 
##STR1149## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR1150## 
##STR1151## 
&gt;250 1725, 1710 
##STR1152## 
##STR1153## 
242-243 
1742 
##STR1154## 
##STR1155## 
195-197 
1715 
##STR1156## 
##STR1157## 
150-165 
1720 
##STR1158## 
##STR1159## 
259-261 
1725, 1710 
##STR1160## 
##STR1161## 
271-273 
1730, 1685 
##STR1162## 
##STR1163## 
190-200 
1720, 1705, 1690 
__________________________________________________________________________ 
EXAMPLE 33 
In 30 ml of N,N-dimethylformamide was dissolved 2.0 g of methyl 
5-(cyclohexen-4-yl)-3-oxo-4-pentenoate and 1.4 g of 
N,N-dimethylformamidodimethylacetal was added thereto. They were reacted 
at 70.degree. C. for 1.5 hours. To the reaction mixture was then added 1.3 
g of 4-hydroxy-2-methylaniline at 70.degree. C., and the resulting mixture 
was subjected to reaction at 80.degree. C. for 2 hours and at 140.degree. 
C. for 3 hours. After completion of this reaction, the reaction mixture 
was cooled to room temperature, and the solvent was removed by 
distillation under reduced pressure. The residue was dissolved in 20 ml of 
dioxane, and a solution of 2.4 g of 2,3,5,6-tetrachloro-p-benzoquinone in 
15 ml of dioxane was added dropwise thereto at 80.degree. C., followed by 
reaction at the same temperature for one hour. After completion of the 
reaction, the solvent was removed by distillation under reduced pressure, 
and the residue was suspended in 30 ml of chloroform and 30 ml of water. 
After adjusting the pH of the suspension to 7.5 with sodium 
hydrogencarbonate, the organic layer was separated, washed successively 
with 10 ml of water and 20 ml of a saturated aqueous solution of sodium 
chloride, and then dried with anhydrous magnesium sulfate. The solvent was 
removed by distillation under reduced pressure to obtain 1.3 g of methyl 
6-(cyclohexen-4-yl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotina 
te having a melting point of 250.degree. C. or more. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1735, 1705. 
NMR (d.sub.6 -DMSO) .delta. values: 
##STR1164## 
TABLE 30 
__________________________________________________________________________ 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR1165## 
##STR1166## 252-254 
1730 
##STR1167## 
##STR1168## &gt;250 1725, 1705 
##STR1169## 
##STR1170## &gt;250 1725, 1700 
##STR1171## 
##STR1172## &gt;250 1725 
##STR1173## 
##STR1174## &gt;250 1730 
##STR1175## 
##STR1176## &gt;250 1735, 1705 
CH.sub.3 CHCH (trans) 
##STR1177## 162-164 
1740 
##STR1178## 
##STR1179## 286-288 
1740 
##STR1180## 
##STR1181## 293-294 
1730-1710 
##STR1182## 
##STR1183## 204-205 
1730 
ClCH.sub.2 CH.sub.2 
##STR1184## 118-120 
1730 
__________________________________________________________________________ 
EXAMPLE 34 
In 80 ml of chloroform was dissolved 2.0 g of methyl 
6-(cyclohexen-4-yl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotina 
te and the solution was cooled to 5.degree. C. To this solution was added 
dropwise a solution of 1.0 g of bromine in 5 ml of chloroform at 5.degree. 
C. over 30 minutes. The mixture was subjected to reaction at room 
temperature for 30 minutes. After completion of the reaction, the solvent 
was removed by distillation under reduced pressure. Then, 50 ml of diethyl 
ether was added to the resulting residue, and the precipitated crystals 
were collected by filtration and washed with 20 ml of diethyl ether to 
obtain 2.5 g of methyl 
6-(3,4-dibromocyclohexyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydroni 
cotinate having a melting point of 197.degree.-200.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1730, 1700 
EXAMPLE 35 
The compounds shown in Table 31 were obtained by hydrolyzing the 
corresponding methyl esters in the same manner as in Example 32-(4). 
TABLE 31 
______________________________________ 
##STR1185## 
IR (KBr) 
m.p. cm.sup.-1 : 
R.sup.3 R.sup.2 (.degree.C.) 
.nu..sub.C.dbd.O 
______________________________________ 
##STR1186## 
##STR1187## 235- 236 
1715 
##STR1188## 
##STR1189## 175- 178 
1725, 1700 
##STR1190## 
##STR1191## 226- 227 
1725 
##STR1192## 
##STR1193## 182- 184 
1720 
##STR1194## 
##STR1195## 171- 174 
1720 
##STR1196## 
##STR1197## &gt;250 1720, 1710 
CH.sub.3 CHCH (trans) 
##STR1198## 245- 248 
1730 
##STR1199## 
##STR1200## &gt;280 1720 
##STR1201## 
##STR1202## &gt;280 1730, 1710, 1690, 1660 
##STR1203## 
##STR1204## 172- 183 
1725 
##STR1205## 
##STR1206## 183- 185 
1725 
______________________________________ 
EXAMPLE 36 
(1) In 5 ml of benzene was dissolved 0.7 g of methyl 
5-(cyclopenten-1-yl)-3-oxo-4-pentenoate, and 0.6 g of 
N,N-dimethylformamidodimethylacetal was added thereto. They were reacted 
at 70.degree. C. for 1.5 hours. The reaction mixture was cooled to room 
temperature, and 0.44 g of 4-hydroxy-2-methylaniline was added thereto. 
The resulting mixture was subjected to reaction for addtional 1.5 hours. 
After completion of the reaction, 5 ml of diethyl ether was added, and the 
precipitated crystals were collected by filtration, and washed with 5 ml 
of diethyl ether to obtain 0.7 g of methyl 
5-(cyclopenten-1-yl)-2-(4-hydroxy-2-methylphenylaminomethylene)-3-oxo-4-pe 
ntenoate having a melting point of 148.degree.-151.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1705. 
The compounds shown in Table 32 were obtained in the same manner. 
TABLE 32 
______________________________________ 
##STR1207## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
______________________________________ 
##STR1208## 
##STR1209## 161-162 1700 
##STR1210## 
##STR1211## 145-148 1660 
##STR1212## 
##STR1213## 168-170 1700 
______________________________________ 
(2) In 5 ml of N,N-dimethylformamide was dissolved 0.7 g of methyl 
5-(cyclopenten-1-yl)-2-(4-hydroxy-2-methylphenylaminomethylene)-3-oxo-4-pe 
ntenoate, and they were reacted at 140.degree. C. for 2 hours. After 
completion of the reaction, the solvent was removed by distillation under 
reduced pressure, and the residue was purified by a column chromatography 
(Wako Silica Gel C-200; eluent: chloroform) to obtain an oily substance. 
This oily substance was dissolved in 10 ml of dioxane, and 0.5 g of 
2,3,5,6-tetrachloro-p-benzoquinone was added thereto. They were reacted at 
80.degree. C. for 30 minutes. The reaction mixture was cooled to room 
temperature, and the precipitated crystals were collected by filtration, 
and washed with 5 ml of dioxane. These crystals were dissolved in a 
mixture of 5 ml of methanol and 5 ml of a 1N aqueous sodium hydroxide 
solution, the resulting mixture was subjected to reaction at room 
temperature for 30 minutes. The reaction mixture was adjusted to a pH of 
5.5 with acetic acid and the precipitated crystals were collected by 
filtration, washed with water, and dried to obtain 1.3 g of 
6-(cyclopenten-1-yl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotin 
ic acid having a melting point of 211.degree.-213.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720, 1700. 
The compounds shown in Table 33 were obtained in the same manner. 
TABLE 33 
______________________________________ 
##STR1214## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
______________________________________ 
##STR1215## 
##STR1216## &gt;250 1720, 1710 
##STR1217## 
##STR1218## &gt;250 1730, 1725 
##STR1219## 
##STR1220## 162-164 1720 
______________________________________ 
EXAMPLE 37 
In 5 ml of benzene was dissolved 0.3 g of methyl 
5-cyclooctyl-3-oxo-4-pentenoate, and 0.3 g of 
N,N-dimethylformamidodimethylacetal was added thereto. They were reacted 
at 70.degree. C. for one hour. Then, the reaction mixture was cooled to 
room temperature, and 0.27 g of 4-hydroxy-2-methylaniline was added 
thereto. The resulting mixture was subjected to reaction at room 
temperature for 2 hours. After completion of this reaction, the solvent 
was removed by distillation under reduced pressure, and the residue was 
purified by a column chromatography (Wako Silica Gel C-200; eluent: 
toluene/ethyl acetate (50:1 by volume) mixture). The fraction containing 
the objective substance was concentrated, and the oily substance thus 
obtained was dissolved in 5 ml of N,N-dimethylformamide and the resulting 
mixture was refluxed for 4 hours. After completion of the reaction, the 
solvent was removed by distillation under reduced pressure, and the 
residue was purified by a column chromatography (Wako Silica Gel C-200; 
eluent: chloroform/ethanol (50:1 by volume) mixture). The fraction 
containing the objective substance was concentrated and the oily substance 
thus obtained was dissolved in 5 ml of dioxane, and 0.2 g of 
2,3,5,6-tetrachloro-p-benzoquinone was added thereto, and they were 
reacted at 80.degree.-90.degree. C. for 30 minutes. The reaction mixture 
was cooled to room temperature, and the precipitated crystals were 
collected by filtration. These crystals were dissolved in 20 ml of 
chloroform, and after removing the insolubles, the chloroform was removed 
by distillation under reduced pressure. To the residue was added 5 ml of a 
1N aqueous sodium hydroxide solution and 5 ml of methanol, and they were 
reacted at room temperature for 30 minutes. After the methanol was removed 
by distillation under reduced pressure, the resulting solution was 
adjusted to a pH of 6.5 with 2N hydrochloric acid, and the precipitated 
crystals were collected by filtration, washed with water, and dried to 
obtain 0.14 g of 
6-cyclooctyl-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid 
having a melting point of 118.degree.-120.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1725, 1710. 
The compounds shown in Table 34 were obtained in the same manner. 
TABLE 34 
__________________________________________________________________________ 
##STR1221## 
IR (KBr) 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
cm.sup.-1 : .nu..sub.C.dbd.O 
__________________________________________________________________________ 
##STR1222## 
##STR1223## 
&gt;270 1720 
##STR1224## 
##STR1225## 
229-232 
1720 
##STR1226## 
##STR1227## 
102-104 
1720 
##STR1228## 
##STR1229## 
115-118 
1720, 1700 
__________________________________________________________________________ 
EXAMPLE 38 
In a mixture of 10 ml of dioxane and 5 ml of water was dissolved 0.15 g of 
6-(4-benzyloxycarbonylaminocyclohexyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo- 
1,4-dihydronicotinic acid, and 0.03 g of 5% by weight palladium carbon was 
added. The above acid was hydrogenated under atmospheric pressure for 3 
hours. The catalyst was removed by filtration and the solvent was then 
removed by distillation under reduced pressure. To the residue was added 3 
ml of diethyl ether, and the precipitated crystals were collected by 
filtration and washed with 3 ml of diethyl ether to obtain 0.095 g of 
6-(4-aminocyclohexyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicoti 
nic acid having a melting point of 237.degree.-250.degree. C. (decomp.). 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1715. 
The compounds shown in Table 35 were obtained in the same manner. 
TABLE 35 
______________________________________ 
##STR1230## 
IR 
(KBr) 
cm.sup.-1 : 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
.nu..sub.C.dbd.O 
______________________________________ 
H.sub.2 NCH.sub.2 CH.sub.2 
##STR1231## 220-225 1725, 1710, 1690 
##STR1232## 
##STR1233## &gt;250 1720 
______________________________________ 
EXAMPLE 39 
In 15 ml of methanol was dissolved 0.2 g of methyl 
6-(4-benzyloxycarbonylaminocyclohexyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo- 
1,4-dihydronicotinate, and 0.05 g of 5% by weight palladium carbon was 
added to the resulting solution, and the above ester was hydrogenated 
under atmospheric pressure for 1.5 hours. Then, the catalyst was removed 
by filtration, and the solvent was removed by distillation under reduced 
pressure. To the residue was added 0.4 g of 37% by weight formalin and 0.1 
g of formic acid, and they were reacted at 100.degree. C. for 7.5 hours. 
After completion of this reaction, the solvent was removed by distillation 
under reduced pressure, and the residue was purified by a column 
chromatography (Wako Silica Gel C-200; eluent: chloroform/ethanol (3:1 by 
volume) mixture) to obtain 0.04 g of 
6-(4-dimethylaminocyclohexyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihyd 
ronicotinic acid having a melting point of 207.degree.-215.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720. 
The compound shown in Table 36 was obtained in the same manner. 
TABLE 36 
______________________________________ 
##STR1234## 
IR (KBr) 
cm.sup.-1 : 
R.sup.3 R.sup.2 m.p. (.degree.C.) 
.nu..sub.C.dbd.O 
______________________________________ 
##STR1235## 
##STR1236## 
177-183 1720 
______________________________________ 
EXAMPLE 40 
(1) In 315 ml of dioxane was dissolved 10.5 g of methyl 
1-(4-acetoxy-2-methylphenyl)-6-methyl-4-oxo-1,4-dihydronicotinate under 
heating, and 4.43 g of selenium dioxide was added thereto. They were 
reacted at 100.degree. C. for 2 hours. After cooling the reaction mixture, 
to room temperature, selenium was removed by filtration, and then the 
solvent was removed by distillation under reduced pressure. The residue 
was purified by a column chromatography (Wako Silica Gel C-200; eluent: 
chloroform/ethanol (25:1 by volume) mixture) to obtain 7.9 g of methyl 
1-(4-acetoxy-2-methylphenyl)-6-formyl-4-oxo-1,4-dihydronicotinate having a 
melting point of 216.degree.-217.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1760, 1730, 1700 (sh) 
(2) To 0.95 g of methyl 
1-(4-acetoxy-2-methylphenyl)-6-formyl-4-oxo-1,4-dihydronicotinate was 
added 5 ml of 6N hydrochloric acid, and they were reacted at 100.degree. 
C. for one hour. The reaction mixture was cooled to room temperature, and 
adjusted to a pH of 7.5 with a saturated aqueous sodium hydrogencarbonate 
solution. Then, 100 ml of acetonitrile was added, and the aqueous layer 
was saturated with sodium chloride. The organic layer was separated, 
washed with a saturated aqueous solution of sodium chloride and then dried 
with anhydrous magnesium sulfate. The solvent was removed by distillation 
under reduced pressure to obtain 0.6 g of 
6-formyl-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid 
having a melting point of 230.degree.-250.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1715. 
(3) In 5 ml of methanol was dissolved 0.15 g of 
6-formyl-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid, and 
0.19 g of ethoxycarbonylmethylenetriphenylphosphorane was added thereto. 
They were reacted at room temperature for one hour. After completion of 
the reaction, the solvent was removed by distillation under reduced 
pressure, and the residue was purified by a column chromatography (Wako 
Silica Gel C-200; eluent: chloroform/ethanol (50:1 by volume) mixture) to 
obtain 0.06 g of 
6-(2-ethoxycarbonylethenyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydro 
nicotinic acid having a melting point of 185.degree.-189.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720, 1705. 
(4) To 0.09 g of 
6-(2-ethoxycarbonylethenyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydro 
nicotinic acid was added 3 ml of 6N hydrochloric acid, and they were 
reacted at 100.degree. C. for 1.5 hours. After completion of the reaction, 
the solvent was removed by distillation under reduced pressure, and to the 
crystals thus formed were added 3 ml of diethyl ether, and the resulting 
mixture was filtered to obtain 0.08 g of 
6-(2-carboxyethenyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotin 
ic acid having a melting point of 280.degree. C. or more. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720. 
NMR (d.sub.6 -DMSO) .delta. values: 
2.0 (3H, s, 
##STR1237## 
6.33--7.7 (6H, m, 
##STR1238## 
C.sub.5 --H, --CH.dbd.CH--), 8.63 (1H, s, C.sub.2 --H) 
EXAMPLE 41 
In 5 ml of methanol was dissolved 0.15 g of 
6-formyl-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydroniotinic acid, and 
0.056 g of N-aminomorpholine was added thereto. They were reacted at 
65.degree. C. for one hour. After completion of this reaction, the solvent 
was removed by distillation under reduced pressure, and the residue was 
purified by a column chromatography (Wako Silica Gel C-200; eluent: 
chloroform) to obtain 0.06 g of 
1-(4-hydroxy-2-methylphenyl)-6-(morpholinoiminomethyl)-4-oxo-1,4-dihydroni 
cotinic acid having a melting point of 267.degree.-268.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1730. 
The compounds shown in Table 37 were obtained in the same manner. 
TABLE 37 
______________________________________ 
##STR1239## 
IR 
(KBr) 
m.p. cm.sup.-1 : 
R.sup.3 R.sup.2 (.degree.C.) 
.nu..sub.C.dbd.O 
______________________________________ 
##STR1240## 
##STR1241## 249-250 1725 
##STR1242## 
##STR1243## 193-199 1725, 1710, 1695 
HONCH 
##STR1244## 268-269 1715 
CH.sub.3 ONCH 
##STR1245## 269-271 1730, 1710 
##STR1246## 
##STR1247## 264-266 1750 
______________________________________ 
EXAMPLE 42 
In 20 ml of N,N-dimethylformamide was dissolved 2 g of methyl 
1-(4-benzyloxy-2-methylphenyl)-6-(2-chloroethyl)-4-oxo-1,4-dihydronicotina 
te, and 0.9 g of 4-ethyl-2,3-dioxopiperazine-1-sodium was added thereto at 
5.degree. C. over 20 minutes, and they were reacted at the same 
temperature for 30 minutes. After completion of the reaction, the solvent 
was removed by distillation under reduced pressure, and the residue was 
dissolved in 20 ml of chloroform, washed successively with 20 ml of water 
and 20 ml of a saturated aqueous solution of sodium chloride and then 
dried with anhydrous magnesium sulfate. The solvent was removed by 
distillation under reduced pressure to obtain an oily substance, and this 
oily substance was dissolved in a mixture of 10 ml of methanol and 10 ml 
of a 1N aqueous sodium hydroxide solution. They were reacted at room 
temperature for 30 minutes. After completion of the reaction, the reaction 
mixture was adjusted to a pH of 6.0 with acetic acid, and the precipitated 
crystals were collected by filtration, washed with water, and then 
dissolved in 10 ml of dioxane and 5 ml of water. Further, 0.2 g of 5% by 
weight palladium carbon was added thereto, and the resulting mixture was 
subjected to hydrogenation for 10 hours. After completion of this 
reaction, the reaction mixture was filtered, and the filtrate was 
concentrated under reduced pressure to obtain 0.8 g of 
6-[2-(4-ethyl-2,3-dioxopiperazin-1-yl)-ethyl]-1-(4-hydroxy-2-methylphenyl) 
-4-oxo-1,4-dihydronicotinic acid having a melting point of 
182.degree.-190.degree. C. (decomp.). 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1730. 
EXAMPLE 43 
In 20 ml of benzene was dissolved 3.0 g of methyl 
7-(4-benzyloxycarbonyl-piperazin-1-yl)-3-oxo-4-heptenoate, and 1.2 g of 
N,N-dimethylformamidodimethylacetal was added thereto. They were reacted 
at 70.degree. C. for 1.5 hours. The reaction mixture was cooled to room 
temperature, and 1.0 g of 4-hydroxy-2-methylaniline was added thereto. The 
resulting mixture was subjected to reaction at the same temperature for 
1.5 hours. After completion of this reaction, the precipitated crystals 
were collected by filtration, and washed with 10 ml of benzene. The 
crystals thus formed were dissolved in 20 ml of N,N-dimethylformamide, and 
they were reacted at 140.degree. C. for 3 hours. After completion of the 
reaction, the reaction mixture was cooled to room temperature, and the 
solvent was removed by distillation under reduced pressure. The residue 
was purified by a column chromatography (Wako Silica Gel C-200; eluent: 
chloroform) to obtain an oily substance. This oily substance was dissolved 
in 20 ml of dioxane, and 0.7 g of 2,3,5,6-tetrachloro-p-benzoquinone was 
added thereto, and they were reacted at 80.degree. C. for 30 minutes. 
After completion of the reaction, the reaction mixture was cooled to room 
temperature, and the precipitated crystals were collected by filtration, 
and washed with 10 ml of dioxane. The resulting crystals were dissolved in 
10 ml of a 1N aqueous sodium hydroxide solution, and the resulting 
solution was subjected to reaction at room temperature for 30 minutes. The 
reaction mixture was adjusted to a pH of 6.0 with acetic acid, and the 
precipitated crystals were collected by filtration, washed with water, and 
then dissolved in 10 ml of dioxane and 5 ml of water. Further, 0.2 g of 5% 
by weight palladium carbon was added thereto. The resulting mixture was 
subjected to hydrogenation under atmospheric pressure for 2 hours. After 
completion of the reaction, to the reaction mixture was added 5 ml of 2N 
hydrochloric acid, and the resulting mixture was filtered, after which the 
filtrate was concentrated to obtain 0.4 g of 
1-(4-hydroxy-2-methylphenyl)-6-[2-(piperazine-1-yl)ethyl]-4-oxo-1,4-dihydr 
onicotinic acid dihydrochloride having a melting point of 
140.degree.-148.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1720 
EXAMPLE 44 
In 5 ml of water was suspended 0.15 g of dimethylaminoethyl 
1-(4-acetyloxyphenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinat 
e at room temperature, and 0.04 g of L-aspartic acid was added thereto. 
They were reacted at 60.degree. C. for 30 minutes, and the reaction 
mixture was cooled to room temperature. The insolubles were removed by 
filtration, and the solvent was removed by distillation under reduced 
pressure. The residue was dehydrated azeotropically with toluene and dried 
to obtain 1.2 g of L-aspartic salt of dimethylaminoethyl 
1-(4-acetyloxyphenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinat 
e having a melting point of 144.degree.-147.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1760, 1725, 1700 
The following compound was obtained in the same manner: 
##STR1248## 
Melting point (.degree.C.): 115-118. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1760, 1725, 1700. 
EXAMPLE 45 
In 20 ml of methylene chloride was dissolved 0.8 g of 
1-(4-acetyloxyphenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinic 
acid, and the resulting solution was cooled to 5.degree. C. To this 
solution was added dropwise 0.3 g of oxalyl chloride at the same 
temperature, and they were reacted for one hour. After completion of the 
reaction, 0.84 g of 1,2-O-isopropylidene glycerin and 0.26 g of 
triethylamine were added successively at the same temperature, and the 
resulting mixture was further subjected to reaction for 2 hours. This 
reaction mixture was introduced into 50 ml of ice water, and the organic 
layer was separated, washed successively with 50 ml of water and then with 
50 ml of a saturated aqueous solution of sodium chloride, and dried with 
anhydrous magnesium sulfate. The solvent was removed by distillation under 
reduced pressure, and the residue was suspended in 15 ml of 60% by weight 
acetic acid. The suspension was subjected to reaction at 60.degree. C. for 
3 hours. After completion of this reaction, the solvent was removed by 
distillation under reduced pressure, and the residue was purified by a 
column chromatography (Wako Silica Gel C-200; eluent: chloroform/ethanol 
(15:1 by volume) mixture) to obtain 0.3 g of 2,3-dihydroxypropyl 
1-(4-acetyloxyphenyl)-6-dimethylaminophenyl-4-oxo-1,4-dihydronicotinate 
having a melting point of 145.degree.-147.degree. C. 
IR (KBr) cm.sup.-1 : .nu..sub.C.dbd.O 1760, 1730, 1680. 
PREATION EXAMPLE 1 
With 50 g of 1-pivaloyloxyethyl 
6-(4-dimethylaminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinate 
were mixed 49 g of crystalline cellulose, 50 g of corn starch and 1 g of 
magnesium stearate, and the resulting mixture was tableted into 1,000 flat 
tablets. 
PREATION EXAMPLE 2 
With 100 ml of 1-pivaloyloxyethyl 
6-(4-dimethylaminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinate 
was mixed 50 g of corn starch, and the resulting mixture was encapsulated 
to from 1,000 capsules. 
PREATION EXAMPLE 3 
In a suitable amount of distilled water for injection were dissolved 200 mg 
of sodium 
1-(2-fluoro-4-hydroxyphenyl)-6-(1-methylindol-5-yl)-4-oxo-1,4-dihydronicot 
inate and 250 mg of dextrose, and this solution was placed in a 5-ml 
ampule. After purging with nitrogen, the ampul was sterilized under 
pressure at 121.degree. C. for 15 minutes to obtain an injection.