AU612993B2 - 1,4-dihydro-4-oxonaphthyridine derivatives and salts thereof, process for producing the same and antibacterial agents comprising the same - Google Patents
1,4-dihydro-4-oxonaphthyridine derivatives and salts thereof, process for producing the same and antibacterial agents comprising the same Download PDFInfo
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- AU612993B2 AU612993B2 AU81804/87A AU8180487A AU612993B2 AU 612993 B2 AU612993 B2 AU 612993B2 AU 81804/87 A AU81804/87 A AU 81804/87A AU 8180487 A AU8180487 A AU 8180487A AU 612993 B2 AU612993 B2 AU 612993B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Description
ONE HUNDRED 6OI.ARS ONIE/1[IN 1ED DOLLA it any Note: No legalization or other witness required 'i 1 TfLAL.L1EMy, C.ULLT STOYA~ ~CHMIAL n CO., L-TD.
iii 111, I I- I PHILLIPS ORMONDE AND FITZPATRICK Patent and Trade Mark Attorneys FE 7STAMP TO VALUE OF 367 Collins Street A Melbourne, Australia
ATACHED
SMAIL OFICER1L' P17/2/83 -7 ii:
AUSTRALIA
Patents Act 612993 CO MPLETE SPECIFICATION
(ORIGINAL)
Class Application Number: Lodged: S Complete Specification Lodged: Accepted: Published: Priority Int. Class Related Art: APPLICANT'S REF.: A9714-42CB DIV. OF 41650/86 Name(s) of Applicant(s): TOYAMA CHEMICAL CO., LTD.
o Address(es) of Applicant(s): Actual Inventor(s): Address for Service is: 2-5, 3-chome, Nishishinjuku, Shinjuku-ku, Tokyo, JAPAN HIROKAZU NARITA YOSHINORI KONISHI JUN NITTA HIDEYOSHI NAGAKI ISAO KITAYAMA YORIKO KOBAYASHI MIKAKO SHINAGAWA YASUO WATANABE AKIRA YOTSUJU SHINZABURO MINAMI ISAMU SAIKAWA PHILLIPS, ORMONDE AND FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne, Australia, 3000 Complete Specification for the invention entitled: 1,4-DIHYDRO-4-OXONAPHTHYRIDINE
DERIVATIVES
AND SALTS THEREOF, PROCESS FOR PRODUCING THE SAME AND ANTIBACTERIAL AGENTS COMPRISING THE SAME The following statement is a full description of this invention, including the best method of performing it known to applicant(s): P19/3/84
A
-la- This application is divided from Australian Patent Application 41650/85, granted as Australian Patent 565087.
I
This invention relates to a novel 1,4-dihydro- 4-oxonaphthyridine derivative having a substituted or unsubstituted aryl group at the 1-position and a halogen atom or a substituted or unsubstituted cyclic amino group at the 7-position and a salt thereof, a process for producing the same and an antibacterial agent comprising the same.
Nalidixic acid, piromidic acid, pipemidic acid and the like have heretofore been widely used as synthetic antibacterial agents. However, none of these agents are satisfactory in therapeutic effects on the infections of Ps.
aeruginosa and a Gram-positive bacteria which are refractory diseases. Therefore, various pyridone carboxylic acid type compounds are being developed, for example, l-ethyl-6-fluoro- 1,4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinolinecarboxylic acid (norfloxacin) or the like, as a substitute for the conventional synthetic antibacterial agents. These compounds have excellent antibacterial activities against various Gram-negative bacteria including Ps. aeruginosa, but are unsatisfactory in antibacterial activities against Gram-positive bacteria. Therefore, the development of a synthetic antibacterial agent having a broad antibacterial spectrum has been desired which agent is effective on not only Gram-negative bacteria but also Gram-positive bacteria.
Under these circumstances, the present inventors have, as a result of extensive research, found that a novel 1,4-dihydro-4-oxonaphthyridine derivative and a salt thereof can solve the aforementioned problems.
An object of this invention is to provide a novel 1,4-dihydro-4-oxonaphthyridine derivative and a salt thereof having excellent properties, for example, strong antibacterial activities against Gram-positive and Gram-negative bacteria, particularly against antibiotic resistant bacteria, and giving high concentrations in blood when administered orally or parenterally, and being high in safety.
Another object of this invention is to provide a process for producing a novel 1,4-dihydro-4-oxonaphthyridine derivative and a salt thereof.
A further object of this invention is to provide an antibacterial agent which in useful for the treatment of 2- -1 infections of bacteria or the like and which comprises a novel 1,4-dihydro-4-oxonaphthyridine derivative or a salt thereof.
According to this invention, there is provided a 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula: 0 RF COOR1 R3.- I [I] R N N 2
R
herein l re sents a hydrogen -atom or a carboxyl-protecting group, R 2 represents a substituted or 3 unsubstituted aryl group, and R represents a halogen atom or a substituted or unsubstituted cyclic amino group, and a 2 salt thereof except for the combination of R bei a 3 2,4-difluoroph .yl group and R being a 3- ino-lpyrrolidinyl group in which the amino group may be p tected.
Further, this invention provides a rocess for producing a 1,4-dihydro-4-oxonaphthyridine de vative represented by the general formula or a salt hereof, and also an antibacterial agent comprising /he 1,4-dihydro-4oxonaphthyridine derivative represe ed by the general formula or a salt thereof.
This invention will be e lained in detail below.
In the compound repre ented by the general formula or a salt thereof, the arboxyl-protecting group for R includes, for example, -ster-forming groups which may be removed by catalytic Dduction, chemical reduction or other treatments under mi conditions; ester-forming groups which may be easily moved in a living body; organic silylcontaining gro s, organic phosphorus-containing groups and organic tin- ontaining groups which may be easily removed by treatment with water or an alcohol; and other various well-kn n ester forming groups.
Among these carboxyl-protecting groups, the pr ferred protecting groups include, for example, carboxylrotecting groups described in Japanese Patent Application R5, .r.
1 wherein R represents a hydrogen atom or a conventional carboxyl-protecting group used in the cephalosporin or 2 Spenicillin art, R represents a 2,4-difluorophenyl group, i'j 3 and R represents a halogen atom or a 1-piperazinyl group in which the imino group may be protected by oer aA c Ij Further, this invention provides a process for producing a l,4-dihydro-4-oxonaphthyridine derivative represented by the general formula or a salt thereof, and also an antibacterial agent comprising the l,4-dihydro-4- S 10 oxonaphthyridine derivative represented by the general formula or a salt thereof.
This invention will be explained in detail below.
In the compound represented by the general formula or a salt thereof, the carboxyl-protecting group for R i includes, for example, ester-forming groups which may be 1 removed by catalytic reduction, chemical reduction or other treatments under mild conditions; ester-forming groups which may be easily removed in a living body; organic silylcontaining groups, organic phosphorus-containing groups and i o, organic tin-containing groups which may be easily removed by j treatment with water or an alcohol; and other various well-known ester forming groups.
j Among these carboxyl-protecting groups, the preferred protecting groups include, for example, carboxylprotecting groups described in Japanese Patent Application r Kokai (Laid-Open) No. 80,665/84.
St
R
3 i 4 Moreover, the halogen atom for R includes, for example, fluorine, chlorine and bromine.
k 11 V5- -i 4-
O!!Z
th e -like; dialkylamin &groups foGr example, di-C -C 4 alkylamino groups such as dimethylamino, diethylamino, di-n-propylamino, methylethylamino and t like; cyano group; oxo group; aralkylamino groups for example, ar-C 1
-C
4 alkylamino groups such as be ylamino, phenethylamino and the like; acylamino groups, or example, C -C 4 acylamino groups such as acetylamino, propionylamino, butyrylamino and the ke; alkoxycarbonyl groups, for example, C 1
-C
4 alkoxyc onyl groups such as methoxycarbonyl, ethoxycarbo 1, n-propoxycarbonyl, isopropoxycarbonyl and the ike; and N-acyl-N-alkylamino groups, for example, N-a -N-alkylamino groups wherein the nitrogen atom of th above-mentioned alkylamino group is substituted by /a C 1
-C
4 acyl group such as acetyl, propionyl, but 1 or the like.
Am g the compounds represented by the general formula those wherein R 2 represents a flu ine-substituted phenyl group and R 3 represents a bstituted or unsubstituted 1-pyrrolidinyl or 1-piperazinyl P rnin amr preferred.
.4,i t 0 4 441 I t 4 4 01
SI-
4 14 <S4 7.
t a <t aS The salt of the compound represented by the general formula includes conventional salts at basic groups such as an amino group and the like, and at acidic groups such as a carboxyl group and the like. The salts at the basic groups include, for example, salts with mineral acids such as hydrochloric acid, sulfuric acid and the like; salts with organic carboxylic acids such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like; salts with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like. The salts at the acidic groups include, for example, salts with alkali metals such as sodium, potassium and the like; salts with alkaline earth metals such as calcium, magnesium and the like; ammonium salts; and salts with nitrogen-containing organic bases such as procaine, dibenzylamine, N-benzyl-B-phenethylamine, 1-ephenamine, N,N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N,N-dimethyl- aniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine and the like.
5 w t If the compound represented by the general formula and a salt thereof have isomers (for example, optical Sisomers, geometrical isomers, tautomers and the like), this invention includes all of the isomers, crystal forms and hydrates thereof.
Antibacterial activities and acute toxicities are illustrated with reference to typical compounds of this invention.
1. Antibacterial activity Test method According to the standard method of Japan Society of Chemotherapy [CHEMOTHERAPY, 29(1), 76-79(1981)], a bacteria solution obtained by culturing in Heart Infusion broth (manufactured by Eiken Kagaku) at 37 C for 20 hours was inoculated onto a Heart Infusion agar containing a drug and cultured at 37°C for 20 hours, after which the growth of the bacteria was observed, to determine the minimum concentration at which the growth of the bacteria was inhibited as MIC (pg/ml). The amount of the inoculated bacteria was 104 cells/plate (106 cells/ml). The MIC j values of the following test compounds are as shown in Table 1.
i Symbols used in Table 1 have the following meanings: penicillinase-producing bacteria, cephalosporinase-producing bacteria, 8 inoculation size: 10 cells/ml, Me: methyl group, Et: ethyl group, n-Pr: n-propyl group, i-Pr: isopropyl group 6 S_ Table 1 F-2 HO 110- F R N I R 3 MeN CN CN- N- ompound Bacteria No. 1 2 3 4 St. aureus FDA209P 0.1 S0.05 0.05 0.1 St. epidermidis IID866 0.1 0.05 S-0.05 0.1 St. aureus F-137*1 0.1 <0.05 $0.050.
E, coi NILLJ $0.05 0.39 0.1 S0.05 E. coli TK-111 <00 00 00 E. coli GN5482* 2 -0.05 0.1 S0.05 0.05 P-s. aeruginosa S-68 0.39 6.25 1.56 1.56 Aci. anitratus A-6 0.2 0.2 S0.05 0.1 Ps. *aeruginosa IF03445 3.13 12.5 3.13 3.13 Ps. aeruginosa GN918* 2 0.39 3.13 0.78 0.78 Cont'd Table 1 (Cont'd) FF Me.
F F 0HO-) oHO- 0 HO 0 HO NCH 2=CH [IN N- C N N N- n-PrN N- i-PrN N-I CH 2N, N- 6 7 8 9 0.2 0.0S 0.2 0.2 0.2 0.2 0.39*3 0.1*3 0.78 0.2 0.2 0.2 0.2 0.05 0.39 0.2 0.2 0.2 0.05 0 .05 0.05 0 05 C0'.05 :0.05 0.05 0.05 0. 05 ~0 05 0 05 :so.0 oo 0.05 <-0.05 <-0.05 O. 5 0. 05 0.05 0.39 1.56 1.56 3.13 3.13 3.13 0.2 0.1 0.2 0.2 0.78 0.2 0.78 3.13 1.56 12.5 6.25 3.13 0.39 0.78 0 78 3.13 1.56 J .13 L 4- Cont 'd Table 1 (Cont'd) F F F -O F 0F- 0- F 0 -i 2=H1E 2 NCMI CMeLIN N- N-N N cil 2 NN 11 12 13 14 0.2 05 0.2 0.2 0.39 0.1 0.2 0.2 0.2 0.1 0.1* 0.2 0 .39 <0.05 <-O.05 o 0.1 0.05 0.05 0.05 0.1 05 05 6.25 0.2 0.78 1.56 0.2 <-0.05 0.1 0.1 12.5 0.2 1.56 1.56 3.13 0.1 j 0.39 0.39 2. Acute toxicity The LD 5 values obtained by intravenously administering the test compounds of No. 5, 6 and 12 as mentioned above to mice (ICR strain, male, body weight: 18-24 g) were 200 mg/kg or more.
Comparative Test Comparative experiments were conducted to compare the effects of the following compound of the present application: 1-(2,4-difluorophenyl)-6-fluoro-4-oxo-7--(l-piperazinyl )-l,4-dihydro-l,8-naphthyridine-3-carboxylic acid with the effects of the following compounds to 6-fluoro-4-oxo-l-phenyl-7-(l-piperazinyl)-1,4-dihydrol,8-naphthyridine-3-carboxylic acid, 6-fluoro-7-(4-methyl-l-piperazinyl)-4-oxo-l-phenyl-1,4 -dihydro-1,8-naphthyridine-3-carboxylic acid, 6-fluoro-l-(4-fluorophenyl)-4-oxo-7-(l--piperazinyl)-l, 4-dihydro--1,8-naphthyridine-3-carboxylic acid, l-(3,4-dichlorophynyl)--6-fluoro-4-oxo-7-(l-piperazinyl )-1,4--dihydro-.,8-naphthyridine-3-carboxylic acid, 6-fluoro-l-(4-hydroxyphenyl)-4--oxo-7-(l-piperazinyl)-1 ,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 6-fluoro-l--(4--fluorophenyl)-7-(4-methyl-l-piperazinyl) -4-oxo--1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 1-(2,4-difluorophenyl)-6-fluoro-7-(4-methyl-l-piperazi nyl)-4-oxo-1,4-dihydro-1, 8-naphthyridine-l3=carboxylic acid, I. Synthesis of the compounds used in the comparative experiments Compounds and (I) were synthesized in the some manner as in the following Examples. The physical properties of the compounds synthesized were identical with those stated in the present specification.
Compound Referential Examples 1 and 2 and ML__ _j A M W l iF~o 0t, ls~U~-11~.~14L Example 1, 2, Compound Referential Examples 1 Examples 1 and 2, Compound Referential Examples 1 Examples 6 and 9, Compound Referential Examples 1 Examples 1 and 2, Compound Referential Examples 1 Examples 1, 2(I) and 7, Compound Referential Examples 1 Examples 1, 2(I) and 9, Compound Referntial Examples 1 Examples 1 and 3, Compound was synthesized as follows: A mixture of 2.00 g of and 2 and and 3 and and 2 and and 2 and and 2 and and 2 and ethyl of
I
1 i
I
d 2,6-dichloro-5-fluoronicotinoylacetate, 2.91 g of acetic anhydride and 4.23 g of ethyl ortho-formate was subjected to reaction under reflux for 1.5 hours. After the completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue obtained was dissolved in 20 ml of ethanol, and 1.16 g of 3.4-dichloroaniline was added to the resulting solution.
The resulting mixture was subjected to reaction at room temperature for 3 hours, and the crystals thus deposited were collected by filtration to obtain 2.90 g (yield 89.8%) of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3-(3,4-dichlorophenylami no)acrylate.
Melting Point: 131-132 C (recrystallized from ethanol) -1 IR (KBr) cm 9 C 1670 C=0 NMR (CDC1 3 )S values: 0.93 (3H, t, J=7Hz), 4.07 (2H, q, J=7Hz), 6.82-7.74 (4H, 8.53 (1H, d, J=14Hz), -11rr ^fl 1 L -L 11.25 (1H, d, J=14Hz) (II) in 27m! of N,N-dimethylformamide was dissolved 1 2.70 g of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl) -3-(3,4-dichlorophenylamino)acrylate, and 0.65 g of sodium 1hydrogencarbonate was added thereto, after which the resulting mixutre was subjected to reaction at 95 C for ij 3 hours. After the completion of the reaction, the lI reaction mixture was allowed to stand at room termperature for 20 hours, and then, the crystals thus deposited were collected by filtration and washed successively with water and methanol to obtain 2.10 g (yield 84.7%) of ethyl 7-chloro-l-(3,4-dichlorophenyl)-6-fluoro-l,4-dihydro-4-oco-l ,8-naphthyridine-3-carboxylate.
Melting point: 243-2440C (recrystallized from chloroforin-methanol mixture) S IR (KBr) um 1685 C=0 NMR (CDCi 3 )8 values: 1.40 (3H, t, J=7Hz), 4.40 (2H,q, J=7Hz), 7.08-7.79 (3H, 8.46 (1H, d, J=7Hz), 8.58 (1H, s) (III) In a mixed solvent of 20 ml of chloroform and W 20ml of ethanol were dissolved 2.00 g of ethyl I 7-chloro-l-(3,4-dichlorophenyl)-6-fluoro-l,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylate, 1.03 g of i N-acetylpiperzine hydrochloride and 1.46 g of i triethylamine, and the resulting solution was subjected to reaction under reflux for 2 hours. After the completion of the reaction, the solvent was removed by distillation under reduced pressure, and 40 ml of chloroform and 20 ml of water were added thereto, after which the organic layer was separated, washed successively with water and saturated aequeos sodium chloride solution, and thereafter dried over anhydrous magnesium sulfate. The solvent was removed by distallation under reduced pressure. The -12- 6 1 I2 r residue thus obtained was purif ied by a column chromatography [Kieselgel 60, Art 7734 (Merck) eluant: ethyl acetate:acetone (10:1 by volume)] to obtain 1.50 g (yield 61.5%) o f ethyl 7-(4-acetyl-1-piperazinyl)-l- (3,4-dichlorophenyl)-6--fluoro-1,4-dihydro-4-oxo-l,8-naphthyr idine-3-carboxy.ate.
Melting point: 200-202 0 C (recrystallized from methanol) IR (KBr) cm 1 :0 1725 c=0 NMR (CDC1 )S values: 1.38 (3H, t, J=7Hz), 2.12. (3H, 3.58 (8H, bs), 4.37 (2H, q, J=7Hz), 7.16-7.78 I (3JOH, in), 8.14 (1H, d, J=l3Hz), 8.44 (1H, s) (IV) In 20 ml of conc. hydrochloric acid was dissolved 1.0 g of ethyl 7-(4-acetyl-l-piperazinyl)-- (3,4-dichlorophenyl)-6-fluoro-1,4-dihydro-4-oxo-l,8-naphthyr idine-3-carboxylate, and the resulting solution was subjected to reaction under reflux of 4 hours. After the completiorn of the reaction, the crystals thus deposited were collected by filtration and then dissolved in a a ago mixture of 10 ml of 1 N aqueous sodium hydroxide solution, ml of ethanol and 20 ml of water, and the pH of the resulting solution was adjusted to 7.0 with 6 N hydrochloric acid. The crystals thus deposited were collected by filtration and washed with water to obtain 0.82 g (yield 95.3%) of 4 l-(3,4-dichlorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(l-piper 4;44 :azinyl)-1,8-naphthyridine-3-carboxylic acid.
a 44 Melting point: 275-278 0 C (recrystallized from ammonia water-ethanol miz-ture) IR (KBr) cm- 1 C=O 1720 NMR (TFA-d 1 )values: 3.40-3.94 (4H, in), 4.00-4.65 (4H, in), 7.15-7.95 (3H, in), 8.37 d, J=l2Hz), -13- 5610r w I I..
1,4-DIHYDRO-4-OXONAPHTHYRIDINE
DERIVATIVES
V AND SALTS THEREOF, PROCESS FOR PRODUCING THE SAME AND ANTIBACTERIAL AGENTS COMPRISING THE SAME The following statement is a full description of this invention, including the best method of performing it known to applicant(s): P19/3/84 1 9.28 (1H, s) II. Pharmacological test I. Antibacterial activity Test method According to the standard method of Japan Society of Chemotherapy [CHEMOTHERAPY, 29 76-79 (1981)], a bacteria solution obtained by cultering in Heart Infusion broth (manufactured by Eiken Kagaku) at 37°C for hours was inoculated onto a Heart Infusion agar containing a drug and cultered at 37°C for 20 hours, after which the growth of the bacteria was observed, to determine the minium concentration at which the growth of the bacteria was inhibited as MIC (ug/nr:' The amount of the S' inoculated bacteria was iO L cells/plate (106 cells/ml). The MIC values of the test compounds are shown in Table la.
Symbols used in Table la have the following meanings: penicillinase-producing bacteria, cephalosporinase-producing bacteria, a mixture of 0.1N aqueous NaOH solution and ethanol (1:1 by volume) was used in place of the 0.1 N aqueous NaOH solution.
2. Protective effect on systemic infection Saureus SA-57 and S. marcescens IID 620 which had been cultured on a Heart Infusion agar medium overnight were suspended in a 5% gastric mucin so that the concentration became 4.0 x 10 and 2.8 x 10 cells/ml, respectively, after which 0.5 ml of each of the resulting suspension was intraperitoneally inoculated into a mouse (ICR strain, male, weight: 20 g 1 g, five mice per group). One hour after the infection, the test compound suspended in 0.5% carboxymethyl cellulose (CMC) was orally administered to the mouse once. The ED50 values were determined from the number of survival mice after 7 days -14- L; iLI~ 1L. jC 1L ~LCU i I LI il 1 iA according to the Van der Waerden method and shown in Table la.
3. Acute toxicity test V The test compound was dissolved in 0.1 N aqueous SNaOH solution (equivalent), and the resulting solution was slowly intravenously administered to the mouse (ICR i strain, male weight: 20 g 1 g, five mice per group) at the tail in a dose of 10 ml/Kg, and after 7 days, the number of survival mice was counted. The LD 50 values of V the test compounds are shown in Table la.
I
r i I' on, y LI Y -1 Table 00 F K, COOH .Compound)(F(H Strains(A(B (C O) CF
C(H
St. aureus FDA209P 0.2 0.78 3.13 0.39 3.13 3.13 0.39 0.39 Str. faecalis IID682 1.56 50 50 3.13 25 12.5 6.25 1.56 C 7 E. coli NIIIJ sO-.05 <0.05 0.1 <0.05 0.2 0.2 <0.05 0.1 E. coli TK-111 0.05 <0.05 0.1 <0.05 0.2 0.1 <0.05 <0.05 K. pneumoniae Y50 0.1 0.39 <0.05 0.1 0.78 0.2 0.39 K. pneuxnoniae Y41 0.2 0.39 0.78 0.2 1.56 6.25 0.39 0.78 Ent. cloacae IID977 0.1 0.1 0.39 0.1 0.39 0.78 0.2 0.39 Ser. marcescens IID620 0.39 0.39 3.13 0.39 1.56 6.25 0.78 3.13 Pro. vulgaris GN3027 -s 0.O05 0.2 0.78 <0.05 1.56 0.78 0.39 0.2 -Ps. aeruginosa IF03445 0.78 1.56 6.25 1.56 6.25 6.25 12.5 3.13 aerugiriosa S-68 0.39 1.56 3.13 0.39 0.78 3.13 1.56 oPro. mirabilis T-111 0.39 1.56 6.25 0.39 6.25 12.5 1.56 3.13 SCit. freundii N-7 0.1 0.2 0.78 0.1 0.39 3.13 0.39 0.78 Aci. anitratus A-6 0.2 0.39 0.39 0.2 0.78 6.25 0.1 0.1 -Cont'd Table 1 (Cont'd) St. epidermidis IID866 St. aureus F-137* 1 E. coli TK-3* 1 E. coli GN5482* 2 K. pneumoniae Y-4l Pro. vulgaris GN76* 2 Ps. aeruginosa GN918* 2 Ps. aeruqinosa GN3379* 1 0.39 0.2 S0.05 4-0.05 0.2 0.1 0.39 0.78 1.56 1.56 0.1 05 0.39 0.39 1.56 1.56 3.13 1.56 0.39 05 1.56 3.13 3.13 6.25 0.39 0.39 05 05 0.2 0.1 0.39 0.78 1.56 3.13 0.78 0.1 1.56 1.56 1.56 3.13 6.25 1.56 0.78 0.1 12.5 1.56 0.78 3.13 0.39 0. 39 0.39 05 0.39 0.39 0-78 3.13 0.39 0.39 0.39 1.56 0 .78 0.78 3.13 S. aureus SA-57 0.038 0.308 >1.07 0.088 >1.41 >1.23 0.154 0.088 Ser. marcescens IID620 077 0.058 0.466 0.101 >1.07 >1.23 0.466 0.177 LD 50 (mg/kg) 1>25 >200 25-50 *4 100-2006-100 50-100 25-50 2 5-50 1. J L L -4 \11'r noi:R -4 W'S ON The process for producing the compounds of this invention will be explained below.
The compounds of this invention can be produced, for example, according to the following production route: COOR la COOR la
[II]
[IV] or a salt thereof OOR la COOR la 0 4 0 CC [III] or a-salt thereof 40 4 4 0000 4004 4 0 0 0 00 0 0 4 0 US or a salt thereof 19 COOR'
F
R3ar
RR
[Ib] or a salt thereof 12
R
[1b] or a salt thereof ~0 00 00 4 0 0 wherein R la represents the same carboxy-protecting group -1s- 5610r
C'
A 1tk, 1 .X dibenzylamine, N-benzyl-B-phenethylamine, l-ephenamine, N,N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, N,N-dimethyl- aniline, N-methylpiperidine, N-methylmorpholine, diethylamine, Sdicyclohexylamine and the like.
Sroy 5 -ui
I
la wherein R 1 represents the same carboxy-protecting group 1 3a as in R R represents the same halogen atom as in 3 R 3 b
R
3 R represents the same substituted or unsubstituted 3 1 2 cyclic amino group as in R 3 and R and R have the same meanings as defined above.
The salts of the compounds represented by the general formulae [III], [IV] and include the same salts as those of the compounds represented by the general formula The compound represented by the general formula [III] or a salt thereof or the compound represented by the general formula or a salt thereof is, respectively, obtained by reacting the compound represented by the general formula [II] or the compound represented by the general formula [IV] or a salt thereof with an acetal such as N,N-diethylformamidodimethylacetal, N,N-dimethylformamidodiethylacetal or the like and then with an amine represented 2 2 by the general formula, R -NH (R has the same meaning as defined above).
The solvent to be used in the above reactions may be any solvent inert to the reactions and includes, though not critical, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; amines such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; etc. and these solvents may be used alone or in admixture of two or more. The amount of the acetal used is preferably 1 mole or more, particularly about 1.0-1.3 moles,' per mole of the compound represented by the general formula [II] or the compound represented by the general formula [IV] or a salt thereof, respectively. The reactions are usually conducted at 0° to 100 C, preferably at 500 to 800C, and usually for 20 minutes to 50 hours, preferably 1 to 3 hours.
And the amine is used in an amount of 1 mole or more per mole of the compound represented by the general formula [II] or the compound represented by the general formula [IV] or a salt thereof, respectively. The reaction is usually
A
conducted at 0° to 100°C, preferably 100 to 60 0 C, and usually for 20 minutes to 30 hours, preferably 1 to 5 hours.
As an alternative method, it is possible to react the compound represented by the general formula [II] or the compound represented by the general formula [IV] or a salt t thereof with ethyl orthoformate or methyl orthoformate in the presence of acetic anhydride, and then with an amine represented by the general formula, R2-NH2 or a salt thereof to obtain the compound represented by the general formula [III] or a salt thereof or the compound represented by the general formula or a salt thereof, respectively.
j (ii) The compound represented by the general formula [Ia] or a salt thereof or the compound represented by the general formula [Ib] or a salt thereof is, respectively, obtained by subjecting the compound represented by the general formula [III] or a salt thereof or the compound represented by the general formula or a salt thereof to ring closure reaction (preferably with heating) in the presence or absence of a base.
The solvent to be used in this reaction may be any solvent inert to the reaction and includes, though not critical, for example, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; ethers such as dioxane, anisole, diethylene glycol dimethyl ether and the like; sulfoxides such as dimethylsulfoxide and the like; etc.
These solvents may be used alone or in admixture of two or more. The base includes, for example, sodium hydrogencarbonate, potassium carbonate, potassium tert-butoxide, sodium hydride and the like. The amount of the base to be used is preferably 0.5 to 5 moles per mole of the compounds represented by the general formula [III] or or a salt thereof, respectively. The reaction is usually conducted at 200 to 160 C, preferably at 1000 to 150 0 C, and usually for 5 minutes to 30 hours, preferably 5 minutes to 1 hour.
(iii) The compound represented by the general formula [IV] or a salt thereof, the compound represented by the general formula or a salt thereof, or the compound represented by the general formula [Ib] or a salt thereof is, respectively, Sobtained by reacting the compound represented by the general j 720 t a U- j~ Sj O Q O -4I Cr 3 fd U U f) U formula [III, the compound represented by the general formula [III] or a salt thereof, or the compound represented by the general formula [Ia] or a salt thereof with a cyclic amine represented by the general formula, R3b-H or a salt thereof (wherein R 3b has the same meaning as above).
The solvent to be used in the reaction may be any solvent inert to the reaction and includes, though not critical, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and the like; halogenated hydrocarbons such as methylene chloride, ,Ia chloroform, dichloroethane and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; suifoxides such as dimethylsulfoxide and the like; alcohols such as methanol, ethanol and the like; nitriles such as acetonitrile and the like; etc., and these solvents may be used alone or in admixture of two or more. The amount of the cyclic amine or a salt thereof to be used is preferably an excess, more preferably 2 to 5 moles per mole of the compound represented by the general formula the compound represented by the general formula [III] or a salt thereof, or the compound represented by the general formula [Ia] or a salt thereof, respectively. If the amount of the cyclic amine used is about 1 to 1.3 moles, it is sufficient that an acid-binding agent is used in an amount of I mole per mole of the compound represented by the general formula [II, the compound represented by the general formula [III] or a salt thereof, or the compound represented by the general formula [Ia] or a salt thereof, respectively. The acid-binding agent i icludes organic or inorganic bases such as triethylamine, 1,8-diazabicyclo[5,4,0lundec-7-ene (DBU), potassium tertbutoxide, potassium carbonate, sodium carbonate, sodium hydride and the like.
The salt of R3b-H includes the same as the salts at the basic group of the compound represented by the general formula The reaction is usually conducted at 0o to 1500C, preferably at 500 to 1000C, and usually for xcminutes to 30 hours, preferably 30 minutes to 3 hours.
'or The compound represented by the general formula formula [I] <2
A
I_ I 1 la U Ia], [Il] (III] or [VI, wherein R or R represents a Vcarboxyl-protecting group, or a salt thereof can, if desired, be converted to the corresponding f ree carboxylic acid by hydrolyzing the same in the presence of a conventional acid or alkali, which is used in hydrolysis, usually at 0 0 to 100 0 C, preferably at 200 to 100 Cfor 5 minutes to Vhours, preferably 5 minutes to 4 hours. Further, the compound represented by the general formula [III] or [iV] or a salt thereof can, if desired, be converted to a salt or an ester of the corresponding compound by subjecting the same to salt-forming reaction or esterification known per Use. If the compound represented by the general formula [Ia], [III], [IV] or or a salt thereof has an active group (for I example, hydroxyl group, amino group or the like) at other positions than the reaction sites, it is possible to I previously protect the active group by the conventional method and remove the protecting group after completion of the reaction.
The compound thus obtained may be subjected to as conventional isolation and purification procedures such as column chromatography, recrystallization, extraction and the if like. The compound represented by the general formula [I] ifor a salt thereof, wherein R represents a halogen atom (corresponding to the compound represented by the general formula lIla]), is also useful as an intermediate for Iobtaining a compound wherein R represents a substituted or iiunsubstituted cyclic amino group (corresponding to the compound represented by the general formula [Ibi).
When the compound of this invention is used as a Idrug or medicine, it is appropriately combined with carriers which are used in conventional pharmaceutical preparations, and is prepared into tablets, capsules, powders, syrups, granules, suppositories, ointments, injeccions and the like in a conventional manner. The administration routes, dosage and number of administrations can be appropriately varied depending upon the symptoms of patients, and it may be usually administered orally or parenterally (for example, by injection, drip, administration to rectum) to an adult in an amount of 0.1 to 100 mg/kg/day in one to several portions.
V This invention will be explained below referring to Referential Examples, Examples and Preparation Examples.
Symbols used in Referential Examples and Examples have the following meanings: Me: methyl group, Et: ethyl group, n-Pr: n-propyl group, i-Pr: isopropyl group, Ac: acetyl group, allyl group, ethylene group.
Referential Example 1 In 210 ml of chloroform was dissolved 21 g of 2,6-dichloro-5-fluoronicotinic acid, and 23.8 g of thionyl chloride and 0.1 g of N,N-dimethylformamide were added to the resulting solution. The resulting mixture was reacted at for 2 'hours. The solvent and the excessive thionyl chloride were removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 21 ml of tetrahydrofuran. In 110 ml of tetrahydrofuran was dissolved 25.1 g of diethyl ethoxymagnesium malonate, and the solution was cooled to -40° to -30 C. Into this solution was dropped a tetrahydrofuran solution of 2,6-dichloro-5-fluoro- Snicotinoyl chloride which had previously been prepared at the same temperature over 30 minutes. This mixed solution was stirred at the same temperature for 1 hour, and then the temperature of the solution was gradually raised to room temperature. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained were added 200 ml of chloroform and 100 ml of water. The pH was adjusted to 1 with 6 N hydrochloric acid. The organic layer was separated, washed successively with 50 ml of water, 50 ml of 5% aqueous sodium hydrogencarbonate solution and 50 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the oily product obtained were added 50 ml of water and 0.15 g of p-toluenesulfonic acid, after which the resulting mixture was subjected to reaction with vigorous stirring at 100 C for 2 hours. The reaction mixture was extracted with 100 ml of chloroform. The organic layer was washed with 50 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, after which the solvent was _i renoved by distillation under reduced pressure. The residue obtained was purified by a column chromatography (WAKO SILICA GEL C-200, eluant: toluene) to obtain 23.5 g of ethyl (2,6-dichloro-5-fluoronicotinoyl)-acetate having a melting point of 64-65 C.
-1 IR (KBr) cm-: VC= 0 1650, 1630, 1620 NMR (CDC1 3 e values: 1.25 (1.29H, t, J=7Hz), 1.33 (1.71H, t, J=7Hz), 4.07 (1.14H, 4.28 (2H, q, J=7Hz), 5.82 (0.43H, 7.80 (1H, d, J=7Hz), 12.62 (0.43H, s) Referential Example 2 In 40 ml of benzene was dissolved 8.8 g of ethyl (2,6-dichloro-5-fluoronicotinoyl)acetate, and 4.5 g of N,N-dimethylformamidodimethylacetal was added thereto, after which the resulting mixture was subjected to reaction at 0 C for 1.5 hours. Then, 4.1 g of 2,4-difluoroaniline was added to the reaction mixture and the resulting mixture was subjected to reaction at room temperature for 4 hours. The solvent was removed by distillation under reduced pressure.
The residue obtained was purified by a column chromatography (WAKO SILICA GEL C-200, eluant: chloroform) to obtain 9.0 g of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3-(2,4difluorophenylamino)acrylate having a melting point of 138-139 C.
-1 IR (KBr) cm C=0 1690 NMR (CDC13) S values: 1.08 (3H, t, J=7Hz), 4.10 (2H, q, J=7Hz), 6.77-7.40 (4H, 8.50 (1H, d, J=13Hz), 12.70 (1H, d, J=13Hz) In a similar manner, the compounds shown in Table 2 were obtained.
-a o y 1 /K7. O -11ai: Table 2 0 F r COOEt
NC
N R2 Cl NH
R
2 4 I 4; 44 4 $i 4 1 444 44 4 4 Comcound J Physical properties -1 2 elting IR(KBr) cmn point (C0)
C=O
87-89 1690 110-114 1710, 1680 92-93 1710, 1680 o F 135-137 1720(sh), 1690.
78-30 1630 cF *1 o Oily 1705, 13.(s) 154-155 1720(sh), 1685 F 100-101 1700(sh), 1685 123-125 1710, 1680 Cont'd AA"It' A' (j to~ -1 I I ~ui rta~s. Table 2 (Cont'd) 145-146 1705, 1680 Br 147-149 1685 Oily 1695 OMe O~Me 119-121 1700 Oily 1700 o 183-186 1685, 1670 136-138 1705, 1680
CF
3 M~e o 114-116 1680 f OMe 137.5-139 1725(sh), 1630
F
:o 92-95 1705 6,Me OMe 125-126 1700(sh), 1660 Me 91-92 1705, 1690 Note, The neat method was used in place of the KBr method.
L .rA/P.; 26 A6.L Referential Example 3 In 55 ml of chloroform were dissolved 5.5 g of ethyl (2,6-dichloro-5-fluoronicotinoyl)acetate, 2.37 g of N-methylpiperazine and 2.37 g of triethylamine, and the resulting solution was subjected to reaction at 600 to for 2 hours. The reaction mixture was washed with ml of water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue obtained was purified by a column chromatography (WAKO SILICA GEL C-200, eluant: chloroform) to obtain 5.4 g of oily ethyl [2-chloro-5-fluoro-6-(4-methyl-lpiperazinyl)nicotinoyl]acetate.
-1 IR (Neat) cm: C= 1750, 1695 NMR (CDC1 3 S values: 1.25 (3H, t, J=7Hz), 2.32 (3H, s), 2.12-2.70 (4H, 3.55-3.96 (4H, m), 4.03 (2H, 4.20 (2H, q, J=7Hz), 7.78 (1H, d, J=13Hz) In a similar manner, the compound shown in Table 3 was obtained.
2? 27 V W Table 3
-I
COOEt
R
3
R
i 4 r; 4 di 4 4 4 Compound Physical Properties -1 3 Melting IR (KBr) cm" R point UC=O AcN N- 67-71 1730 In 22.5 ml of benzene was dissolved 4.5 g of ethyl [2-chloro-5-fluoro-6-(4-methyl-l-piperazinyl)-nicotinoyl]acetate, and 1.87 g of N,N-dimethylformamidodimethylacetal was added to the resulting solution, after which the resulting mixture was subjected to reaction at 70 C for 2 hours. To the reaction mixture was added 1.8 g of 4-methoxy-2-methylaniline, and the resulting mixture was subjected to reaction at room temperature for 4 hours. Then, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [WAKO SILICA GEL C-200, eluant: I chloroform:ethanol 100:1 (by volume)]. The crystalline substance obtained was washed with 10 ml of diethyl ether to obtain 5.0 g of ethyl 2-[2-chloro-5-fluoro-6-(4-methyl-1piperazinyl)nicotinoyl]-3-(4-methoxy-2-methylphenylamino)acrylate having a melting point of 141-142 C.
-1 IR (KBr) cm-: VC= 0 1710(sh), 1695 NMR (CDC13) values: 1.08 (3H, t, J=7Hz), 2.32 (3H, 2.40 (3H, s), 2.23-2.68 (4H, 3.47-3.83 (4H, m), 3.75 (3H, 4.07 (2H, q, J=7Hz), 6.65-7.25 (3H, 7.20 (1H, d, J=13Hz), 8.48 (1H, d, J=13Hz), 12.82 (1H, d, J=13Hz) In a similar manner, the compounds shown in Table 4 were obtained.
29 MfW .Fsi -J 4~Cy .L i i Table 4 0 Compound J Physical Properties
R
2 3 Melting point IR(*)
R(R
0 C) cm1 V= *2 o MeN- ily1720 (sh), M e NL IN -O i l y1 7 1 *2
F
o oily 1735, 1700
F
*2 ooily 1695 O\4= *1 o6-6 1685, I 16-1641670 NHAc *2 o 1720 (sh), F Oily 1715 Ome Cont Id 2q? I I Table 4 (Cort'd) 4- t 0 -e Ome MeN N- *1 1705 (sh), 1685 132-136 I. IMe Ome AcN N- *2 1720 (sh), 1700 ciLy o ro 00 0 0 0 C. 00 o 0 Note: KBr Neat o 00 0 0o 0 00 00 0 <V-o o rl ic
J
AL (asnu/ W4 OSC
AG
Example 1 rn 90 ml of N,N-dimethylformamide was dissolved 9.0 g of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3- (2,4-difluorophenylamino)acrylate, 3.6 g of sodium hydrogencarbonate was added to the resulting solution, after which the resulting mixture was subjected to reaction at 120 C for 20 minutes.
Then, the solvent was removed by distillation under reduced pressure, and the residue obtained was dissolved in 50 ml of chloroform. The resulting solution was washed successively with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under S reduced pressure, and the crystalline substance obtained was ""oo washed with 30 ml of diethyl ether to obtain 7.0 g of ethyl So 7-chloro-6-fluoro-l-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8- S naphthyridine-3-carboxylate having a melting point of a ooon 0 o 220-222 C.
0co -1 o IR (KBr) cm: C= 1730, 1690 NMR (CDC1 3 S values: 1.36(3H, t, J=7Hz), 4.30(2H, q, J=7Hz),
S
o o 6.80-7.60(3H, 8.27(1H, d, J=7Hz), oo 8.42(1H, s) In a similar manner, the compounds shown in Table o 00000 o were obtained.
000000 1 0 o 0 00 S0 0 -18- 56 Table 'COOEt Compound Physical Properties Melin point IR(KBr) o 22-2241730, 222-2241685 0 1730, F231-232 1705
F
1735, O205-208 1685 *0244-2 46 1720, F 16PO
F
Cont'd 32- Table 5 (Cont'd) 0 207-209.5
F
00-0 1730, 1680
F
1685 070 Br 0 1735, 0 216-218 1695 Me 0196-198 1685, OMe Cont'd
'IR
-J a salt thereof, the compound represented by the general formula or a salt thereof, or the compound represented by the general formula [Ib] or a salt thereof is, respectively, obtained by reacting the compound represented by the general T, i: -L .71 LC~ Table 5 (Cont'd) Cont'd 4 VS 31r- .1.
Table 5 (Cont'd) )J OMe 0 163-165 1730, Me o-4 1735, 160-162 1690 OMe Example 2 In 35 ml of chloroform was dissolved 3.5 g of ethyl 7-chloro-6-fluoro-l-(2,4-difluorophenyl)-l,4-dihydro-4-oxo-1,8naphthyr idine-3 -ca rboxyl ate, and 1.5 g of N-acetylpiperazine and 1.6 g of triethylamine were then added to the resulting solution, after which the resulting mixture was subjected to reaction at 60 0 C for 1 hour. Then, the solvent was removed by distillation under reduced pressure, and the residue obtained was purified by a column chromatography [WAKO SILICA GEL C-20)0, eluant: chloroform :ethanol 30 :1 (by volume)] to obtain 3.5 g of ethyl 7-(4-acetyl--l-piperazinyl)-6fluoro-l-(2 ,4-difluorophenyl) 4dihydro-4-oxol,8-naphthyridine-3-carboxylate nef melting point -1--of 207-2090C and number of administrations can be appropriately varied depending upon the symptoms of patients, and it may be usually administered orally or parenterally (for example, by injection, drip, administration to rectum) to an adult in an amount of 0.1 to 100 mg/kg/day in one to several portions.
i 2ev -1 IR (KBr) cm-: 1730, 1695 NMR (eDC13) J values: 1.38(3H, t, J=7HL), 2.05(3H, 3.53(8H, bs), 4.30(2H, q, J=7Hz), 6.80-7.75(3H, 8.00(1H, d, J=13Hz), 8.30(1H, s) In a similar manner, the compounds shown in Table 6 were obtained.
I
1.
4 o Table 6 .COOEt, Compound Physical Properties 2 3 elting point IR(KBr) R R (OC) cm'l: "c=o A c 216-218 1730, 0 1690 (sh) Ac 1730, o MeN- N- 155-156 1690 1730, MeN N- 217-218 1695 1730, HN N- 1 16 1690 Me HN N- 143 1730 me 1725, HN N 198-202 1690 Me__ -Cont'dt~Th~ S7 Table 6 (Cont'd) HO N- 220-222 19 I. F AcN 253-255 1730, 1690 0 203-205 170, Ac~.J 211-213 1735
F
F1 1725, 0 ~206 19 1730, 0 MeN -1319 1700 I F 1725, -c 244-246 1690
ID
F Ac 196-1871725, MeN IN-8-8 1690 (sh) W ~I.)L Table 6 (Cont'd) 1720, I N- 155-157 1685 Me, 1730, itUMeN -153-154 1700 Me Ij ]1730, MeN 1531551695 1730 (sh), 1 N- 166-168 1690 1730, I EtOCN N- 202-2041 2 1690 1725 (sh) AcN\U- 230-231 1695 F* F 1720 (Fh), 193-194 1680, tJ 0 1675 1725, 1695 Cl Cont'd R,1
A
Lps Note: The neat metnoa was usea in piace or tne i r method.
\Jtr Y~i Table 6 (Cont'd) 1730, AcN j\I- 254 1690 Cl 101 2081730, Ne~j-208 1690 Br 1730, AcE~- 246-247 1690 1730, oe Me. 167-169 1695 Me 1730, Ac N- 206-207.5 1690 17135, 0 -163-165 1700 1700 OMe 1730, Mel 174-176 1690 1735, E t N 180-181 1695 169 u; ~./2/2.P3 .i, q-b Contd P I 4 tt;, Table 6 (Cont'd) 1730, o n-PrN N- 171-172.5 1685 OMe n_0 -1 1730, i-PrN N- 28-101690 1730, HO-x\-N N- 200-202 1690 1725, 162-163 1690 1735, AcN N- 197-199 1690 OMe o 1725, MeN 136-138 1685 0 Ac 20-2721730, 0 AcN/- 27-2721690 CN__ o 24-2491730, 245-2491695 N HAc 1-1 Cont'd
"S
i Table 6 (Cont'd) AcND 1730, 1695 249-252 Me 263-264 1730 Me N 1730, 1685 166-169
I
AcN IN- 222.5-223.5 1730, 1690
F
O Ie M e N I- 16 5-168 1730, 1685
N-
215-219 1730, 1695 I I+ OMe Met N 17 0-171 1725, 1690 AcN N- 16 9-172 1725, 1690 I I. A47~ 4', Cont 'd Table 6 44 4 44 4 4' 14
I
4 4~ '4 4 4444 41.~ 444 0- 231-233 1730 Me 2
N
156 1730, N- 161690 AcHN 1725, H -203-205 1690 M e 1725, Ac N- 201-202 1695 0 FMe2 1730, N- 165 1600
F
MeN 1 1730, A c UN- 196-197 1695 1 Cont'd- -1 3C) Table 6 F AcHN 0 241-244 1725, F 1700
F
o0N 153-155 1735 OMe
HO
I 1730, N- 185-187 1690 '4 4 4 $41
'II
In 25 ml of 6 N hydrochloric acid was dissolved g of ethyl 7-(4-acetyl-l-piperazinyl)-6-fluoro-l- (2,4-difluorophenyl)-1,4-dihydro-4-oxo-l,8-naphthyridine- 3-carboxylate, and the resulting solution was heated under reflux for 2 hours. Then, the reaction mixture was cooled to room temperature, and the pH thereof was adjusted to 12 with 1 N aqueous sodium hydroxide solution and then to 6.5 with acetic acid. The crystals thus deposited were collected by filtration, washed with 30 ml of water, and then dried to obtain 1.8 g of 6-fluoro-l-(2,4-difluorophenyl)-l,4dihydro-4-oxo-7-(1-piperazinyl)-l, 8-naphthyridine-3-carboxylic acid.
NMR (TFA-d 1 )c values: 3.30-4.50(8H, in), 7.00-7.85(3H, in), 8.33(111, d, J=l3Hz), 9.21(111, s) In a similar manner, the compounds shown in Table 7 were obtained.
7 7; ,AATf YXFV(V.) U A Table 7 Compound ]Physical Properties R2R3 Melting point R(KBr) 0 c) j cm1 V= HN~-252.5-254.5 1730 MeHN CN- >280 1720 (sh)
F
H 2 79-280 1725 (sh) o U234-236 1720
F
o U222-224 1725 (0 >280 1720
F
Cont'd-
"/VK
1.
Cont'd Table 7 (Cont'd) i i MeNHK N- 254-2 58 1725 HN N- 205-207 1730 22 5-2 27 1725 0 'I>280 1725 cl o0I 273-277 1720 B r o245-246' 1725 Me~ 0>280 1725 0 1730, >280 1710 N H 2 A-Z Conttd O~e I I -Cont'd- Table 7 (Cont'd) I. I I 0 N HAc CF3 Mew- 1725, 1710, 1690 232-236 I. i.
HN-
>280 1.725 230-23 2 1730
I
4-7
F>F
MeH VC N- 269-263 1720 (h
F
4 1720 (sh) IiF HN 0)N 278-280 1720
F
Note: The nujol method was used in place of the KBr method.
I
Example 3 In 15 ml of 6 N hydrochloric acid was suspended 0.50 g of ethyl 7-chloro-6-fluoro-l-(2,4-difluorophenyl)-1,4dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, and the suspension was heated under reflux for 3 hours. Then, the reaction mixture was diluted with 50 ml of water and extracted with three 50-ml portions of chloroform. The combined extracts were washed with 100 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 15 ml of diethyl ether to obtain 0.40 g of 7-chloro-6-fluoro-l-(2,4-difluorophenyl)-l,4dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid having a I melting point of 244-248 C.
-1 IR (KBr) cm UC=0 1720 NMR (d 6 -DMSO) Y values: 7.26-8.56 (3H, 8.86 (1H, d, J=7Hz), 9.18 (1H, s) i In 3 ml of dimethylsulfoxide was suspended 0.30 g of S7-chloro-6-fluoro-l-(2,4-difluorophenyl)-l,4-dihydroi 4-oxo-l,8-naphthyridine-3-carboxylic acid, and then 0.25 g of N-methylpiperazine was added to the resulting suspension, 1 after which the resulting suspension was subjected to Sreaction at 60C for 30 minutes. Then, the solvent was I removed by distillation under reduced pressure, and to the residue thus obtained was added 30 ml of water. The pH of the resulting mixture was adjusted to 12 with 10% aqueous sodium hydroxide solution, then to 7 with acetic acid. The crystalline substance deposited was collected by filtration and washed with 5 ml of water to obtain 0.24 g of 6-fluoro-l- (2,4-difluorophenyl)-l,4-dihydro-7-(4-methyl-l-piperazinyl)- 4-oxo-1,8-naphthyridine-3-carboxylic acid having a melting point of 208-209 0
C.
IR (KBr) cm-l: C=0 1730 NMR (TFA-dl) g values: 3.30 (3H, 3.45-5.25 (8H, m), 7.12-8.10 (3H, 8.49 (1H, d, J=13Hz), 9.38 1H s) i 3 i Example 4 In 50 ml of N,N-dimethylformamide was dissolved g of ethyl 2-[2-chloro-5-fluoro-6-(4-methyl-l-piperazinyl) nicotinoyl]-3-(4-methoxy-2-methylphenylamino)acrylate, then 1.03 g of sodium hydrogencarbonate was added. To the resulting solution, and the resulting mixture was subjected 0 to reaction at 120 C for 3 hours. Then, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 50 ml of chloroform.
The resulting solution was washed successively with 30 ml of I water and 30 ml of saturated aqueous sodium chloride I solution, and then dried over anhydrous magnesium sulfate.
The solvent was removed by distillation under reduced pressure, and the crystalline substance obtained was washed with 30 ml of diethyl ether to obtain 2.38 g of ethyl 6-fluoro-1,4-dihydro-l-(4-mthxy--methoxy-2-methylphenyl)-7-(4methyl-1-piperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 144-145 0
C.
-1 IR (KBr) cm C= 1730, 1690 NMR (CDC1 3 S values: 1.33 (3H, t, J=7Hz), 1.95 (3H, s), I 2.20 (3H, 2.05-2.62 (4H, m), 3.32-3.63 (4H, 3.82 (3H, s), I 4.32 (2H, q, J=7Hz), 6.60-7.15 (3H, m), 8.02 (1H, d, J=13Hz), 8.23 (1H, s) SIn a similar manner, the compounds shown in Table 8 I were obtained.
ii
V
SAt-^ v 9 4y jj 4 V^
A
Cont'd T0 Table 8 F COQEt 3 N N)'
RI
Compound 1 Physical properties 3 Melting IR (KBr) RR 3point (OC) cm 01: =0 1725, VMeN N- 199-202 0 \-/1685 1735, 0 168-171 1720
F
0 ~174-175170 OMe 1695 o 1725, am.0rp,'o US 19 1725, Q FI 186-189 19 OMe 1730, o Me 166-168 19 Me 19 0 AcN N- {169-172175 OMe 119 -6 I I I I
-(I
Example In 5 ml of 47% hydrobromic acid was dissolved 2.0 g of ethyl 6-fluoro-1,4-dihydro-1-(4-methoxy-2-methylphenyl)- 7-(4-methyl-1-piperazinyl)-4-oxo-1,8-naphthyridine-3carboxylate, and the resulting solution was subjected to reaction at 1200 to 1250C for 2 hours. The pH of the reac- tion mixture was adjusted to 13 with 10% aqueous sodium hydroxide solution, then to 6.5 with acetic acid. The crystals thus deposited were collected by filtration and washed with 10 ml of water to obtain 1.8 g of 6-fluoro-1,4dihydro-l-(4-hydroxy-2-methylphenyl)-7-(4-methyl-lpiperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid having a melting point of 280 0
C.
IR (KBr) cm 1 C 1725, 1700 (sh)
C=O
NMR (TFA-dl) values: 2.08 (3H, 3.12 (3H, 2.88-5.12 (8H, m), 6.93-7.62 (3H, 9.25 (1H, s), 9.43 (1H, d, J=13Hz) In a similar manner, the compounds shown in Table 9 were obtained.
(A
Table 9 0
F
3 R N N 2
R
COOH
1 4 4 *1 4 Compound J Physical properties Melting !R (KBr) R 2 R3point v (OC) cm ~C=O C N- 143-1416175 OH 1710 FN N >280 1710 MeN N- >280 1710 EtN N- I >280 1730 n-PrN N- >280 1725 Ui-PrN N- >280 1715 1720, HO-0-N N- 200-205 1705 4 \N N- >280 1725 -Conft t d-
(V
I,
A
Table 9 (Cot'd) Cont'd ~p4V~
A
546- Table 9 (cont'd) Me Q HN N- 275 1720
OH
Example In 10 ml of 47% hydrobromic acid was dissolved 0.40 g of ethyl 6-fluoro-1,4-dihydro-l-(4-methoxyphenyl)- 7-(l-pyrrolidinyl)-4-oxo-1,8-naphthyridine-3-carboxylate, and the resulting solution was subjected to reaction at 120 to 125 C for 2 hours. The pH of the reaction mixture was U adjusted to 13 with 10% aqueous sodium hydroxide solution, then to 6.5 with acetic acid. The crystals thus deposited were collected by filtration and washed with 4 ml of water to obtain 0.30 g of 6-fluoro-1,4-dihydro-1-(4- hydroxyphenyl) -7-(1-pyrrolidinyl)-4-oxo-1,8-naphthyridine- 3-carboxylic acid having a melting point of 263-265 0
C.
IR (KBr) cm-l: VC=0 1725, 1705 NMR (TFA-dl)N values: 1.54-2.40 (4H, 3.14-4.14 (4H, m), 6.95-7.69 (4H, 8.09 (1H, d, J=12Hz), 9.14 (1H, s) In a similar manner, the following compound was obtained: 6-Fluoro-1,4-dihydro-1-(4-hydroxyphenyl)-7-(3hydroxy-1-pyrrolidinyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid Melting point: 180-183C IR (KBr) cm-1: VC=0 1725, 1705 Example 7 To 0.1 g of ethyl 7-(4-acetyl--piperazinyl)-6fluoro-l-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine
A,
S J AcN 169-172 1690 -3-carboxylate were added 2 ml of 1 N aqueous sodium hydroxide -solution and 2 ml of ethanol, and the resulting solution was subjected to reaction at 400 to 500C for minutes. Subsequently, acetic acid was added to the reaction mixture to adjust the pH thereof to 6.5. Then, the mixture was extracted with two 5-ml portions of chloroform. The combined extracts were washed successively with 5 ml of water and 5 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the I crystalline substance thus obtained was washed with 2 ml of I diethyl ether to obtain 0.08 g of 7-(4-acetyl-l-piperazinyl)- 6-fluoro-l-(4-fluorophenyl)-l ,4-dihydro-4-oxo-l ,8naphthyridine-3-carboxylic acid having a melting point of 0 0 280°C.
IR (KBr) cm-: 1730 NMR (d 6 -DMSO) 2 values: i 2.05 (3H, 3.57 (8H, bs), 7.13-7.80 (4H, 8.13 (1H, d, J=13Hz), 1 8.70 (IH, s) In a similar manner, the compounds shown in Table i were obtained.
I4 Ii ii j >j4V 'fI Table
COOH
R
3
N
12
R
Compound Physical properties 2) 3 Melting IP. (KBr) R R point -1 v 0 IC) cm C=0 oMeN N- 277-280 1720 o292-290 1725,shl F170 sh Me HN N- 268-270 j 1725 Me HN N- 283-285 1720 Me Me itHN IN 267-270 1730 Me Cont'd 37 Mv; Table 10 (Cont'd) 0000 0 0000 0000 o o 0000 0 00 00 0 000000 0 0 0 00 00 0 0 00 0 0 0 000 0 00 0 0 O 00 0 0 00 0 00 0 0 0 00000* 00 0 00 00 0 000 0 00 0 0 0* 0 00 oHO/\-N N- 138-139 1690
F
1730, 0 N- >280 1700 (sh) oMeN N- >280 1720
F
F
o208-209 1730
F
Me RN N- >280 1720 Me MeN N- 210-211 1735 M~e MeN N- 225-226 1720 NI ~N 219-220 1730 0 MeN N- 283-284170 1700 (sh) -Cant' d- Table 10 (Cont'd) -1730, MeN N- 277-280 170 1700 (sh) Br 271-274 1725 Me 250-252 1725 OMe Example 8 To 0.10 g of ethyl 6-fluoro-l-(4-fluorophenyl)-1,4jdihydro-7-(3-hydroxy-l-pyrrolidinyl)-4-oxo-l,8-naphthyridine-3carboxylate were added 2 ml of 1 N aqueous sodium hydroxide solution and 2 ml of ethanol, and the resulting mixture was subjected to reaction at 400 to 50 0 C for 10 minutes.
Subsequently, acetic acid was added to the reaction mixture to adjust the pH thereof to 6.5. Then, the mixture was extracted with two 5 ml portions of chloroform. The combined extracts were washed successively with 5 ml of water and 5 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 2 ml of diethyl ether to' obtain 0.08 g of 6-fluoro-l-(4-fluorophenyl)-1,4-dihydro -7-(3-hydroxy-l-pyrrolidinyl)-4-oxo-1,8-naphthyridine-3carboxylic acid having a melting point of 280 C.
-1 IR (KBr) cm C=O 1730 NMR (d 6 -DMSO) a values: 1.92-2.52 (2H, 3.22-5.00 (5H, m), 6.97-7.60 (4H, 8.01 (1H, d, J=llHz), 9.00 (1H, s) In a similar manner, the compounds shown in Table 11 i4 were obtained.
S' 2 Table 11 0 F CO0 H R N N 12
R
Compound Physical properties 2 3 Melting IP. (K~r) R R point -l1 j(OC) cm 0=0 M 2N N- 264-265 1725
F
F
of 227 1725
F
f4i~ i cm
I-
Example 9 Ln 2.5 ml of cone. hydrochloric acid was dissolved 0.25 g of 6-fluoro-l,4-dihydro-l-(4-hydroxy-2-methylphenyl)- 4-oxo-7-(l-piperazinyl)-l,8-naphthyridine-3-carboxylic acid, and then 20 ml of ethanol was added to the resulting solution, after which the resulting mixture was stirred at room temperature for 15 minutes. The crystals thus deposited were collected by filtration and washed with 5 ml of ethanol to obtain 0.2 g of the hydrochloric acid salt of 6-fluoro-1,4dihydro-l-(4-hydroxy-2-methylphenyl)-4-oxo-7-(1-piperazinyl)- 1,8-naphthyridine-3-carboxylic acid having a melting point of >280 0
C.
-l1 IR (KBr) cm-l: C=0 1725 1705 In a similar manner, the compounds shown in Table 12 were obtained.
II
I I A Table 12 Hydrochloric acid salt of 0 F COOH R N N Compound Physical properties 23Melting I IR (KBr)
R
2
R
3 point
I
(OC) cm: ~CO MeN N- 283 1730
F
o N N- 275-278 1720
F
F
o 249-252 (decomp.) 1730 o U>2B0 1710
OH
UMeN N- 280-282 1730
F
1720 (sh) oN M N- 279-283 1705
OH
Cont'd- L7 A I NMR (TFA-d) values: 3.30 (3H, 3.45-5.25 (8H, mn), 7.12-8.10 (3H, mn), 8.49 (1H, d, J=l3Iiz), 9.38 (1H, s) 1170 ii MN N-2829 1730
OH
i Example In 2.5 ml of chloroform were dissolved 0.5 g of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3-(2,4-difluorophenyl amino) acryl ate, 0.143 g of N-methylpiperazine and 0.1:45 g of triethylamine, and the resulting solution was heated under reflux for 3.5 hours. Then, the reaction mixture was washed successively with 3 ml of water and 3 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [WAKO SILICA GEL C-200, eluant: chloroform ethanol 50 1 (by volume)] to obtain 0.294 g of oily ethyl 2-12-chloro-5-fluoro-6- (4-methyl-l.-piperazinyl)nicotinoyl]-3-( 2 4 difluorophenylaiino)acrylate.
IR (Neat) cm- )C=0 1735, 1700 NMR (CDCl 3 1 values: 1.13 (3H, t, J=7Hz), 2.36 (3H, s), 2.55 (4H, t, J=5Hz), 3.70 (4H, t, 4.15 (2H, q, J=7Hz), 6.77-7.90 O4H, in), 8.51 (1H, d, J=l3Hz), 12.5G (1H, d, J=l3Hz)
F
By treating 0.2 g of ethyl 2-[2-chloro-5-fluoro- 6-(4-methyl-l-piperazinyl)nicotinoyl-3-(2,4-difluorophenylamino)acrylate in the same manner as in Examples 6 and 9, 0.12 g of 6-fluoro-l-(2,4-difluorophenyl)-1,4-dihydro-7-(4- Smethyl-l-piperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid having a melting point of 208-2090C was obtained.
Example 11 I To 0.3 g of ethyl 7-(4-ethoxycarbonyl-2-methyl-lpiperazinyl)-6-fluoro-l-(2,4-difluorophenyl)-1,4-dihydro-4oxo-1,8-naphthyridine-3- carboxylate were added 5 ml of I N aqueous sodium hydroxide solution and 5 ml of ethanol, and the resulting mixture was subjected to reaction at 90C for 2 hours. Then, acetic acid was added to the reaction mixture to adjust the pH thereof to 6.5. The crystals thus deposited were collected by filtration, washed with water and then dried to obtain 0.2 g of 6-fluoro-1-(2,4-difluorophenyl)-1,4dihydro-7-(2- methyl-l-piperazinyl)-4-oxo-1,8-naphthyridine- 3-carboxylic acid having a melting point of 230-239 0
C.
-1 IR (KBr) cm 1 1730 C=0 NMR (TFA-dl) values: 1.50 (3H, 3.20-5.15 (7H, m), 7.00-7.90 (3H, 8.35 (1H, d, J=13Hz), 9.20 (1H, s) Preparation Example 1 With 50 g of 6-fluoro-1-(2,4-difluorophenyl)-1,4dihydro-4-oxo-7-(l-piperazinyl)-1,8-naphthyridine-3- K carboxylic acid were blended 49 g of crystalline cellulose, g of corn starch and 1 g of magnesium stearate, and the blend was compressed into 1,000 flat-type tablets.
Preparation Example 2 With 100 g of 6-fluoro-1-(2,4-difluorophenyl)- 1,4-dihydro-4-oxo-7-(l-piperazinyl)-1,8-naphthyridine-3carboxylic acid was blended 50 g of corn starch, and 1,000 capsules were filled with the resulting blend to obtain capsules.
4c-l\~ 7 t l
Claims (8)
1. A 1,4-dihydro-4-oxonaphthyridine derivative i represented by the formula, or a salt thereof: 0 COOR 1 R N N R 1 wherein R represents a hydrogen atom or a conventional carboxyl-protecting group used in the cephalosporin or 2 Spenicillin art, R represents a 2,4-difluorophenyl group, 6 3 and R represents a halogen atom or a l-piperazinyl group in which the imino group may be protected ky o4er ^Aqi Q
2. 1-(2,4-Difluorophenyl)-6-fluoro-l,4-dihydro-4-oxo-7- (1-piperazinyl-i,8-naphthyridine-3-carboxylic acid or a salt thereof,
3. A process for producing a 1,4-dihydro-4-oxo- naphthyridine derivative represented by the formula, or a salt thereof: F 0 A COOR 3 R N N 1 R wherein R represents a hydrogen atom or a conventional carboxyl-protecting group used in the cephalosporin or penicillin art, R represents a 2,4-difluorophenyl group, 65 J a. ,il and R represents a halogen atom or a 1-piperazinyl group I 6h o/Ae-r -I A iL'{y/ e-igrou Ssubjecting the compound represented by the formula, or a salt j thereof: 0 Fi l COOR 3 N2 R c l NHR 2 la wherein R represents a conventional carboxyl-protecting group used in the cephalosporin or penicillin art, and R and R have the same meanings as defined above to ring closure reaction, and then, if desired, removing the carboxyl-protecting group.
4. A process according to claim 3 wherein the ring closure reaction is conducted at a temperature of 200 to 160 0 C. 4 4
5. A process for producing a 1,4-dihydro-4-oxo- naphthyridine derivative represented by the formula, or a salt thereof: tF OOR F 00LOR 1 3b R N N 12 R wherein R represents a hydrogen atom or a conventional carboxyl-protecting group, R represents a 2,4-difluoro- iRiA phenyl group, and R 3 b represents a l-piperazinyl group in l .66. N. I I -Z W 4i L-4~ *P~I-I~T~UITU -d: I~smaa~ l~iii 4 4 4. C e ar y which the imino group may be p/otected 4 characterized by reacting the compound represented by the formula, or a salt thereof: iCOOR 1 wherein R 3 a represents a halogen atom, and R 1 and R 2 have the same meanings as defined above, with a compound represented by the formula, or a salt thereof: R3bH Ri 3b wherein R has the same meaning as defined above.
6. A process according to claim 5 wherein the reaction is conducted at a temperature of 0° to 150 C.
7. An antibacterial composition comprising a 1, 4 -dihydro-4-oxonaphthyridine derivative represented by the formula or a salt thereof: wherein R represents a hydrogen atom or a conventional carboxyl-protecting group used in the cephalosporin or penicillin art, R represents a 2,4-difluorophenyl group, I '-67- 4i7 -68- and R 3 represents a halogen atom or a 1-piperazinyl gr3:u~ in wh-ich the imino group may be poe d l' Ya~ pharmaceutically acceptable carrier or excipient.
8. An antibacterial composition comprising l-(2,4- difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo--7-(l-piperazinyl)- 1, 8-naphthyridine-3-c,o-oxylic acid or a salt thereof and a pharmaceutically ac.;-eptable carrier or excip.ient. DATED: 5 February, 1991 TOYAM4A CHEMICAL CO., LTD. By their Patent Attorneys: PHILLIPS ORMONDE FITZPATRIC 7- frIU4
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59084963A JPS60228479A (en) | 1984-04-26 | 1984-04-26 | 1,4-dihydro-4-oxonaphthyridine derivative and salt thereof |
| JP59-84963 | 1984-04-26 |
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|---|---|---|---|
| AU41650/85A Division AU565087B2 (en) | 1984-04-26 | 1985-04-24 | 1,4-dihydro-4-oxonaphthyridine derivatives |
Publications (2)
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| AU612993B2 true AU612993B2 (en) | 1991-07-25 |
Family
ID=13845280
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|---|---|---|---|
| AU41650/85A Expired AU565087B2 (en) | 1984-04-26 | 1985-04-24 | 1,4-dihydro-4-oxonaphthyridine derivatives |
| AU81804/87A Expired AU612993B2 (en) | 1984-04-26 | 1987-11-25 | 1,4-dihydro-4-oxonaphthyridine derivatives and salts thereof, process for producing the same and antibacterial agents comprising the same |
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| AU41650/85A Expired AU565087B2 (en) | 1984-04-26 | 1985-04-24 | 1,4-dihydro-4-oxonaphthyridine derivatives |
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Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6172753A (en) * | 1984-09-18 | 1986-04-14 | Dainippon Pharmaceut Co Ltd | Pyridyl ketone derivative |
| AU576657B2 (en) * | 1985-01-23 | 1988-09-01 | Toyama Chemical Co. Ltd. | Naphthyridine and pyridine derivatives |
| AT392789B (en) | 1985-01-23 | 1991-06-10 | Toyama Chemical Co Ltd | METHOD FOR PRODUCING 1-SUBSTITUTED ARYL-1,4-DIHYDRO-4-OXONAPHTHYRIDINE DERIVATIVES |
| DE3525108A1 (en) * | 1985-06-07 | 1986-12-11 | Bayer Ag, 5090 Leverkusen | ANTIBACTERIAL EFFECT OF CHINOLON CARBON ACID ESTERS |
| EP0207420B1 (en) * | 1985-06-26 | 1992-05-06 | Daiichi Pharmaceutical Co., Ltd. | Pyridonecarboxylic acid derivatives |
| IE62600B1 (en) * | 1987-08-04 | 1995-02-22 | Abbott Lab | Naphtyridine antianaerobic compounds |
| US4962112A (en) * | 1987-08-04 | 1990-10-09 | Abbott Laboratories | 7-(2-methyl-4-aminopyrrolidinyl)naphthryidine and quinoline compounds |
| US4859776A (en) * | 1988-03-11 | 1989-08-22 | Abbott Laboratories | (S)-7-(3-aminopyrrolidin-1-yl)-1-(ortho, para-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid and method for its preparation |
| JP2844079B2 (en) * | 1988-05-23 | 1999-01-06 | 塩野義製薬株式会社 | Pyridonecarboxylic acid antibacterial agent |
| DE3934082A1 (en) * | 1989-10-12 | 1991-04-18 | Bayer Ag | CHINOLON CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS AN ANTIVIRAL AGENT |
| AU1161492A (en) * | 1991-01-14 | 1992-08-17 | Hanmi Pharmaceutical Co., Ltd. | Novel quinolone compounds and processes for preparation thereof |
| FR2692577B1 (en) * | 1992-05-26 | 1996-02-02 | Bouchara Sa | NOVEL FLUORINATED QUINOLONES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
| KR940014395A (en) * | 1992-12-09 | 1994-07-18 | 강박광 | Novel quinolone derivatives and preparation methods thereof |
| KR0148277B1 (en) * | 1993-01-18 | 1998-11-02 | 채영복 | Novel fluoroquinolone derivatives and process for the preparation thereof |
| WO1994025464A1 (en) * | 1993-04-24 | 1994-11-10 | Korea Research Institute Of Chemical Technology | Novel quinolone carboxylic acid derivatives and process for preparing the same |
| KR950018003A (en) * | 1993-12-09 | 1995-07-22 | 스미스클라인 비참 피엘씨 | Novel quinolone derivatives and methods for their preparation |
| EP0787720B1 (en) * | 1994-10-20 | 2003-07-16 | Wakunaga Seiyaku Kabushiki Kaisha | Pyridonecarboxylate derivative or salt thereof and antibacterial containing the same as active ingredient |
| US6211375B1 (en) | 1996-04-19 | 2001-04-03 | Wakunaga Pharmaceutical Co., Ltd. | Pyridonecarboxylic acid derivatives or salts thereof and antibacterial agents containing the same as the active ingredient |
| PL332941A1 (en) * | 1996-10-30 | 1999-10-25 | Bayer Ag | Method of obtaining naphtyridinic compounds and novel intermediate compounds |
| DE19713506A1 (en) | 1997-04-01 | 1998-10-08 | Bayer Ag | Process for the preparation of 2,6-dichloro-5-fluoronicotinonitrile and the chemical compound 3-cyano-2-hydroxy-5-fluoropyrid-6-one monosodium salt and its tautomers |
| EP2275141A1 (en) | 1999-03-17 | 2011-01-19 | Daiichi Pharmaceutical Co., Ltd. | Tastemasked pharmaceutical compositions |
| DE19926400A1 (en) | 1999-06-10 | 2000-12-14 | Bayer Ag | Improved process for the preparation of 2,6-dichloro-5-fluoro-nicotinic acid and coarse and particularly pure 2,6-dichloro-5-fluoro-nicotinic acid |
| JP3477466B2 (en) | 1999-09-02 | 2003-12-10 | 湧永製薬株式会社 | Quinolinecarboxylic acid derivatives or salts thereof |
| WO2002018345A1 (en) * | 2000-08-29 | 2002-03-07 | Chiron Corporation | Quinoline antibacterial compounds and methods of use thereof |
| KR100981351B1 (en) * | 2003-10-29 | 2010-09-10 | 주식회사 엘지생명과학 | Process for preparing 7-chloro-1-cyclopropyl-6- fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid |
| CN101792443A (en) * | 2010-03-09 | 2010-08-04 | 北京欧凯纳斯科技有限公司 | Fluoro-carbostyril derivative as well as preparation method and application thereof |
| JOP20190045A1 (en) | 2016-09-14 | 2019-03-14 | Bayer Ag | 7-substituted 1-aryl-naphthyridine-3-carboxylic acid amides and use thereof |
| CN114369092A (en) * | 2021-12-20 | 2022-04-19 | 赤峰万泽药业股份有限公司 | Tosufloxacin tosylate and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3799385A (en) * | 1984-01-26 | 1985-08-01 | Abbott Laboratories | Naphthyridine antibacterial compounds |
| AU5254386A (en) * | 1985-01-23 | 1986-07-31 | Toyama Chemical Co. Ltd. | Naphthyridine and pyridine derivatives |
| AU5760786A (en) * | 1985-06-07 | 1986-12-11 | Bayer Aktiengesellschaft | Quinolone carboxylic acid esters |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2125310A1 (en) * | 1971-05-21 | 1972-11-30 | Sterling Drug Inc , New York, NY (V St A) | 1-alkyl-1,4-dihydro-4-oxo-1,8-naphtyridine 3-carboxylic acids antibac |
| AR223983A1 (en) * | 1978-08-25 | 1981-10-15 | Dainippon Pharmaceutical Co | A PROCEDURE FOR PREPARING 6-HALOGEN-4-OXO-7- (1-PIPERAZINYL) -1,8-NAFTIRIDIN-3-CARBOXYLIC ACID DERIVATIVES |
| DE3033157A1 (en) * | 1980-09-03 | 1982-04-01 | Bayer Ag, 5090 Leverkusen | 7-AMINO-1-CYCLOPROPYL-4-OXO-1,4-DIHYDRO-NAPHTHYRIDINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM |
| US4382937A (en) * | 1981-02-27 | 1983-05-10 | Dainippon Pharmaceutical Co., Ltd. | Naphthyridine derivatives and their use as anti-bacterials |
| IE55898B1 (en) * | 1982-09-09 | 1991-02-14 | Warner Lambert Co | Antibacterial agents |
| IL74064A (en) * | 1984-01-26 | 1988-09-30 | Abbott Lab | 1,7-disubstituted-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid derivatives and antibacterial compositions containing them |
-
1984
- 1984-04-26 JP JP59084963A patent/JPS60228479A/en active Granted
-
1985
- 1985-04-18 DE DE19853514076 patent/DE3514076A1/en active Granted
- 1985-04-18 DE DE3546658A patent/DE3546658C2/de not_active Expired - Lifetime
- 1985-04-23 NL NLAANVRAGE8501172,A patent/NL187314C/en not_active IP Right Cessation
- 1985-04-23 GB GB08510297A patent/GB2158825B/en not_active Expired
- 1985-04-23 PH PH32174A patent/PH22801A/en unknown
- 1985-04-24 PT PT80349A patent/PT80349B/en unknown
- 1985-04-24 AU AU41650/85A patent/AU565087B2/en not_active Expired
- 1985-04-24 RO RO118517A patent/RO91871B/en unknown
- 1985-04-24 NO NO851643A patent/NO162238C/en not_active IP Right Cessation
- 1985-04-24 IL IL7502185A patent/IL75021A/en not_active IP Right Cessation
- 1985-04-24 AT AT0122485A patent/AT389698B/en not_active IP Right Cessation
- 1985-04-24 EG EG261/85A patent/EG17339A/en active
- 1985-04-24 DD DD85275518A patent/DD238795A5/en unknown
- 1985-04-24 RO RO126286A patent/RO95509B/en unknown
- 1985-04-24 NZ NZ211895A patent/NZ211895A/en unknown
- 1985-04-25 CH CH1798/85A patent/CH673458A5/de not_active IP Right Cessation
- 1985-04-25 FI FI851637A patent/FI80453C/en not_active IP Right Cessation
- 1985-04-25 SE SE8502017A patent/SE463102B/en not_active IP Right Cessation
- 1985-04-25 FR FR858506327A patent/FR2563521B1/en not_active Expired
- 1985-04-25 BE BE0/214909A patent/BE902279A/en not_active IP Right Cessation
- 1985-04-25 CS CS853035A patent/CS250684B2/en not_active IP Right Cessation
- 1985-04-25 HU HU851599A patent/HU194226B/en unknown
- 1985-04-25 ZA ZA853102A patent/ZA853102B/en unknown
- 1985-04-25 HU HU873675A patent/HU197571B/en unknown
- 1985-04-25 KR KR1019850002822A patent/KR870001693B1/en not_active IP Right Cessation
- 1985-04-25 ES ES542584A patent/ES8700256A1/en not_active Expired
- 1985-04-25 AR AR85300190A patent/AR241911A1/en active
- 1985-04-25 DK DK185685A patent/DK165877C/en not_active IP Right Cessation
- 1985-04-25 ID IDP980525A patent/ID21142A/en unknown
- 1985-04-26 PL PL1985253108A patent/PL147392B1/en unknown
- 1985-04-26 IT IT8548002A patent/IT1209953B/en active
- 1985-04-26 LU LU85871A patent/LU85871A1/en unknown
-
1986
- 1986-01-31 ES ES551538A patent/ES8706673A1/en not_active Expired
-
1987
- 1987-07-17 GB GB8716897A patent/GB2191776B/en not_active Expired - Lifetime
- 1987-10-20 PH PH35958A patent/PH25046A/en unknown
- 1987-10-20 PH PH35960A patent/PH25228A/en unknown
- 1987-11-25 AU AU81804/87A patent/AU612993B2/en not_active Expired
-
1988
- 1988-06-30 FR FR888808836A patent/FR2614620B1/en not_active Expired - Lifetime
- 1988-10-31 AT AT0267888A patent/AT390258B/en not_active IP Right Cessation
- 1988-12-20 SE SE8804586A patent/SE501412C2/en not_active IP Right Cessation
-
1991
- 1991-04-15 NL NL9100648A patent/NL9100648A/en not_active Application Discontinuation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3799385A (en) * | 1984-01-26 | 1985-08-01 | Abbott Laboratories | Naphthyridine antibacterial compounds |
| AU5254386A (en) * | 1985-01-23 | 1986-07-31 | Toyama Chemical Co. Ltd. | Naphthyridine and pyridine derivatives |
| AU5760786A (en) * | 1985-06-07 | 1986-12-11 | Bayer Aktiengesellschaft | Quinolone carboxylic acid esters |
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