IL75021A - 1-(2, 4-difluorophenyl)-6-fluoro-7- halo-1,4-dihydro-4-oxo-1,8-naphthydridine-3-carboxylic acid and esters thereof - Google Patents

1-(2, 4-difluorophenyl)-6-fluoro-7- halo-1,4-dihydro-4-oxo-1,8-naphthydridine-3-carboxylic acid and esters thereof

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Publication number
IL75021A
IL75021A IL7502185A IL7502185A IL75021A IL 75021 A IL75021 A IL 75021A IL 7502185 A IL7502185 A IL 7502185A IL 7502185 A IL7502185 A IL 7502185A IL 75021 A IL75021 A IL 75021A
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dihydro
fluoro
oxo
salt
difluorophenyl
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IL7502185A
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Hebrew (he)
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IL75021A0 (en
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Hirokazu Narita
Yoshinori Konishi
Jun Nitta
Hideyoshi Nagaki
Isao Kitayama
Yoriko Kobayashi
Mikako Shinagawa
Yasuo Watanabe
Akira Yotsuji
Shinzaburo Minami
Isamu Saikawa
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Toyama Chemical Co Ltd
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Application filed by Toyama Chemical Co Ltd filed Critical Toyama Chemical Co Ltd
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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
    • 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
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hydrogenated Pyridines (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Description

75021/3 - 1 σρ 1H- ITT > m-4 ,1- 1 !?n-7- 1 niNt?o-6- ( > J D I ~> N^O > i- ,2 ) -1 n*oi n nby O'IODNI n>i?>D i3-i -3- 1 >"T,"i,n-i J-8 ,1 l-(2,i+-Difluorophenyl)-6-fluoro-7-halo-l , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylic acid and esters thereof TOYAMA CHEMICAL CO., LTD.
C: 73Z+23/6 75021/2 This invention relates to novel 7-halo-l ,4-dihydro-4-oxonaphthyridine-3-carboxylic acid derivatives having 2,4-difluorophenyl groups at the 1-position and salts thereof.
The compounds are useful as antibacterial agents.
Nalidixic acid, piromidic acid, pipemidic acid and the like have heretofore been widely used as synthe-tic 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- ( 1-pipera-zinyl) -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. 75021/2 Under these circumstances, the present inventors have, as a result of extensive research, found that certain novel 1 , 4-dihydro-4-oxonaphthyridine derivatives and salts' thereof can solve the aforementioned problems.
An object of this invention is to provide novel 1 , 4-dihydro-4-oxonaphthyridine derivatives and salts 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.
According to this invention, there are provided 1 , 4-dihydro-4-oxonaphthyridine derivatives represented by the general formula: wherein R represents a hydrogen atom or a carboxyl-protecting group, R2 represents a 2,4-difluorophenyl group, and R represents a halogen atom, and salts thereof.
The invention will be explained in detail below.
In the compound represented by the general formula [I] or a salt thereof, the carboxyl-protecting group for R1 includes, for example, ester-forming groups which may be 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 silyl-containing groups, organic phosphorus-containing groups and organic tin-containing groups which may be easily removed by treatment with water or an alcohol; and other various well-known ester forming groups.
Among these carboxyl-protecting groups, the preferred protecting groups include, for example, carboxyl-protecting groups described in Japanese Patent Application Kokai (Laid-Open) No. 80,665/84.
The hal ogen atom for R3 incl udes , for example fl uorine , chlorine and bromi ne .
The following description may contain subject matter which exceeds the Scope of the claims, but is being included for the sake of clarity and better understanding.
The salt of the compound represented by the • general formula [I] 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 methane- sulfonic 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-3-phenethylamine, 1- ephenamine, N,N-dibenzylethylenediamine, triethylamine , trimethylamine, tributylamine, pyridine, N,N-dimethyl- aniline, N-methylpiperidine, N-methylmorpholine, diethyl- amine, dicyclohexylamine and the like.
If the compound represented by the general formula [I] and a salt thereof have isomers (for example, optical isomers, 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. - 7 - 1. Antibacterial activity Test method According to the standard method of Japan Society of Chemotherapy [CHEMOTHERAPY, 2^(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 (yg/ml) . The amount of the inoculated 4 6 bacteria was 10 cells/plate (10 cells/ml) . The MIC values of the following test compounds are as shown in Table 1.
Symbols used in Table 1 have the following meanings': *1: penicillinase-producing bacteria, *2: cephalosporinase-producing bacteria, Q *3: inoculation size: 10 cells/ml, Me: methyl group, Et: ethyl group, n-Pr: n-propyl group, i-Pr: isopropyl group - 8 - Table 1 Table 1 (Cont'd) Table 1 (Cont'd) 2. Acute toxicity The 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.
The process for producing the compound of this invention will be explained below.
The compound of this invention can be produced, for example, according to the following production route: [III] or a salt thereof [V] or a salt thereof tla] or a salt thereof [lb] or a salt thereof wherein R represents the same carboxy-protecting group - 12 - as in R ; R represents the same halogen atom as in R ; 3b R represents the same substituted or unsubstituted cyclic ammo group as in R 3 ; and R1 and R2 have the same meanings as defined above.
The salts of the compounds represented by the general formulae [la], [lb], [III], [IV] and [V] include the same salts as those of the compounds represented by the general formula [I] . (i) The compound represented by the general formula [III] or a salt thereof or the compound represented by the general formula [V] 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, Ν,Ν-dimethylformamido-diethylacetal or the like and then with an amine represented 2 2 by the general formula, R - I^ (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, Ν,Ν-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; etc. and these solvents may be used alone or in - 13 - 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. The reactions are usually conducted at 0° to 100°C, preferably at 50° to 80°C, 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. The reaction is usually conducted at 0° to 100°C, preferably 10° to 60°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 thereof with ethyl orthoformate or methyl orthoformate in the presence of acetic anhydride, and then with an amine 2 represented by the general formula, R - H2 or a salt there-of to obtain the compound represented by the general formula [III] or a salt thereof or the compound represented by the general formula [V] or a salt thereof, respectively. (ii) The compound represented by the general formula [la] or a salt thereof or the compound represented by the general formula [lb] 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 [V] or a salt thereof - 14 - 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 Ν,Ν-dimethylformamide, Ν,Ν-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 hydrogen-carbonate, 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 [V] or a salt thereof. The reaction is usually conducted at 20° to 160°C, preferably at 100° to 150°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 [V] or a salt thereof, or the compound represented by the general formula [lb] or a salt thereof is, respectively, obtained by reacting 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 [la] or a salt thereof with a cyclic amine represented by the general formula, R 3b-H or a salt thereof (wherein R3b has the same meaning as above) . - 15 - 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, tetrahydro-furan, anisole, diethylene glycol diethyl ether and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; amides such as N,N-di-methylformamide , N,N-dimethylacetamide and the like; sulfoxides 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 [II] , the compound represented by the general formula [III] or a salt thereof, or the compound represented by the general formula [la] or a salt thereof. 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 1 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 [la] or a salt thereof. The acid-binding agent includes organic or inorganic bases such as triethylamine , 1, 8-diazabicyclo [5,4,0] undec-7-ene (DBU) , potassium tert-butoxide, potassium carbonate, sodium carbonate, sodium hydride and the like. - 16 - The salt of R -H includes the same as the salts at the basic group of the compound represented by the general formula [I] .
The reaction is usually conducted at 0° to 150°C, preferably at 50° to 100°C, and usually for 5 minutes to 30 hours, preferably 30 minutes to 3 hours.
The compound represented by the general formula [la], [lb], [III] or [V], wherein R''" represents a carboxyl-protecting group, or a salt thereof can, if desired, be converted to the corresponding free carboxylic acid by hydrolyzing the same in the presence of a conventional acid or alkali, which is used in hydrolysis, usually at 0° to 100°C, preferably at 20° to 100°C for 5 minutes to 50 hours, preferably.5 minutes to 4 hours. Further, the compound represented by the general formula [la], [lb], [III] or [V] 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 se. If the compound represented by the general formula [la] , [III] t [IV] or [V] or a salt thereof has an active group (for example, hydroxyl group, amino group or the like) at other positions than the reaction sites, it is possible to 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 like. - 17 - The compound represented by the general formula 3 [I] or a salt thereof, wherein R represents a halogen atom (corresponding to the compound represented by the general formula [la]), is also useful as an intermediate for 3 obtaining a compound wherein R represents a substituted or unsubstituted cyclic amino group (corresponding to the compound represented by the general formula [lb]).
When the compound of this invention is used as a drug 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, injections 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.
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. - 18 - 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 Ν,Ν-dimethylformamide were added to the resulting solution. The resulting mixture was reacted at 70 °C 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-nicotinoyl ■ 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 - 19 - 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 removed 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.
IR (KBr) cm"1: vc=Q 1650, 1630, 1620 N R (CDC13) δ values: 1.25 (1.29H, t, J=7Hz), 1.33 (1.71H, t, J=7Hz), 4.07 (1.14H, s), 4.28 (2H, q, J=7Hz), 5.82 (0.43H, s) , 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 Ν,Ν-dimethylformamidodimethylacetal was added thereto, after which the resulting mixture was subjected to reaction at 70°C for 1.5 hours. Then, 4.1 g of 2 , 4-difluoro- aniline was added to the reaction mixture and the result- ing 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 , 4-difluorophenylamino) acrylate having a melting point of 138-139°C.
IR (KBr) cm"1: c=0 1690 NMR (CDCI3) δ values: 1.08 (3H, t, J=7Hz), 4.10 (2H, q, J=7Hz), 6.77-7.40 (4H, m) , 8.50 (1H, d, J=13Hz), 12.70 (1H, d, J=13Hz) In a similar manner, the compounds shown in Table 2 were obtained. - 21 - Table 2 - Cont'd - - 22 - Table 2 (Cont'd) Note: The neat method was used in place of the KBr method. - 23 - Referential Example 3 (1) 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 60° to 65 °C for 2 hours. The reaction mixture was washed with 30 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-l-piperazinyl) nicotinoyl] acetate. IR (Neat) cm-1: c=Q 1750, 1695 NMR (CDC13) δ values: 1.25 (3H, t, J=7Hz) , 2.32 (3H, s) , 2.12-2.70 (4H, m) , 3.55-3.96 (4H, m) , 4.03 (2H, s) , 4.20 (2H, q, J=7Hz) , 7.78 (1H, d, J=13Hz) In a similar manner, the compound shown in Table 3 was obtained.
Table 3 (2) 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-dimethylformamido-dimethylacetal 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: 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-l-piperazinyl) nicotinoyl] - - 25 - 3- (4-methoxy-2-methylphenylamino) acrylate having a melting point of 141-142°C.
IR (KBr) cm"1: c=0 1710 (sh) , 1695 NMR (CDC13) 6 values: 1.08 (3H, t, J=7Hz), 2.32 (3H, a), 2.40 (3H, s) , 2.23-2.68 (4H, m) , 3.47-3.83 (4H, m) , 3.75 (3H, s) , 4.07 (2H, q, J=7Hz) , 6.65-7.25 (3H, m) , 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. - 26 - Table 4 - Cont'd - - 27 - Table 4 (Cont'd) Note: *1: KBr *2: Neat - 28 - Example 1 In 90 ml of Ν,Ν-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 reduced pressure, and the crystalline substance obtained was washed with 30 ml of diethyl ether to obtain 7.0 g of ethyl 7-chloro-6-fluoro-1- ( 2, 4-difluorophenyl) -1 , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylate having a melting point of 220-222°C.
IR (KBr) cm""1: vc=0 1730, 1690 NMR (CDC13) δ values: 1.36 (3H, t, J=7Hz) , 4.30 (2H, q, J=7Hz) , 6.80-7.60 (3H, m) , 8.27(1H, d, J=7Hz) , 8.42(1H, s) In a similar manner, the compounds shown in Table 5 were obtained. - 29 - Table 5 - on - - 30 - Table 5 (Cont'd) - - - 31 - Table 5 (Cont'd) - - - 32 - Table 5 (Cont'd) Example 2 (1) In 35 ml of chloroform was dissolved 3.5 g of ethyl 7-chloro-6-fluoro-1- ( 2 , 4-difluoropheny1 ) -1,4-dihydro-4-oxo-l, 8-naphthyridine-3-carboxylate, 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°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-200, eluant: chloroform : ethanol = 30 : 1 (by volume)] to obtain 3.5 g of ethyl 7- (4-acetyl-l-piperazinyl) -6-fluoro-1- ( 2 , 4-difluoropheny1 ) -1 , 4-dihydro-4-oxo-1 , 8-naphthyridine-3-carboxylate having a melting point of 207-209°C.
IR (KBr) cm"1: c=Q 1730, 1695 NMR (CDC13) δ values: - 33 - 1.38(3H, t, J=7Hz), 2.05(3H, s) , 3.53(8H, bs) , 4.30(2H, q, J=7Hz) , 6.80-7.75 (3H, m) , 8.00(lH, d, J=13Hz) , 8.30(1H, s) In a similar manner, the compounds shown in Table 6 were obtained. - 34 - Table 6 - Cont'd - - 35 - Table 6 (Cont'd) - 36 - Table 6 (Cont'd) - 37 - Table 6 (Cont'd) - 38 - Table 6 (Cont'd) - 39 Table 6 (Cont'd) - 40 - (2) In 25 ml of 6 N hydrochloric acid was dissolved 2.5 g of ethyl 7- (4-acetyl-l-piperazinyl) -6-fluoro-1- ( 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-1- (2, 4-difluorophenyl) -1 , 4-dihydro-4-oxo-7-(1-piperazinyl) -1 , 8-naphthyridine-3-carboxylic acid.
NMR (TFA-d^) δ values: 3.30-4.50 (8H, m) , 7.00-7.85 ( 3H, m) , 8.33(1H, d, J=13Hz), 9.21(1H, s) In a similar manner, the compounds shown in Table 7 were obtained. - 41 - Table 7 - 42 - - 43 - Table 7 (Cont'd) Note: * The nujol method was used in place of the KBr method . - 44 - Example 3 (1) In 5 ml of chloroform was dissolved 0.50 g of ethyl 7-chloro-6-fluoro-1- ( 2 , 4-difluorophenyl ) -1, 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylate, and to the resulting solution were added 0.20 g of 3-acetyl-aminopyrrolidine and 0.15 g of triethylamine , after which the resulting mixture was subjected to reaction at 60 °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-200, eluant: chloroform : ethanol = 30 : 1 (by volume)] to obtain 0.5 g of ethyl 7- (3-acetylamino-l-pyrrolidinyl) -6-fluoro-1- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxo-l, 8-naphthyridine-3-carboxylate having a melting point of 233-235°C. -1 IR (KBr) cm v 1725, 1700 C=0 N R (CDC1,) δ values: 1.32(3H, t, J=7Hz) , 1.77-2.27(m) } (5H) , 2.08 (s) 3.12-3.74 (4H, m) t 4.02-4.74(m) : 4.29(q, J=7Hz)} (3H) , 6.75-7.60(4H, m) , 7.93 (1H, d, J=8Hz) , 8.24(1H, s) In a similar manner, the compounds shown in Table 8 were obtained. - 45 - Table 8 46 - Table 8 (Cont'd) - 47 - (2) In 2.5 ml of 6 N hydrochloric acid was dissolved 0.25 g of ethyl 7- ( 3-acetylamino-l-pyrrolidinyl) -6-fluoro-1- (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 2 ml of water and then dried to obtain 0.18 g of 7- (3-amino-l-pyrrolidinyl ) -6-fluoro-1- ( 2 , 4-difluorophenyl ) -1 , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylic acid.
NMR (TFA-d^) δ values: 2.25-2.85(2H, m) , 3.37-4.69 ( 5H , m) , 6.93-7.81 (3H, m) , 8.22(1H, d, J=llHz) , 9.16(1H, s) In a similar manner, the compounds shown in Table 9 were obtained. - 48 - Example 4 (1) In 20 ml of chloroform were dissolved 2.0 g of - 49 - ethyl 2 , 6-dichlorc—5-fluoronicotinoylacetate , 0.96 g of 3-acetylaminopyrrolidine and 0.8 g of triethylamine and the resulting solution was subjected to reaction at 60° to 65°C for 2 hours. The reaction mixture was washed with 30 ml of water, 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: benzene : ethyl acetate = 1 : 1 (by volume)] to obtain 1.8 g of oily ethyl [2-chloro-5-fluoro-6- (3-acetylamino-l-pyrrolidinyl) -nicotinoyl] acetate.
IR (Neat) cm-1: C=0 1740, 1650 NMR (CDC13) 6 values: 1.28 (3H, t, J=7Hz) , 1.97 (3H, s) , 1.90-2.62 (2H, m) , 4.02 (2H, s) , 4.15 (2H, q, J=7Hz), 3.50-4.70 (5H, m) , 7.06 (1H, d, J=6Hz) , 7.57 (1H, d, J=13Hz) (2) In 10 ml of benzene was dissolved 0.7 g of ethyl 2^chloro-5-fluoro-6- ( 3-acetylamino-l-pyrrolidinyl) nicotinoyl-acetate, and to the resulting solution was added 0.235 g of Ν,Ν-dimethylformamidodimethylacetal , after which the resulting mixture was subjected to reaction at 70 °C for 2 hours. To the reaction mixture was added 0.243 g of 2,4-difluoroaniline, and the resulting mixture was subjected to reaction at room temperature for 8 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column - 50 - chromatography [WAKO SILICA GEL C-200, eluant: benzene : ethyl acetate = 1 : 1 (by volume) ] , and the oily product thus obtained was triturated with diisopropyl ether to obtain 0.25 g of ethyl 2- [2-chloro-5-fluoro-6- (3-acetylamino-l-pyrrolidinyl) nicotinoyl] -3- (2 , 4-difluorophenylamino) acrylate having a melting point of 82-85°C.
IR (KBr) cm"1: VC=0 1695 (sh) , 1660 NMR (CDC13) δ values: 1.25 (3H, t, J=7Hz) , 2.07 (3H, s) , 1.90-2.30 (2H, m) , 4.19 (2H q, J=7Hz) , 3.60-4.70 (5H, m) , 6.49 (1H, d, J=6Hz) , 6.80-7.50 (4H, m) , 8.53 (1H, d, J=13Hz) , 12.46 (1H, d, J=13Hz) (3) In 3 ml of Ν,Ν-dimethylformamide was dissolved 0.2 g of ethyl 2- [2-chloro-5-fluoro-6- ( 3-acetylamino-l-pyrrolidinyl) nicotinoyl] -3- (2 , 4-difluorophenylamino) acrylate , and to the resulting solution was added 0.04 g of sodium hydrogencarbonate , after which the resulting mixture was subjected to reaction at 120°C for 1 hour. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 10 ml of chloroform. The resulting solution was washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution, and thereafter dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 5 ml of diethyl ether to obtain 0.13 - 51 - g of ethyl 7- (3-acetylamino-l-pyrrolidinyl) -6-fluoro-1- ( 2 , 4-difluorophenyl) -1 , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylate having a melting point of 233-235°C.
In a similar manner, ethyl 7- (3-acetylamino-l-pyrrolidinyl) -6-fluoro-1- (4-fluorophenyl) -1 , 4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylate was obtained. The physical properties of this product were identical with those obtained in Example 3-(l).
Example 5 (1) In 15 ml of 6 N hydrochloric acid was suspended 0.50 g of ethyl 7-chloro-6-fluoro-1- (2 , 4-difluorophenyl) -l,4-dihydro-4-oxo-l,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 extract-ed 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-1- (2 , 4-difluorophenyl) -1 , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylic acid having a melting point of 244-248°C.
IR (KBr) cm"1: C=0 1720 N R (dg-DMSO) 6 values: 7.26-8.56 (3H, m) , 8.86 (1H, d, J=7Hz) , - 52 - 9.18 (1H, s) (2) In 3 ml of dimethylsulfoxide was suspended 0.30 g of 7-chloro-6-fluoro-1- ( 2 , 4-difluorophenyl) -1 , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylic acid, and then 0.25 g of N-methylpiperazine was added to the resulting suspension, after which the resulting suspension was subjected to reaction at 60°C for 30 minutes. Then, the solvent was 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) -1 , 4-dihydro-7- (4-methyl-l-piperazinyl) -4-oxo-l , 8-naphthyridine-3-carboxylic acid having a melting point of 208-209°C.
IR (KBr) cm-1: C=0 1730 NMR (TFA-d^) δ values: 3.30 (3H, s) , 3.45-5.25 (8H, m) , 7.12-8.10 (3H, m) , 8.49 (1H, d, J=13Hz) , 9.38 (1H, s) Example 6 In 50 ml of , -dimethyIformamide was dissolved 5.0 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 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 water and 30 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 obtained was washed with 30 ml of. diethyl ether to obtain 2.38 g of ethyl 6-fluoro-1 , 4-dihydro-l- ( 4-methoxy-2-methylphenyl) -7- (4-methyl-l-piperazinyl) -4-oxo-l , 8-naphthyridine-3-carboxylate having a melting point of 144-145°C. -1 v IR (KBr) cm 1730, 1690 NMR (CDC1,) δ values: 1.33 (3H, t, J=>7Hz), 1.95 (3H, s) , 2.20 (3H, s) , 2.05-2.62 (4H, m) , 3.32-3.63 (4H, m) , 3.82 (3H, s) , 4.32 (2H, q, J=7Hz) , 6.60-7.15 (3H, m) , 8.02 (1H, d, J=13Hz) , 8.23 (1H, s) In a similar manner, the compounds shown in Table 10 were obtained. - 54 - COOEt - 55 - Example 7 In 5 ml of 47% hydrobromic acid was dissolved 2.0 g of ethyl 6-fluoro-1 , 4-dihydro-l- (4-methoxy-2-methylphenyl) -7- (4-methyl-l-piperazinyl) -4-oxo-l , 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 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 , 4-dihydro-1- (4-hydroxy-2-methylphenyl) -7- (4-methyl-l-piperazinyl) -4-oxo-l , 8-naphthyridine-3-carboxylic acid having a melting point of >280°C.
IR ( Br) cm"1: C=0 1725, 1700 (sh) NMR (TFA-d1) δ values: 2.08 (3H, s) , 3.12 (3H, s) , 2.88-5.12 (8H, m) , 6.93-7.62 (3H, m) , 9.25 (1H, s) , 9.43 (1H, d, J=13Hz) In a similar manner, the compounds shown in Table 11 were obtained. - 56 - Table 11 - Cont'd - - 57 - Table 11 (Cont'd) - Cont'd - - 58 - Table 11 (Cont'd) Example 8 In 10 ml of 47% hydrobromic acid was dissolved 0.40 g of ethyl 6-fluoro-1 , 4-dihydro-l- (4-methoxyphenyl) -7- ( 1-pyrrolidinyl ) -4-oxo-l , 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 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-l- ( 4-hydroxyphenyl) -7- (1-pyrrolidinyl) -4-o'xo-l , 8-naphthyridine-3-carboxylic acid having a melting point of 263-265°C.
IR (KBr) cm"1: C=0 1725, 1705 NMR (TFA-d- 6 values: 1.54-2.40 (4H, m) , 3.14-4.14 (4H, m) , 6.95-7.69 (4H, m) , 8.09 (1H, d, J=12Hz) , 9.14 (1H, s) In a similar manner, the following compound was obtained: - 59 - 6-Fluoro-1 , 4-dihydro-l- (4-hydroxyphenyl) -7- (3-hydroxy-l-pyrrolidinyl) -4-oxo-l , 8-naphthyridine-3-carboxylic acid Melting point: 180-183°C IR (KBr) cm"1: VC=0 1725, 1705 Example 9 To 0.1 g of ethyl 7- (4-acetyl-l-piperazinyl) -6-fluoro-1- (4-fluorophenyl) -1 , 4-dihydro-4-oxo-l , 8-naphthyri-dine-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 40° to 50 °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 com-bined 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 7- (4-acetyl-l-piperazinyl) -6-fluoro-1- (4-fluorophenyl) -1 , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylic acid having a melting point of >280°C.
IR (KBr) cm"1: VC=0 1730 NMR (dg-DMSO) 6 values: 2.05 (3H, s) , 3.57 (8H, bs) , - 60 - 7.13-7.80 (4H, m) , 8.13 (1H, d, J=13Hz) , 8.70 (1H, s) In a similar manner, the compounds shown in Table were obtained.
- Cont'd - - 61 - Table 12 (Cont'd) - Cont'd - - 62 - Table 12 (Cont'd) Example 10 To 0.10 g of ethyl 6-fluoro-1- ( 4-fluorophenyl) -1, 4-dihydro-7- (3-hydroxy-l-pyrrolidinyl) -4-oxo-l , 8-naphthyridine-3-carboxylate 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 40° to 50 °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-1- (4-fluorophenyl) -1 ,4-dihydro-7- (3-hydroxy-l-pyrrolidinyl) -4-oxo-l , 8-naphthyridine-3-carboxylic acid - 63 - having a melting point of >280°C.
IR (KBr) cm"1: C=0 1730 NMR (dg-DMSO) 6 values: 1.92-2.52 (2H, m) , 3.22-5.00 (5H, m) , 6.97-7.60 (4H, m) , 8.01 (1H, d, J=llHz), 9.00 (1H, s) In a similar manner, the compounds shown in Table 13 were obtained.
Table 13 - 64 - Example 11 In 2.5 ml of cone, hydrochloric acid was dissolved 0.25 g of 6-fluoro-1 , 4-dihydro-l- (4-hydroxy-2-methylphenyl) -4-OXO-7- (1-piperazinyl) -1 , 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 , 4-dihydro-l- (4-hydroxy-2-methylphenyl) -4-oxo-7- (1-piperazinyl) -1 , 8-naphthyridine-3-carboxylic acid having a melting point of >280°C.
IR (KBr) cm"1: VC=0 1725 (sh) , 1705 In a similar manner, the compounds shown in Table 14 were obtained. - 65 - Table 14 - Cont'd - - 66 - Table 14 (Cont'd) Example 12 In 20 ml of cone, hydrochloric acid was dissolved 2.0 g of 7- (3-amino-l-pyrrolidinyl) -6-fluoro-1- (2 , 4-difluorophenyl ) -1 , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylic acid, then 200 ml of ethanol was added to the resulting solution at room temperature, and the resulting solution was stirred for 15 minutes. The crystals thus deposited were collected by filtration and washed with 40 ml of ethanol to obtain 1.4 g of the hydrochloric acid salt of 7- (3-amino-l-pyrrolidinyl) -6-fluoro-1- (2 , 4-difluorophenyl) -1 , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylic acid having a melting point of 247-250°C (decomp.).
IR (KBr) cm"1: VC=0 1730 Example 13 (1) In 2.5 ml of chloroform were dissolved 0.5 g of ethyl 2- (2 , 6-dichloro-5-fluoronicotinoyl) -3- (2 , 4-difluoro- - 67 - phenylamino) acrylate , 0.143 g of N-methylpiperazine and 0.145 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- [2-chloro-5-fluoro-6- (4-methyl-l-piperazinyl) nicotinoyl] -3- (2,4-difluorophenylamino) acrylate.
IR (Neat) cm"1: VC=0 1735, 1700 NMR (CDC13) δ values: 1.13 (3H, t, J=7Hz), 2.36 (3H, s) , 2.55 (4H, t, J=5Hz) , 3.70 (4H, t, J=5Hz) , 4.15 (2H, q, J=7Hz), 6.77-7.90 (4H, m) , 8.51 (1H, d, J=13Hz) , 12.50 (1H, d, J=13Hz) (2) 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-methyl-l-piperazinyl) -4-oxo-l , 8-naphthyridine-3-carboxylic acid having a melting point of 208-209°C was obtained.
Example 14 To 0.3 g of ethyl 7- (4-ethoxycarbonyl-2-methyl- - 68 - 1-piperazinyl) -6-fluoro-1- (2 , 4-difluorophenyl) -1 , 4-dihydro-4-oxo-1 , 8-naphthyridine-3-carboxylate were added 5 ml of 1 N aqueous sodium hydroxide solution and 5 ml of ethanol , and the resulting mixture was subjected to reaction at 90 °C 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 , 4-dihydro-7- (2-methyl-l-piperazinyl) -4-oxo-1 , 8-naphthyridine-3-carboxylic acid having a melting point of 230-239°C.
IR (KBr) cm"1: VC=0 1730 NMR (TFA-d- 6 values: 1.50 (3H, s) , 3.20-5.15 (7H, m) , 7.00-7.90 (3H, m) , 8.35 (1H, d, J=13Hz) , 9.20 (1H, s) Example 15 In 20 ml of ethanol was suspended 1.0 g of dihydro-chloric acid salt of 3-aminopyrrolidine , and 2.06 g of triethylamine was added to the resulting suspension to form a solution. Then, 2.0 g of ethyl 7-chloro-6-fluoro-1- (2 , 4-difluorphenyl) -1 , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylate was added to the solution at 30°C over 15 minutes, and the resulting mixture was subjected to reaction at the same temperature for 3 hours. After the completion of the reaction, 30 ml of water was added to the reaction - 69 - mixture, and the crystals thus deposited were collected by filtration and washed with 4 ml of water. The crystalline substance thus obtained was suspended in 13 ml of 6 N hydrochloric acid, and the resulting suspension was heated under reflux for 2 hours. Subsequently, the reaction mixture was cooled, and the crystals thus deposited were collected by filtration and washed with two 2-ml portions of water to obtain 1.97 g of hydrochloric acid salt of 7- (3-amino-l-pyrrolidinyl) -6-fluoro-1- (2 , 4-difluorophenyl) -1 , 4-dihydro-4-oxo-1 , 8-naphthyridine-3-carboxylic acid.
IR (KBr) cm-1: C=0 1730 Example 16 .
In 75 ml of ethanol and 75 ml of water was suspended 10.0 g of 7- (3-amino-l-pyrrolidinyl) -6-fluoro-1- (2 , 4-difluorophenyl) -1 , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylic acid. To the resulting suspension was added 5.2 g of p-toluenesulfonic acid monohydrate at 40 °C, and the resulting mixture was stirred at the same temperature for 30 minutes. Subsequently, the reaction mixture was cooled to 15 °C, and the crystals thus deposited were collected by filtration and washed with a mixed solvent of 5 ml of ethanol and 5 ml of water to obtain 12.8 g of the p-toluenesulfonic acid monohydrate salt of 7- (3-amino-l-pyrrolidinyl) -6-fluoro-1- (2 , 4-difluorophenyl) -1 , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylic acid having a melting point of 258-260 °C. - 70 - NMR (DMSO-d δ values: 6.92-8.17 (8H, m) , 8.79 (1H, s) In a similar manner, the following compound was obtained: Oxalic acid salt of 7- (3-amino-l-pyrrolidinyl) -6-fluoro-1- (2 ,4-difluorophenyl) -1 , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylic acid Melting point (°C): 250-253 IR (KBr) cm"1: VC=0 1730 Example 17 To the solution of 1.6 g of methanesulfonic acid and 25 ml of acetic acid was added 5.00 g of 7- (3-amino-l-pyrrolidinyl) -6-fluoro-1- (2 , 4-difluorophenyl) -1 , 4-dihydro-4-oxo-l,8-naphth'yridine-3-carboxylic acid, after which the resulting suspension was stirred at room temperature to form a solution. To the solution was added 100 ml of ethanol at 40° to 45°C over 30 minutes. Subsequently, the reaction mixture was cooled to room temperature, and stirred for 30 minutes. The crystals thus deposited were collected by filtration and washed with three 20-ml portions of ethanol to obtain 3.12 g of methanesulfonic acid salt of 7- (3-amino-l-pyrrolidinyl) -6-fluoro-1- (2 ,4-difluorophenyl) -1 , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylic acid having a melting point of >300°C.
IR (KBr) cm"1: VC=0 1735 In a similar manner, the following compound was obtained : Sulfuric acid salt of 7- (3-amino-l-pyrrolidinyl) 6-fluoro-1- (2 , 4-difluorophenyl) -1 , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylic acid Melting point (°C): 220-230 IR (KBr) cm"1: C=0 1735 Preparation Example 1 With 50 g of 6-fluoro-l- (2 , 4-difluorophenyl) -1 , dihydro-4-oxo-7- (1-piperazinyl) -1 , 8-naphthyridine-3-carboxylic acid were blended 49 g of crystalline cellulose 50 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- (1-piperazinyl) -1 , 8-naphthyridine-3-carboxylic acid was blended 50 g of corn starch, and 1,000 capsules were filled with the resulting blend to obtain capsules .
Preparation Example 3 With 50 g of 7- ( 3-amino-l-pyrrolidinyl) -1- (2 , 4- - 72 - difluorophenyl) -6-fluoro-1 , 4-dihydro-4-oxo-1 , 8-naphthyridine-3-carboxylic acid were blended 49 g of crystalline cellulose, 50 g of corn starch and 1 g of magnesium stearate, and the blend was compressed into 1,000 flat-type tablets.
Preparation Example 4 With 100 g of 7- (3-amino-l-pyrrolidinyl) -1- (2 , 4-difluorophenyl) -6-fluoro-1 , 4-dihydro-4-oxo-l , 8-naphthyridine-3-carboxylic acid was blended 50 g of corn starch, and 1,000 capsules were filled with the resulting blend to obtain capsules. - 73 -

Claims (4)

75021/4 Claims;
1. A l,4-dihydro-4-oxonaphthyridine derivative represented by the formula or a salt thereof: wherein R1 represents a hydrogen atom or a carboxyl-protecting group, R2 represents a 2,4-difluorophenyl group and R3 represents a halogen atom.
2. A l,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 1, wherein R1 represents an alkyl group.
3. A l,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 2, wherein R1 represents an ethyl group.
4. A 1 ,4-dihydro-4-oxonaphthyridine derivative or a salt thereof according to Claim 1, 2 or 3, wherein R3 represents a chlorine atom. - 74 -
IL7502185A 1984-04-26 1985-04-24 1-(2, 4-difluorophenyl)-6-fluoro-7- halo-1,4-dihydro-4-oxo-1,8-naphthydridine-3-carboxylic acid and esters thereof IL75021A (en)

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