LU85871A1 - 1,4-DIHYDRO-4-OXONAPHTYRIDINE DERIVATIVES AND SALTS THEREOF, PROCESS FOR THEIR PREPARATION AND ANTIBACTERIAL AGENTS CONTAINING THEM - Google Patents

1,4-DIHYDRO-4-OXONAPHTYRIDINE DERIVATIVES AND SALTS THEREOF, PROCESS FOR THEIR PREPARATION AND ANTIBACTERIAL AGENTS CONTAINING THEM Download PDF

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LU85871A1
LU85871A1 LU85871A LU85871A LU85871A1 LU 85871 A1 LU85871 A1 LU 85871A1 LU 85871 A LU85871 A LU 85871A LU 85871 A LU85871 A LU 85871A LU 85871 A1 LU85871 A1 LU 85871A1
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Prior art keywords
group
sait
dihydro
substituted
amino
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LU85871A
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French (fr)
Inventor
Hirokazu Narita
Jun Nitta
Isamu Saikawa
Isao Kitayama
Hideyoshi Nagaki
Yoshinori Konishi
Yoriko Kobayashi
Mikako Shinagawa
Yasuo Watanabe
Akira Yotsuji
Shinzaburo Minami
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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
Publication of LU85871A1 publication Critical patent/LU85871A1/en

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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)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • 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

? i 1 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 5 at the 7-position and a sait thereof, a process for producing the same and an antibacterial agent comprising the same.
Nalidixic acid, piromidic acid, pipemidic acid and the like hâve heretofore been widely used as synthe-10 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 15 example, l-ethyl-6-fluoro-l,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 hâve excellent antibacterial activities against various Gram-negative bacteria 20 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 ; 25 bacteria but also Gram-positive bacteria.
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\ ï 1 Under these circumstances, the present inventors * hâve, as a resuit of extensive research, found that a novel l,4-dihydro-4-oxonaphthyridine derivative and a sait ’ thereof can solve the aforementioned problème.
5 An object of this invention is to provide a « novel 1,4-dihydro-4-oxonaphthyridine derivative and a sait thereof having excellent properties, for example, strong antibacterial activities against Gram-positive and Gram-negative bacteria, particularly against antibiotic-10 résistant 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 l,4-dihydro-4-oxonaphthyri-15 dine derivative and a sait thereof.
A further object of this invention is to provide an antibacterial agent which in useful for the treatment of infections of bacteria or the like and which comprises a novel 1,4-dihydro-4-oxonaphthyridine derivative or a sait 20 thereof.
According to this invention, there is provided a Γ,4-dihydro-4-oxonaphthyridine derivative represented by the general formula: R3 \ & ς wherein R"*- represents a hydrogen atom or a carboxyl- 2 / protectmg group, R represents a substituted or >L· 3
J
1 unsubstituted aryl group, and R represents a halogen atom or a substituted or unsubstituted cyclic amino group, and a sait thereof.
, Further, this invention provides a process for 5 producing a 1,4-dihydro-4-oxonaphthyridine derivative repre- « sented by the general formula [I] or a sait thereof, and also an antibacterial agent comprising the 1,4-dihydro-4-oxonaphthyridine derivative represented by the general formula [I] or a sait thereof.
10 This invention will be explained in detail below.
In the compound represented by the general formula [I] or a sait thereof, the carboxyl-protecting group for includes, for example, ester-forming groups which may be removed by catalytic réduction, Chemical réduction or other 15 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 a treatment with water or an alcohol? and other various well- 20 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.
2 25 The aryl group for R includes, for example, phenyl, naphthyl and the like. The aryl group may be substituted by one or more substituents selected from the - group consisting of halogen atoms, for example, fluorine, - 4 - ί 1 chlorine, bromine, iodine and the like; alkyl groups, for - example, straight or branched chain C^-C^Qalkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, » sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the 5 like; hydroxyl group; alkoxy groups, for example, straight or branched chain C^-C^qalkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the like; cyano group; amino group; acylamino groups, 10 for example, C^-C4acylamino groups such as formylamino, acetylamino, propionylamino, butyrylamino and the like; and trihalogenoalkyl groups, for example, trihalogeno-C^-C^-alkyl groups such as trifluoromethyl, trichloromethyl and the like. · 3 15 Moreover, the halogen atom for R mcludes, for example, fluorine, chlorine and bromine. The cyclic amino 3 “ group for R have at least one nitrogen atom and may have additionally one or more oxygen atoms as the hetero atoms e forming the ring, and includes 5-# or 6-membered cyclic 20 amino groups such as 1-pyrrolidinyl, piperidino, 1-pipe-razinyl, morpholino and the like. The aforementioned cyclic amino groups may be substituted by one or more substituents selected from the group consisting of alkyl groups, for example, straight or branched chain C^-C^alkyl 25 groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; amino group; aminoalkyl groups, for example, amino-C^-C^alkyl groups such as aminomethyl, 2-aminoethyl, 3-aminopropyl and the like; :.L - 5 - ! 1 hydroxyalkyl groups, for example, hydroxy-C^-C^alkyl groups such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like; hydroxyl group; alkenyl groups, for example, 5 C2-C4alken^rl 9rouPs such as vinyl, allyl and the like; 5 acyl groups, for example, C^-C^acyl groups such as formyl, acetyl, propionyl, butyryl and the like; alkylamino groups, for example, C^-C^alkylamino groups such as methylamino, ethylamino, n-propylamino, isopropylamino and the like; dialkylamino groups, for example, di-C^-C^alkylamino groups 10 such as dimethylamino, diethylamino, di-n-propylamino, methylethylamino and the like; cyano group; oxo group; aralkylamino groups, for example, ar-C^-C^alkylamino groups such as benzylamino, phenethylamino and the like; acylamino groups, for example, C^-C^acylamino groups such as acetyl-15 amino, propionylamino, butyrylamino and the like; alkoxy-carbonyl groups, for example, C^-C^alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and the like; and N-acyl-N-alkylamino a groups, for example, N-acyl-N-alkylamino groups wherein the 20 nitrogen atom of the above-mentioned alkylamino group is substituted by a C^-C^acyl group such as acetyl, propionyl, butyryl or the like.
Among the compounds represented by the general 2 formula [I], those wherein R represents a fluorine- 3 25 substituted phenyl group and R represents a substituted or unsubstituted 1-pyrrolidinyl or 1-piperazinyl group are 2 preferred, and those wherein R is a 2,4-difluorophenyl 3 ; group and R is a 3-ammo-l-pyrrolidinyl group are more / préférable.
: c.
T i 1 The sait of the compound represented by the general formula [I] includes conventional saits 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 5 at the basic groups include, for example, salts with minerai 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-10 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, magnésium and the like; ammonium salts; 15 and salts with nitrogen-containing organic bases such as procaine, dibenzylamine, N-benzyl-ß-phenethylamine, 1-- ephenamine, Ν,Ν-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, Ν,Ν-dimethyl-aniline, N-methylpiperidine, N-methylmorpholine, diethyl-20 amine, dicyclohexylamine and the like.
If the compound represented by the general formula [I] and a sait theredf hâve isomers (for example, optical isomers, geometrical isomers, tautomers and the like), this invention includes ail of the isomers, crystal 25 forms and hydrates thereof.
Antibacterial activities and acute toxicities are illustrated with reference to typical compounds of this invention.
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* / i 1 1. Antibacterial activity
Test method
According to the standard method of Japan Society of Chemotherapy [CHEMOTHERAPY, 29(1), 76-79(1981)], 5 a bacteria solution obtained by culturing in Heart Infusion s 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 détermine the 10 minimum concentration at which the growth of the bacteria was inhibited as MIC (jag/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.
15 Symbols used in Table 1 hâve the following meanings: i *1: penicillinase-producing bacteria, *2: cephalosporinase-producing bacteria, v g *3: inoculation size: 10 cells/ml, 20 Me: methyl group,
Et: ethyl group, n-Pr: n-propyl group, i-Pr: isopropyl group - 8 -
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a u ‘ l / ' î 1 2. Acute toxicity - The LDjq values obtained by intravenously administering the test compounds of No. 5, 6 and 12 as i- mentioned above to mice (ICR strain, male, body weight: 5 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: 0 0 r -^NjX^COOR13 p -^yK^COOR1* 3AAci ** ΛνΧ-ci » . s3b [II] [IV] or a sait thereof | o io pYrvC00Rla 'YYY“0'1' /^N2 NH-R2 R3a CI ^NH-R^ R3b [III] or a sait thereof [V] or a sait thereof 1 0 |0 R3a r2 R3b J^2 [lai or a sait thereof [Ib] or a sait thereof 1 ci 10 wherein R represents the same carboxy-protecting group /i^ -12 - : i 1 as in R^; R^a represents the same halogen atom as in R^; 3k RJ represents the same substituted or unsubstituted 3 12 cyclic amino group as in R ; and R and R hâve the same meanings as defined above.
5 The salts of the compounds represented by the general formulae [la], [Ib], [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 10 [III] or a sait thereof or the compound represented by the general formula [V] or a sait 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 sait thereof with an acetal such as 15 N/N-diethylformamidodimethylacetal, N,N-dimethylformamido- diethylacetal or the like and then with an amine represented 2 2 by the general formula, R (R has the same meaning as defined above).
The solvent to be used in the above reactions may 20 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 25 Chloride, Chloroform, dichloroethane and the like; amines such as N,N-dimethylformamide, Ν,Ν-dimethylacetamide and the like; suifoxides such as dimethylsulfoxide and the like; etc. and these solvents may be used alone or in '/f
V
i /{__ - 13 - 1 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 5 [IV] or a sait 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 10 compound represented by the general formula [IV] or a sait 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 15 the compound represented by the general formula [II] or the compound represented by the general formula [IV] or a sait 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 -NH2 or a sait there-20 of to obtain the compound represented by the general formula [III] or a sait thereof or the compound represented by the general formula [V] or a sait thereof, respectively.
(ii) The compound represented by the general formula [la] or a sait thereof or the compound represented by the 25 general formula [Ib] or a sait thereof is, respectively, obtained by subjecting the compound represented by the general formula [III] or a sait thereof or the compound represented by the general formula [V] or a sait thereof Ί L - 14 - - i 1 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 5 critical, for example, amides such as N,N-dimethylformamide, Ν,Ν-dimethylacetamide and the like; ethers such as dioxane, anisole, diethylene glycol dimethyl ether and the like; suifoxides such as dimethylsulfoxide and the like; etc.
These solvents may be used alone or in admixture of two or 10 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 sait 15 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 sait thereof, the compound represented by the 20 general formula [V] or a sait thereof, or the compound represented by the general formula [Ib] or a sait thereof is, respectively, obtained by reacting the compound represented by the general formula [II], the compound represented by the general formula [III] or a sait thereof, 25 or the compound represented by the general formula [la] or a sait thereof with a cyclic amine represented by the 3k 3b general formula, RJ -H or a sait thereof (wherein has the same meaning as above).
(- - 15 - : / 1 The solvent to be used in the reaction may be any i solvent inert to the reaction and includes, though not cri'tical, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydro-5 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, Ν,Ν-dimethylacetamide and the like; suifoxides such as dimethylsulfoxide and the like; alcohols 10 such as methanol, éthanol 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 sait thereof to be used is preferably an excess,.more preferably 2 to 5 moles per mole of the 15 compound represented by the general formula [II], the compound represented by the general formula [III] or a sait thereof, or the compound represented by the general formula [la] or a sait thereof. If the amount of the cyclic amine used is about 1 to 1.3 moles, it is sufficient that an 20 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 sait thereof, or the compound represented by the general formula [la] or a sait thereof. The acid-binding agent 25 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 - ' ί i θ’}-.
1 The sait of RJ -H includes the saine 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, 5 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], [Ib], [III] or [V], wherein represents a carboxyl-protecting group, or a sait thereof can, if desired, be 10 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 15 represented by the general formula [la], [Ib], [III] or [V] or a sait thereof can, if desired, be converted to a sait or an ester of the corresponding compound by subjecting the same to salt-forming reaction or estérification known per se. If the compound represented by the general formula [la], 20 [III], [IV] or [V] or a sait 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 25 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 " * ί 1 The compound represented by the general formula 3 [I] or a sait 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 5 obtaming a compound wherein R represents a substituted or unsubstituted cyclic amino group (corresponding to the compound represented by the general formula [Ib]).
When the compound of this invention is used as a drug or medicine, it is appropriately combined with carriers 10 which are used in conventional pharmaceutical préparations, 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 15 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 20 to Referential Examples, Examples and Préparation Examples.
Symbols used in Referential Examples and Examples hâve the following meanings:
Me: methyl group, Et: ethyl group, n-Pr: n-propyl group, i-Pr: isopropyl group, 25 Ac: acetyl group, : allyl group, : ethylene group.
' ^ L- - n 1 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 5 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 10 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 15 at the same température over 30 minutes. This mixed solution was stirred at the same température for 1 hour, and then the température of the solution was gradually raised to room température. The solvent was removed by distillation under reduced pressure, and to the 20 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 25 aqueous sodium chloride solution, and dried over an-hydrous magnésium 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
L
·* 1 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 5 50 ml of saturated aqueous sodium Chloride solution and dried over anhydrous magnésium 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) ta 10 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 NMR (CDC13) δ values: *1.25 (1.29H, t, J=7Hz), 1.33 (1.71H, t, J=7Hz), 15 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 20 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-25 ing mixture was subjected to reaction at room température for 4 hours. The solvent was removed by distillation under reduced pressure. The residue obtained was purified / /L_ - 20 - v / 1 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.
5 IR (KBr) cm“1: vc=Q 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) 10 In a similar manner, the compounds shown in
Table 2 were obtained.
- 21 -
Table 2 Ο P COOE t .ΑΛοι?«
NH
R2
Compound Physical properties r2 Melting IR(KBr) cm-^: point (°C) vc=0 87-89 1690 (O) 110-114 1710, 1680 _F___ KM 92-93 1710, 1680 (^fF 135-137 1720 (sh), 1690, 78-80 1690 _F F___ JOy Oily 1705, 1680 (sh)
F I F
JqY 154-155 1720 (sh), 1685 ^$Îp 100-101 1700 (sh), 1685 _F___ (έ) 123-125 1710, 1680 __CI___
U
/ - 22 - ί - Cont'd - *
Table 2 (Cont'd) (Ο) 145-146 1705, 1680 _Br___ (ο) 147-149 1685 (Ο) Oily 1695* _OMe___ j^j-0Me 119-121 1700 (O) Oily 1700* __ÇN___ (O) 183-186 1685, 1670 _NHÄC___ (O) 136-138 1705, 1680 _CF3___ (θΓΜθ 114-116 1680 _F___ ΓηΤ0Μθ IMJ 137.5-139 1725(sh), 1680 _F___ (θΓΡ 92-95 1705 _OMe_ r^Sv-OMe 125-126 1700 (sh), 1660 _Me___ (OTMe 91-92 1705, 1690 _OMe___
Note : The neat method was used in place of the KBr method.
L
1k 1 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 5 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 magnésium sulfate. The solvent was removed by distillation under reduced pressure, and the residue obtained was purified 10 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: vc=Q 1750, 1695 NMR (CDCl^) δ values: 15 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 20 Table 3 was obtained.
L
ί - 24 - %
Table 3 Ο
Il COOEt
’XC
RJ
Compound Physical Properties 3 Melting IR (KBr) cm-1: K point (°C) vc=0 s—\
AcN^_N- 67-71 1730 1 (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, 5 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 température for 4 hours. Then, the solvent was removed by 10 distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [WAKO SILICA GEL C-200, eluant: Chloroform:éthanol = 100:1 (by volume)]. The crystalline substance obtained was washed with 10 ml of diethyl ether to obtain 5.0 g of ethyl 15 2-[2-chloro-5-fluoro-6-(4-methyl-l-piperazinyl)nicotinoyl]- L·
V
1 3-(4-methoxy-2-methylphenylamino)acrylate having a melting point of 141-142°C.
IR (KBr) cm"1: vc=Q 1710(sh) , 1695 NMR (CDCl^) <5 values: 5 1.08 (3H, t, J=7Hz), 2.32 (3H, s), 2.40 (3H, s), « 2.23-2.68 (4H, m) , 3.47-3.83 (4H, m) , 3.75 (3Hf 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 (lH, d, J=13Hz) 10 In a similar manner, the compounds shown in
Table 4 were obtained.
k - 26 - *
Table 4 Ο F \αΑ/οοκ R3)QCf NH 1 ο
Compound Physical Properties ~ Z Melting pointI IR(*) R (°C) cm x: vc=0 i *2 fcT) Mel^ y- Oily 1720 (sh) ' (Of ’ . Oily 1735' i7oo
F
1 *2 |0] " Oily 1695 OMe _ f0l 1685, ^ " 161-164 1670 NHAc fOl 1720 (sh), " 0ily 1715 OMe - Cont'd - .r-^ - 27 - i *
Table 4 (Cont'd) I *1 (O) MeN^ N- 132-136 1705 *sh*' γ^Μβ ^—/ 1685 OMe I ,Me *2
CpJ Acn" ^N- Oily 1720 (sh)' N—/ 1700 OMe
Note: *1: KBr *2: Neat l^\ - 28 - ÿ * 1 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 5 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.
10 The resulting solution was washed successively with 30 ml of water and 30 ml of saturated agueous.sodium chloride solution, and then dried over anhydrous magnésium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance obtained was washed with 30 ml 15 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-g naphthyridine-3-carboxylate having a melting point of 220-222°C.
IR (KBr) cm"1: vc=Q 1730, 1690 20 NMR (CDClg) 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.
. U
- 29 -
Table 5 Ο
FwVC00Et „Xy 2
R
Compound Physical Properties „2 Melting point IR(KBr) (°C) cm : VC=0 ΓηΊ 1730' ISJ 222'224 1685 Ü) 1730, I 231-232 1705 239-241 1685 205-208 1111' 244-246 1720, I F 1680
F
- ,? - Cont’d - - 30 - *·. %
Table 5 (Cont'd)
Jx^F 1730, j[Oj 207-209.5 1690
F
«
F ! F
V-V 1735 (sh)' L°J 210-214 1705 207-208 1730, • 1680
F
[O) 1730, ηρ 181 186 1685
Cl ÎOl 1730, V 204”205 1685
Br Φ1735, 216‘218 1695
Me ÎOl 1735, Y 196"198 1685 OMe ä L~ - Cont'd - - 31 -
Table 5 (Cont'd)
* X
JL/0"· 1730, (Of 156'160 1690 L9J 1730, T 231-236 1685
CN
270-273 1730, T 1690 NHAc Φ1730, 199-201 1680 . cf3 : ΑΥ1 ΙΟΙ 1735, Y 199-202 1685
F
λ/Μθ fOJ 1730, Y 208“211 1695
F
(of 1740, V 142‘144 1695 OMe „ - Cont'd -
A
- 32 -
L
%
Table 5 (Cont'd) i/°Me foT 1730' 163-165 1695
Me ΓοΤ^1 1735, 160-162 1690 OMe 1 Example 2 (1) In 35 ml of Chloroform was dissolved 3.5 g of ethyl 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate, and 1.5 g » 5 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 10 purified by a column chromatography [WAKO SILICA GEL C-200, eluant: Chloroform : éthanol = 30 : 1 (by volume)] to obtain 3.5 g of ethyl 7-(4-acetyl-l-piperazinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylate having a melting point 15 of 207-209°C.
IR (KBr) cm“1: vQ=:Q 1730, 1695 J NMR (CDCl^) 6 values: / L·^—'v. - 3 3 - . * 1 1.38(3Η, t, J=7Hz), 2.05(3Η, s), 3.53(8Η, bs) , 4.30(2H, g, J=7Hz), 6.80-7.75 (3H, m) , 8.00(1H, d, J=13Hz)r 8.30(1H, s)
In a similar manner, the compounds shown in • 5 Table 6 were obtained.
U
- 34 - λ
Table 6 ’rA“"
3/kNANJ
R I
R2 •s
Compound Physical Properties ο o Melting point IR(KBr) R R /0_. -1 (°C) cm x: vc=0 (O) “O- 216-218 1690* (sh) JL Àc φ M^O' 155'156 1690 '
F
/—\ 1730, " MeN N- 217-218 \_/ 1695
Me λ~\ 1730, " HN N" 144-146 1 \_( 1690
Me HN N- 143 1730 \_t '__Mé____
Me N)—\ 1725, " HN N- 198-202 \_/ 1690 ____Me__ ή - Cont'd - - 35 -
Table 6 (Cont'd) > ΦΗΟ^-ΐ/ ^ί- 220-222 1730/ Ν—f 1695
F
" Ad/ N- 253-255 1730, '—' 1690 " O N- 203-205 1730, \—/ 1700 211-213 1735
F
1725, (Oj " 206 1690 /—\ 1730, [Oj^ 193-194 „„„
F
Q1725, 244'246 1690 (θΐ! ! /-λ 1725, V ΜβΝ-^J,- 186-187 1690 (sh)
F
L
-- - 36 -
Table 6 (Cont'd) * j (Ο^ hH- 155-157 1720' T W 1685
F
Ma / \ 1730,
153-154 170Q
_^Me ΓΛ 1730, 153-155 1695 /—\ 1730 (sh), ^Vv- 166"168 1690
Me /—\ 1730,
Et02CN_^N- 202-204 169Q
ΓΛ 1725 (sh), J®) 230-231 1695
F
f\JwF 1720 (sh), [OJ " 193-194 1^°' ΓΛ 1725, [OJ Me«207 1695
Cl - Cont'd - /
Table 6 (Cont'd) * ΓπΊ ΛΛ 1730, L^J AC^JÎ- 254 1690
Cl ΙΟΙ Λ“\ 1730,
208 169Q
Br /—\ 1730,
Ac\_/- 246-247 169Q
fOl /“Λ 1730' lUJ . Mel167-169 1695
Me /—\ 1730,
Ac^N- 206-207.5 169Q
(O) Qï- 163-165 OMe ΓΛ 1730, "“W" 174-176 1690 01735, 18°-181 1695 / - Cont'd - / - 38 -
Table 6 (Cont’d) * (ol /-\ 1730' 1ψ n-Pr^N- 171-172.5 lß85 OMe /—\ 1730,
" i-Prt^ y- 208.5-210 16gQ
/-\ 1730, HO-^N N- 200-202 Ί rnn \_/ löyu /—\ 1725, 162-163 1690 /“Λ 1735,
Ac\_/- 197-199 169Q
OMe fOf Λ"Λ !725,
MeN^N- 136-138 1685 fol ΓΛ 1730,
[ψ 270-272 169Q
CN
fOl 1730, TOJ 245-249 1695 NHAc / - Cont'd -
L
Table 6 (Cont'd) * Φ *0- 249-252 «IS'
CF J
ér“ ^y' " 263-264 1730
F
i^OMe ΙΟΙ /“A 1730, lyj 166-169 1685
F
/ \ 1 77η " AcN N- 222.5-223.5 /JU' ’—' 1690 f<0'P / \ 1730, [OJ Mel^yi- 165-168 1685 OMe /—\ 1730, “U" 215-219 1695 X^OMe ΛΛ 1725, [OJ *\_J~ 170-171 1650
Me (Of ΓΛ 1725,
Ac^N- 169-172 169Q
OMe * /L^\ - 40 - ' /· ^ * 1 (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 , 5 under reflux for 2 hours. Then, the reaction mixture was cooled to room température, 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, 10 washed with 30 ml of water, and then dried to obtain 1.8 g of 6-fluoro-l-(2,4-difluorophenyl)-l,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid.
NMR (TFA-d^) $ values: 3.30-4.50(8H, m), 7.00-7.85(3H, m), 15 8.33(1H, d, J=13Hz), 9.21(1H, s)
In a similar manner, the compounds shown in Table 7 were obtained.
; ' - 41 -
- X
Table 7 ;χϊΤ“
R J
R2
Compounä Physical Properties r2 r3 Melting point IR(KBr) ___i^ç}__cm"1; vc=0 (O) HN 252.5-254.5 1730 φ MeHN-Q,- >280 1720 (sh,
F
“O- 279-280 1725 (sh) (O)^ ” 234-236 1720 ^yp |OJ " 222-224 1725 ^ " >280 3-720
F
- Cont'd - ____—>. — 4 2 — *
Table 7 (Cont'd)
rofF
MeNH C N- 254-258 1725
F
JaJJ HN_205-207 1730
F
pvV
|OJ " 225-227 1725 ~~ώ · " >280 1725
Cl :: (O) " 273-277 1720
Br (o) > 245-246 1725
Me (o) Y " >280 1725
CN
Φ1730, >28° 1710 nh2 / - Cont'd - - 43 -
Table 7 (Cont'd) * ,Α. _ 1725, LOJ MetQï- 232-236 NHAc * l.l Il···· Il I·· —— III I —-— I·· I I II l.l. .1.1 I II I II—I. — fol / \ HN^_>280 1725 CP3 » 230-232 1730
F
Note: * The nujol method was used in place of the KBr method.
- 44 - * 1 Example 3 (1) In 5 ml of Chloroform was dissolved 0.50 g of ethyl 7-chloro-6-fluoro-l-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate, and to . 5 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 10 obtained was purified by a column chromatography [WAKO SILICA GEL 0200, eluant: Chloroform : éthanol = 30 : 1 (by volume)] to obtain 0.5 g of ethyl 7-(3-acetylamino-l-pyrrolidinyl) -6-fluoro-l- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate having a 15 melting point of 233-235°C.
IR (KBr) cm"1: vc=0 1725, 1700 NMR (CDCl^) δ values: 1.32 (3H, t, J=7Hz) , 1.77-2.27 (m) -, ,_ .
2.08 (s)J' 3.12-3.74(4H, m), 4.02-4.74(m) .
4.29 (q, J=7Hz) î '' 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.
; L· ! - 45 -
Table 8 * F ° X^lxOOEt R2
Compound Physical Properties „2 3 Melting point IR(KBr) (°C) cm”·1·: Vq=q
Ai H0\ ΙΟ ΓΛ 1730, V LZ" 231-233 1700
F
Me2N
\ 1730, L/· 156 1690
AcHN
—\ 1725, L/" 2°3"205 1690
MeN
'jTA 1725, L/' 201-202 1695
Me9N.
fOJ VA 1730, Ύ LÀ 165 1690
F
MeN
iN|—\ 1730, " AC /N" 196-197 1 _/ 1695 - Cont'd - . - 46 - ψ
Table 8 (Cont'd)
X.F AcHN
ΓηΤ ΓΛ 1725, 1_>- 241'244 1700
F
ο fOl ΓΛ
In- 153-155 1735 OMe Η0\ >”\ 1730, LÀ 185-187 1690 i 1 - 47 - 5 * 1 (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 . 5 solution was heated under reflux for 2 hours. Then, the reaction mixture was cooled to room température, 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, 10 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^) 5 values: 2.25-2.85(2H, m), 3.37-4.69(5H, m), 15 6.93-7.81(3H, m), 8.22(lH, d, J=llHz), 9.16(1H, s)
In a similar manner, the compounds shown in , Table 9 were obtained.
- 48 - »
Table 9 Ο
P II COOH
,3'XïJ
R I
R2
Compound Physical properties 2 .. Melting IR (KBr) K R"3 point η (°C) cm : C=0
Col Η2^ N- 260-263 1720
F
MeHN
" N- 259-261 1720 (sh)
~V
, ’ [OJ " 275-278 1720 (sh)
F
A/F H2N.
[01 N- 278-280 1720 I F ^ F 1 - 49 -
Example 4 : (1) In 20 ml of Chloroform were dissolved 2.0 g of t V > 1 ethyl 2/6-dichloro-5-fluoronicotinoylacetatef 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 » 5 water, and then dried over anhydrous magnésium 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 10 ethyl [2-chloro-5-fluoro-6-(3-acetylamino-l-pyrrolidinyl)-nicotinoyl] acetate.
IR (Neat) cm“1: VC=0 1740, 1650 NMR (CDClg) δ values: 1.28 (3H, t, J=7Hz), 1.97 (3H, s), 15 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-20 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 25 reaction at room température for 8 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column - L--- 50 - > ► 1 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-’ 5 pyrrolidinyl) nicotinoyl]-3- (2,4-dif luorophenylami.no) 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), 10 1.90-2.30 (2H, m) , 4.19 (2H, g, 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, dr J*13Hz) (3) In 3 ml of Ν,Ν-dimethylformamide was dissolved 15 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 20 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 25 magnésium 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 . L· - 51 - v *>- 1 g of ethyl 7-(3-acetylamino-l-pyrrolidinyl)-6~fluoro-l-(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-5 pyrrolidinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate was obtained. The physical properties of this product were identical with those obtained in Example 3-(l).
Example 5 10 (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-15 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 magnésium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed 20 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: VC=0 1720 NMR (dg-DMSO) 6 values: 7.26-8.56 (3H, m), 8.86 (1H, d, J=7Hz),
' L
1 9.18 (1H, s) (2) In 3 ml of dimethylsulfoxide was suspended 0.30 g of 7-chloro-6-fluoro-l-(2,4-difluorophenyl)-1,4-dihydro- 4-oxo-l,8-naphthyridine-3-carboxylic acid/ and then 0.25 g 5 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 10 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)-15 4-oxo-l,8-naphthyridine-3-carboxylic acid having a melting point of 208-209°C.
IR (KBr) cm"1: VC=0 1730 NMR (TFA-d^) <S values: 3.30 (3H, s), 3.45-5.25 (8H, m) , 20 7.12-8.10 (3H, m), 8.49 (1H, d, J=13Hz), 9.38 (1H, s)
Example 6
In 50 ml of Ν,Ν-dimethylformamide was dissolved 5.0 g of ethyl 2-[2-chloro-5-fluoro-6-(4-methyl-l-25 piperazinyl)nicotinoyl]-3-(4-methoxy-2-methylphenylamino)-acrylate, then 1.03 g of sodium hydrogencarbonate was added - 53 - 1 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 . 5 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 magnésium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance obtained was 10 washed with 30 ml of diethyl ether to obtain 2'.38 g of ethyl 6-fluoro-l,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.
IR (KBr) cm"1: VC=0 1730, 1690 15 NMR · (CDCl^) 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) , 20 8.02 (1H, d, J=13Hz), 8.23 (1H, s)
In a similar manner, the compounds shown in Table 10 were obtained.
/K
- 54 - - - *
Table 10 ^ Ο F I COOEt
YrV
K I
R2
Compound Physical properties ~ -, Melting IR (KBr) R^ RJ point , (°C) cm" : VC=0 1 /—\ 1725,
MeN N- 199-202 lyj \-1 1685 rnT^ 1735, LUJ " 168-171 T ' 1720
F
’ ΓτΓΓ 1730, " 174-175 OMe 1695 fOl 1725' " amorphous NHAC 1690 ΓηΊ 1725' LUI " 186-189 T ^F 1690 OMe fOl 1730' " 166-168 T Me 1695 OMe j Me rrV 1725, lAJJ AcN N- 169-172 T N-1 1690 OMe * 1 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-* 5 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 10 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 (KBr) cm”1: VC=0 1725, 1700 (sh) 15 NMR (TFA-d-^) 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), â 9.43 (1H, d, J=13Hz)
In a similar manner, the compounds shown in Table 20 11 were obtained.
/ - 56 -
Table 11 * : Ο
F II COOH
Tri i*
Compound Physical properties 2 3 Melting IR (KBr) RJ point (°C) cm : VC=0 foi /”\ 112Si ( N- 143-146 T \_/ 1710
OH
/~\ " HN^ N- >280 1710 /~\ " MeN N- >280 1710 v_y " EtN ^N- >280 1730
; V.V
; " n-Prl·/ N- >280 1725 /—\ '' i-PrN N- >280 1715 N_/ /—\ 1720, " HO-\-N N- 200-205 N—/ 1705 " N- >280 1725 - Cont'd -
; U
- 57 - *
Table 11 (Cont'd) JL Me/~V 245-250 1725 ' W (decomp.) 1700 (sh)
OH
Λ/οη 1725 ' ίο] " >280 ^ 1690 rrY0B /~Λ 1725, L^J HN N- 220-224 I \—f 1710
P
/—\ 1730/ >28° 1710 (sh) ÎC^ ' " >280 1730
OH
„ /“λ " HN^ N- >255 1725 rVF Λ-Λ (OJ MeN^_N- 251-252 1720
OH
,1725 (sh), ψ " >28° 1700
Me ÎOl 1730' V-Me " 228"230 1700 (sh)
OH
/ - Cont’d -
U
- 58 - *
Table 11 (Cont'd) i^^Me ^ [OJ HN N- 275 1720
OH
1 Example 8
In 10 ml of 47% hydrobromic acid was dissolved 0.40 g of ethyl 6-fluoro-l,4-dihydro-l-(4-methoxyphenyl)- 7- (1-pyrrolidinyl)-4-oxo-l,8-naphthyridine-3-carboxylate, 5 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% agueous sodium hydroxide solution, then to 6.5 with acetic acid. The crystals thus deposited were collected by filtration and washed with 4 ml 10 of water to obtain 0.30 g of 6-fluoro-l,4-dihydro-l-(4-hydroxyphenyl)-7-(1-pyrrolidinyl)-4-oxo-l,8-naphthyridine-3-carboxylic acid having a melting point of 263-265°C.
IR (KBr) cm“1: VC=0 1725, 1705 NMR (TFA-d^) δ values: 15 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: L--·>ν - 59 -
J
1 6-Fluoro-l,4-dihydro-l- (4-hydroxyphenyl) -7- (3- hydroxy-l-pyrrolidinyl)-4-oxo-l,8-naphthyridine-3-carboxylic acid *
Melting point: 180-183°C
5 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)-l,4-dihydro-4-oxo-l,8-naphthyri-dine-3-carboxylate were added 2 ml of 1 N aqueous sodium 10 hydroxide solution and 2 ml of éthanol, and the resulting solution was subjected to reaction at 40° to 50°C for 10 minutes. S.ubsequently, 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-15 bined extracts were washed successively with 5 ml of water and 5 ml of saturated aqueous sodium Chloride solution and then dried over anhydrous magnésium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was washed with 2 ml of 20 diethyl ether to obtain 0.08 g of 7-(4-acetyl-l-piperazinyl)- 6-fluoro-l-(4-fluorophenyl)-l,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 (d,-DMS0) δ values:
O
2.05 (3H, s), 3.57 (8H, bs), - I^\ / - 60 - * 1 7.13-7.80 (4H, in), 8.13 (1H, d, J=13Hz) , 8.70 (1H, s)
In a similar manner, the compounds shown in Table 12 were obtained.
Table 12 0
F ^ j| COOH
YrV
r3^n^n^
1 2 R
Compound Physical properties 2 2 Melting IR (KBr) R R-5 point , (°C) cm”1: VC=0 |^0) MeN N- 277-280 1720 iol 1725 ' IMJ " 282-290 £ 1700 (sh)
Me " Va HN_N- 268-270 1725
Me
/“X
" HN N- 283-285 1720 )—/
Me
Me /~\ " HN N- 267-270 1730 X—(
Me r “ Cont'd - - 6! -
Table 12 (Cont'd) » ΦΗΟ/Vn ^N- 138-139 1690
V-V
l·' /—\ 1730 , " O N- >280 \ f 1700 (sh)
MeN SK- >280 1720 F X / lOJ " 208-209 1730
F
Me / \ " ‘ HN N- >280 1720 \_v
Me )—\ " MeN_N- 210-211 1735
Me /—c " MeN_N- 225-226 1720 * /—\ " _/N" 219-220 1730 [O] MeN ^N- 283-284 1730, N ' 1700 (sh) / - Cont'd -
/U
- 62 -
Table 12 (Cont'd) Ά [O] Mel·/ ^N- 277-280 1730 ' Y \—! 1700 (sh)
Br " 271-274 1725
Me " 250-252 1725 OMe 1 Example 10
To 0.10 g of ethyl 6-fluoro-l-(4-fluorophenyl)- l,4-dihydro-7-(3-hydroxy-l-pyrrolidinyl)-4-oxo-l,8-naphthyridine-3-carboxylate were added 2 ml of 1 N aqueous 5 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 10 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 magnésium sulfate. The solvent was removed by distillation under reduced pressure, and the crystalline substance thus obtained was 15 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-l,8-naphthyridine-3-carboxylic acid - ' - 63 - 1 having a melting point of >280°C.
IR (KBr) cm“1: VC=0 1730 : ^ NMR (dg-DMSO) 6 values: 1.92-2.52 (2H, m) , 3.22-5.00 (5H, m) , 5 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 0
P II COOH
χσ î-
Compound Physical properties o ? Melting IR (KBr) R R-3 point (°C) cm : VC=0 ΦΜε0Ν p _N- 264-265 1725
, F
ÎyJ " 227 1725
F
/U
- 64 - ~x 1 Example 11
In 2.5 ml of conc. hydrochloric acid was dissolved 0.25 g of 6-fluoro-l,4-dihydro-l-(4-hydroxy-2-methylphenyl)- «s 4-OXO-7-(1-piperazinyl)-l,8-naphthyridine-3-carboxylic acid, > 5 and then 20 ml of éthanol was added to the resulting solu tion, after which the resulting mixture was stirred at room température for 15 minutes. The crystals thus deposited were collected by filtration and washed with 5 ml of éthanol to obtain 0.2 g of the hydrochloric acid sait of 6-fluoro— 10 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 15 14 were obtained.
(y~\ - 65 - »
Table 14 Ο
F 11 COOH
Hydrochloric \^γγ acid sait of „ Γ ' " 83Λν l2
Compound Physical properties 7 -, Melting IR (KBr) R point (°C) cm : C=0
fol /“"N
Kry MeN N- 283 1730 X N_/
F
(Ol HN/ N- 275-278 1720
Xi F V-/
F
249-252 Y " (decomp.) 1730
F
(ο) " >280 1710
OH
/ \ " MeN_N- 280-282 1730
F
/ \ 1720 (sh) ,
KjJ HN N- 279-283 I N—( 1705
OH
- Cont’d - - 66 -
Table 14 (Cont'd) Λ 1* /—\ 1720 (sh), [pj MeN N- 266-269 ^ V_/ 1700
OH
i Me [qY''' " 282 1730
OH
1 Example 12
In 20 ml of conc. hydrochloric acid was dissolved 2.0 g of 7-(3-amino-l-pyrrolidinyl)-6-fluoro-l-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-l,8-naphthyridine-3-5 carboxylic acid, then 200 ml of ethanol was added to the resulting solution at room température, 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 sait of 10 7-(3-amino-l-pyrrolidinyl)-6-fluoro-l-(2,4-difluorophenyl)- l,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 15 (1) In 2.5 ml of Chloroform were dissolved 0.5 g of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3-(2,4-difluoro-
: U
/ - 67 - t 1 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 5 of saturated aqueous sodium chloride solution and then dried over anhydrous magnésium 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 : éthanol = 50 : 1 10 (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 (Ne.at) cm"1: VC=0 1735, 1700 NMR (CDCl^) δ values: 15 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- 20 6-(4-methyl-l-piperazinyl)nicotinoyl]-3-(2,4-difluorophenyl amino) acrylate in the same manner as in Examples 6 and 9, 0.12 g of 6-fluoro-1-(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.
25 Example 14
To 0.3 g of ethyl 7-(4-ethoxycarbonyl-2-methyl- Ιλ - « -
X
1 1-piperazinyl)-6-fluoro-l-(2/4-difluorophenyl)-1,4-dihydro- 4-oxo-l,8-naphthyridine-3-carboxylate were added 5 ml of 7 1 N aqueous sodium hydroxide solution and 5 ml of éthanol, and the resulting mixture was subjected to reaction at . 5 90°C for 2 hours. Then, acetic acid was added to the reac tion 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)-l,4-dihydro-7-(2-methyl-1-piperazinyl)-4-oxo-10 1,8-naphthyridine-3-carboxylic acid having a melting point of 230-239°C.
IR (KBr) cm"1: VC=0 1730 NMR (TFA-d^) δ values: 1.50 (3H, s), 3.20-5.15 (7H, m), 15 7.00-7.90 (3H, m), 8.35 (1H, d, J=13Hz), 9.20 (1H, s)
Example 15
In 20 ml of éthanol was suspended 1.0 g of dihydro-chloric acid sait of 3-aminopyrrolidine, and 2.06 g of 20 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 25 at the same température for 3 hours. After the completion of the reaction, 30 ml of water was added to the reaction
U
X
1 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 hydro- chloric acid, and the resulting suspension was heated under 5 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 sait of 7-(3-amino-l-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-10 oxo-1,8-naphthyridine-3-carboxylic acid.
IR (KBr) cm"1: VC=0 1730 Example 16 .
In 75 ml of éthanol and 75 ml of water was suspended 10.0 g of 7-(3-amino-l-pyrrolidinyl)-6-fluoro-1-(2,4-15 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 température for 30 minutes. Subsequently, the reaction mixture was cooled to 20 15°C, and the crystals thus deposited were collected by filtration and washed with a mixed solvent of 5 ml of éthanol and 5 ml of water to obtain 12.8 g of the p-toluenesulfonic acid monohydrate sait of 7-(3-amino-l-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-l,8-naphthyridine-25 3-carboxylic acid having a melting point of 258-260°C.
: ^ ( - 70 - y 1 IR (KBr) cm'1: VC=0 1735 NMR (DMSO-d6) δ values: 1.82-2.42 (m) ") 3.12-4.30 (5H, m) , (5H) ,
2.27 (s) J
5 6.92-8.17 (8H, m), 8.79 (1H, s)
In a similar manner, the following compound was obtained:
Oxalic acid sait of 7-(3-amino-l-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-lr4-dihydro-4-oxo-l,8-10 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 15 and 25 ml of acetic acid was added 5.00 g of 7-(3-amino-l-pyrrolidinyl) -6-fluoro-l-(2,4-difluorophenyl)-1,4-dihydro- 4-oxo-l/8-naphthyridine-3-carboxylic acid/ after which the resulting suspension was stirred at room température to form a solution. To the solution was added 100 ml of éthanol at 20 40° to 45°C over 30 minutes. Subsequently, the reaction mixture was cooled to room température, and stirred for 30 minutes. The crystals thus deposited were collected by filtration and washed with three 20-ml portions of éthanol to obtain 3.12 g of methanesulfonic acid sait of 7-(3-amino-l-25 pyrrolidinyl)-6-fluoro-l-(2,4-difluorophenyl)-1,4-dihydro-·: 4-oxo-l/8-naphthyridine-3-carboxylic acid having a melting - /-^ - 71 - > 1 point of >300°C.
' IR (KBr) cm"1: VC=0 1735 Ά
In a similar manner, the following compound was * obtained: 5 Sulfuric acid sait 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: VC=0 1735 10 Préparation Example 1
With 50 g of 6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-7-(1-piperazinyl)-l,8-naphthyridine-3-carboxylic acid were blended 49 g of crystalline cellulose, 50 g of corn starch and 1 g of magnésium stéarate, and the 15 blend was compressed into 1,000 flat-type tablets.
Préparation 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 20 capsules were filled with the resulting blend to obtain capsules.
Préparation Example 3
With 50 g of 7-(3-amino-l-pyrrolidinyl)-1-(2,4- :/L· 1 difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-l,8-naphthyridine- 3-carboxylic acid were blended 49 g of crystalline cellulose, s 50 g of corn starch and 1 g of magnésium stéarate, and the * blend was compressed into 1,000 flat-type tablets.
5 Préparation 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 10 capsules.
^ .
- 73 -

Claims (39)

  1. 2. A l,4-dihydro-4-oxonaphthyridine derivative or a 2 sait thereof according to Claim 1, wherein R represents a substituted or unsubstituted phenyl group.
  2. 3. A l,4-dihydro-4-oxonaphthyridine derivative or 3 3 a sait thereof according to Claim 2, wherein R represents a substituted or unsubstituted cyclic amino group selected from the group consisting of 1-pyrrolidinyl, piperidino, 1-piperazinyl and morpholino group.
  3. 4. A 1,4-dihydro-4-oxonaphthyridirie derivative or 2 a sait thereof according to Claim 3, wherein R represents a phenyl group which may be substituted by at least one substituent selected from the group consisting of a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a cyano group, an amino group, an acylamino group and a /trihalogenoalkyl group. t
  4. 5. A l,4-dihydro-4-oxonaphthyridine derivative or a 3 sait thereof according to Claim 4, wherein R represents ' a 1-pyrrolidinyl, piperidino, 1-piperazinyl or morpholino * group which may be substituted by at least one substituent selected from the group consisting of alkyl, amino, amino-alkyl, hydroxyalkyl, hydroxyl, alkenyl, acyl, alkylamino, dialkylamino, cyano, oxo, aralkylamino, acylamino, alkoxy-carbonyl and N-acyl-N-alkylamino groups.
  5. 6. A l,4-dihydro-4-oxonaphthyridine derivative or a 3 sait thereof according to Claim 5, wherein R represents a 1-pyrrolidinyl, piperidino, 1-piperazinyl, or morpholino group which may be substituted by at least one substituent selected from the group consisting of alkyl, amino, hydroxyalkyl, hydroxyl, alkenyl, acyl, alkylamino, dialkylamino, acylamino, alkoxycarbonyl and N-acyl-N-alkylamino groups.
  6. 7. A 1,4-dihydro-4-oxonaphthyridine derivative or a 2 sait thereof according to Claim 6, wherein R represents a , phenyl group substituted by at least one halogen atom.
  7. 8. A 1,4-dihydro-4-oxonaphthyridine derivative or a sait thereof according to Claim 7, wherein R represents a 4-fluorophenyl or 2,4-difluorophenyl group.
  8. 9. A l,4-dihydro-4-oxonaphthyridine derivative or a 3 sait thereof according to Claim 2, wherein R represents a 1-pyrrolidinyl group which may be substituted by at least one substituent selected from the group consisting of amino, hydroxyl, alkylamino, dialkylamino, acylamino and N-acyl-N-alkylamino groups.
  9. 10. A l,4-dihydro-4-oxonaphthyridine derivative lU 2 2 or a sait thereof according to Claim 9, wherein R représente a phenyl group which may be substituted by at least one substituent selected from the group consisting of a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a cyano group, an amino group, an acylamino group and a tri-halogenoalkyl group.
  10. 11. A l,4-dihydro-4-oxonaphthyridine derivative or a 3 sait thereof according to Claim 10, wherein R represents a 1-pyrrolidinyl group substituted by an amino or acylamino group.
  11. 12. A l,4-dihydro-4-oxonaphthyridine derivative or a 2 sait thereof according to Claim 11, wherein R represents a phenyl group substituted by at least one halogen atom.
  12. 13. A 1,4-dihydro-4-oxonaphthyridine derivative or a 2 sait thereof according to Claim 12, wherein R represents a 4-fluorophenyl or 2,4-difluorophenyl group. - 14. A l,4-dihydro-4-oxonaphthyridine derivative or a s 3 s sait thereof according to Claim 2, wherein R represents a 3-amino-l-pyrrolidinyl group.
  13. 15. A l,4-dihydro-4-oxonaphthylidine derivative or a sait thereof according to Claim 14, wherein R represents a phenyl group which may be substituted by at least one substituent selected from the group consisting of a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a cyano group, an amino group, an acylamino group and a trihalogenoalkyl group.
  14. 16. A l,4-dihydro-4-oxonaphthylidine derivative or a 2 sait thereof according to Claim 15, wherein R represents !ï a phenyl group substituted by at least one halogen atom. „ 17. A l,4-dihydro-4-oxonaphthyridine derivative or a ο “· sait thereof accordmg to Claim 16, wherein R represents a 4-fluorophenyl or 2,4-difluorophenyl group. ' 18. A l,4-dihydro-4-oxonaphthyridine derivative or a sait thereof accordmg to Claim 2, wherein R represents a 1-piperazinyl group which may be substituted by at least one substituent selected from the group consisting of alkyl, hydroxylalkyl, alkenyl, acyl and alkoxycarbonyl groups.
  15. 19. A l,4-dihydro-4-oxonaphthyridine derivative or a 2 sait thereof according to Claim 18, wherein R represents a phenyl group which may be substituted by at least one substituent selected from the group consisting of a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a cyano group, an amino group, an acylamino group and a tri-halogenoalkyl group.
  16. 20. A l,4-dihydro-4-oxonaphthyridine derivative or a v 3 sait thereof according to Claim 19, wherein R represents a 1-piperazinyl group.
  17. 21. A l,4-dihydro-4-oxonaphthyridine derivative or a 2 sait thereof according to Claim 20, wherein R represents a phenyl group substituted by at least one halogen atom.
  18. 22. A l,4-dihydro-4-oxonaphthyridine derivative or a 2 sait thereof according to Claim 16, wherein R represents a 4-fluorophenyl or 2,4-difluorophenyl group. 23. 7-Chloro-l-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid or a sait thereof. < L·'—N. λ - 77 - Ä 24. 7-(3-Amino-l-pyrrolidinyl)-1-(2,4-difluorophenyl)- 6-fluoro-1,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic 1 acid or a sait thereof. 25. 1-(2,4-Difluorophenyl)-6-fluoro-1,4-dihydro-4- * oxo-7-(1-piperazinyl)-l,8-naphthyridine-3-carboxylic acid or a sait thereof. 26. 7- (3-Amino-l-pyrrolidinyl)-6-fluoro-l-(4—fluorophenyl) -1,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid or a sait thereof.
  19. 27. A process for producing a l,4-dihydro-4-oxo-naphthyridine derivative represented by the formula, or a sait thereof:
  20. 0. F II COOk - ΪΓ ! wherein represents a hydrogen atom or a carboxyl-protect-. 2 mg group, R represents a substituted or unsubstituted 3 aryl group, and R represents a halogen atom or a substituted or unsubstituted cyclic amino group, characterized by sub-jecting the compound represented by the formula, or a sait thereof: 0 1 F H COOR a χχΧ Ε3ΑΝ C1\hR2 : A * la 2 wherein R represents a carboxyl-protecting group, and R 3 and R hâve the same meanings as defined above to ring closure reaction, and then, if desired, removing the carboxyl-protecting group. 2 * 28. A process according to Claim 27, wherein R represents a substituted or unsubstituted phenyl group. 3
  21. 29. A process according to Claim 28, wherein R represents a 1-pyrrolidinyl group which may be substituted by at least one substituent selected from the group consisting of amino, hydroxyl, alkylamino, acylamino and N-acyl-N-alkylamino groups. 3
  22. 30. A process according to Claim 29, wherein R represents a 1-pyrrolidinyl group substituted by an amino or acylamino group. 2
  23. 31. A process according to Claim 30, wherein R represents a phenyl group substituted by at least one halogen atom. »· 2
  24. 32. A process according to Claim 31, wherein R represents a 4-fluorophenyl or 2,4-difluorophenyl group. 3
  25. 33. A process according to Claim 28, wherein R represents a 1-piperazinyl group which may be substituted by at least one substituent selected from the group consisting of alkyl, hydroxylalkyl, alkenyl, acyl and alkoxycarbonyl groups. 3
  26. 34. A process according to Claim 33, wherein R represents a 1-piperazinyl group. * 2
  27. 35. A process according to Claim 34, wherein R represents a phenyl group substituted by at least one /-—\ - 79 - * τ* 2 halogen atom.
  28. 36. A process according to Claim 35, wherein R represents a 4-fluorophenyl or 2,4-difluorophenyl group. * 37. A process according to Claim 27, wherein the ring * closure reaction is conducted at a température of 20° to 160°C.
  29. 38. A process for producing a l,4-dihydro-4-oxo- naphthyridine derivative represented by the formula, or a sait thereof: 0 1 F II COOR i2 wherein R^ represents a hydrogen atom or a carboxyl- 2 _ protecting group, R represents a substituted or unsubsti- A . tuted aryl group, and R represents a substituted or unsubstituted cyclic amino group, characterized by reacting the compound represented by the formula, or a sait thereof: 0 1 F IJ COOR R3 I , R^ 3a 1 2 wherein R represents a halogen atom, and R and R hâve the same meanings as defined above, with a compound - 80 - represented by the formula, or a sait thereof: _3b _ R -H L. ~ i 3b , wherein R° has the same meaning as defined above. 2
  30. 39. A process according to Claim 38, wherein R represents a substituted or unsubstituted phenyl group. ou
  31. 40. A process according to Claim 39, wherein R represents a 1-pyrrolidinyl group which may be substituted by at least one substituent selected from the group consist-ing of amino, hydroxyl, alkylamino, dialkylamino, acylamino and N-acyl-N-alkylamino groups. IL
  32. 41. A process according to Claim 40, wherein R represents a 1-pyrrolidinyl group substituted by an amino or acylamino group. 2
  33. 42. A process according to Claim 41, wherein R represents a phenyl group substituted by at least one halogen ^ atom. \ 2 ^ 43. A process according to Claim 42, wherein R represents a 4-fluorophenyl or 2,4-difluorophenyl group. 3b
  34. 44. A process according to Claim 39, wherein R represents a 1-piperazinyl group which may be substituted by at least substituent selected from the group consisting of alkyl, hydroxylalkyl, alkenyl, acyl and alkoxycarbonyl groups. 3b
  35. 45. A process according to Claim 44, wherein RJ represents a 1-piperazinyl group. 2
  36. 46. A process according to Claim 45, wherein R represents a phenyl group substituted by at least one halogen ;Ά 2 U atom.
  37. 47. A process according to Claim 46, wherein R - représente a 4-fluorophenyl or 2,4-difluorophenyl group. * 48. A process according to Claim 37, wherein the % * reaction is conducted at a température of 0° to 150°C.
  38. 49. An antibaceterial agent comprising a 1,4- dihydro-4-oxonaphthyridine derivative represented by the formula or a sait thereof:
  39. 0. F v II COOR l2 wherein R^ représente a hydrogen atom or a carboxyl-protect-. 2 mg group, R représente a substituted or unsubstituted aryl 3 group, and R represents a halogen atom or a substituted or 1 unsubstituted cyclic amino group. % λ vÀÀXHa - 82 - 3¾
LU85871A 1984-04-26 1985-04-26 1,4-DIHYDRO-4-OXONAPHTYRIDINE DERIVATIVES AND SALTS THEREOF, PROCESS FOR THEIR PREPARATION AND ANTIBACTERIAL AGENTS CONTAINING THEM LU85871A1 (en)

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