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WO1996033992A1 - Derives d'acide quinolinecarboxylique optiquement actifs et sels de ces derives - Google Patents

Derives d'acide quinolinecarboxylique optiquement actifs et sels de ces derives Download PDF

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Publication number
WO1996033992A1
WO1996033992A1 PCT/JP1996/001120 JP9601120W WO9633992A1 WO 1996033992 A1 WO1996033992 A1 WO 1996033992A1 JP 9601120 W JP9601120 W JP 9601120W WO 9633992 A1 WO9633992 A1 WO 9633992A1
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Prior art keywords
group
optically active
carbon atoms
salt
atom
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PCT/JP1996/001120
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English (en)
Japanese (ja)
Inventor
Tetsuo Shibata
Hideto Fukui
Takanobu Naito
Jun Nakano
Tetsuro Maejima
Yoshiyuki Tatsumi
Tadashi Arika
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Kaken Pharmaceutical Co., Ltd.
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Priority to AU61812/96A priority Critical patent/AU6181296A/en
Publication of WO1996033992A1 publication Critical patent/WO1996033992A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • the present invention relates to a novel optically active quinol having antibacterial activity that is useful as a pharmaceutical, veterinary drug, aquatic medicine, pesticide, preservative, industrial bactericide, etc.
  • Linkonic acid derivatives and their salts, antibacterial agents containing them as active ingredients, and optically active quinolincarbons It relates to an optically active pyrrolidine derivative and a salt thereof, which are intermediates of the synthesis of an acid derivative.
  • the present inventors obtained an optically active form of this compound, and the optically active form having a specific rotation (+) was about twice that of the ( ⁇ ) form. They have antibacterial activity and found that the (Soil) body is less toxic than the body, thus completing the present invention.
  • the present invention provides a compound of the general formula (I):
  • R 1 may be substituted, and may be an alkyl group having 1 to 6 carbon atoms, an alkyl group having 2 to 6 carbon atoms, or 3 to 7 carbon atoms.
  • R 2 is a hydrogen atom; a halogen atom; an optionally protected hydroxyl group; Amino group or alkynoleamino group having 1 to 6 carbon atoms; diaminoquinole amino group having 1 to 6 carbon atoms in each alkynole group: Represents an alkyl group having 1 to 6 carbon atoms, R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and A represents a nitrogen atom or a nitrogen atom. Is
  • a ' is a hydrogen atom; a halogen atom; an alkyl group having 1 to 6 carbon atoms: an alkyl group having 1 to 6 carbon atoms which may be substituted.
  • R 4 represents a hydrogen atom or an amino protecting group
  • * 1 and * 2 represent an asymmetric carbon atom having a trans-substituted substituent.
  • a salt thereof which is an optically active quinoline carboxylate derivative represented by the formula:
  • a ' is a hydrogen atom; a halogen atom: an alkyl group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms which may be substituted.
  • R 1 is a power mouth profile
  • R 2 is a hydrogen atom and A is
  • the present invention relates to an acid derivative or a salt thereof.
  • the present invention is based on (+)-7-((3R.4S))-translation 1-amino-methylation 4-trino-methylation 1 (1 opening mouth) 1 1 1 Cyclo bropinol 1 6 — Fluoro ⁇ -1,4 ⁇ P P-8-METHOXY 4 1 oxoquinoline 131-Carbonic acid or a salt thereof.
  • the present invention relates to an antibacterial agent containing the above-mentioned optically active quinoline carboxylic acid derivative or a salt thereof as an active ingredient.
  • the present invention relates to a method for treating bacterial infection using the above-mentioned optically active quinolincanolevonic acid derivative or a salt thereof.
  • R 4 represents a hydrogen atom or an amino protecting group, and * 1 and * 2 each have a substitution group for a transgenic bond.
  • Optically active pillory represented by an asymmetric carbon atom Related to derivatives or salts thereof.
  • the present invention is based on (1) -1 (3R, 4S) -1trans 13-1 Or about its salt.
  • the compound of the present invention is an optically active compound in which the aminoamino group at position 3 and the trifluoromethyl group at position 4 are in the trans configuration.
  • the pyrrolidine residue is bonded to the carbon atom at position 7 of the quinoline carboxylate derivative.
  • the compound of the present invention is characterized in that the optically active substance having a specific rotation (+) has about twice the antibacterial activity of the ( ⁇ ) form, and has a higher activity than the (soil) form. It is less toxic.
  • the substituted C 1 to C 6 carbon atoms represented by R 1 Alkyl residues of a alkyl group include, for example, a methylene group, an ethyl group, an isopropyl group and a tert-butyl group.
  • the substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a methoxy group, an ethoxy group, and an iso group.
  • Alkoxy groups having 1 to 6 carbon atoms, such as a poxy group and a tert-butoxy group, are obtained.
  • alkyl group having 1 to 6 carbon atoms which may be replaced include, for example, a methyl group, an ethyl group, and an isopro group.
  • Examples of the optionally substituted alkenyl group having 2 to 6 carbon atoms include, for example, an isopropioninole group and 2 —fluoroiso Pronyl group etc. are required.
  • cycloalkyl group having 3 to 7 carbon atoms examples include a cyclopropynole group, a cyclopropyl group, and a 2-phenylphenylene group.
  • a cyclopropynole group examples include a cyclopropynole group, a cyclopropyl group, and a 2-phenylphenylene group.
  • aryl group which may be replaced include halogen atoms such as fluorine atoms, chlorine atoms, and bromine atoms, and methoxy groups.
  • R 1 may be substituted with a C 3 to C 7 cycloanolequinolene group, particularly a cyclopropyl group Is preferred o
  • R 2 Ru As a c b gain down atoms in R 2 Ru is I table, it was example, if full Tsu crowd atom, chlorine atom is Ru is Oh-up et al.
  • Protecting groups for hydroxyl groups that may be protected include, for example, acetyl groups and tetrahydrovinyl benzoyl groups.
  • Protecting groups for the amino group and the alkylamino group having 1 to 6 carbon atoms which may be used include, for example, an acetyl group and a tert- group. Butoxycarbonyl and benzyloxycarbonyl groups are available.
  • alkylamino groups with 1 to 6 carbon atoms each with an alkyl group of 1 to 6 carbon atoms that may be protected
  • alkylamino group of the alkylamino group and the alkyl group having 1 to 6 carbon atoms include, for example, a methyl group and an ethyl group. It is.
  • alkyl group having 1 to 6 carbon atoms represented by R 3 for example, a methyl group, an ethyl group, an isopropynole group, a tert-butynole group
  • R 3 for example, a methyl group, an ethyl group, an isopropynole group, a tert-butynole group
  • the halogen atom represented by A ' is, for example, a fluorine atom, a chlorine atom, or a bromine atom.
  • the phenol group having 1 to 6 carbon atoms for example, a methyl group, a methyl group and the like can be mentioned.
  • the anoreoxy group having 1 to 6 carbon atoms which may be substituted include, for example, a methoxy group, a fluoromethyoxy group, and a difluoro group.
  • melody ethoxy, 1-noreth ethoxy, 2 phenol, etc.
  • the tricyclic quinoline skeleton in which A 'forms a ring with R 1 is, for example, 2,3-dihydro 7 7 H — pyrido [1,2,3-de] [1,4] benzoxazines, 2.3 — dihydro 17-oxo 17 H — Pylori K [1,2,3-de] [1,4] Benzothiazines
  • Examples of the amino-protecting group represented by R 4 include an acetate group, a tert-butoxycarbonyl group, a benzyloxy group, and a benzyloxy group. Bonyl groups are required.
  • R 1 is a cyclopropyl
  • R 2 is a hydrogen atom
  • A is (In the formula, A 'is a hydrogen atom; a halogen atom: an alkyl group having 1 to 6 carbon atoms; a 1-6 carbon atom which may be substituted. (A cyano group or a nitro group) are preferred in terms of antibacterial activity.
  • optically active quinoline carboxylic acid derivative of the present invention represented by the general formula (I) has been described above, but specific examples will be given.
  • Toxicone 4 Oxoquinoline 3 — Power such as oleonic acid.
  • (+) — 7 — ((3R, 4S)-1-3- (Pinoret 11) Pyrole 6 1 — Cyclic opening 1 — 4-Hole 1 — 4, 4-Hydrogen 8 — Methoxy 4 1 Oxoquinoline 3 — phenolic acid is preferred.
  • the optically active quinoline carboxylic acid derivative of the present invention can form an acid or a base and an acid addition salt or a base addition salt.
  • acid addition salts include salts with mineral acids such as hydrochloric acid, sulfuric acid, etc., acetic acid, trifenorole acetic acid, p-toluenesolenoic acid, and meta-acid. Salts with organic acids such as sulfonate may be removed.
  • the base addition salt include salts with an anolycal metal such as sodium and potassium, magnesium salt, potassium salt and the like.
  • RRR 3 R 4 , A, * 1 and * 2 are the same as described above, and Y represents a halogen atom or a snolephonate ester residue.
  • the optically active quinoline carboxylate derivative (I) is capable of condensing the quinoline derivative (III) with the optically active pyrrolidine derivative (II). It is manufactured.
  • the raw material of the optically active pyrrolidine derivative (II) can be obtained by the following production method 5 or
  • the quinoline derivative (III) is a known substance, and is disclosed in Japanese Patent Application Laid-Open No. Sho 59-212474, Japanese Patent Publication No. Production by a method described in, for example, JP-A-81-181, JP-A-62-252772, JP-A-62-277362, etc., or a method analogous thereto. can do .
  • Examples of the halogen atom represented by Y include a fluorine atom and a chlorine atom, and examples of the sulfonate ester residue include methane.
  • Sulfonate residue, P-Tonolenesulfonate residue, 2,4,6 — Triisopropynolebenzensulfonate residue Etc. are exterminated.
  • Condensation reactions include aromatic carbohydrates such as benzene, tonolene or xylene, methanol, ethanol or ethanol.
  • Alcohols having 1 to 4 carbon atoms such as propanol, d-tetrahydrofuran, dioxan or monoglyme, etc.
  • -Non-protons such as tenorene, acetonitrile, dimethyl alcohol, amide methyl sulfonide, or dimethyl alcohol It is performed in a polar solvent.
  • the reaction temperature is usually from 0 eC to 200 ° C, and the reaction time is usually from 10 minutes to 24 hours.
  • the condensation reaction usually involves the use of 1 to 5 equivalents of a pyrrolidine derivative (III) per 1 equivalent of a quinoline derivative (III) in the presence of a deoxidizing agent. It is done using.
  • a deoxidizing agent include anolyte metal hydroxide such as sodium hydroxide or hydroxide hydroxide, magnesium hydroxide or water.
  • Alkaline earth metal hydroxides such as oxidized canoledium, sodium carbonate, sodium carbonate, sodium carbonate, sodium carbonate or carbonated water
  • Alkali metal carbonates such as common potassium, tri-tin oleamine, pyridin, N-methyl mono-ole or 1,8- diaza Organic bases such as bicyclo [5,4,0] decane 7-ene (DBU) can be removed.
  • the amount of the deoxidizing agent used varies depending on the amount of the pyrrolidine derivative (II), and is usually 1 to 7 equivalents to 1 equivalent of the quinoline derivative (III). .
  • the compound of the formula (Ia) is produced by subjecting the compound (1 ′) of the general formula (I) in which R is an alkyl group having 1 to 6 carbon atoms to a hydrolytic decomposition. It can be used under both anodic and acid conditions.
  • Examples of the alkyl group having 1 to 6 carbon atoms represented by R 3 include a methyl group, an ethyl group, an isopropyl group and the like. If the reaction is carried out under the alkaline conditions, sodium hydroxide, potassium hydroxide, magnesium hydroxide, or hydroxylate may be used as the basic reactant. Hydrolysis is performed using barium or ammonia water, etc., and using methanol, ethanol or water as the solvent. . The reaction temperature is usually 0 to 100 ° C, and the reaction time is usually 10 minutes to 5 hours.
  • the acidic reactant may be hydrochloric acid, sulfuric acid, formic acid, acetic acid or trifluoroacetic acid, or a mixture thereof.
  • methanol Usually used as a solvent, methanol, Hydrolysis is carried out using alcohol such as ethanol, isobrono, 'nonore', etc. with 1 to 4 charcoals or water.
  • the reaction temperature is usually 0 to 13 (TC, and the reaction time is usually 10 minutes to 10 hours.
  • an acid addition salt of the compound of the general formula (Ia) in which R 4 is a hydrogen atom may be directly attached.
  • the compound represented by the general formula (Ia) is converted into a boron chelate compound (IV) by adding a boron reagent to the quinoline derivative (III). After condensing with a pyrrolidine derivative (II) to form a boron chelate (V), the boron reagent is removed using a salt group. It can be manufactured by
  • the borination reaction of the quinoline derivative (III) can be carried out by using boron trifluoride, boron trifluoride, a diethyl ether complex, and boron as a boron reagent.
  • a mixture of an acid and anhydrous acetic acid is used in excess of 1.2 equivalents to 1 equivalent of the quinoline derivative (III).
  • ethereal solvents such as ether ether, tetrahydrofuran or dioxan, at 20 ° C power, if necessary, 100 ° C
  • the heating is performed up to the heating.
  • the reaction time is usually 30 minutes to 24 hours.
  • the condensation reaction between the home chelate compound (IV) and the pyrrolidine derivative (II) can be carried out by a metanole, an ethanole or an isopropane.
  • Acetanols such as phenols with 1 to 4 carbon atoms, such as phenols, ethers such as tetrahydrofuran or monogram, acetonitrile Deoxidizers in non-protonic polar solvents such as nore, dimethyl norm amide, dimethyl nore foxide or snore holane
  • 1 to 5 equivalents of the pyrrolidine derivative (II) is used per 1 equivalent of the boron chelate compound (IV).
  • the reaction temperature is usually from 0 to 100 ° C, and the reaction time is usually from 30 minutes to 24 hours.
  • the deoxidizing agent include anolyte metal hydroxide such as sodium hydroxide or hydroxylate, magnesium hydroxide or water.
  • Alkaline earth metal hydroxides such as calcium oxide, sodium carbonate, Metals such as sodium hydrogen carbonate, potassium carbonate, or sodium hydrogen carbonate, metal carbonates, triethylamines, pi Resin, N—Methyl phenol or 1,8-diazabicyclo [5,4,0] Organic base is exposed.
  • the amount of the deoxidizing agent to be used is usually 1 to 7 equivalents to 1 equivalent of the boron chelate compound (IV).
  • the base used for removing the boron reagent from the boron chelate form (V) is sodium hydroxide, calcium hydroxide, or the like.
  • Alkali metal hydroxides such as rubber, hydroxide magnesium, magnesium hydroxide, etc., etc. Earth metal hydroxides, carbonic acid, etc.
  • Metals such as sodium, sodium carbonate, sodium carbonate, potassium carbonate, etc., triethylamine, trimethylamine, etc. , N—Can be used to remove third-order amides such as methyl morpholine.
  • the amount of the base used is from 2 equivalents to a large excess with respect to 1 equivalent of the boron chelate (V) o
  • This reaction is usually carried out using a lower alcohol containing water as a solvent. As a rule, the reaction is usually carried out at 20 to 100 times and at a reaction time of 30 minutes to 12 hours.
  • R 1 is a cyclopropyl
  • R 2 is a hydrogen atom
  • A is
  • a ' is a hydrogen atom; a halogen atom: an alkyl group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms which may be substituted. A cyano group or a nitro group).
  • R 1 is a cyclopropyl group
  • R 2 is a hydrogen atom
  • A is (In the formula, A 'is a hydrogen atom: a halogen atom: an alkyl group having 1 to 6 carbon atoms: an alkyl group having 1 to 6 carbon atoms which may be substituted.
  • the above reaction is carried out using a quinoline derivative (III), which is a xyl group (which represents a cyano group or a nitro group) as a starting compound. It is manufactured by this method.
  • R R RA, * 1 and * 2 are the same as described above, and R represents an amino protecting group.
  • the compound represented by the general formula (I-b) is a compound represented by the general formula (1), (2) or (3), wherein R 4 is an amino protecting group R 4.
  • the compound (I) can be produced by removing the protecting group of the compound (1 ").
  • Examples of the amino-protecting group represented by R 4 include an acetyl group, a tert-butoxycarbonyl group, a benzyloxy group and the like. Poinole groups are exposed.
  • Removal of the protecting group is not routinely performed according to the protecting group used, for example, when the protecting group is tert-butoxycarbonyl.
  • a group treatment with an acid such as hydrochloric acid or trifluoroacetic acid, and the protecting group is a benzyloxy group
  • this can be achieved by hydrogenation in the presence of a catalyst such as palladium carbon.
  • the optically active pyrrolidine derivative represented by the formula: is a novel compound.
  • Examples of the amino-protecting group represented by R 4 include an acetyl group, a tert-butoxycarbonyl group, a benzyloxy group, and a benzyloxy group. Boninole groups are exposed.
  • optically active pyrrolidine derivative represented by the general formula (II) is, for example, (1) one (3R, 4S) one trans. 1 3 — Amino Methylinole 4 1 Trifluoromethylpyrrolidin, (1) 1 (3S, 4S) — Trans 1 3 — (tert 1 (4,1S)-Trans 3----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  • the optically active pyrrolidine derivative of the present invention can be obtained.
  • the conductor is;
  • the optically active pyrrolidine derivative (II) can form an acid and an acid addition salt.
  • the above-mentioned acid addition salts include salts with mineral acids such as hydrochloric acid, sulfuric acid, etc., acetic acid, trifluoroacetic acid, and P-tonolene sulphonic acid. And salts with organic acids such as methanophoric acid.
  • Production method 5 Production method of compound (II-a) of general formula (II) wherein R 4 is an amino protecting group
  • the compound (VI) is hydrolyzed by a conventional method to give a (Sat) 1 trans 1 1 benzene 1 4 1 trifluoromethyl pyrrolidine 3 —
  • the optically active compound is subjected to optical separation by an ordinary method using an optically active amine to obtain an optically active compound.
  • the compound (IX) is obtained by allowing the compound (VI II) to act with a reducing agent such as hydrogen hydride or the like.
  • the compound (X) is obtained by allowing the compound (IX) to act on phthalenoimide.
  • the compound (X) is treated with hydrazine or the like to give the compound (XI).
  • the benzyl group of compound (XII) can be removed by a conventional method to produce compound (II-a).
  • the compound can be converted to the compound (II-a) by the following method.
  • a suitable amino-protecting group R is introduced by a conventional method to obtain the compound (XII).
  • the benzyl group of the compound (XII) can be removed by a conventional method to produce the compound (IIa).
  • the compound represented by the general formula (II-b) is a compound obtained by the production method 5 (II- a) that Ki ⁇ Mi Roh protecting group R 4 and out and this you Concrete made Ri by the and the child you divided Ri by the conventional method.
  • optically active quinoline carboxylate derivative (I) of the present invention has strong antibacterial activity, it can be used for medicines, animals and marine medicines. It can then be used as a food preservative or as a pesticide.
  • the dosage When the compound of the present invention is used as a medicament, the dosage usually varies depending on the administration method and the dosage form, but is 10 mg per day for an adult. ⁇ Lg.
  • the 1 dose should be administered in one or several divided doses. In addition, the above-mentioned dose may not be over-administered if necessary.
  • the dosage to be used as a veterinary drug will vary depending on the type and size of the animal and the type of the infectious agent, but usually it will be different. , 1 mg / kg to 200 rag / kg / day It is an enclosure.
  • an antibacterial preparation containing the compound of the present invention select an appropriate preparation method according to the administration method, and use excipients, binders, diluents, and other pharmaceutical additives. It is prepared by the preparation method of each type of drug which is usually performed using Antibacterial preparations include oral preparations such as tablets, powders, granules, capsules, capsules, solutions and syrups, as well as injections, external preparations, and solid preparations. Medicines, eye drops, nasal drops, etc.
  • optically active salt was dissolved in 244 ml of a 2N aqueous solution of sodium hydroxide and washed with diethyl ether. Under ice-cooling, add 40.7 ml of pus-hydrochloric acid to the aqueous layer, extract with ethyl acetate, dry with magnesium sulfate, and reduce the pressure of the ethyl acetate layer. Shrunk. 200 ml of n-hexane was added to the residue, and the precipitated crystals were collected. 56 g of the target substance was obtained with an optical purity of 98% or more (yield 12.6%).
  • Hydrogenated lithium medium 700 mg, 18.4 mniol was suspended in anhydrous tetrahydrofuran (100 ml), and the suspension was cooled under ice cooling in Reference Example 2.
  • (1) (3 S. 4 S) 1 Trans 1 1 1 Benzino 1 4-Trifolene Oromethylmethylpyrrolidin 13 3-Force A solution of 5 g (18.3 mmol) of the acid in 150 ml of anhydrous tetrahydrofuran was added dropwise over 10 minutes. After stirring at room temperature for 2 hours, excess reagent was decomposed by adding 10 g of sodium sulfate decahydrate.
  • Boc represents a tert-butoxycarbonyl group
  • the same operation as above is used for the method using the Romenopyrrolidin.
  • the obtained precipitate is suspended in a mixture of 80% ethanol, 1.6 liters and 400 ml of triethylamine, and is returned for 1.5 hours. I washed away. The reaction solution is concentrated under reduced pressure, isopropanol is added to the residue, and the pale yellow crystals precipitated are collected. The isopropanol is added to the residue. After washing with ethyl ether, 29.8 g of a crude product of the intended product was obtained.
  • the antibacterial activity of the (+) form and the (1) form of the optically active form obtained in Example 3 was compared with the racemic form (Sat) form obtained in Reference Example 9. And compared.
  • the antibacterial activity is shown in Table 1 below as the minimum inhibitory concentration.
  • the test method was measured by the agar plate dilution method according to the standard method specified by the Japanese Society of Chemotherapy. Inoculum volume was 1 0 4 CFUZ scan pop Bok, use the medium had use of the sensitivity disk medium one N (Japan made this made medicine).
  • Enterococcus faecalis 0.025 Enterococcus faecalis 1373 Escherichia coli 0.025 0.1 0.2 (Escherichia coli) NIHJ JC-2
  • Klebsiella pneumoniae 0.12 0.39 (Proteus vulgaris) No.33 Proteus mirabilis . 2 (Proteus mirabilis) JY-10
  • Test compound LD 50 (mg / kg)
  • Example 3 Compound ((+) form) obtained in Example 3 100 g Conta start 40 g Avisenole 30 g Magnesium stearate 3 g
  • the compound obtained in Example 3 ((+)-isomer), Consort, Abicell (trade name, manufactured by Asahi Kasei Corporation) and stearic acid Tablets containing 100 mg of the above compound per tablet were produced by mixing magnesium in the amount described above and tableting.
  • optically active quinoline carboxylate derivatives and salts thereof in the trans configuration of the present invention have a broad antibacterial spectrum, and It has strong antibacterial activity against ram-positive bacteria, especially drug-resistant bacteria, especially MRSA, and has low mutagenicity. Therefore, it is useful for pharmaceuticals and the like.
  • optically active quinoline carboxylate derivative of the present invention has about twice the antibacterial activity of its racemic form, and is toxic. Due to the low tilting power, the dosage is reduced and the side effects can be reduced.
  • optically active pyrrolidine derivative which is another invention, is an intermediate for the production of the optically active quinoline carboxylic acid derivative of the present invention. It is useful as such.

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dérivés d'acide trans-quinolinecarboxylique optiquement actifs représentés par la formule générale (I), exerçant une activité antibactérienne puissante contre les bactéries gram-positives et les staphylocoques dorés résistants à la pénicilline, et sels de ces dérivés. L'invention porte en outre sur des agents antibactériens renfermant ces dérivés comme principes actifs et sur des dérivés de pyrrolidine optiquement actifs représentés par la formule générale (II) et sur les sels de ces dérivés utilisés comme intermédiaires pour la synthèse des dérivés précités d'acide quinolinecarboxylique.
PCT/JP1996/001120 1995-04-27 1996-04-24 Derives d'acide quinolinecarboxylique optiquement actifs et sels de ces derives WO1996033992A1 (fr)

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JP10445495 1995-04-27

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001066542A1 (fr) * 2000-03-10 2001-09-13 Dainippon Pharmaceutical Co., Ltd. Derives de l'acide pyridonecarboxylique
JPWO2005026147A1 (ja) * 2003-09-10 2007-11-08 杏林製薬株式会社 ７−（４−置換−３−シクロプロピルアミノメチル−１−ピロリジニル）キノロンカルボン酸誘導体
JP2008208057A (ja) * 2007-02-26 2008-09-11 Dainippon Sumitomo Pharma Co Ltd カルボン酸の製造方法およびその中間体
JP5154402B2 (ja) * 2006-03-09 2013-02-27 杏林製薬株式会社 ３，４−ジ置換ピロリジン誘導体の製造方法及び製造中間体
US10377745B2 (en) 2014-02-27 2019-08-13 Merck Patent Gmbh Heterocyclic compounds as NaV channel inhibitors and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995010519A1 (fr) * 1993-10-14 1995-04-20 Abbott Laboratories Composes du type de la quinolizinone
WO1995011902A1 (fr) * 1993-10-28 1995-05-04 Kaken Pharmaceutical Co., Ltd. Derive d'acide quinoleine-carboxylique et son sel

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995010519A1 (fr) * 1993-10-14 1995-04-20 Abbott Laboratories Composes du type de la quinolizinone
WO1995011902A1 (fr) * 1993-10-28 1995-05-04 Kaken Pharmaceutical Co., Ltd. Derive d'acide quinoleine-carboxylique et son sel

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001066542A1 (fr) * 2000-03-10 2001-09-13 Dainippon Pharmaceutical Co., Ltd. Derives de l'acide pyridonecarboxylique
JPWO2005026147A1 (ja) * 2003-09-10 2007-11-08 杏林製薬株式会社 ７−（４−置換−３−シクロプロピルアミノメチル−１−ピロリジニル）キノロンカルボン酸誘導体
US7514451B2 (en) 2003-09-10 2009-04-07 Kyorin Pharmaceutical Co., Ltd. 7-(4-Substituted-3-cyclopropylaminomethyl-1 pyrrolidinyl) quinolonecarboxylic acid derivative
JP4639149B2 (ja) * 2003-09-10 2011-02-23 杏林製薬株式会社 ７−（４−置換−３−シクロプロピルアミノメチル−１−ピロリジニル）キノロンカルボン酸誘導体
JP5154402B2 (ja) * 2006-03-09 2013-02-27 杏林製薬株式会社 ３，４−ジ置換ピロリジン誘導体の製造方法及び製造中間体
JP2008208057A (ja) * 2007-02-26 2008-09-11 Dainippon Sumitomo Pharma Co Ltd カルボン酸の製造方法およびその中間体
US10377745B2 (en) 2014-02-27 2019-08-13 Merck Patent Gmbh Heterocyclic compounds as NaV channel inhibitors and uses thereof

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