WO1995005373A1 - Novel quinolone carboxylic acid derivatives - Google Patents
Novel quinolone carboxylic acid derivatives Download PDFInfo
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- WO1995005373A1 WO1995005373A1 PCT/KR1994/000006 KR9400006W WO9505373A1 WO 1995005373 A1 WO1995005373 A1 WO 1995005373A1 KR 9400006 W KR9400006 W KR 9400006W WO 9505373 A1 WO9505373 A1 WO 9505373A1
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- fluoro
- pyridyl
- dihydro
- carboxylic acid
- preparation
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- 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
- C07D401/14—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 three or more hetero rings
-
- 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 the novel quinolone carboxylic acid
- X is a hydrocarbon, fluorocarbon or nitrogen atom
- Y is a hydrogen or methyl group
- R 1 is a hydrogen or C 1 -C 5 alkyl group
- R 4 is an amino group to make a racemate or (S) -enantiomer.
- R 5 , R 6 and R 7 are C 1 - C 3 alkyl groups.
- quinolone-type antibiotics which have been heretofore developed are ones having small alkyl and cycloalkyl group at N-1 position [e.g. Norfloxacin : IBP 4,146,719, Ciprofloxacin : USP 4,620,007 ] and ones having aromatic group at N-1 position [e.g. Temafloxacin : J. Med. Chem., 34, 168 (1991), Tosufloxacin : USP4.704.459].
- the compounds developed up to now generally have good in vitro activity, but such in vitro activity could not leads to in vivo because of poor pharmacokinetics including half-life(t 1/2 ), maximum blood level (Cmax), bioavi lability (BA), area under curve(AUC) etc, which are important, properties of a compound for good in vitro activity to be maintained in vivo.
- the object of this invention is to develope compounds having excellent pharmacokinetic properties by introducing fluoro pyridyl group which is a heteroaromatic group at N-1 position, thereby to produce compounds having good antibiotic power in vivo and long half-life(t 1/2) which enable once a day of dose. Therefore, the present invention provides a series of compounds having even more excellent pharmacokinetic properties than those of the conventional quinolone antibiotics by introducing 5-fluoro-2-pyridyl group and 3-fluoro-4-pyridyl group into mother nuclei of quinolone and naphthyridine.
- the present invention relates to novel quinolone carboxylic acid derivatives which have a f1uoropyridine group at N - 1 position.
- the object of the present invention is to provide the novel quinolone carboxylic acids, their esters, their pharmaceutically acceptable salts, and their hydrates in which are some compounds having broad spectrums, excellent
- Some of these quinolone derivatives have longer half-life(t 1/2 ), even higher maximum blood level (Cmax) and bioavailability(BA) and even larger area under curve (AUC) compared to ciprofloxacin of the prior art. In addition, they have still far longer half-life(t 1/2 ) and larger area under curve (AUC) compared to ofloxacin which is known to have excellent pharmacokinetics. Accordingly, some of the novel quinolone carboxylic acid derivatives of the present invention are expected to have highly increased in vivo activity.
- X is a hydrocarbon, fluorocarbon or nitrogen atom
- Y is a hydrogen or methyl group
- R 1 is a hydrogen or C 1 -C 5 alkyl group
- R 3 is (wherein R 4 is an amino group to make a racemate
- the compound of the formula (I) can be prepared as follows. Each compound in the formula (I) is prepared by the substantially same method except the reaction temperature, irrespective of the kind of X, Y, Z in the compound of the formula (II).
- the above reaction is carried out in a solvent selected from the alcohols such as methanol, ethanol, the ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, aromatic hydrocarbons such as benzene, toluene, xylene, and the inert, solvents such as acetonitrile, N,N-dimethylformamide, dimethyl suIfoxide, pyridine etc., at 0 °C to 150 °C temperature for 5 minutes to 48 hours.
- the above reaction is generally carried out in the presence of an acid-acceptor, the desirable amount of which is 1 to 3 equivalent of the compound (II).
- an excess of the compound (VI) may be used as an acid-acceptor.
- an acid-acceptor a tertiary amine such as pyridine, triethylamine or 1,8-diazabicyclo[5.4.0] undec-7-ene, or an alkali metal carbonate such as sodium hydrogen carbonate, sodium carbonate or potassium carbonate may be used.
- the compound of the formula (II) wherein R 1 is a hydrogen the compound of the formula (II") (wherein R 1 is a hydrogen) and HR 3 of the formula (VI) (wherein R 3 is the same as described above) can be reacted; or otherwise the compound of the formula (II') (wherein R 1 is an alkyl group) and HR 3 of the formula(VI) (wherein R 3 is the same as described above) can be reacted first and then hydrolysis using an acid or alkali can be carried out.
- an acid such as hydrochloric acid and sulfuric acid
- in the alkaline hydrolysis may be used an alkali such as sodium hydroxide and potassium hydroxide.
- the acid or alkali may be used in the hydrolysis as a solution in water or water-containing ethanol or methanol.
- the obtained compound of the formula (V) is subjected to a ring-closing reaction using potassium carbonate and 18-crown-6 in acetonitrile, or a ring-closing reaction using sodium hydride in N.N-dimethyl formamide, to obtain the compound of the formula (II').
- the reaction temperature is desirably from 0"C to the reflux temperature.
- the compound of the formula (II') is hydrolyzed by treatment with an acid or alkali to obtain the compound of the formula (II") and the compounds of the formula (II') and (II") are designated totally as the formula (II).
- an acid such as hydrochloric acid or sulfuric acid
- an alkali such as sodium hydroxide or potassium hydroxide
- the acid or alkali may be used in the hydrolysis as a solution in water or water-containing ethanol or methanol.
- novel quinolone carboxylic acid derivatives according to this invention may be used as free compounds, acid addition salts thereof or salts of the carboxyl groups thereof.
- suitable acids for salt formation include inorganic acids such as hydrochloric acid, phosphoric acid and organic acids such as acetic acid, oxalic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid, gluconic acid.
- Pharmaceutically acceptable base salts of the above described compounds of the formula (I) are formed with alkali metals such as sodium, potassium or alkaline earth metals such as magnesium, calcium.
- alkali metals such as sodium, potassium or alkaline earth metals such as magnesium, calcium.
- the free compounds of the present invention, their acid addition salts and their salts of the carboxyl groups of pyridone carboxylic acid derivatives may exist as hydrates.
- the mixture is refluxed for 3 hours and then cooled, added with 100ml of water and stirred during 30 minutes, then filtered and dried to obtain 1.3g of the desired compound.
- the residue is recrystallized in a mixed solvent of ethanol and water to obtain 0.22g of the desired compound.
- ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is added to 10ml of water and 10ml of cone, hydrochloric acid. The mixture is refluxed for 24 hours, cooled to room
- ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(acetamido-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is added to 10ml of water and 10ml of cone, hydrochloric acid.
- the mixture is refluxed for 24 hours, cooled to room temperature and concentrated under a reduced pressure.
- the concentrate is added with 20ml of ethanol and dissolved completely. After then. 70ml of ethvl ether is added for precipitation, and then stirred at room temperature for 2 hours, filtered and dried.
- the product is recrystallized in a mixed solvent of methanol and water to obtain 0.35g of the desired compound
- the in vitro antibiotic activity of the present compound is measured using 2-fold dilution method with a micro-well plate and the bacteria are inoculated in about 10 5 cfu/ml after an overnight culture in a brain-heart infusion(BHI) broth at 37oC
- the novel compounds of the present invention are converted to a hvdrochloride salt form and diluted with a sterilized distilled water to make 10mg/ml aqueous solution.
- the respective 0.1ml of diluted liquor is transferred to a well and is inoculated with 0.1ml of the culture fluid to make about (10 5 -10 6 )/2 cfu/ml.
- Table I -V show the minimum inhibitory concentrations(MIC).
- Streptococcus faecal is ATCC 19433
- the pharmacokinetic properties are tested by orallv administrating and subcutaneously injecting a test compound and a substance for control to a ICR Mouse with 22g ⁇ 10% weight, drawing blood after 10, 20, 30, 45, 60, 90, 120, 150, 180 and 240 minutes and analyzed by Bio-Assay(Agar well method).
- the LD 50 of example 13 was about l,000g/kg and example 18 about > 3,000g/kg. (Oral, mice)
Abstract
The present invention relates to the novel quinolone carboxylic acid derivatives of formula (I) and their pharmaceutically acceptable salts and their hydrates. In said formula, X is a hydrocarbon, fluorocarbon or nitrogen atom, Y is a hydrogen or methyl group, R1 is a hydrogen or alkyl group having 1 to 5 carbon atom, R2 is (a) (wherein A and B are a fluorocarbon or nitrogen atom, provided that, if A=CF, B=N and if A=N, B=CF) and R3 is (b) (wherein R4 is an amino group which makes a racemate or (S)-enantiomer) or (c) (wherein R?5, R6 and R7¿ are respectively hydrogen or alkyl group having 1 to 3 carbon atom). The quinolone carboxylic acid derivative of formula (I) is prepared by the condensation of the compound of formula (II) and the compound of formula HR3 in a solvent in the presence of an acid-acceptor or an excess of the compound of formula HR3 which is a reactant; and the solvent is selected from the group consisting of pyridine, acetonitrile and N,N-dimethylformamide. In formula (II) and HR3 X, Y, Z, R?1, R2 and R3¿ are each as described. The compounds according to the present invention are used for antibacterial agent.
Description
NOVEL QUINOLONE CARBOXYLIC ACID DERIVATIVES
BACKGROUND OF THE INVENTION
The present invention relates to the novel quinolone carboxylic acid
derivatives, their esters, their pharmaceutically acceptable salts and their hydrates as shown in formula (I) and a process for preparing these compounds. Furthermore, some of the invented quinolone carboxylic acid derivatives as shown in fornula (I) show broad spectrum and excellent pharmacokinetic properties and low toxicity.
Wherein X is a hydrocarbon, fluorocarbon or nitrogen atom,
Y is a hydrogen or methyl group,
R1 is a hydrogen or C1-C5 alkyl group,
R2 is (wherein A and B are fluorocarbon or nitrogen atom, provided that if A=CF, B=N and if A=N, B=CF)
(wherein R4 is an amino group to make a racemate or (S) -enantiomer. ) or (wherein R5, R6 and R7 are C1- C3 alkyl groups.)
In general, most of the quinolone-type antibiotics which have been heretofore developed are ones having small alkyl and cycloalkyl group at N-1 position [e.g. Norfloxacin : IBP 4,146,719, Ciprofloxacin : USP 4,620,007 ] and ones having aromatic group at N-1 position [e.g. Temafloxacin : J. Med. Chem., 34, 168 (1991), Tosufloxacin : USP4.704.459].
However, a noticeable quinolone antibiotic having heteroaromatic group at N-1
position has not been yet developed. Otsuka, Toyama and others reported their researches upon introducing heteroaromatic group such as furyl, thienyl, thiazol, imidazol, pyridyl, pyrimidyl group at. N-1 position, but a compound available in vivo has not been yet developed. (JPK 61-251667-A, 62-174053-A, 02-85255-A).
In particular, the compounds developed up to now generally have good in vitro activity, but such in vitro activity could not leads to in vivo because of poor pharmacokinetics including half-life(t1/2), maximum blood level (Cmax), bioavi lability (BA), area under curve(AUC) etc, which are important, properties of a compound for good in vitro activity to be maintained in vivo.
Therefore, the object of this invention is to develope compounds having excellent pharmacokinetic properties by introducing fluoro pyridyl group which is a heteroaromatic group at N-1 position, thereby to produce compounds having good antibiotic power in vivo and long half-life(t1/2) which enable once a day of dose. Therefore, the present invention provides a series of compounds having even more excellent pharmacokinetic properties than those of the conventional quinolone antibiotics by introducing 5-fluoro-2-pyridyl group and 3-fluoro-4-pyridyl group into mother nuclei of quinolone and naphthyridine.
SUMMARY OF THE INVENTION The present invention relates to novel quinolone carboxylic acid derivatives which have a f1uoropyridine group at N - 1 position.
The object of the present invention is to provide the novel quinolone carboxylic acids, their esters, their pharmaceutically acceptable salts, and their hydrates in which are some compounds having broad spectrums, excellent
pharmacokinetic properties and low toxicity which are important factors for a drug to be administrated and function in the body, and a process for preparing these compounds.
Some of these quinolone derivatives have longer half-life(t1/2), even higher maximum blood level (Cmax) and bioavailability(BA) and even larger area under curve (AUC) compared to ciprofloxacin of the prior art. In addition, they have still far longer half-life(t1/2) and larger area under curve (AUC) compared to ofloxacin which is known to have excellent pharmacokinetics. Accordingly, some of the
novel quinolone carboxylic acid derivatives of the present invention are expected to have highly increased in vivo activity.
DETAILED DESCRIPTION OF THE INVENTION
Wherein X is a hydrocarbon, fluorocarbon or nitrogen atom,
Y is a hydrogen or methyl group,
R1 is a hydrogen or C1-C5 alkyl group,
R2 is (wherein A and B are fluorocarbon or nitrogen atom, provided that if A=CF, B=N and if A=N, B=CF)
R3 is (wherein R4 is an amino group to make a racemate
-
or (S) -enantiomer.) or (wherein R5, R6 and R7 are C1- C3 alkyl groups.)
The compound of the formula (I) can be prepared as follows. Each compound in the formula (I) is prepared by the substantially same method except the reaction temperature, irrespective of the kind of X, Y, Z in the compound of the formula (II).
The above reaction is carried out in a solvent selected from the alcohols such as methanol, ethanol, the ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, aromatic hydrocarbons such as benzene, toluene, xylene, and the inert, solvents such as acetonitrile, N,N-dimethylformamide, dimethyl suIfoxide, pyridine etc., at 0 °C to 150 °C temperature for 5 minutes to 48 hours. In addition, the above reaction is generally carried out in the presence of an acid-acceptor, the desirable amount of which is 1 to 3 equivalent of the compound (II). Alternatively, an excess of the compound (VI) may be used as an acid-acceptor. As an acid-acceptor, a tertiary amine such as pyridine, triethylamine or 1,8-diazabicyclo[5.4.0] undec-7-ene, or an alkali metal carbonate such as sodium hydrogen carbonate, sodium carbonate or potassium carbonate may be used.
In order to prepare the compound of the formula (I) wherein R1 is a hydrogen, the compound of the formula (II") (wherein R1 is a hydrogen) and HR3 of the formula (VI) (wherein R3 is the same as described above) can be reacted; or otherwise the compound of the formula (II') (wherein R1 is an alkyl group) and HR3 of the formula(VI) (wherein R3 is the same as described above) can be reacted first and then hydrolysis using an acid or alkali can be carried out. At this time, in the acidic hydrolysis may be used an acid such as hydrochloric acid and sulfuric acid and in the alkaline hydrolysis may be used an alkali such as sodium hydroxide and potassium hydroxide. The acid or alkali may be used in the hydrolysis as a solution in water or water-containing ethanol or methanol.
The compound of the formula (II) can be prepared as follows. (II = II' +II")
Wherein X, Y, Z, R1 and R2 are each as defined above. The compound of the formula (III) is prepared by the conventional method [Ger. Offen. DE 3, 142, 854; Ger. Offen. DE 3, 318, 145 ; J. Med. Chem., 29, 2363(1986)] and thereby obtained compound of the formula (III) is reacted with the compound of the formula(IV) prepared by the conventional method [Rocz. chem., 38, 777-783(1964); Synthesis, 12, 905-908(1989)] in an alcohol solvent such as methanol and ethanol, or a haloformic solvent such as dichloromethane and chloroform at -10 °C - 30ºC to obtain the compound of the formula (V). The obtained compound of the formula (V) is subjected to a ring-closing reaction using potassium carbonate and 18-crown-6 in acetonitrile, or a ring-closing reaction using sodium hydride in N.N-dimethyl formamide, to obtain the compound of the formula (II'). At this time the reaction temperature is desirably from 0"C to the reflux temperature. The compound of the formula (II') is hydrolyzed by treatment with an acid or alkali to obtain the compound of the formula (II") and the compounds of the formula (II') and (II") are designated totally as the formula (II). At this time, in the acidic hydrolysis may be used an acid such as hydrochloric acid or sulfuric acid, and in the alkaline hydrolysis may be used an alkali such as sodium hydroxide or potassium hydroxide. The acid or alkali may be used in the hydrolysis as a solution in water or water-containing ethanol or methanol.
Representative examples of the novel quinolone carboxylic acid derivatives according to the present invention are as follows ;
1. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-
carboxylic acid
2. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4- oxoquinoline-3-carboxylic acid
3. 1-(3-fluorx)-4-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4- oxoquinoline-3-carboxylic acid
4. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4- oxoquinoline-3-carboxylic acid
5. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4- oxoquinoline-3-carboxylic acid
6. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl]-1,4-dihydro-4- oxoquinoline-3-carboxylic acid
7. 1-(3-fluoro-4-pyτidyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid
8. 1-(3-fluoro-4-pyridyl)-6-f]uoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8 -naphthyridine-3-carboxylic acid
9. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8 -naphthyridine-3-carboxylic acid
10. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid
11. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl)-1,4-dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid
12. 1-(5-fluoro-2-pyridy1)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid
13. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylic acid
14. 1-(5-fluoro-2-pjα-idyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylie acid
15. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid
16. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylic acid
17. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid
18. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4- oxoquinoline-3-carboxylic acid
19. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4- oxoquinoline-3-carboxylic acid
20. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4- oxoquinoline-3-carboxylic acid
21. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4- oxoquinoline-3-carboxylic acid
22. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl)-1,4-dihydro-4- oxoquinoline-3-carboxylic acid
23. 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4- oxoquinoline-3-carboxylic acid
24. 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4- oxoquinoline-3-carboxylic acid
25. 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4- oxoquinoline-3-carboxylic acid
26. 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3,5-di_ιιethyl-1-piperazinyl)-1,4-dihydro- 4-oxoquinoline-3-carboxylic acid
27. 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3-amino-1-pyrrolidinyl)-1,4~dihydro-4- oxoquinoline-3-carboxylic acid
28. 5-methyl-7-(4-methyl-1-piperazinyl)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4-dihydro -4-oxoquinoline-3-carboxylic acid
29. 5-methyl-7-(3-methyl-1-piperazinyl)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4-dihydro -4-oxoquinoline-3-carboxylic acid
Meanwhile, the novel quinolone carboxylic acid derivatives according to this invention may be used as free compounds, acid addition salts thereof or salts of the carboxyl groups thereof. The suitable acids for salt formation include inorganic acids such as hydrochloric acid, phosphoric acid and organic acids such as acetic acid, oxalic acid, succinic acid, methanesulfonic acid, maleic acid, malonic acid, gluconic acid.
Pharmaceutically acceptable base salts of the above described compounds of the formula (I) are formed with alkali metals such as sodium, potassium or alkaline earth metals such as magnesium, calcium. The free compounds of the present
invention, their acid addition salts and their salts of the carboxyl groups of pyridone carboxylic acid derivatives may exist as hydrates.
The following examples are provided to illustrate the desirable preparation of the compounds of the present invention.
Preparation 1
Preparation of ethyl 3-(3-fluoro-4-pyridyl)amino-2-(2,4,5-trifluorobenzoyl)aerylate 2.5g of ethyl 2,4,5-trifluorobenzoyl acetate, 2.55ml of triethyl o-formate,
12ml of acetic anhydride are mixed together and refluxed for 3 to 5 hours, cooled to room temperature, and distilled under a reduced pressure. The obtained product is dissolved in 50ml of anhydrous dichloromethane and added with 1.26g of
4-amino-3-fluoropyridine and stirred at room temperature for 5 hours, and then concentrated under a reduced pressure. The product is used in the next reaction without further purification.
Preparation 2
Preparation of ethyl 3-(3-fluoro-4-pyridyl)amino-2-(2,6-dichloro-5-fluoronicotinyl) aerylate
A procedure substantially similar to the procedure in Preparation 1 is carried out to prepare the title compound.
Preparation 3
Preparation of ethyl 3-(5-fluoro-2-pyridyl)amino-2-(2,6-dichloro-5-fluoronicotinyl) aerylate
A procedure substantially similar to the procedure in Preparation 1 is carried out to prepare the title compound.
Preparation 4
Preparation of ethyl 3-(5-fluoro-2-pyridyl)amino-2-(2,3,4,5-tetrafluorobenzoyl)aerylate
A procedure substantially similar to the procedure in Preparation 1 is carried out to prepare the title compound.
Preparation 5
Preparation of ethyl 3-(5-fluoro-2-pyridyl)amino-2-(2,4,5-trifluorobenzoyl)acrylate A procedure substantially similar to the procedure in Preparation 1 is carried out to prepare the title compound.
Preparation 6
Preparation of ethyl 3-(5-fluoro-2-pyridyl)amino-2-(3-methyl-2,4,5-trifluorobenzoyl )acrylate
A procedure substantially similar to the procedure in Preparation 1 is carried out to prepare the title compound.
Preparation 7
Preparation of ethyl 1-(3-fluoro-4-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline
-3-carboxylate
2.0g of ethyl 3-(3-fluoro-4-pjτidy])amino-2-(2,4,5-trifluorobenzoyl)acrylate,
1.50g of potassium carbonate and 0.43g of 18-crown-6 are mixed with 40ml of anhydrous acetonitrile.
The mixture is refluxed for 3 hours and then cooled, added with 100ml of water and stirred during 30 minutes, then filtered and dried to obtain 1.3g of the desired compound.
m.p. : 212°C
1H-NMR(CDCl3, ppm) : 1.26 (t,3H,J=7.20Hz), 4.40(q,2H,J=7.20Hz), 6.50-6.80(m,1H),
7.40-7.60(m,1H), 8.22-8.42(m,2H), 8.68-8.96(m,2H) Preparation 8
Preparation of ethyl 1-(3-fluoro-4-pyridyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate
A procedure substantially similar to the procedure in Preparation 7 is carried out to prepare the title compound.
m.p. : 226ºC
1H-NMR(CDCl3, ppm) : 1.42 (t,3H,J=7.20Hz), 4.42(q,2H,J=7.20Hz) , 7.46-7.50(m, 1H),
8.48-8.54(m,2H), 8.70-8.82(m,2H)
Preparation 9
Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8 -naphthyridine-3-carboxylate
A procedure substantially similar to the procedure in Preparation 7 is carried out to prepare the title compound,
m.p. : 230ºC
1H-NMR(CDCl3, ppm) : 1.36 (t,3H,J=7.20Hz), 4.38(q,2H,J=7.20Hz), 7.60-7.80(m,2H),
8.36-8.54(m,2H), 8.94(s,1H) Preparation 10
Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate
A procedure substantially similar to the procedure in Preparation 7 is carried out to prepare the title compound.
m.p. : 210-213ºC
1H-NMR(CDCl3, ppm) : 1.50 (t,3H,J=8.00Hz), 4.70(q,2H,J=8.00Hz), 7.42(dd,1H,
J=3.04Hz,J=10.04Hz), 7.92-8.19(m,2H), 8.50-8.79(m,2H), 9.45(s,1H) Preparation 11
Preparation of ethyl 1-(5-fluorc-2-pyridyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate
A procedure substantially similar to the procedure in Preparation 7 is carried out to prepare the title compound.
m.p. : 203-205°C
1H-NMR(CDCl3, ppm) : 1.32 (t,3H, J=7.20Hz), 4.32<q,2H,J=7.20Hz), 7.36-7.72(m,2H),
8.00-8.22(m,1H), 8.30-8.50(m,2H)
Preparation 12
Preparation of 1-(3-fluoro-4-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid
5g of ethyl 1-(3-fluoro-4-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate is added with 20ml of water, 30ml of ethanol and 15 ml of conc.
hydrochloric acid and refluxed for 8 hours. After cooling to room temperature and standing for 2 hours, filtering and drying are carried out to obtain 4.2g of the desired compound,
m.p. : 271-273°C
1H-NMR(CF3COOD, ppm) : 7.28-7.58(m,1H) , 8.26-8.88(m,2H) , 9.22-9.62(m,3H)
Preparation 13
Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3- carboxylic acid
A procedure substantially similar to the procedure in Preparation 12 is carried out to prepare the title compound.
m.p.: 228-230T.
1H NMR(CDCl3, ppm) : 8.50-8.74(m,2H), 9.16-9.42(m,3H) Preparation 14
Preparation of 1-(5-fluoro-2-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid
A procedure substantially similar to the procedure in Preparation 12 is carried out to prepare the title compound.
m.p.: 275-280ºC
1H NMR(CF3COOD, ppm) : 7.40(dd,1H,J=3.02Hz,J=10.06Hz), 7.92-8.18(m,2H),
8.39-8.78(m,2H), 9.50(s,1H)
Preparation 15
Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
A procedure substantially similar to the procedure in Preparation 12 is carried out to prepare the title compound.
m.p.: 234-238T.
1H NMR(CDCl3, ppm) : 8.58-8.84(m,2H) , 9.18-9.42(m,3H)
Preparation 16
Preparation of ethyl 1-(5-f1uorc-2-pyridyl)-6-f1uoro-7-(1-piperazinyl)-1,4-
dihydro-4-oxo-1,8-naphthyridine-3-carboxylate
0.5g of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 0.35g of piperazine are added to 45ml of pyridine.
The mixture is stirred at 10ºC for 1 hour and then concentrated under a reduced pressure and subjected to a column chromatography (acetone/n-hexane=5/2) to obtain
0.47g of the desired compound, which is then subjected to the next reaction to identify its structure, (next reaction : Example 12)
Preparation 17
Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate
A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.
Yield : 85.0%
Preparation 18
Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate
A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.
Yield : 91.5%
Preparation 19
Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate
A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.
Yield : 84.1%
m.p. : 165º0
1H NMR(CDCl3, ppm) : 0.94(s,3H), 1.00(s,3H), 1.35(t,3H,J=6.40Hz), 2.24-3.06(m,4H),
4.00-4.42(m,4H), 7.44-8.24(m,3H), 8.38-8.52(m, 1H), 8.76(s,1H)
Preparation 20
Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-acetamido-1-pyrrolidinyl)
-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate
A procedure substantially siailar to the procedure in Preparation 16 is carried out to prepare the title compound.
Yield : 90.3%
m.p. : 200-202ºC
1H NMR(CDCl3, ppm) : 1.30(t,3H,J=6.40Hz), 1.90-2.16(m,5H), 3.40-3.94(m,4H),
4.28(q,2H,J=6.40Hz), 4.76(m,1H), 7.44-8.06(m,3H),
8.32-8.46(m,1H), 8.68(s,1H) Preparation 21
Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.
Yield : 90.3%
Preparation 22
Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.
Yield : 91.3%
Preparation 23
Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.
Yield : 87.5%
Preparation 24
Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.
Yield : 89.3% Preparation 25
Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3-acetamido-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
A procedure substantially similar to the procedure in Preparation 16 is carried out. to prepare the title compound.
Yield : 90.3%
Preparation 26
Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.
Yield : 84.5%
Preparation 27
Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4 -dihydro-4-oxoquinoline-3-carboxylate
A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.
Yield : 88.7%
Preparation 28
Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4 -dihydro-4-oxoquinoline-3-carboxylate
A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.
Yield : 83.7%
Preparation 29
Preparation ofethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.
Yield : 88.7%
Preparation 30
Preparation of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-acetamido-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate
A procedure substantially similar to the pιrχ.edure in Preparation 16 is carried out to prepare the title compound.
Yield : 92.7%
Preparation 31
Preparation of 1-(5-fluoro-4-pyridyl)-6-fluoro-7-(3-acetamido-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid
0.22g of 1-(3-fluoro-4-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0. llg of 3-acetamidopyrrolidine are added to 12ml of pyridine, and added with 0.13ml of l,8-diazabicyclo[5.4.0]undec-7-ene. The mixture is stirred at room temperature for 24 hours, and then concentrated under a reduced pressure to remove the solvent completely. The residue is added with 20ml of acetone and stirred at room temperature for 1 hour to obtain a product, which is then filtered and dried and used in the next reaction, (next reaction : Example 5) Preparation 32
Preparation of ethyl 5-methyl- 7-(4-methyl-1-piperazinyl)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate
A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.
Yield : 82.5%
Preparation 33
Preparation of ethyl 5-methyl-7-(3-methyl-1-piperazinyl)-1-(5-fluoro-2-pyridyl)-6-
fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate
A procedure substantially similar to the procedure in Preparation 16 is carried out to prepare the title compound.
Yield : 85.0%
Example 1
Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
0.66g of 1-(3-fluoro-4-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3- carboxylic acid and 0.22mg of piperazine are added to 30ml of pyridine. The mixture is added with 0.39ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, stirred at. room temperature for 24 hours and concentrated under a reduced pressure. The concentrate is subjected to a column chromatography(chloroform/methanol/ammonia water=15/12/1) to seperate the desired product, which is then concentrated under a reduced pressure. After then, the residue is added with 15ml of ethanol, 10ml of water and 5ml of cone, hydrochloric acid and stirred at room temperature for 3 hours, filtered and dried. The obtained product is recrystallized in a mixed solvent of methanol or ethanol and water to obtain 0.47g of the desired compound, m.p.: 284-286ºC(dec. )
1H NMR(CF3COOD, ppm) : 3.26-4.24(m,8H), 6.84(d,1H,J=4.82Hz) ,
8.38(d.1H,J=12.82Hz), 8.70-9.02(m,1H), 9.20-9.62(m,3H)
Example 2
Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound.
m.p. : 274-276°C(dec.)
1H NMR(CF3COOD, ppm) : 3.12(s,3H), 3.28-4.32(m,8H), 6.88(d,1H,J=4.80Hz) ,
8.38(d,1H,J=12.80Hz), 8.68-8.98(m, 1H), 9.20-9.60(m,3H)
Example 3
Preparation of 1-(3-fluoro-4-pyridyl )-6-fluoro-7-(3-methyl-1-piperazinyl )-1 , 4-
dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound.
m.p. : 270-272ºC(dec.)
1H NMR(CF3COOD, ppm) : 1.52(d,3H,J=5.62Hz) , 3.36-4.24(m, 7H) , 6.86(d, 1H,J=4.80Hz),
8.36(d,1H,J=12.80Hz), 8.70-8.92(m, 1H), 9.26-9.60(m,3H)
Example 4
Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3,5-difflethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound.
m.p. : 285-287°C(dec.)
1H NMR(CF3COOD, ppm) : 1.38-1.62(m,6H), 3.20-4.28(m,6H), 6.90(d,1H,J=4.80Hz),
8.38(d,1H,J=12.80Hz), 8.68-9.00(m,1H), 9.20-9.56(m,3H)
Example 5
Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
0.5g of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-acetamidc-1-pyrrolidyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is added to 15ml of ethanol, 10ml of water and 5ml of cone, hydrochloric acid. The reaction mixture is refluxed for 18 hours, cooled and concentrated under a reduced pressure to remove the solvent completely.
The residue is recrystallized in a mixed solvent of ethanol and water to obtain 0.22g of the desired compound.
m.p.: 274-276°C(dec.)
1H NMR(CF3COOD, ppm) : 2.38-2.70(m,2H) , 3.60-4.08(m,2H) , 4.10-4.52(m,3H),
6.24(d,1H.J=4.80Hz), 8.22(d,1H,J=12.82Hz), 8.68-9.00(m,1H),
9.16-9.60(m,3H)
Example 6
Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid
A procedure substantially similar to the procedure in Example 1 is carried out
to prepare the title compound.
m.p. : 225-227ºC(dec.)
1H NMR(CF3COOD, ppm) : 2.38-2.72(m,2H), 3.60-3.98(m,2H), 4.18-4.60(m,3H),
6.26(d,1H,J=4.80Hz), 8.28(d,1H,J=12.82Hz), 8.58-8.84(m, 1H), 9.12-9.52(m,3H)
Example 7
Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound,
m.p. : 273-275ºC(dec.)
1H NMR(CF3COOD, ppm) : 3.42-4.60(m,8H), 8.32(d,1H,J=12.02Hz), 8.60-8.86(m,1H),
9.10-9.58(m,3H)
Example 8
Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound,
m.p. : 275°C
1H NMR(CF3COOD, ppm) : 3.10(s,3H), 3.14-4.10(m,6H) . 4.26-4.92(m,2H) ,
8.30(d,1H,J=12.00Hz), 8.60-8.88(m,1H), 9.20-9.50(m,3H) Example 9
Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound.
m.p. : 277-279ºC(dec.)
1 H NMR(CF3COOD, ppm) : 1.32-1.68(m,3H), 3.32-4.08(m,5H), 4.34-4.84(m,2H),
8.32(d,1H,J=12.02Hz), 8.60-8.90(m,1H) , 9.20-9.50(m,3H)
Example 10
Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthjτidine-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound,
m.p. : 270°C(dec.)
1H NMR(CF3COOD, ppm) : 1.30-1.60(m,6H), 3.32-3.92(m,4H), 4.44-4.92(m, 2H),
8.36(d,1H,J=12.02Hz), 8.62-8.90(m,1H), 9.16-9.52(m,3H) Example 11
Preparation of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound.
m.p. : 269ºC
1H NMR(CF3COOD, ppm) : 2.14-2.84(n,2H) , 3.56-4.64(m,5H), 8.23(d,1H,J=12.04Hz),
8.62-8.96(m,1H), 9.10-9.52(m,3H)
Example 12
Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydrc-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride
0.5g of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is added to 10ml of water and 10ml of cone, hydrochloric acid. The mixture is refluxed for 24 hours, cooled to room
temperature and concentrated under a reduced pressure. The concentrate is added with 20ml of ethanol and stirred at room temperature for 2 hours, filtered and dried. The product is recrystallized in a mixed solvent of water and methanol to obtain 0.39g of the desired compound,
m.p.: >300°C
»H NMR(CF3COOD, ppm) : 3.60-3.80(m,4H), 4.14-4.46(m,4H) , 7.92-8.50(m,3H),
8.70(bs,1H), 9.40(s,1H)
Example 13
Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1.8-naphthyridine-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.
m.p. : 275-277T,
1H NMR(CF3COOD, ppm) : 3.10(s,3H), 3.60-5.00(m,8H) , 7.84-8.50(m,3H), 8.68(bs,1H),
9.38(s,1H)
Example 14
Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound,
m.p. : 268ºC(dec.)
1H NMR(CF3COOD, ppm) : 1.40-1.60(m,3H), 3.50-3.90(m,5H), 4.56-4.80(m,2H),
8.12-8.46(m,3H), 8.74(bs,1H), 9.40(s,1H)
Example 15
Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound,
m.p. : 289°C(dec.)
1H NMR(CF3COOD, ppm) : 1.30-1.64(m,6H), 3.28-4.00(m,4H) , 4.52-4.92(m,2H) ,
7.96-8.48(m,3H), 8.78(bs,1H), 9.40(s,1H)
Example 16
Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride
0.5g of ethyl 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(acetamido-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate is added to 10ml of water and 10ml of cone, hydrochloric acid. The mixture is refluxed for 24 hours, cooled to room temperature and concentrated under a reduced pressure. The concentrate is
added with 20ml of ethanol and dissolved completely. After then. 70ml of ethvl ether is added for precipitation, and then stirred at room temperature for 2 hours, filtered and dried. The product is recrystallized in a mixed solvent of methanol and water to obtain 0.35g of the desired compound
m.p. : 208-210°C
1H NMR(CF3COOD, ppm) : 2.30-2.80(m,2H) , 3.78-4.68(m,5H) , 7.96-8.32(m,3H),
8.70(bs,1H), 9.32(s,1H)
Example 17
Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound,
m.p. : 300°C(dec. )
1H NMR(CF3COOD, ppm) : 3.51-4.05(m,8H), 6.80(d,1H,J=7.60Hz), 7.84-8.21(m,2H),
8.32(d,1H,J=12.04Hz), 8.70(bs,1H) 9.30(s,1H)
Example 18
Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound,
m.p. : > 300°C(dec.)
1H NMR(CF3COOD, ppm) : 3.12(s,3H), 3.28-4.29(m,8H), 6.81(d,1H,J=7.60Hz),
7.84-8.15(m,2H), 8.33(d, 1H,J=12.20Hz), 8.71(bs,1H),
9.29(s,1H)
Example 19
Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound,
m.p. : 295ºC(dec.)
1H NMR(CF3COOD, ppm) : 1.51 (d.3H.J=4.40Hz), 3.23-4.11(m,7H). 6.80(d,1H.J=6.20Hz) ,
7.96-8.16(m,2H), 8.30(d.1H,J=14.00Hz) , 8.69(s,1H),
9.30(s,1H) Example 20
Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3.5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.
m.p. : 297ºC(dec.)
1H NMR(CF3COOD, ppm) : 1.30-1.65(m,6H), 3.10-4.57(m,6H), 6.89(d,1H,J=6.20Hz),
7.93-8.20(m,2H), 8.70(d,1H,J=12.82Hz), 8.48(s,1H),
9.32(s,1H) Example 21
Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 16 is carried out to prepare the title compound.
m.p. : 275°C(dec.)
1H NMR(CF3COOD. ppm) : 2.40-2.73(m.2H), 3.60-4.56(m,5H) . 6.33(d,1H,J=6.20Hz),
7.98-8.37(m,3H), 8.75(s,1H). 9.24(s.1H)
Example 22
Preparation of 1-(5-fluoro-2-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl.]-1.4-dihydro-4-oxoquinoline-3-carboxylic acid hvdrochloride
A procedure substantially similar to the procedure in Example 1 is carried out to prepare the title compound,
m.p. : 268-272ºC(dec. )
1H NMR(CF3COOD. ppm) : 2.40-2.73(m.2H) , 3.60-4.56(m,5H) . 6.33(d.1H,J=6.20Hz),
7.98-8.37(m,3H). 8.75(s.1H). 9.24(s.1H)
Example 23
Preparation of 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(1-piperazinyl)-1.4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.
m.p. : 300ºC(dec.)
1H NMR(CF3COOD, ppm) : 3.76-4.02(m.8H) . 8.00-8.48(m,3H) . 8.68(bs,1H), 9.32(s,1H)
Example 24
Preparation of 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound,
m.p. : 247°C(dec.)
1H NMR(CF3COOD, ppm) : 3.10(s,3H), 3.20-4.00(m,8H), 7.98-8.38(m.3H) , 8.58(bs,1H),
9.30(s,1H)
Example 25
Preparation of 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound,
m.p. : 295°C(dec.)
1H NMR(CF3COOD, ppm) : 1.45-1.60(d,3H, J=3.20Hz) , 3.38-4.02(m,7H), 7.92-8.50(m,3H),
8.70(bs,1H), 9.30(s,1H)
Example 26
Preparation of 1-(5-fluoro-2-pyridyl)-6,8-difluoro-7-(3,5-dimethyl-1-piperazinyl)- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound,
m.p. : 297ºC(dec.)
1H NMR(CF3COOD, ppm) : 1.32-1.60(m,6H), 3.38-3.90(m, 6H) , 7.96-8.41(m,3H) .
8.64(bs,1H), 9.32(ss1H)
Example 27
Preparation of 1-(5-fluorc-2-pyridyl)-6,8-difluoro-7-(3-ammo-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 16 is carried out to prepare the title compound,
m.p. : 275°C(dec.)
1H NMR(CF3COOD. ppm) : 2.40-2.60(m,2H) , 3.98-4.24(m,5H) , 8.08-8.38(m,3H) ,
8.64(s,1H), 9.24(s.1H) Example 28
Preparation of 5-methyl-7-(4-methyl-1-piperazinyl)- 1-(5-fluoro-2-pyridyl)-6-fluoro-1.4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.
m.p. : 262ºC(dec.)
1H NMR(CF3COOD, ppm) : 2.99(s,3H), 3.10(s,3H), 3.15-4.20(m,8H),
6.60(d,1H,J=7.20Hz), 8.02(m,2H), 8.70<s,1H), 9.24(s,1H)
Example 29
Preparation of 5-methyl-7-(3-methyl-1-piperazinyl)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hvdrochloride
A procedure substantially similar to the procedure in Example 12 is carried out to prepare the title compound.
m.p. : 276ºC(dec.)
1H NMR(CF3COOD, ppm) : 1.60(d,3H.J=6.00Hz), 2.97(s,3H), 3.15-4.21(m.7H),
6.60(d,1H,J=8.00Hz), 8.40(m,2H), 8.65(s,1H), 9.25(s,1H)
The in vitro antibiotic activity of the present compound is measured using 2-fold dilution method with a micro-well plate and the bacteria are inoculated in about 105 cfu/ml after an overnight culture in a brain-heart infusion(BHI) broth at 37ºC The novel compounds of the present invention are converted to a hvdrochloride salt form and diluted with a sterilized distilled water to make 10mg/ml aqueous solution. After the mother liquor wherein the compound is diluted to the two-fold
concentration has been obtained in the form of an aqueous solution, the respective 0.1ml of diluted liquor is transferred to a well and is inoculated with 0.1ml of the culture fluid to make about (105-106)/2 cfu/ml.
After cultivation at 37ºC, the minimum inliibitory concentration(MIC) is measured and recorded in Table I-V.
Table I -V show the minimum inhibitory concentrations(MIC).
Acinetobacter calcoaceticus ATCC 19606
Citrobacter freundii ATCC 8090
Enterobacter aerogenes ATCC 13048
Enterobacter cloacae ATCC 23355
Escherichia coli ATCC 25922
Haemophilus influenza ATCC 35056
Klebsiella pneumoniae ATCC 13883
Proteus vulgaris ATCC 13315
Pseudomonas aeruginosa ATCC 27853
Salmonella typhimurium ATCC 14028
Shigella flexneri ATCC 12022
Shigella sonnei ATCC 25931
Serratia marcescens ATCC 8100
Streptococcus faecal is ATCC 19433
Streptococcus faecalis ATCC 29212
Streptococcus pneumoniae ATCC 6303
Streptococcus pyrogens ATCC 19615
The pharmacokinetic properties are tested by orallv administrating and subcutaneously injecting a test compound and a substance for control to a ICR Mouse with 22g±10% weight, drawing blood after 10, 20, 30, 45, 60, 90, 120, 150, 180 and 240 minutes and analyzed by Bio-Assay(Agar well method).
The average values from four tests for each compound are recorded in the following Table VI.
Claims
What is claimed is : 1. Quinolone carboxylic acid derivatives of the formula (I), their
pharmaceutically acceptable salts and their hydrates.
Wherein X is a hydrocarbon, fluorocarbon or nitrogen atom,
Y is a hydrogen or methyl group,
R1 is a hydrogen or alkyl group having 1 to 5 carbon atom,
R2 is (wherein A and B is a fluorocarbon or nitrogen
atom, provided that, if A=CF, B=N and if A=N, 
B=CF) and R3 is (wherein R4 is an amino group which makes a racemate 
or (S)-enantiomer) or (wherein R5, R6 and R7 are respectively hydrogen or alkyl group having 1 to 3 carbon atom.).
2. The compound as claimed in claim 1. corresponding to the following formula (IA), wherein R3 is piperazine derivatives
3. The compound as claimed in claim 1, corresponding to the following formula (IB), wherein R3 is pyrolidine derivatives
4. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxo- l,8-naphthyridine-3-carboxylic acid, according to claim 2.
5. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylic acid, according to claim 2.
6. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, according to claim 2.
7. 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, according to claim 2.
8. 5-methyl-7-(4-methyl-1-piperazinyl)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4-dihydro- 4-oxoquinoline-3-carboxylic acid, according to claim 2.
9. 5-methyl-7-(3-methyl-1-piperazinyl)-1-(5-fluoro-2-pyridyl)-6-fluoro-1,4-dihydro- 4-oxoquinoline-3-carboxylic acid, according to claim 2.
10. 1-(3-fluoro-4-pyridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl]-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, according to claim 3.
11. 1-(5-fluoro-2-pvridyl)-6-fluoro-7-[(3S)-3-amino-1-pyrrolidinyl]-1.4-dihydro-4- oxoquinoline-3-carboxylic acid, according to claim 3.
12. A process for preparing the compound of the formula (I) and its
pharmaceutically acceptable salts, which comprises the condensation of the compound of the formula (II) and the compound of the formula (VI) in a solvent in the presence of an acid-acceptor
wherein X, Y, Z, R1 , R2 and R3 are each as described in the claim 1.
13. The process according to claim 12, wherein the acid-acceptor is selected from the group consisting of tertiary amines including pyridine, triethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene and alkali metal carbonates including potassium carbonate, or an excess of the compound of the formula (VI) which is a reactant; and the solvent is selected from the group consisting
of pyridine, acetonitrile and N,N-dimethylformamide; and the reaction mixture consisting of 1 to 3 mo1 of the compound of the formula(VI) per 1 mol of the compound of the formula (II) is subjected to a condensation at a temperature from 0°C to 150°C depending on the kind of the mother nucleus.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU58666/94A AU679961B2 (en) | 1993-08-13 | 1994-01-21 | Novel quinolone carboxylic acid derivatives |
| BR9407283A BR9407283A (en) | 1993-08-13 | 1994-01-21 | Derivatives of quinolonic carboxylic acid and preparation process |
| JP7506869A JP2758722B2 (en) | 1993-08-13 | 1994-01-21 | New quinolone carboxylic acid derivatives |
| DE69424052T DE69424052T2 (en) | 1993-08-13 | 1994-01-21 | NEW CHINOLON CARBONIC ACID DERIVATIVES |
| EP94904772A EP0713487B1 (en) | 1993-08-13 | 1994-01-21 | Novel quinolone carboxylic acid derivatives |
| CA002168764A CA2168764C (en) | 1993-08-13 | 1994-01-21 | Novel quinolone carboxylic acid derivatives |
| AT94904772T ATE191911T1 (en) | 1993-08-13 | 1994-01-21 | NEW QUINOLOONECARBONIC ACID DERIVATIVES |
| US08/193,475 US5496947A (en) | 1993-08-13 | 1994-02-08 | Quinolone carboxylic acid derivatives |
| FI960634A FI960634A (en) | 1993-08-13 | 1996-02-12 | New quinolone carboxylic acid derivatives |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1993/15724 | 1993-08-13 | ||
| KR1019930015724A KR0169500B1 (en) | 1993-08-13 | 1993-08-13 | Novel quinolone carboxylic acid derivatives and their preparation method |
| US08/193,475 US5496947A (en) | 1993-08-13 | 1994-02-08 | Quinolone carboxylic acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1995005373A1 true WO1995005373A1 (en) | 1995-02-23 |
Family
ID=26629827
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR1994/000006 WO1995005373A1 (en) | 1993-08-13 | 1994-01-21 | Novel quinolone carboxylic acid derivatives |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US5496947A (en) |
| EP (1) | EP0713487B1 (en) |
| JP (1) | JP2758722B2 (en) |
| CN (1) | CN1041202C (en) |
| AU (1) | AU679961B2 (en) |
| BR (1) | BR9407283A (en) |
| CA (1) | CA2168764C (en) |
| FI (1) | FI960634A (en) |
| HU (1) | HU216803B (en) |
| WO (1) | WO1995005373A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0911327A4 (en) * | 1995-09-22 | 1999-04-28 | ||
| EP1193266A1 (en) * | 1999-07-01 | 2002-04-03 | Wakunaga Pharmaceutical Co., Ltd. | Quinolinecarboxylic acid derivative or salts thereof |
| EP2275141A1 (en) | 1999-03-17 | 2011-01-19 | Daiichi Pharmaceutical Co., Ltd. | Tastemasked pharmaceutical compositions |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4342186A1 (en) * | 1993-12-10 | 1995-06-14 | Bayer Ag | One-pot process for the production of 3-quinolonecarboxylic acid derivatives |
| AU7940598A (en) | 1997-06-26 | 1999-01-19 | Dong Wha Pharmaceutical Industrial Co., Ltd. | Quinolone carboxylic acid derivatives |
| US20050239061A1 (en) * | 2000-03-01 | 2005-10-27 | Marshall William S | Identification and use of effectors and allosteric molecules for the alteration of gene expression |
| ES2320360T3 (en) * | 2004-08-13 | 2009-05-21 | Schering-Plough Ltd. | PHARMACEUTICAL FORMULATION THAT INCLUDES AN ANTIBIOTIC, A TRIAZOL AND A CORTICOSTEROID. |
| WO2016198342A1 (en) | 2015-06-09 | 2016-12-15 | Bayer Pharma Aktiengesellschaft | Positive allosteric modulators of muscarinic m2 receptor |
| JP2019524722A (en) | 2016-07-11 | 2019-09-05 | バイエル・ファルマ・アクティエンゲゼルシャフト | 7-substituted 1-pyridyl-naphthyridine-3-carboxylic acid amides and uses thereof |
| EP3296298A1 (en) * | 2016-09-14 | 2018-03-21 | Bayer Pharma Aktiengesellschaft | 7-substituted 1-aryl-naphthyridin-3-carboxamides and their use |
| JOP20190045A1 (en) | 2016-09-14 | 2019-03-14 | Bayer Ag | 7-substituted 1-aryl-naphthyridine-3-carboxylic acid amides and use thereof |
| PT3512849T (en) * | 2016-12-06 | 2021-09-08 | Bayer Pharma AG | 7-substituted 1-aryl-naphthyridine-3-carboxylic acid amides and use thereof |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0911327A4 (en) * | 1995-09-22 | 1999-04-28 | ||
| EP0911327A1 (en) * | 1995-09-22 | 1999-04-28 | Wakunaga Pharmaceutical Co., Ltd. | Novel pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising the same as the active ingredient |
| US5998436A (en) * | 1995-09-22 | 1999-12-07 | Wakunaga Pharmaceuticals Co., Ltd. | Pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising the same as the active ingredient |
| EP0992501A2 (en) * | 1995-09-22 | 2000-04-12 | Wakunaga Pharmaceutical Co., Ltd. | Pyridonecarboxylic acid derivatives as antibacterial agents |
| US6133284A (en) * | 1995-09-22 | 2000-10-17 | Wakunaga Pharmaceutical Co., Ltd. | Pyridonecarboxylic acid derivatives or their salts, and antibacterial agents containing the same as their effective components |
| US6156903A (en) * | 1995-09-22 | 2000-12-05 | Wakunaga Pharmaceutical Co., Ltd. | Pyridonecarboxylic acid derivatives or their salts, and antibacterial agents containing the same as their effective components |
| EP0992501A3 (en) * | 1995-09-22 | 2001-09-05 | Wakunaga Pharmaceutical Co., Ltd. | Pyridonecarboxylic acid derivatives as antibacterial agents |
| CN1105715C (en) * | 1995-09-22 | 2003-04-16 | 涌永制药株式会社 | Novel pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising same as active ingredient |
| EP2275141A1 (en) | 1999-03-17 | 2011-01-19 | Daiichi Pharmaceutical Co., Ltd. | Tastemasked pharmaceutical compositions |
| EP1193266A1 (en) * | 1999-07-01 | 2002-04-03 | Wakunaga Pharmaceutical Co., Ltd. | Quinolinecarboxylic acid derivative or salts thereof |
| EP1193266A4 (en) * | 1999-07-01 | 2002-08-14 | Wakunaga Pharma Co Ltd | Quinolinecarboxylic acid derivative or salts thereof |
| US6858625B1 (en) | 1999-07-01 | 2005-02-22 | Wakunaga Pharmaceutical Co., Ltd. | Quinolinecarboxylic acid derivative or salts thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0713487A1 (en) | 1996-05-29 |
| JPH09500143A (en) | 1997-01-07 |
| CA2168764A1 (en) | 1995-02-23 |
| US5496947A (en) | 1996-03-05 |
| AU5866694A (en) | 1995-03-14 |
| BR9407283A (en) | 1996-10-01 |
| CN1041202C (en) | 1998-12-16 |
| CA2168764C (en) | 2000-01-18 |
| EP0713487B1 (en) | 2000-04-19 |
| JP2758722B2 (en) | 1998-05-28 |
| FI960634A0 (en) | 1996-02-12 |
| CN1128995A (en) | 1996-08-14 |
| HU216803B (en) | 1999-08-30 |
| AU679961B2 (en) | 1997-07-17 |
| HUT75640A (en) | 1997-05-28 |
| FI960634A (en) | 1996-02-12 |
| HU9600322D0 (en) | 1996-04-29 |
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