CN1038326C - 5-aminoquinolone carboxylic acid derivative and antibacterial agent containing the same as active ingredient - Google Patents
5-aminoquinolone carboxylic acid derivative and antibacterial agent containing the same as active ingredient Download PDFInfo
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- CN1038326C CN1038326C CN93108977A CN93108977A CN1038326C CN 1038326 C CN1038326 C CN 1038326C CN 93108977 A CN93108977 A CN 93108977A CN 93108977 A CN93108977 A CN 93108977A CN 1038326 C CN1038326 C CN 1038326C
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Abstract
The present invention relates to a 5-aminoquinolone carboxylic acid derivative expressed by the general formula (1) (disclosed in the specification) or the salt thereof, and an antimicrobial agent using the derivative or the salt thereof as an active ingredient. The derivative or the salt thereof has strong antibacterial activity on gram-positive bacteria comprising drug resistant bacteria, and can be absorbed in organisms with satisfaction.
Description
The present invention relates to a kind of novel 5-aminoquinolone carboxylic acid derivative or its salt, they have fabulous anti-microbial activity to Gram-negative bacteria and the gram-positive microorganism of the bacterium that comprises drug resistance, and a kind of antiseptic-germicide that contains such derivative or salt as activeconstituents.
The phonetic acid of synthetic antibacterial agents such as nalidixic acid and Pyrrolizidine is commonly referred to as therapeutic agent for infections so far.But these therapeutical agents have a shortcoming: they are relatively poor to the effect of stubborn disease such as the infection of green pus bacterium.
Simultaneously, developed the Carbostyril carboxylic acid derivatives of fluorine atom, as norfloxacin, ofloxacin, cyprofloxacin and spafloxacin, because they have strong anti-microbial activity and be widely used in clinical Gram-negative bacteria the 6th replacement.
But, because traditional synthetic antibacterial agents specific absorption in vivo is low, so they have the low shortcoming of bioavailability, and they also have to gram-positive microorganism particularly the bacterium of drug resistance as anti-2, the low shortcoming of anti-microbial activity of the streptococcus aureus of 6-dimethoxy phenyl penicillin.
So an object of the present invention is to provide a kind ofly has strong anti-microbial activity to Gram-negative bacteria and gram-positive microorganism (bacterium that comprises drug resistance) both, also has the antiseptic-germicide of good absorption rate simultaneously.
In view of these former situations, the inventor has synthesized a large amount of Carbostyril derivatives, has studied their anti-microbial activity and specific absorption in vivo.Therefore, find to compare with traditional Carbostyril carboxylic acid derivatives with the 5-aminoquinolone carboxylic acid derivative (they will be described below) and the salt thereof of general formula (1) expression, to gram-positive microorganism particularly the bacterium of drug resistance very high anti-microbial activity is arranged, simultaneously Gram-negative bacteria is kept the excellent antibiotic activity, they also have fabulous specific absorption, thereby obtain the present invention.
The present invention relates to 5-aminoquinolone carboxylic acid derivative or its salt of the following general formula of a kind of usefulness (I) expression, and contain such derivative or salt antiseptic-germicide as activeconstituents:
R wherein
1For hydrogen atom, amino, the straight or branched alkyl of 1～5 carbon atom is arranged and contains the alkylamino of the straight or branched alkyl of 1～5 carbon atom, R
2For hydrogen atom or the straight or branched alkyl of 1～5 carbon atom is arranged, X is a halogen atom, and Y is CH
2, NH, CHR
3, NR
3(R
3For straight or branched alkyl that 1～5 carbon atom is arranged or Sauerstoffatom and Z are Sauerstoffatom or two hydrogen atoms.
Represent with general formula (1) according to 5-aminoquinolone carboxylic acid derivative of the present invention.In the formula, there is the example of the straight or branched alkyl of 1～5 carbon atom to comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl and n-pentyl.
Example according to the salt of The compounds of this invention (1) comprises an alkali metal salt, inorganic acid salt and organic acid salt.More particularly, basic metal comprises lithium salts, sodium salt and sylvite etc.Inorganic acid salt comprises hydrochloride, vitriol, nitrate, hydrobromate, phosphoric acid salt etc.Organic acid salt comprises acetate, fumarate, maleate, lactic acid salt, succinate, Citrate trianion, malate, oxalate, mesylate, benzene sulfonate, tosilate etc.
Compound of the present invention (1) can be pressed reaction scheme and pass through compound (3) and compound (2) prepared in reaction:
R wherein
1, R
2,, X, Y and Z each have and the as above implication of regulation.
Initial compounds (2) used in the aforesaid method is a kind of compound known, and for example it can prepare by Japanese Patent 201869/1987 or 187459/1987 method of describing.Compound (3) also can prepare in accordance with known methods, for example the method for the 630th page of (1984) description of " Journal of the American Chemical Society " the 106th volume.
In order to prepare compound of the present invention (1) by compound (2) and (3), every mole compound (2) only needs to use 1～5 mole compound (3), allow them at room temperature or under refluxing, in solvent such as acetonitrile, methyl-sulphoxide, dimethyl formamide, hexamethylphosphoramide, pyridine or 1-Methyl-2-Pyrrolidone, reacted 1～10 hour.After reacting completely, obtain thick product with the precipitation of filtering generation or the method for evaporating solvent.With the resulting thick product of the method purifying of silica gel column chromatography or recrystallization, thereby must be listed as compound of the present invention (1) straight product.
If need, use this professional known method as mentioned above, can change into salt according to the resulting compound of the present invention (1), for example an alkali metal salt, inorganic acid salt and organic acid salt.
When resulting compound (1) was used as antiseptic-germicide, its dosage was according to administration patient's variations such as body weight, age, sex, prescribe medicine method, physical qualification and ill situation.But for oral, dosage is preferably about 100～800 mg/day, or for administered parenterally, dosage is preferably about 5～40 mg/day.
Compound of the present invention (1) can be made various forms of antiseptic-germicides such as tablet, granula, pulvis, capsule, suspension, injection and suppository by usual method.In order to produce solid preparation, preferably add vehicle, also but adding additives, disintegrating agent, lubricant, tinting material, spices, weighting agent, coating, sugar-coat are waited until in the compound (1) as required, make the mixture of generation be shaped as tablet, granula, pulvis, capsule, suppository etc. then.Under the situation of preparation injection, only compound (1) need be dissolved, disperseed or be emulsified in matchmaker's liquid of water for injection or only need make the injection powder, so that it is dissolved in the water for injection when using.The medication of injection comprises intravenously administrable, artery administration, anum administration, intraperitoneal administration, muscle administration and subcutaneous administration.
Hereinafter will the present invention be described in more detail with following embodiment and experimental example.But, should be kept in mind that the present invention is not limited in these embodiment or is limited by these embodiment.
Embodiment 1
(R)-and 5-amino-7-(3-amino-2,3,4,5,6,7-hexahydro-1 H-azepines-1-yl)-1-cyclopropyl-6,8-two fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (compound 1-1):
With 100 milligrams of (0.34 mmole) 5-amino-1-cyclopropyl-6,7,8-three fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (2-1) and 114 milligrams (1.0 mmole) (R)-heating 3 hours under refluxing of the suspension of 3-amino-hexahydro-1 H-azepines in acetonitrile.After the suspension cooling, with filtering method collecting precipitation.The thick product that generates mixes recrystallization the molten profit from chloroform and alcoholic acid, obtains 52 milligrams of desired compounds of (productive rate 39%) the present invention (1-1).
Pale yellow powder (CHCl
3-EtOH);
Fusing point: 235～238 ℃ of (decomposition) IR (KBr): 3475,2940,1630cm
-1 1H-NMR (D
2O+NaOD) δ: 0.65-1.89 (10H, m), 2.83-3.48 (5H, m),
3.68(1H，m)，8.27(1H，s).
Embodiment 2
5-amino-1-cyclopropyl-6,8-two fluoro-7-(2,3,4,5,6,7-six hydrogen-1H-1,4-two azepines-5-carbonyl-1-yl)-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (compound 1-2)
With 100 milligrams of (0.34 mmole) compounds (2-1) and 114 milligrams of (1.0 mmoles) 2,3,4,5,6,7-six hydrogen-1H-1, the 4-two azepines-5-ketone suspension (2 milliliters) in hexamethylphosphoramide (HMPA) heated 4 hours down at 100 ℃ in oil bath.The product that generates carries out suction filtration, washs with ether, and recrystallization from chloroform and ethanol mixed solvent obtains 68 milligrams of desired compounds of (productive rate 51%) the present invention (1-2) then.
Yellow needles (CHCl
3-EtOH);
Fusing point:＞300 ℃; IR (KBr): 3410,1725,1630cm
-1 1H-NMR (DMSO-d
6) δ: 0.98-1.13 (4H, m), 2.55-2.74 (2H, m),
3.25-3.52(7H，m)，4.02(1H，m)，
7.27(2H，brs)，7.71(1H，brs)，8.51(1H，s).
Embodiment 3
Obtain following compound (compound 1-3 to 1-8) with the reaction that is similar to embodiment 1 or 2.
Compound (1-3): 5-amino-1-cyclopropyl-6,8-two fluoro-7-(2,3,4,5,6,7-hexahydro-1 H-azepines-1-yl)-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid:
Yellow small pieces (CHCl
3-EtOH);
Fusing point: 234～236 ℃; IR (KBr): 3455,2940,1710,1635cm
-1 1H-NMR (CDCl
3) δ: 0.90-1.25 (4H, m), 1.50-1.90 (8H, m),
3.35-3.58(4H，m)，3.92(1H，m)，4.90(2H，brs)，
8.62(1H，s).
Compound (1-4):
5-amino-1-cyclopropyl-6,8-two fluoro-7-(3,3,5-trimethylammonium-2,3,4,5,6,7-hexahydro-1 H-azepines-1-yl)-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid:
Yellow small pieces (Et
2The O-hexane) fusing point: 148.5～150 ℃; IR (KBr): 3450,2950,1715,1630cm
-1 1H-NMR (CDCl
3) δ: 0.79-1.43 (15H, m), 1.62-1.80 (2H, m),
2.09(1H，br)，3.12-3.53(4H，m)，3.93(1H，m)，
5.17(2H，brs)，8.63(1H，s).
Compound (1-5):
(S)-and 5-amino-7-(3-amino-2,3,4,5,6,7-hexahydro-1 H-azepines-1-yl)-1-cyclopropyl-6,8-two fluoro-1,4-dihydro-4-oxidation quinoline-3-carboxylic acid:
Pale yellow powder (CHCl
3-EtOH)
Fusing point: 249-252 ℃ (decomposition); IR (KBr): 3475,2940,1635cm
-1 1H-NMR (D
2O+NaOD) δ: 0.62-1.91 (10H, m), 2.75-3.45 (5H, m),
3.66(1H，m)，8.31(1H，s).
Compound (1-6):
5-amino-7-(3-amino-2,3,4,5,6,7-hexahydro-1 H-azepines-1-yl)-1-cyclopropyl-6,8-two fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid:
Pale yellow powder (CHCl
3-EtOH)
Fusing point: 245～248 ℃ (decomposition); IR (KBr): 3475,2940,1635cm
-1 1H-NMR (D
2O+NaOD) δ: 0.70-1.84 (10H, m), 2.80-3.48 (5H, m),
3.70(1H，m)，8.28(1H，s).
Compound (1-7):
5-amino-1-cyclopropyl-6,8-two fluoro-7-(4-ethyl-2,3,4,5,6,7-six hydrogen-1H-1,4-two azepines-5-carbonyl-1-yl)-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid:
Yellow needles (CHCl
3-EtOH)
Fusing point: 276～278 ℃; IR (KBr): 3420,3290,1725,1630cm
-1 1H-NMR (CDCl
3) δ: 1.03-1.30 (7H, m), 2.79-2.95 (2H, m),
3.36-3.69(8H，m)，3.92(1H，m)，5.17(2H，brs)，
8.65(1H，s).
Compound (1-8):
5-amino-1-cyclopropyl-6,8-two chloro-7-(4-methyl-2,3,4,5,6,7-six hydrogen-1H-1,4-two azepines-5-carbonyl-1-yl)-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid:
Yellow powder (CHCl
3-EtOH)
Fusing point: 281～283 ℃: IR (KBr): 3430,3305,1725,1635cm
-1 1H-NMR (CDCl
3) δ: 1.05-1.30 (4H, m), 2.85-2.90 (2H, m),
3.07(3H，s)，3.40-3.75(6H，m)，3.93(1H，m)，
6.50(2H，brs)，8.66(1H，s).
Embodiment 4
5-amino-7-(3-amino-2,3,4,5,6,7-hexahydro-1 H-azepines-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-Oxoquinoline-3-hydroxy acid (compound 1-9):
With 100 milligrams of (0.32 mmole) 5-amino-8-chloro-1-cyclopropyl-6,7-two fluoro-4-Oxoquinoline-3-carboxylic acids (2-2) and 114 milligrams of (1.0 mmole) DL-3-amino-hexahydro-1 H-azepines are suspended in 5 milliliters of acetonitriles, and the suspension of generation heated 5 hours under refluxing.After the suspension cooling, with filtering method collecting precipitation, recrystallization from acetonitrile obtains 32 milligrams of desired compounds of (productive rate 25%) the present invention (1-9) then.
Pale yellow powder (CH
3CN);
Fusing point: 145～147 ℃); IR (KBr): 1627cm
-1 1H-NMR (DMSO-d
6) δ: 0.88-1.20 (4H, m), 1.40-1.90 (6H, m),
2.80-3.30(5H，m)，4.15-4.40(1H，m)，
4.70(2H，brs)，6.36(2H，brs)，8.65(1H，s).
Embodiment 5
Reaction with similar embodiment 4 obtains following compound (compound 1-10 to 1-12).
Compound (1-10):
5-amino-8-chloro-1-cyclopropyl-6-fluoro-7-(2,3,4,5,6,7-six hydrogen-1H-1,4-two azepines-5-carbonyl-1-yl)-4-Oxoquinoline-3-carboxylic acid:
Yellow spicule (CHCl
3EtOH)
Fusing point: 265～268 ℃ (decomposition); IR (KBr): 1715,1650,1625cm
-1 1H-NMR (DMSO-d
6) δ: 0.80-1.25 (4H, m), 2.55-2.70 (2H, m),
3.20-3.40(6H，m)，4.10-4.40(1H，m)，
7.57(2H，brs)，8.67(1H，s).
Compound (1-11):
R-5-amino-7-(3-amino-2,3,4,5,6,7-hexahydro-1 H-azepines-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-Oxoquinoline-3-carboxylic acid:
Pale yellow powder (CH
3CN);
Fusing point: 146～149 ℃:
1H-NMR (DMSO-d
6) δ: 0.80-1.20 (4H, m), 1.40-1.90 (6H, m),
2.60-3.30(5H，m)，4.10-4.40(1H，m)，
4.70(2H，brs)，7.52(2H，brs)，8.65(1H，s).
Compound (1-12):
S-5-amino-7-(3-amino-2,3,4,5,6,7-hexahydro-1 H-azepines-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-Oxoquinoline-3-carboxylic acid:
Pale yellow powder (CH
3CH);
Fusing point: 208～211 ℃ (decomposition); IR (KBr): 1636cm
-1 1H-NMR (DMSO-d
6) δ: 0.78-1.22 (4H, m), 1.40-1.95 (6H, m),
2.60-3.40(5H，m)，4.10-4.40(1H，m)，
5.50(2H，brs)，7.54(2H，brs)，8.64(1H，s).
Experimental example 1:
Antibacterial tests:
Table the anti-microbial activities of various microorganisms is measured according to the MIC measuring method of Japanese chemotherapy association shown in the 1-3.The sparfolxacin China fir compares agent.Test-results is listed table 1-3 in.
Medium: Mueller Hinton Medium
Diluted sample:
Every milliliter of solution that 1000 microorganisms are arranged of preparation in 25% dimethyl sulfoxide (DMSO).Prepare a series of solution that different concns (100 microorganism to 0.006 microorganisms) arranged with sterilized water by the method for 1/2 times of diluting soln in turn.
The quantity of inoculation bacterium: 10
6Individual/milliliter
Culture condition: 37 ℃, 48 hours
Measure: after 24 hours.
Industrial usability
5-amino-Carbostyril carboxylic acid derivatives of the present invention exists to the bacterium that comprises drug resistance Interior gram-positive bacteria has strong antibacterial activity, also keeps simultaneously Gram-negative bacteria is had Good antibacterial activity, and absorbed satisfactorily in vivo, so they are used for various The prevention of clinical communicate illness and treatment.
Table 1
| Test strain | MIC(μg/ml) | |||
| Compound N o. (1-2) | Compound N o. (1-8) | Compound N o. (1-10) | Spafloxacin | |
| Gram-positive bacteria 1. hay bacillus ATCC 6633 | 0.006 | 0.006 | 0.012 | 0.024 |
| 2. staphylococcus aureus FDA 209P | 0.012 | 0.006 | 0.012 | 0.024 |
| 3. staphylococcus aureus Terashima | 0.05 | 0.05 | 0.10 | 0.10 |
| 4. staphylococcus aureus Smith | 0.006 | 0.012 | 0.006 | 0.05 |
| 5. MRSE ATCC 12228 | 0.05 | 0.10 | 0.024 | 0.20 |
| 6. sarcina lutea ATCC 9341 | 0.39 | 0.39 | 0.20 | 1.56 |
| 7. streptococcus fecalis IFO 12964 | 0.20 | 0.20 | 0.20 | 0.39 |
| 8.Micrococcus lysodeikticus IFO 3333 | 0.05 | 0.10 | 0.05 | 0.39 |
Table 2
| Test strain | MIC(μg/ml) | |||
| Compound N o. (1-2) | Compound N o. (1-8) | Compound N o. (1-10) | Spafloxacin | |
| Gram-negative bacteria 9. Escherichia coli o-1 | 0.05 | 0.10 | 0.10 | 0.012 |
| 10. Escherichia coli k-12 | 0.05 | 0.10 | 0.10 | 0.012 |
| 11. typhoid bacillus TD | 0.05 | 0.10 | 0.10 | 0.006 |
| 12. paradysenteriae Bacillus 2b | 0.006 | 0.006 | 0.006 | 0.006 |
| 13. Pseudomonas aeruginosa IFO 13736 | 3.13 | 3.13 | 6.25 | 0.78 |
| 14. Pseudomonas aeruginosa p2 | 6.25 | 12.5 | 12.5 | 1.56 |
| 15. Pseudomonas aeruginosa IFO 12582 | 3.13 | 6.25 | 3.13 | 1.56 |
| 16. pneumobacillus ATCC 10031 | 0.006 | 0.006 | 0.05 | 0.006 |
| 17. pneumobacillus IFO 13541 | 0.05 | 0.10 | 0.10 | 0.012 |
| 18. proteus OXK | 0.05 | 0.10 | 0.20 | 0.05 |
| 19. chi mycetozoan | 0.39 | 0.39 | 0.78 | 0.10 |
| 20. Bacterium prodigiosum | 0.78 | 1.56 | 1.56 | 0.20 |
Table 3
| Test strain | MIC(μg/ml) | |||
| Compound N o. (1-2) | Compound N o. (1-8) | Compound N o. (1-10) | Spafloxacin | |
| Anti-2, the staphylococcus aureus (MRSA) of 6-dimethoxy phenyl penicillin, gram-positive bacteria 21.M.R. staphylococcus aureus 395 | 0.05 | 0.05 | 0.024 | 0.10 |
| 22.M.R. staphylococcus aureus 415 | 0.024 | 0.024 | 0.012 | 0.05 |
| 23.M.R. staphylococcus aureus 419 | 0.024 | 0.024 | 0.024 | 0.05 |
| 24.M.R. staphylococcus aureus 420 | 0.05 | 0.05 | 0.012 | 0.10 |
| 25.M.R. staphylococcus aureus 421 | 0.012 | 0.024 | 0.024 | 0.05 |
Claims (2)
1. one kind with the 5-aminoquinolone carboxylic acid derivative of following general formula (1) expression or its salt:
R wherein
1For hydrogen atom, amino, the straight or branched alkyl of 1～5 carbon atom is arranged and contains the alkylamino of the straight or branched alkyl of 1～5 carbon atom, R
2For hydrogen atom or the straight or branched alkyl of 1～5 carbon atom is arranged, X is a halogen atom, and Y is CH
2, NH, CHR
3, NR
3(R
3For the straight or branched alkyl of 1～5 carbon atom is arranged) or Sauerstoffatom and Z be Sauerstoffatom.
2. one kind contains just like the 5-aminoquinolone carboxylic acid derivative shown in the claim 1 or its salt antiseptic-germicide as activeconstituents.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93108977A CN1038326C (en) | 1993-07-20 | 1993-07-20 | 5-aminoquinolone carboxylic acid derivative and antibacterial agent containing the same as active ingredient |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93108977A CN1038326C (en) | 1993-07-20 | 1993-07-20 | 5-aminoquinolone carboxylic acid derivative and antibacterial agent containing the same as active ingredient |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1097750A CN1097750A (en) | 1995-01-25 |
| CN1038326C true CN1038326C (en) | 1998-05-13 |
Family
ID=4987411
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93108977A Expired - Fee Related CN1038326C (en) | 1993-07-20 | 1993-07-20 | 5-aminoquinolone carboxylic acid derivative and antibacterial agent containing the same as active ingredient |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1038326C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012264A (en) * | 2012-12-25 | 2013-04-03 | 常州市亚邦医药研究所有限公司 | Method for resolving 3-substituted amino-hexahydro-1H-azacycloheptane |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4795751A (en) * | 1985-10-29 | 1989-01-03 | Dainippon Pharmaceutical Co., Ltd. | 5-substituted-6,8-difluoroquinolines useful as antibacterial agents |
| EP0493608A1 (en) * | 1990-07-19 | 1992-07-08 | Ss Pharmaceutical Co., Ltd. | Quinolonecarboxylic acid derivative |
-
1993
- 1993-07-20 CN CN93108977A patent/CN1038326C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4795751A (en) * | 1985-10-29 | 1989-01-03 | Dainippon Pharmaceutical Co., Ltd. | 5-substituted-6,8-difluoroquinolines useful as antibacterial agents |
| EP0493608A1 (en) * | 1990-07-19 | 1992-07-08 | Ss Pharmaceutical Co., Ltd. | Quinolonecarboxylic acid derivative |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012264A (en) * | 2012-12-25 | 2013-04-03 | 常州市亚邦医药研究所有限公司 | Method for resolving 3-substituted amino-hexahydro-1H-azacycloheptane |
| CN103012264B (en) * | 2012-12-25 | 2018-01-19 | 常州亚邦制药有限公司 | The method for splitting of 3 substituted-amino hexahydro 1H azepans |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1097750A (en) | 1995-01-25 |
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