前苏联专利SU1442075A3 Method of producing derivatives of 1,8-naphthyridin or salts thereof

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专利摘要:
NEW MATERIAL:The compound of formula I (X is halogen; R<1> and R<2> are H, lower alkyl or R<1> and R<2> together form a 3-7-membered ring; R<3> is H or lower alkyl; R<4> is lower alkyl, R<5> is lower alkyl, alkenyl or cycloalkyl). EXAMPLE:7-( 3-Amino-4-methyl-1-pyrrolidinyl )-1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid. USE:An antibacterial agent. PREPARATION:The compound of formula I can be prepared by reacting the pyrrolidine derivative of formula III with the carboxylic acid of formula II (Z is functional group which can be substituted with said pyrrolidine derivative) or its ester, in a solvent such as ethanol, acetonitrile, etc. at 20-180 deg.C.
公开号:SU1442075A3
申请号:SU853884501
申请日:1985-04-29
公开日:1988-11-30
发明作者:Мацумото Дзюн-Ити；Накамура Синити；Миямото Теруюки；Уно Хитоси
申请人:Дайниппон Фармасьютикал Ко., Лтд. (Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of new 1,8-naphthyridine derivatives of the general formula
soon
RI-NH
where RYjRj and R are the same or different and each represents hydrogen or (Cf-C,; -) - alkyl, or their sodas, which have bactericidal activity and can be used in medicine.
The aim of the invention is a method for producing new 1,8-naphthyridine derivatives having a higher activity than structural analogues having the same kind of activity.
Example 1. T- (3-Amino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride (1).
2-GB- (3-acetylamino-1-pyrrolidinyl) -2-chloro-5-fluoro-nicotinoyl J-3-cyclopropylaminoacrylic acid ethyl ester (0.4 g) in dioxane (5 ml) is stirred for 30 minutes at room temperature. - temperature with 60% sodium hydride (45 mg). After distilling off the solvent under reduced pressure, water is added to the residue and the mixture is extracted with chloroform. Extracts are dried with sodium sulfate yad. After distilling off the solvent, the residue is recrystallized from ethanol to give 7- (3-acetyl-amino-1-pyrrolidinyl) -1-cyclop ethyl ester-6-ft or-1,4-dihydro-4-oxo-1 B ethyl ester - naphthyridine-3- carboxylic acid (0.25 g), mp, 246-248 s.
A mixture of the indicated ester (0.25 g) and 20% hydrochloric acid (5 ml) was heated under reflux for 10 hours. The solvent was distilled off under reduced pressure, and ethanol was added to the residue. The precipitate was filtered off and 0.19 g of compound (1) was obtained. M.p. 275-280 ° С (decomp.)
Example 2. 1-Cyclopropyl-6-fluoro-7- (3-methylamino-1-pyrrolidinyl) 1,4-dihydro-4-oxo-1,8-naphthyridine 3-carboxylic acid hydrochloride (2)
2- {6- 3- (L-acetylmethylamino) -1-pyrrolidinyl 2-chloro-5 ethyl ester
five
0
five
thirty
0
40
five
five
D5
0
Fluoronicotinoyl-3-cyclopropylaminoacrylic acid (2.5 g) in tetrahydrofuran (10 ml) is stirred at n-butyl lithium (2.1 ml of a 20% solution in hexane) for 30 minutes, the reaction mixture is treated to the procedure of Example 1 to obtain 1-cyclopropyl-6-fluoro-7-t3- (N-acetyl Imethylamino) -1-pyropolyidinyl -1,4,4-DIHYDRO-4-OXO-1,8-naphthyri - dine ethyl ester -3-carboxylic acid (1.44 g) | m.p. 203-204 ° C (ethanol).
This ester (1.34 g) is treated according to the procedure of Example 1 to give compound (2) (900 mg), mp. 284-289 ° C (decomp.) (Water-ethanol).
Example 3 .. 7- (3-Amino-4-meth-1-pyropolydinyl) -1-cyclopropyl-b-fluor-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride (stereoisomers A and B) (3).
2-Sat- (3-acetyl-amino-4-methyl-1-pyrrolidinyl) -2-chloro-5-fluoronicotinoyl-3-cyclopropylaminoacrylic acid ethyl ester (4.53 g) in t-butanol (20 ml) is stirred at at room temperature with potassium t-butylate (1.34 g) for 1 h.
After the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extracts are washed with dilute hydrochloric acid and then with water and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue is chromatographed on silica gel to give three fractions.
Fraction (a): stereoisomer A (1.2 g); Fraction (c): a mixture of stereo: isomer B and a small amount of stereoisomer A (2.8 g); fraction (s): stereoisomer B (0.1 g).
Each of the fractions (a) and (c) is recrystallized from ethanol-isopropyl ether to obtain the stereoisomer A, m.p. 280-282 ° C, and stereoisomer B, so pl. 209-210 ° C, 7- (3-acetylamino-4-metsh1-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-OKCo-1, 8-naphthyridine ethyl ester 3-carboxylic acid, respectively.
A mixture of the ester (stereoisomer A) (0.97 g) and 20% hydrochloric acid (10 ml) was refluxed for 3 hours. After distillation under reduced pressure
ethanol is added to the residue, the precipitate is filtered off and recrystallized from a water-ethanol mixture to give 7- (3-amino-4-methyl-1-pyrrole-schip) -1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-1,8-yaftyridine-3-carboxylic acid hydrochloride (0.57 g) corresponding to the stereoisomer A, m.p., 234-238 ° C (decomp.); NMR (), f: 1.32 (ZN, n, Hz, CH3), 7.42 (1H, d, Hz,); 8.40 (1H, s, Su-H) The fraction (c) (2.8 g) is treated in an analogous way with the acid to obtain co10
for 1 hour. The reaction mixture was worked up as described in Example 3 to give compound 5 as stereoisomers.
The stereoisomer A (5/4 hydrate) (0.23 g), so pl. 263-267 0 (rael.), NMR (NaOD-Dj6), “f: 1.29 (3N, d, J- 6 Hz, CHj) 7.74 (1H, d, J-13 Hz, Su-N ); 8.39 (1H, s, Cj-H) and a mixture of stereoisomer A and B (2 hydrate) (0.78 g), mp. 205-208 С and 241-244 ° С (decomp.). The ratio, according to ghavd-analysis. Stereo NMR (3) as a mixture of stereoisome -., G isomer B (NaOD-Dj O), tf: 1.28 (3N, ditch A and B in the ratio of 6 and 94%, respectively, according to HPLC analysis. Exit 2 , 02 g.Pl. 270-278 C (decomp.) FlMP (DjO), s: 1.32 (ZN, d, L Hz, CH); 7.38 (1H, d, L-13 Hz, Cd-H); 8.41 (1H, s,).
.Prm. 4. 4. 7- (3-Amino-2-metsh1-1-pyrrho-olidinyl) -1-diclopropyl-6-fluoro-1,4-DIGIDRO-4-OXO-1,8-naphthyridine- Zcarboxylic acid padrochloride (stereoisomers A and B chloro-5-fluoro-nicotine-3-cycloprop 1 -reoisomers) (4). aminoacrylic acid (2.26 g).
A mixture of ethyl ether, 2-GB- (3-acetic, Hz, CH3) 7.70 (1H, d, J 13 Hz, CS-H); 8.39 (1H, s, Cj-H),
EXAMPLE 6 7- (3-Amino-3-metsh1-1-pyrrolidinyl) -1-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyri- din-3-carboxylic acid hydrochloride (6).
A mixture of ethyl 2-Sat- (3-acetylamino-3-methyl-1-pyrrolidinyl) -2 potassium carbonate (830 mg) and dimethylformamide (10 ml) is stirred for 1 hour at 150 ° C, the reaction mixture is worked up according to the procedure of example 3 to give compound (6) (5/4 hydrate) (0.71 g), m.p. 285-287 with (decomp.). NMR (DJO), /: 1.74 (3N, s, CH3), 7.45 (1H, d, Hz, CS-H); 8.42 (1H, s, Sc-H).
Tylamino-2-methyl-1-pyrrolidinyl) -2-chlorop-5-fluorocinosine IZ-3-cyclopropyl-aminoacrylic acid (2.26 g), 1.8-diazabicyclo (5.4.0) undecane-7 (DBU) „ (910 mg) and xylene (10 ml) are heated under reflux for one hour. The reaction mixture is treated according to the procedure of Example 3 to obtain compound (4) as two stereo isomers;
The stereoisomer A (3/2 hydrate) (01.34 g), so pl. 215-217 ° C, NMR (NaOD-Djb), 4A 1.03 (3N, d, Hz, CH3), 7.63 (1H, rd, Hz, Cj-H) -, 8.32 (1H, s ,) and a mixture of stereoisomers A and B (3/2 hydrate) (0.94 g); m.p. 276-280 with (decomp.). (A: B) in 1: 4, according to ghavd-analysis). NMR erased isomer. B (NaOD-Rjj), “: 1.17 (3N, d, J 6 Hz, CH3); 7.75 (1H, d, Hz, Cj-H), - 8.33 (1H, s, Ci-H).
Ethyl 2-2-chloro-5-fluoro-6- (4-methyl-3-methylamino-1-pyrrolidinyl) nicotinyl-3-cyclopropylaminoacrylate (2.12 g) in dioxane (10 ml) was stirred at room temperature with 60% hydro-: sodium RIDOM (480 mg) for 1 hour. The reaction mixture was worked up as in Example 1. to give compound (7) (5/4 hydrate) (1.03 g).
tfl 258-277 C (decomp.), NMR (NaODP r and m e r 5. 7- (4-Amino-2-methyl1-pyrrolidinyl) -1-cyclopropyl-; b-fluoro-50 D, b), cP: 1.07 (3N, d, Hz, CH,): 1,4-dihydro-4-oxo-1,8-naphthyridine-3- 2.34 (3N, s, N-CH,) i 7.52 ( 1H, d,
Hz, Cj-H); 8.27 (1H, s,).
- EXAMPLE 8. 7- (3-Amino-4-ethyl-gg pyrrolidinyl) -1-cyclopro-1 -6-fluoro; 1,4-DIGIDRO-4-OXO-1,8-naphthyridine-3 - carboxylic acid hydrochloride (8), Ethyl-2-Sat- (3-amino-4-ethyl-1-pyro-.
cyrboxylic acid hydrochloride (stereoisomers A and B) (5).
A mixture of ethyl (3-acetylamino-5-methyl-1-pyrrolidinyl) 2-chloro-5-fluoronicotinoyl-3-cycl6propyl-amino acrylic acid (2.26 g), triethylamine (610 mg) and toluene (10 ml) is boiled under reflux in
lidinyl) -2-chloro-5-fluoro-nicotinoyl 3
for 1 hour. The reaction mixture was worked up as described in Example 3 to give compound 5 as stereoisomers.
The stereoisomer A (5/4 hydrate) (0.23 g), so pl. 263-267 0 (rael.), NMR (NaOD-Dj6), “f: 1.29 (3N, d, J- 6 Hz, CHj) 7.74 (1H, d, J-13 Hz, Su-N ); 8.39 (1H, s, Cj-H) and a mixture of stereoisomer A and B (2 hydrate) (0.78 g), mp. 205-208 С and 241-244 ° С (decomp.). The ratio, according to ghavd-analysis. NMR of stereoisomer B (NaOD-Dj O), tf: 1.28 (3N,
chloro-5-fluoro-nicot-3-cyclopropsh-aminoacrylic acid (2.26 g).
d, Hz, CH3) 7.70 (1H, d, J 13 Hz, CS-H); 8.39 (1H, s, Cj-H),
EXAMPLE 6 7- (3-Amino-3-metsh1-1-pyrrolidinyl) -1-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyri- din-3-carboxylic acid hydrochloride (6).
A mixture of ethyl ester 2-Sat- (3-acetylamino-Z-methyl-1-pyrrolidinyl) -2
potassium carbonate (830 mg) and dimethylformamide (10 ml) was stirred for 1 hour at 150 ° C. The reaction mixture was worked up as described in Example 3 to obtain compound (6) (5/4 hydrate) (0.71 g), t. square 285-287 with (decomp.). NMR (DJO), /: 1.74 (3N, s, CH3), 7.45 (1H, d, Hz, CS-H); 8.42 (1H, s, Sc-H).
P re p 7. 1-Cyclopropyl-6-fluoro-7- (4-methyl-3-methylamino-1-pyrrolidinium) -, 4-dihydro-4-oco-1,8-na--: ftiridine -3-carboxylic acid hydrochloride (7).
Ethyl 2-2-chloro-5-fluoro-6- (4-methyl-3-methylamino-1-pyrrolidinyl) nicotinyl-3-cyclopropylaminoacrylate (2.12 g) in dioxane (10 ml) was stirred at room temperature with 60% sodium hydride (480 mg) for 1 h. The reaction mixture was worked up as in Example 1. to give compound (7) (5/4 hydrate) (1.03 g).
tfl 258-277 C (decomp.), NMR (NaODD, b), cP: 1.07 (ZN, d, Hz, CH,): 2.34 (ZN, s, N-CH,) i 7.52 ( 1H, d,
lidinyl) -2-chloro-5-fluoro-nicotinoyl-3-cyclopropylaminoacrylate (2.12 g) B dioxane (10 ml) is stirred at room temperature with 60% sodium hydride (480 mg) for 1 hour. The reaction mixture is worked up by the method of example. 1 to give Compound 8 (0.95 g), m.p. 232-237 C (decomp.), NMR (NaOD-D O), fl 0.95 (GH, t, Hz, -CH-jCHj) 1.66 (2H, q, Hz, -SHGH; 7, 55 (1H, d, J- 13 Hz, Su-H), 8.33 (1H, s, Ci-H).
Example 9. 1-Cyclo-II-propyl-6-fluorop-7- (3-n-propylamino-1-pyropolydinyl) -1, 4-dihydro-4-oxo-1,8-naphthyridine-3 -carboxylic acid hydrochloride (9).
Ethyl ester of 2-b-C3- (N-acetyl-n-propylamino) -1-pyrrolidylin-2-chloro-5-fluorophenico-j-3-cyclopropylamino-aprilic acid (2.40 g) in dioxane (10 ml) is stirred at room temperature with 60% sodium hydride
The known compound 2,6-dichloro-5-fluoro-nicotinonitrile (60 g) in concentrated sulfuric acid is heated at 65-75 C for 1 h. Water is added to the reaction mixture and the mixture is heated at 100-111 ° C for 2 h, which gives 2, 6 (480 mg) for 1 h. The reaction mixture is treated by the procedure described in: Dichloro-5-fluoro-nicotinic acid
(59.8 g), m.p. 155-156 S.
This compound is treated with thionyl chloride to give 2.6 dichloro-5-fluoro-nicotinoyl chloride (47.5 g) as an oil.
In dry ether, this compound is reacted with diethyl ethoxymagnemagnonate to give diethyl 2,6-dichloro-5-fluoro-nicotinoylmalonate as an oil. Water 35 and a catalytic amount of p-toluen sulphonic acid are added to it, then the mixture is heated.
ra 1 to obtain compound (9) (1.03 g), so pl. 265-280 0 (decomp.), NMR (DjO), 1.05 (3N, t, Hz, CH, CH2CH, NH-)) 7.63 (1H, d, Hz, Cj-H)} 8.54 (1H, s,).
Example 10. 1-Cyclopropyl-6-fluoro-7- (3-isopropylamino-1-pyrrolidine) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride (10).
2- 6-GZ- (N-acetyl-isoproxy-1-amino) -1-pyrrolvdinyl} -2-chloro-5-fluoro-nicotino-1-3-cycloprop-1-amino-acrylic acid (2.40 g) ethyl ester (2.40 g) in dioxane (10 ml) is stirred at room temperature temperature with sodium hydride (480 mg) for 1 h. The reaction mixture was worked up as described in Example 1 to give compound (10) (1.05 g), m.p. 273-284 ° C (decomp.), NMR (B20), cG; 1.47 (6H, d, Hz, (CH3 / aCHNH-); 7.57 (1H, d, Hz, C5-H); 8.49 (1H, s,
).
Example 11. 7- (3-Amino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1j4-dihydro-4-oxo-1,8-naphthyridine-3-carboxyl hydrochloride (11).
Methyl (3-acetylamino-1-pyrrolidinsh1) -2,5-difluoro-nicotinoyl 3-3-cyclopropylaminoacrylate in the amount of 2.04 g, obtained in accordance with the procedure similar to that indicated in Reference Example 12, of 2,5,6-three -.
thirty
at 140 C for 2 h, which gives ethyl 3- (2p6-dichloro-5-fluoro-pyridine-3-Sh1) -3-oxo-propionate (46 g), m.p. 69-70 C.
40
Ethyl 3- (2,6-dichloro-5-fluoropyridin-3-yl) -3-oxopropionate (1.4 g) is reacted with 3-acetylamino-pyrrolidone to give ethyl 3-GB- (3-acetyl 45 amino acid). 1-pyrrolidinyl) -2-chloro-5-fluoropyridin-3-yl-3-oxopropionate (0.78 g) as an oil. This compound (0.74 g) is treated with ethyl fluoroformate and acetic acid.
50 anhydride, which gives ethyl (3-acetylamino-1-pyrrolidinyl) -2 chloro-5-fluoro-nicotinoyl-3-ethoxyacryloxy as an oil. This compound is reacted with cyclopropamine,
55 which gives ethyl 2-G6- (3-acetslamino-1-pyropolyde) I-2-chloro-5-fluorocino-ylo-7-3-cyclopropylaminococrylate (0.43 g) as a complex powder, mp. 71 75 C.
fluoronicotinonitrile, stirred in 10 ml of dioxane at room temperature with 60% sodium hydride, 480 mg, for 1 h. The resulting mixture was processed in accordance with the method similar to example 1 and get 7- (3-amino-1- Pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-di-hydro-4-1,8-naphthyridine-3-carboxylic acid hydrochloride, 0.96 g, m.p. (decomposition) 275-280 C.
Example 12 (reference). The preparation of the starting compound is ethyl-2 GB- (3-acetylamino-1-pyrrolidine) -2-chloro-5-fluoro-nicotinoyl} -3-cyclopropylaminoacrylate.
The known compound 2,6-dichloro-5-fluoro-nicotinonitrile (60 g) in concentrated sulfuric acid is heated at 65-75 C for 1 h. Water is added to the reaction mixture and the mixture is heated at 100-111 ° C for 2 h, which gives 2, 6Dichloro-5-fluoro-nicotinic acid
at 140 C for 2 h, which gives ethyl 3- (2p6-ichloro-5-fluoro-pyridine-3-Sh1) -3-oxo-propionate (46 g), mp. 69-70 C.
Ethyl 3- (2,6-dichloro-5-fluoropyridin-3-yl) -3-oxopropionate (1.4 g) is reacted with 3-acetylamino-pyrrolidone, which gives ethyl 3-GB- (3-acetyltamine-1 -pyrrolidinyl) -2-chloro-5-fluoropyridin-3-yl-3-oxopropionate (0.78 g) as an oil. This compound (0.74 g) is treated with ethyl fluoroformate and acetic acid.
anhydride, which gives ethyl (3-acetylamino-1-pyrrolidinyl) -2 chloro-5-fluoro-nicotinoyl-3-ethoxyacryloxy as an oil. This compound is reacted with cyclopropamine,
what gives ethyl 2-G6- (3-atstshlamino-1-pyropolyde I) -2-chlorop-5-fluorocinotinoyl-7-3-cyclopropylaminococrylate (0.43 g) as a complex powder, so pl. 71 75 C.
The study of the biological activity of the target compounds.
Determination of acute toxicity.
A solution containing i52j3 or 6 compounds in various concentrations is orally administered to samyam (ddY) mice. at a dosage of 0.1 ml per 10 g of body weight. The number of dead mice was counted after 7 days, the average lethal dose (LDjp, mg / kg) was calculated according to the method of Beren sa-Kerber, the results are shown below.
Compound LDjj, mg / kg
12,000
22,000
32000 62000
The in vitro antibacterial activity is shown in Table 1. Minimum inhibitory concentrations (MICs) (µg / ml) are calculated for the free base. The minimum inhibitory concentrations are determined according to the method of diluting the agar recommended by the Japanese Chemotherapy Society.
The antibacterial activity of the compounds was studied in comparison with the structural analogues - 7- (3-amino-1-pyrrolidinyl) -1-ethyl-6-fluoro-1, A-di-HYDRO-1-OXO-1,8-naphthyridine-3 -carboxylic acid with hydrochloride (compound A) and 1-ethyl-6-fluoro-7- (3-methylamino-1-pyrrolidinyl) -1,4-dihydro-A-ox-1,8-naphthyridine- 3-carboxylic acid hydrochloride (compound B)
The effectiveness of compounds against common infection in the body was also studied. The compounds are dissolved in deionized water. The solution is administered via the mouth (ro) miL intravenously (iv) to infected mice, and the average effective dose (EDj ()) is calculated by reliable analysis.
Table 2 shows the values of EDso.- ,. (mg / kg) calculated for free base.
Experimental conditions: male mouse (ddY-S) weighing about 20 g,
Infectious diseases; Streptococcus pneumoniae.
Intraperitoneal infection of 3x10 cells per mouse suspended in infusion brain-heart broth. Streptococcus pyogenes A-65
Intraperitoneal infection with 3x10 cells per 1 mouse, suspended
bathrooms in infusion broth brain-heart. Escherichia coli PS-101.
Intraperitoneal infection of approximately 9x10 cells for 1 slurry suspended in tryptic acid broth with 4% mucin. Pseudomonas aeruginosa 12.
Intraperitoneal infection of approximately 5x10 cells per mouse suspended in tryptosoic broth with 4% mucin.
Drug treatment. In the case of Streptococcus pneumoniae, 4 times, immediately after 6, 24 and 30 hours after infection. In the case of other organisms, immediately and 6 hours after infection.
Observation In the case of Streptococcus pneumoniae 1 after 14 days.
In the case of other organisms after 7 days.
Thus, these compounds have high bactericidal activity, exceeding the activity of structural analogues. In addition, they have low toxicity, as a result, can be used in medical practice.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining the 1,8-naphthyridine derivatives of the general formula
ABOUT
soon
40
RI-NH
where Kz is the same or different and each represents hydrogen or lower alkyl, contents from 1 to 5 carbon atoms, provided that at least one of Rj and RJ is hydrogen,
or salts thereof, characterized in that the p-amino-acrylate derivatives of the general formula
p .COOY "3
agl
n -2 CH I
1442075
where RI.R and Rj have the indicated meanings;
Z is chlorine or fluorine;
U is alkyl,
subjected to cyclization in an inert solvent, in the presence of a base, at a temperature from 0 to and the resulting compound of the general formula
2075
10 o
v Rj- n 2l
where R, R, Rj and Y have the indicated meanings, they are hydrolyzed to isolate the desired product as base fQ or as salt.
eleven
U42075
12 .Table2
7,082,51
11,24,26
6,81rl, 47 7,432,46 25, 5
J
48,
15.28,610,444 0.03551.85 0.516 21.5 15.80.413 0.09682.02 0.902
9.64 9.610.589 0.09862.01 1.05
7.27 3.640.456 0.08011.70 0.968
109 16,81,73 0,4344,49 1,56
67.333,61,54 0,6056,25 g4,61

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引用文献:

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

JPS6113717B2|1979-09-28|1986-04-15|Dainippon Pharmaceutical Co|

DE3033157A1|1980-09-03|1982-04-01|Bayer Ag, 5090 Leverkusen|7-AMINO-1-CYCLOPROPYL-4-OXO-1,4-DIHYDRO-NAPHTHYRIDINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM|

JPH0212230B2|1981-02-27|1990-03-19|Dainippon Pharmaceutical Co|

IE55898B1|1982-09-09|1991-02-14|Warner Lambert Co|Antibacterial agents|US4665079A|1984-02-17|1987-05-12|Warner-Lambert Company|Antibacterial agents|

JP2640967B2|1987-04-30|1997-08-13|大日本製薬株式会社|Quinolonecarboxylic acid derivatives and salts thereof|

EP1304329B1|1995-02-02|2008-10-15|Daiichi Sankyo Company, Limited|Pyridonecarboxylic acid derivatives and their use as antibacterial agents|

ES2199278T3|1995-02-07|2004-02-16|Daiichi Pharmaceutical Co., Ltd.|HIPEROCICLIC DERIVATIVES OF ESPIRO.|

法律状态:

优先权:

申请号 | 申请日 | 专利标题

JP59117266A|JPH0568477B2|1984-06-06|1984-06-06|

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