JPS63284171A - Quinoline-3-carboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R1 is lower alkyl or lower cycloalkyl; R2-R4 are H or lower alkyl; R5 is H or halogen) and salt thereof. EXAMPLE:1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-[3-(methylaminomethyl )-1-pipe razinyl]-4-oxoquinoline-3-carboxylic acid. USE:A medicine and antimicrobial agent, exhibiting wide antimicrobial action on Gram-positive and Gram-negative bacteria and capable of being orally or parenterally administered. The dose is normally 50-1,000mg administered at a time in the case of an adult by oral administration. PREPARATION:For example, a 7-halogenoquinonline-3-carboxylic acid derivative expressed by formula II (X is halogen) is reacted with a novel piperazine deriva tive expressed by formula III without or in a solvent, such as pyridine, at room temperature - 200 deg.C to afford the aimed compound expressed by formula I.

Description

[Detailed Description of the Invention] Sho (7) L'L-1 The present invention provides a novel quinoline-3-carboxylic acid derivative that has excellent antibacterial activity and is useful as a pharmaceutical, and a pharmacologically acceptable derivative thereof. It's about salt.

Although many antibacterial agents having a quinoline carboxylic acid skeleton are known, including norfloxacin, the quinoline-3-carboxylic acid derivative according to the present invention is completely unknown.

B Synthetic antibacterial agents are being actively researched both domestically and internationally, and the results have brought ground-breaking progress in clinical practice, and are effective for all kinds of infections, not just urinary tract infections. It has been shown that It is also known that its mechanism of action is the inhibition of DNA gyrase, which is a DNA steric enzyme, and that transmission of resistance by plasmids such as antibiotics does not occur. However, it is difficult to say that synthetic antibacterial agents are perfect drugs, and the emergence of new antibacterial agents is strongly desired due to their usefulness.

As a result of intensive research in view of the above-mentioned circumstances, the present inventors discovered that quinoline-3-carboxylic acid derivatives and pharmacologically acceptable salts thereof have excellent antibacterial effects.
The present invention has been completed.

That is, the present invention relates to the general formula (I) (wherein R represents a lower alkyl group or a lower cycloalkyl group, R2* R3 and R4 are the same or different and represent a hydrogen atom or a lower alkyl group, and R5 represents a hydrogen atom or This invention relates to a quinoline-3-carboxylic acid derivative represented by (representing a halogen atom) and a pharmacologically acceptable salt thereof.

In the general formula (I) of the present invention, the lower alkyl groups represented by R1, R2* R3 and R4 include, for example, methyl, ethyl, fI-propyl, isopropyl, n-butyl, 5ea-butyl, tert-butyl. Examples include groups. Further, examples of the lower cycloalkyl group represented by R1 include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, and examples of the halogen atom represented by R5 include fluorine.

Examples include chlorine and bromine atoms.

Examples of the pharmacologically acceptable salts of the compound represented by the general formula (I) of the present invention include acid addition salts and alkali addition salts; examples of the acid addition salts include hydrochloric acid, hydrobromic acid , mineral acid salts such as hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid,
Alternatively, acetic acid, maleic acid, fumaric acid, citric acid,
Organic acid salts such as oxalic acid and tartaric acid are used as alkali addition salts such as sodium, potassium, and calcium.

Examples include inorganic alkali salts such as silver, zinc, lead, and ammonium, and salts of organic bases such as ethanolamine and N,N-dialkylethanolamine.

A novel quinoline represented by the general formula (I) of the present invention
3-carboxylic acid derivatives can be produced by various methods.

According to the first mode of the method for producing a compound according to the present invention,
The compound represented by the general formula CI) is represented by the following general formula (n
) (wherein, R1 and R5 have the same meanings as above, and X represents a halogen atom) and the following general formula (III) (wherein, R2e R3 and R4 have the same meanings as described above.) The solvent used in the method of the present invention includes a piperazine derivative represented by Any substance may be used as long as it does not inhibit the
Methanol, ethanol, n-propanol, n-butanol, 3-methoxybutanol.

Alcohols such as isoamyl alcohol, ethylene glycol dimethyl ether diethylene glycol dimethyl ether (diglyme)
, ethers such as triethylene glycol dimethyl ether (triglyme), aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, and hexamethylphosphoric triamide, aromatic solvents such as benzene and toluene. Examples include hydrocarbon solvents and organic bases such as pyridine, picoline, lutidine, collidine, and triethylamine.

Further, the reaction is carried out at a temperature ranging from room temperature to 200°C.

The 7-halogenoquinoline-3-carboxylic acid derivative represented by the general formula (n) which is the starting material in the production method of the present invention is disclosed in, for example, JP-A-56-30964 and JP-A-58-74887.

JP-A-59-212474, JP-A-80-72885
No., Japanese Patent Application Publication No. 1987-IEEE No. 7, Japanese Patent Application Publication No. 1987-59283
It is a known substance already disclosed in No.

Furthermore, the general formula (II) used in the method of the present invention
The piperazine derivative represented by I) is a new compound, and its production method is described in Reference Examples.

According to the second mode of the method for producing a compound according to the present invention,
Among the compounds represented by the general formula (I), the compound in which R2 is a lower alkyl group is the compound represented by the following formula (IV) in which R2 is a hydrogen atom (wherein R=R3 *
R4 and R5 have the same meanings as above. ) 7-biperazinoquinoline-3-carboxylic acid derivative represented by the following general formula (V) R2-Y (V ) (wherein, R2 has the same meaning as above, and Y represents a halogen atom.) It can be produced by reacting the alkyl halide represented by in a solvent in the presence or absence of a base as a deoxidizing agent.

The solvent used in the method of the present invention may be any solvent as long as it does not inhibit the reaction, such as acetone, ethanol, ether, tetrahydrofuran,
Examples include dimethylformamide, dioxane, benzene, toluene, and chloroform.

Examples of the base used as a deoxidizing agent in the method of the present invention include triethylamine.

Examples include pyridine and potassium carbonate.

Further, the reaction is carried out at a temperature ranging from room temperature to the reflux temperature of the solvent used.

According to the third mode of the method for producing a compound according to the present invention,
Among the compounds represented by the general formula (I), the compound in which R2 is a lower alkyl group is a 7-biverazinoquinoline-3-carboxylic acid derivative represented by the general formula (IV);
The following general formula (VI) R6-C-H(VI) (wherein R6 represents a hydrogen atom or a lower alkyl group).

) can be produced by reacting the carbonyl compound shown in the following in the presence of formic acid.

Examples of the carbonyl compound represented by the general formula (Vl) used in the method of the present invention include formaldehyde, acetaldehyde, propionaldehyde, etc. Formaldehyde is preferably used as an aqueous formaldehyde solution (formalin), and acetaldehyde When using propionaldehyde, it is preferable to use nitrobenzene as a solvent.

Further, the reaction is carried out at a temperature ranging from room temperature to 200°C.

The novel quinoline-3-carboxylic acid derivative represented by the general formula (I) and its pharmacologically acceptable salts produced in this manner can be prepared into tablets, powders, capsules, injections, etc. by conventional methods. It can be made into formulations such as eye drops, nasal drops, or external preparations, and is clinically administered by oral or parenteral administration. The dosage depends on the symptoms to be treated and the administration method, but when administered orally to adults, it is usually 50
~10001g.

Hereinafter, the present invention will be explained by reference examples and examples.
The invention is not limited to the specific details of this embodiment.

Reference example 1 2-(methylaminomethyl)piperazine lithium aluminum hydride 2.74 g of anhydrous 1,4-dioxane 10
0+sl! ! ! In the suspension, 5.15 g of N-methyl-2-piperazinecarboxamide in anhydrous 1,4-dioxane 5
Solution No. 31 was added dropwise at room temperature, and the mixture was heated under reflux for 23 hours. Cold pumped water 101 is added dropwise and insoluble matter is filtered off. The filtrate was concentrated and the residue was distilled off under reduced pressure to obtain 2.05 g of a pale yellow liquid with a boiling point of θO~75° (6-h).

Mass spectrum -/Z: 12B (N)NMR
Spectrum δ (CDCl2) pI)l: 1.5
0 (3H, br-s), 2.42 (3B, s), 2.
38-3.0G (9B.

Reference example 2 2-(dimethylaminomethyl)piperazine lithium aluminum hydride 2. OOg of anhydrous 1,4-dioxane 1
A solution of 4.70 g of N,N-dimethyl-2-piperazinecarboxamide in anhydrous 1,4-dioxane 501 was added dropwise to the 00ml suspension at room temperature, and the mixture was heated under reflux for 21 hours.

Add 8 ml of cold water dropwise and filter off insoluble matter. The filtrate was concentrated and the residue was distilled off under reduced pressure to obtain a boiling point of 90-96° (15mmHg
2.03 g of colorless hygroscopic crystals of ) are obtained.

Mass spectrum Sono/Z: 143 (M”) NMR
Spectrum δ (CDCl2) pp = 1.90-
3.08 (11B, g+), 2.21 (8H, s
) Reference Example 3 2-(diethylaminomethyl)piperazine 1) N, N-
Diethyl-2-pyratine carboxamide5. OOg is hydrogenated in 800ml of ethanol using 0.20g of platinum oxide as a catalyst at 50a1100atm for 6 hours. The cooled catalyst was filtered off and the filtrate was concentrated to obtain 3.08 g of a yellow liquid of N,N-diethyl-2-piperazinecarboxamide.

Mass spectrum intestine/z: 185 (M”) IR spectrum v (liquid) crl: 1G3
B (C:O) NMR spectrum δ (CDC13) pp ■: 1.
11 (31, t, J near H2), 1.21 (3H, t
, J=7H2), 2.47 (2H, br-s), 2.5
0-3.30 (GO, l), 3.37 (4H, Q, J=
7Hz), 3.73 (1B, dd, J:10.
3.5Hz) 2) Lithium aluminum hydride 2.4
N in a suspension of 8 g of anhydrous 1,4-dioxane 1501
, N-diethyl-2-piperazinecarboxamide 6.0
0 g of anhydrous 1,4-dioxane 501 solution was added dropwise at room temperature, and the mixture was heated under reflux for 18.5 hours. Cold water 101 is added dropwise and insoluble matter is filtered off. The filtrate was concentrated and the residue was distilled under reduced pressure to obtain 2.54 g of a colorless liquid of 2-(diethylaminomethyl)piperazine with a boiling point of 90-93" (11-8 g).

Mass spectrum ■/z: 171 (father) NMR spectrum δ (CDCl2) 99 sets: 0.99 (8
H, t, J=7Hz), 1.91 (211, br-s)
, 2.49 (2B.

q, J=7Hz), 2.52 (2H, q, J near Hz)
, 2.20-3.011i (9B.

Intestine) Reference Example 4 2-(tert-butylaminomethyl)piperazine 1)
N-tert-butyl-2-pyratine carboxamide5. 0g of platinum oxide in ethanol 8001.
Hydrogenation was carried out at 50' and 100 atm for 8 hours using 20 g as a catalyst. The cold soaked catalyst is filtered off and the filtrate is concentrated. The residue was recrystallized from ethanol to obtain N-te with a melting point of 151-152°.
2.1 Gg of pale yellow prismatic product of rt-butyl-2-piperazinecarboxamide was obtained.

Mass spectrum Zen/z: 185 (M") 1R spectrum ν (Br) e-: 1G72 (C: 0) NMR spectrum δ (CD30D) pp intestine: Seal,
33 (9H, s), 2.40-3.35 (7H, m
)2) N-tert in a suspension of 3.08 g of lithium aluminum hydride in anhydrous 1,4-dioxane 2501
Add 7.50 g of -butyl-2-piperazinecarboxamide and heat under reflux for 21 hours. 12.5 ml of cold water was added dropwise, and insoluble matter was filtered off. The filtrate was concentrated and the residue was distilled under reduced pressure to obtain 2-(te) with a boiling point of 105-107" (13 mmBg)
rt-butylaminomethyl)piperazine pale yellow liquid 5
．． Obtain 02g.

? SX vector mHz: 171 (M”) NMR
Spectrum δ (CDCl2) pp■: 1.07 (
9H, S), 1.54 (3H, br), 2.31-3
．． 05 (9■,■) Example 1 1-Cyclopropyl-8,8-difluoro-1,4-dihydro-7-[3-(methylaminomethyl)-1-piperazinyl]-4-oxoquinoline-3- Carboxylic acid 1-cyclopropyl-6,7,8-)refluoro-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid 0
．． 75 g, 2-(methylaminomethyl)piperazine 0.
A mixture of 50 g and 7.51 g of pyridine is heated under reflux for 1 hour. The cold solvent is distilled off, and methanol is added to the residue.

The precipitated crystals were collected by suction filtration and recrystallized from a dimethylformamide/ether mixture to give a melting point of 224-228° (decomposition).
0.13 g of pale yellow crystals were obtained.

Mass spectrum Intestine/z: 392 (M") IR spectrum v (KBr) cm-': 1620 (
C: 0) NMR spectrum δ (DMSO-d6) I) peng: 1.18-1.27 (4H, l), 2.31 (31,
s), 2.41-2.55 (2■, Sono), 2.71-3
．． 51()H9■), 3.97-4.27(Ill,■
).

4.75 (3■, br), 7.77 (1B, dd
, J: 12.2Hz), 8.1lf5 (1B, s) Example 2 1-Cyclopropyl-7-[3-(dimethylaminomethyl)-1-piperazinyl]-6.8-difluoro-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-8,7,8-)lifluoro-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid 1
．． Heat the mixture of OOg, 2-(dimethylaminomethyl 1) under reflux for 1 hour. The cold solvent is distilled off, and methanol is added to the residue. The precipitated crystals are collected by suction filtration.
Recrystallized from a chloroform-benzene mixture to a melting point of 166.
~168° pale yellow crystals 0. Obtain 73g.

Mass spectrum Peng/z: 40G (M") IR spectrum v (KBr) cm-': 173G (
COOB), 1G24 (C:0) NMR spectrum δ
(DNSO-d6) PpH: 1, 1G-1.29
(4B, +s), 2.18 (6H.s), 2.09-2
．． 29 (2a+mL2.) 7-3.52 (711, Peng)
, 3.95-4, 22 (III, intestine) 7, 77 (I
II, dd, J=12,2Hz), 8.85 (111
,S) Example 3 7-[3-(dimethylaminomethyl)-1-piperazinyl]-1-ethyl-8.8-difluoro-1.4-
1-ethyl-8,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate
4-oxoquinoline-3-carboxylic acid 0, 54g, 2-
A mixture of 0.47 g of (dimethylaminomethyl)piperazine and 5.41 g of pyridine is heated under reflux for 2 hours. The cold solvent is distilled off, and methanol is added to the residue. The precipitated crystals are collected by suction filtration and recrystallized from a chloroform/methanol mixture to obtain 0.34 g of pale yellow crystals with a melting point of 175-178°.

Mass spectrum -/z: 394 (N) IR spectrum v (KBr) cm-': 1728 (
COO old, IG24 (C=0) NMR spectrum δ
(DMSO-d6) pp Otori: 1, 44 (3■, t.J
near Hz), 2.17 (G■.S), 2.10-2.
24 (2H, Peng), 2.74-3.48 (7H, ■),
4.39-4, Fu 4 (211, ■) 7, 80 (II, d
-d. J=12,1.5Hz), 8.85(IH,s
) Elemental analysis value C engineering 9 H24 F2 N4 03 theoretical value C, 57.88; H. G, 13 N, 14
．． 20 Experimental value C, 57.50; H, 6.19
N, 14.21 Example 4 1-Cyclopropyl-7-[3-(diethylaminomethyl)-1-piperazinyl]-6,8-difluoro-1
．． 4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-8.7.8-trifluoro-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid 0
．． 85g, 2-(diethylaminomethyl)piperazine 0
．． 70g and pyridine 6.

The mixture of 51 is heated to reflux for 1 hour. The cold solvent is distilled off, and methanol is added to the residue. The precipitated crystals are collected by suction filtration,
Recrystallization from benzene gives 0.42 g of pale yellow crystals with a melting point of 155-158°.

Mass spectrum intestine/z: 434 (M”) IR spectrum !/ (KBr) am-1:1732 (
COOH), 62G (C:0) NMR spectrum δ
(DMSO-d6) pp-:0.95 (811st
, J Near Hz), 1.09-Sen, 28 (4H, +s)
, 2.32 (2H, d, J=6H2), 2.48 (4H
, Q, J=IH2), 2.74-3.56 (7■, ■)
, 3.95-4.27 (IH, m), F, 7 F (IB,
dd, J: 12.211z), 8.65 (IH, g
) Example 5 1-Cyclopropyl-7-[:3- (diethylaminomethyl)-4-methyl-1-piperazinyl]-6,8-
Difluoro-1,4-dihydro-4-oxoquinoline-
3-Carboxylic acid dihydrochloride 1-cyclopropyl-7-C
A mixture of 0.33 g of 3-(diethylaminomethyl)-1-piperazinylco-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 37% formalin 11 and formic acid 11 was heated for 1.5 hours. Reflux.

After cooling, the reaction solution is concentrated, and ethanolic hydrochloric acid is added to the residue to make it acidic (pH=3). The precipitated crystals are collected by suction filtration and recrystallized from ethanol to obtain 0.13 g of pale yellow crystals with a melting point of 228-2406° (decomposition).

Mass spectrum Peng/z: 448 (M”) 1R spectrum v (KBr) cm: 1730 (C0
011), 11128 (C=0) NMR spectrum δ
(DMSO-d6) ppm: 1.27 (8H, t
, J Near 12), 1.11-1.38 (4B, 1),
2.95 (3H, S), 3.18 (411, Q, J Near H2), 3.20-4.25 (IOH.

m), 7.88 (lH, dd, J: 11.5, 211
Example 6 7-[3-(tert-butylaminomethyl)-1-
piperazinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-8,7,8-)difluoro-1
, 0-80 g of 4-dihydro-4-oxoquinoline-3-carboxylic acid + 3 g of 2-(tert-butylaminomethyl)piperazine and 81 g of pyridine are heated under reflux for 1 hour. The cold solvent is distilled off, and methanol and isopropyl ether are added to the residue. The precipitated crystals were collected by suction filtration and recrystallized from methanol to a melting point of 222~
0.36 g of pale yellow crystals of 22θ6 are obtained.

Mass spectrum mHz: 434 (If”)I
R spectrum ν(KBr) cm-': 1732(
Cooly), 182B (C:O) NMR spectrum
δ (DMSO-d6) ppm: 1, (1B(911
,s) ,1.10-1.25(4H,m) ,2.4
0-3.52 (9B, m), 3.93-4.30 (Seal I
I)), F, F8 (lH, dd, J: 12.2Hz)
, 8.85 (1B, s) i 匪 BAOXIA l A novel quinoline-3-carboxylic acid derivative represented by the above general formula (I) produced in this way, and a pharmacologically acceptable salt thereof has a broad antibacterial effect against Durham-positive and Durham-negative bacteria, and is extremely useful as a medicine.

Patent applicant: Hokuriku Pharmaceutical Co., Ltd. Procedural amendment (voluntary) February 1986 Yu day

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ , R_5 represents a hydrogen atom or a halogen atom).
-Carboxylic acid derivatives and pharmacologically acceptable salts thereof.