JPS63196580A - Quinoline-3-carboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A quinoline-3-carboxylic acid derivative expressed by formula I (R is H, lower alkyl, lower alkanoyl or halogeno lower alkanoyl) and salt thereof. EXAMPLE:8-Chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(4-trifluoroacetyl-1- homopiperazinyl)quinoline-3-carboxylic acid. USE:With wide antimicrobial action on Gram-positive and Gram-negative bacteria, useful as a medicine and capable of being orally or parenterally administered. PREPARATION:A 7-halogenoquinoline-3-carboxylic acid derivative expressed by formula II (X is halogen) is reacted with a homopiperazine derivative expressed by formula III in or without a solvent at a temperature of room temperature-200 deg.C to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel quinoline-3-
This invention relates to carboxylic acid derivatives and pharmacologically acceptable salts thereof.

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 not known at all.

[I　(′　　・　　.

Synthetic antibacterial agents are being actively researched both domestically and internationally, and the results have brought groundbreaking advances in clinical practice, and are effective for all kinds of infections, not just urinary tract infections. It is shown. It is also known that its mechanism of action is the inhibition of DNA gyrase, which is a DNA stericase, 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 circumstances, the present inventors have discovered that quinoline-3-carboxylic acid derivatives and pharmacologically acceptable salts thereof have excellent antibacterial activity. Finally, the present invention was completed.

That is, the present invention provides a quinoline-3-carboxylic acid derivative represented by the general formula (I) (wherein R represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, or a halogeno-lower alkanoyl group), and its pharmacology. This relates to salts that are acceptable.

In the general formula (I) of the present invention, examples of the lower alkyl group represented by R include methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.
-butyl group, etc., and lower alkanoyl groups include, for example, formyl and acetyl.

Examples of the propionyl and butyryl groups, and examples of the halogeno lower alkanoyl groups include fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, and trichloroacetyl groups. .

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 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 (I) is represented by the following general formula (I).
I) 7- represented by (wherein, X represents a halogen atom)
A halogenoquinoline-3-carboxylic acid conductor and a homopiperazine derivative represented by the following general formula (III) (wherein R represents the same meaning as above) are reacted in a solvent or in a solvent. It can be manufactured by

Any solvent may be used in the method of the present invention as long as it does not inhibit the reaction, such as water,
Methanol, ethanol, n-propanol, n-butanol, 3-methoxybutanol.

Alcohols such as inamyl alcohol, ethylene glycol dimethyl ether (monoglyme).

Diethylene glycol dimethyl 1,000-ter (diglyme)
, ethers such as triethylene glycol dimethyl ether (triglyme), aprotic polar solvents such as dimethylformamide, N-notyl-2-viclidone, dimethyl sulfoxide, hexamethylphosphoric triamide, and benzene.

Examples include aromatic hydrocarbon solvents such as toluene, 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 (If), which is a starting material in the production method of the present invention, is described in, for example, JP-A-61-1887 and JP-A-61-205258. This is a known substance that has already been disclosed.

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 CI), the compound in which R is a lower alkyl group is a 7-homobiperazinoquinoline represented by the following formula (IV), in which R is a hydrogen atom in the general formula (I). -3-carboxylic acid derivative and the following general formula (V) (wherein, R represents a lower alkyl group and Y represents a halogen atom), and a halogenated alkyl shown in a solvent. It can be produced by reacting in the presence or absence of a base as a deoxidizing agent.

Any solvent may be used in the method of the present invention as long as it does not inhibit the reaction, and examples thereof include acetone, ethanol, ether, tetrahydrofuran, dimethylformamide, dioxane, benzene, toluene, chloroform, and the like.

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 R is a lower alkyl group is a 7-homobiperazinoquinoline-3-carboxylic acid derivative represented by the general formula (IV) and the following general formula ( VI) R2-C-H(Vl) (wherein, R2 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 aldehyde, etc. Formaldehyde is preferably used as an aqueous formaldehyde solution (formalin), and acetaldehyde and propionaldehyde are preferably used. When used, it is preferred to use nitrohenzene as a solvent.

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

According to the fourth 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 R is a lower alkanoyl group or a notulogeno lower alkanoyl group is a 7-homobiperazinoquinoline-3-carboxylic acid derivative represented by the general formula (IV). , the following general formula (
(2) (In the formula, R3 represents a lower alkyl group or) a 10-geno lower alkyl group. ), or the following general formula % formula %
() (wherein R3 and Y represent the same meanings as above), in the presence or absence of a base, in the absence of a solvent or in a solvent. be able to.

Any solvent may be used in the method of the present invention as long as it does not inhibit the reaction, such as water,
Alcohols such as n-butanol, 3-methoxybutanol, isoamyl alcohol, ethylene glycol dimethyl ether im), diethylene glycol dimethyl ether (diglyme), triethylene glycol dimethyl ether (
ethers such as triglyme), halogenated hydrocarbons such as chloroform, dichloromethane, and 1,2-dichloroethane, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide, and aromas such as benzene and toluene. Group hydrocarbon solvents, or pyridine, picoline, lutidine.

Examples include organic bases such as collidine and triethylamine.

Examples of the base used in the method of the present invention include triethylamine, pyridine, potassium carbonate, etc., and the reaction is carried out under water cooling at a temperature of 2,000 °C.

According to the fifth 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 R is a lower alkyl group, a lower alkanoyl group, or a halogeno lower alkanoyl group is a compound represented by the following general formula ([X) (wherein R4 is a lower alkyl group, a lower It can be produced by directly chlorinating the 8-position of a 7-homopiverazinoquinoline-3-carboxylic acid derivative represented by an alkanoyl group or +thalogeno-lower alkanoyl group.

The chlorinating agent used in the method of the present invention includes:
Examples include chlorine and sulfuryl chloride.

Examples of solvents include alcohols such as methanol, ethanol, and n-propanol;
Examples include rem, dichloromethane, 1,2-dichloroethane, acetic acid, etc., and the reaction is carried out under water cooling at a temperature of 200 @.

According to the sixth mode of the method for producing a compound according to the present invention,
Among the compounds represented by the above general formula (I), the compound in which R is a hydrogen atom is a compound represented by the following general formula (where R in the above general formula (I) is a lower alkanoyl group or a halogeno lower alkyl group)
X) (wherein, R3 represents the same meaning as above) 7
-It can be produced by hydrolyzing a homobiperazinoquinoline-3-carboxylic acid derivative.

Hydrolysis is carried out using an acid or alkali using a method known per se. For acidic hydrolysis, an acid such as hydrochloric acid or sulfuric acid is used, and for alkaline hydrolysis, an alkali such as sodium hydroxide or potassium hydroxide is used. , an aqueous solution of these acids or alkalis, a solution of ethanol, methanol, etc., or a solution of a water-containing organic solvent can be used in the reaction, and the reaction is carried out from room temperature to the heating reflux temperature of the solvent.

Practical Ju1 Hereinafter, the present invention will be explained by way of examples, but the present invention is not limited to the specific details of these examples.

Reference Example 1 7-(4-acetyl-1-homopiperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-
oxoquinoline-3-carboxylic acid l-cyclopropyl-
6-Fluoro-1,4-dihydro-7-(1-homopiperazinyl)-4-oxoquinoline-3-carboxylic acid 1.
70g,) ethylamine 0.99g and pyridine 17
1. Add acetic anhydride at room temperature to a mixture of 1. After dropping OOg, the mixture is heated under reflux for 30 minutes. After cooling, the reaction solution was distilled off, and 20 ml of water was added to the residue. The precipitated crystals were collected by filtration and recrystallized from chloroform-ethanol to obtain 1.80 g of a pale yellow powder with a melting point of 229-234@.

Elemental analysis value C20B22 F N304 theoretical value C,
82,01; H, 5, F2; N, 10.85 Experimental value C, 81, B2; H, 5,84; N, 10.8
3 Reference Example 2 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-trifluoroacetyl-1-
homopiperazinyl)quinoline-3-carboxylic acid l-cyclopropyl-8-fluoro-1,4-dihydro-7-(1-homopiperazinyl)-4-oxoquinoline-3-carboxylic acid 3.78 g, L2-dichloroethane 3
81 suspension, add 8.90 g of trifluoroacetic anhydride at room temperature.
is added dropwise and stirred for 1.5 hours at 50-60". After cooling, the reaction solution is distilled off and ethanol is added to the residue. The precipitated crystals are filtered and recrystallized from chloroform-ethanol to give a melting point of 228-231. 3.48 g of pale yellow needle crystals were obtained.

Elemental analysis value C20B19 F4N304 theoretical value C,
54,42; H, 4,34; N, 9.52 Experimental value C, 54J3; H, 4,39; N, 9.41
Example 1 8-chloro-1-cyclopropyl-8-fluoro-1,
4-dihydro-4-oxo-7-(4-trifluoroacetyl-1-homopiperazinyl)quinoline-3-carboxylic acid l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4 -) Lifluoroacetyl-1-
homopiperazinyl) quinoline-3-carboxylic acid 3.20
1.18 g of sulfuryl chloride was added dropwise to a suspension of 321 g of 1,2-dichloroethane under water cooling, and stirring was continued for an additional 5 minutes at room temperature. After washing the reaction solution with water and dehydrating, the solvent was distilled off, and the resulting residue crystals were recrystallized from chloroform-ethanol to give a yellow prism product 2 with a melting point of 186-189°.
．． Obtain 58g.

rR spectrum v (KBr) ell″″1:+7
30, IG96, 1GI4 NMR spectrum δ(CDCl2) pI)m:0.
95-1.42 (4H, ■), 1.95-2.25 (2
11, ■), 3.35-4.01 (111) 1. ■),
4.20-4.48 (IH, cod), 8.05 ([, d.

J: IO, 5Hz), 8.90 (IH, s), 14.
1. G (1■, br-s) elemental analysis value C20H18C
I F4N304 theoretical value C, 50, 48; H, 3,
81; N, 8.83 experimental value C, 50, 29; H
, 3,85; N, 8.84 Example 2 8-chloro-1-cyclopropyl-6-fluoro-1,
4-dihydro-7-(1-homopiperazinyl)-4-oxoquinoline-3-carboxylic acid 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-tri 8.6 of 2.20 g of fluoroacetyl-1-homopiperazinyl)quinoline-3-carboxylic acid
% hydroxide) U ram aqueous solution 221 suspension 50-60
Heat for 5 minutes at °C. Cool the solution to pH 8 with 10% hydrochloric acid and collect the precipitated crystals by filtration. The obtained crystals are dissolved in water and 10% aqueous sodium hydroxide solution. After filtering the aqueous solution, the pH was adjusted to 8 with 10% hydrochloric acid. The precipitated crystals were collected by filtration and had a melting point of 229~
1.58 g of a pale yellow powder of 233" (decomposition) is obtained.

1R spectrum v (KBr) cvx :IIl
i2GNMR spectrum δ(DMSO-d6) pp
m: 0.82-1.35 (4H, ugly), 1.70-2.
03 (2H, m), 2.82-3.01i (4[1,■
), 3.31-3.55 (4B, ■), 4.24-4.
53 (l ■, l), 7.91 (IB, d, J: 11.5
H2), 8.81 (111, S) elemental analysis value C18N
19 CI F N304・1/4 H20 theoretical value C
,5B,25; H,5,11i N,10.93 Experimental value C,5B,33; H,5,19; N,10
．． 74 Example 3 8-chloro-1-cyclopropyl-6-fluoro-1,
4-dihydro-7-(4-methyl-1-homopiperazinyl)-4-oxoquinoline-3-carboxylic acid (a) 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-( 1-homopiperazinyl)-
4-oxoquinoline-3-carboxylic acid 0. Bog, 37
2.0 ml of formalin and 2.0 ml of formic acid.
Heat to reflux for an hour. After cooling, the reaction solution was distilled off, water was added to the residue, and the mixture was extracted with chloroform. After dehydrating the extract, the solvent is distilled off, ethanol is added to the residue, and the precipitated crystals are collected by filtration. Recrystallization from ethanol yields 0.13 g of a pale yellow powder with a melting point of 177-179'.

IR spectrum! / (KBr) crl:lfu30
．． IG14NMR spectrum δ(oMsO-d6)I
) I) If: 0.85-1.35 (4Hv), 1.79
-2.09 (2H, Peng), 2.34 (3■, S), 2.
GO-2, 81 (4f [, m), 3.35-3.87 (
4■1m).

4.25-4.52 (1B, m), 7.92 (1■, d
, J=11.5Hz).

8.81UH, s) Elemental analysis value C19N21 CI F N303 theoretical value C,57,94; H,5,37; N,IO,G7
Experimental value C, 58,01; H, 5,52; N, 10
．． 53(b) 1,2- of 1-cyclopropyl-6-fluoro-1°4-dihydro-7-(4-methyl-1-homopiperazinyl)-4-oxoquinoline-3-carboxylic acid
0.44 g of sulfuryl chloride was added dropwise to the dichloroethane 101 suspension at room temperature, and stirring was continued for 5 minutes at the same temperature. The reaction solution was distilled off, and the residue was made alkaline by adding 10% aqueous sodium hydroxide solution, adjusted to pH 8 with 10% hydrochloric acid, and extracted with chloroform. After dehydrating the extract, the solvent is distilled off, ethanol is added to the residue, and the precipitated crystals are collected by filtration to obtain 0.08 g of a pale yellow powder. This is the compound obtained in (a), NMR spectrum, and mass spectrum.

The IR spectra match perfectly.

Example 4 7-(4-acetyl-1-homopiperazinyl)-8-rib-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 7-(4-acetyl -1-homopiperazinyl)-1-
cyclopropyl-8-fluoro-1,4-dihydro-4
1.28 g of sulfuryl chloride was added dropwise to a solution of 1.20 g of -oxoquinoline-3-carboxylic acid in 12.8 ml of chloroform at room temperature, and the mixture was further stirred for 5 minutes. After the reaction solution was washed with water and dehydrated, the solvent was distilled off, and the resulting residue was purified using a silica gel column (solvent: chloroform-methanol) to obtain 0.70 g of a yellow oil cane substance.

IR spectrum v (fllm) cm-”: Otori 82
2NMR spectrum δ(DNSO-ds) pp-:
0.90-1.35 (4H, s), Otori, Fu 5-'2.1
0 (21, koji), 2.04゜2.08 (total 3
11. each s), 3.25-3.78 (811,
w).

4.25-4.46 (lH, m), 7.92 (lH, d
, cll, 511z).

8.79 (1B, s) Light! The novel quinoline-3-carboxylic acid derivative represented by the general formula (I) and its pharmacologically acceptable salt produced in this way are effective against Durum-positive bacteria and Durum-negative bacteria. It has a wide range of antibacterial effects and is extremely useful as a medicine.

The novel quinoline-3-carboxylic acid derivative represented by the general formula (I) thus produced, and its pharmacologically acceptable salts can be prepared into tablets, powders, capsules, It can be made into formulations such as injections, 9 eye drops, 1 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 1.
50 to 1000 mg per dose.

Claims (1)

[Claims] Quinoline-3- represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, or a halogeno lower alkanoyl group. Carboxylic acid derivatives and pharmacologically acceptable salts thereof.