JPH02279673A - Quinolone derivative - Google Patents

Abstract

NEW MATERIAL:A quinolone derivative shown by formula I (X is halogen; R<1> and R<2> are H or alkyl and at least one of R<1> and R<2> is alkyl) and a salt thereof. EXAMPLE:1-Cyclopropyl-6,8-difluoro-7-dimethylamino-1,4-dihydro-4-oxoqu inoline-3- carboxylic acid. USE:An oral antimicrobial agent showing highly antimicrobial activity against both gram-positive and gram-negative bacteria, having high concentration in blood after oral administration, capable of maintaining high concentration for many hours and reducing the number of times of administration. PREPARATION:A 1-cyclopropyl-6,7-difluoro-8-halogeno-1,4-dihydro-4- oxoquinoline-3-carboxylic acid shown by formula II is reacted with a primary or secondary amine hydrochloride shown by formula III in an aprotic solvent such as dimethylformamide in the presence of a base such as Et2NH to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to novel quinolone derivatives useful as oral antibacterial agents and pharmaceutically acceptable salts thereof.

(Prior art and problems to be solved by the invention) The history of the development of pyridonecarboxylic acid antibacterial agents began with the discovery of nalidixic acid, and began with the appearance of so-called new quinolones that have fluorine at the 6th position and piperazine at the 7th position. It has made great progress. Subsequent improvement research revealed that compounds with a cyclic amine other than piperazine attached to the 7-position, such as 2'-aminomethylpyrrolidine, also have high antibacterial activity; The common problem of new quinolones, that is, low levels, remained unresolved. Therefore, we focused on quinolone compounds and conducted intensive research with the aim of finding a compound that can achieve high blood concentrations when administered orally and maintain this concentration for a long time.

As a result, a cyclopropyl group is bonded to the 1st position of the quinolone ring, a fluoro group is bonded to the 6th position, and a monoalkylamine such as monomethylamine or monoethylamine, or a dialkyl group such as dimethylamine, diethylamine, or methylethylamine is bonded to the 7th position. It has been found that a compound to which an amine is bonded and a halogen atom is bonded to the 8-position has high antibacterial activity.

JP-A-59-212474 proposes compounds in which a cyclic amine such as piperazine, piperidine, pyrrolidine, morpholine, thiomorpholine, etc. is bonded to the 7-position of the quinolone ring as a compound similar to such quinolone compounds. However, there is no description of specific examples of the above-mentioned quinolone compounds, nor is there any description of them having antibacterial activity.

(Means for Solving the Problems) The present invention provides a quinolone derivative represented by the following formula and a pharmaceutically acceptable salt thereof.

(In the formula, X represents a halogen atom, R1 and R1 each independently represent a hydrogen atom or an alkyl group, and R
At least one of 1 and R2 represents an alkyl group. ) Hereinafter, the present invention will be explained in detail.

The quinolone derivative of the present invention is represented by the above general formula (I). In the formula, X represents a halogen atom such as a chlorine atom, a fluorine atom, or an iodine atom, and R1 and R2 represent a hydrogen atom or an alkyl group having 1 to 1 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, etc. represents an alkyl group of 4,
At least one of them represents an alkyl group.

In the present invention, X represents a fluorine atom, R1 and R
It is preferred that both 1's represent an alkyl group, in particular both methyl groups.

Specific examples of the compounds of the present invention include the compounds listed in Table 1 below.

No. table (II) Next, a method for producing compound (1) of the present invention will be described.

The compound of the present invention can be easily synthesized, for example, by the following method.

Medicinal Chemistry Volume 30, Page 504,
l-cyclopropyl-6,7-difluoro-8-halogeno-1, which can be synthesized by applying
4-dihydro-4-oxoquinoline-3-carboxylic acid (
n) in an aprotic solvent such as dimethylformamide (DMF) or N-methylpyrrolidone, and reacted with triethylamine (EL3N), a base such as potassium carbonate, and a -class or secondary amino acid 150"C for several hours. Compound (1) can be obtained in good yield.

Compound (1) of the present invention is most effective when administered as an oral preparation, but it can also be administered as an injection.

Examples of dosage forms for oral administration include powders, granules, tablets, sugar-coated tablets, capsules, and liquids. Furthermore, the compound (1) of the present invention can be formulated by conventional methods in this field.

The dosage of the compound of the present invention is determined by a physician, taking into account age, sex, body weight, type of dye, administration method, administration time/interval, degree of medical condition, etc.

For example, when administered orally, per 1 kg body weight per day,
A dose of about 0.1 to 20 mg is administered once a day or divided into 2 or 3 doses, but is not limited thereto.

Compound (1) of the present invention is usually administered as it is, but it can also be administered as a pharmaceutically acceptable salt. Examples of the salt include metal salts such as sodium salt, potassium salt, and calcium salt, inorganic salts such as ammonium salt, and organic amine salts such as dicyclohexylamine salt.

The compound (1) of the present invention has strong activity against Durham-negative bacteria, and is also effective against Durham-positive bacteria, which has been said to have a problem of relatively weak activity with conventional quinolone antibacterial agents. It has strong activity.

In particular, compound No. 1 shown in Table 1 has a broad antibacterial spectrum and high antibacterial activity. Furthermore, this compound kl exhibits strong activity against new quinolone-resistant Staphylococcus aureus, which is currently becoming a problem.

Furthermore, when the compound (1) of the present invention is orally administered, a high blood concentration can be obtained and the concentration can be maintained for a long time, whereas most conventional quinolone antibacterial agents need to be administered three times a day. In contrast, sufficient therapeutic effects may be obtained with once-daily administration.

(Example) Hereinafter, the present invention will be explained in more detail with reference to Examples.

In this example, the compound was determined and identified by melting point, IR (infrared absorption spectrum), and NMR (nuclear magnetic resonance spectrum).

Example 1 1-Cyclopropyl-6,8-difluoro-7-dimethylamino-1,4-dihydro-4-oxoquinoline-3
-Preparation of carboxylic acid (compound Nα1 in Table 1) l-cyclopropyl-6,7,8-)refluoro-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid 4
．． 25 g and 6.12 g of dimethylamine hydrochloride were dissolved in dimethylformamide 40111, and 7.58 g of triethylamine was added. After stirring at 140°C for 3 hours, the solvent was distilled off under reduced pressure, 200 nl of water was added to the residue, and the resulting crude crystals were stirred in a furnace and washed with water. This was recrystallized from a mixed solvent of ethanol and dimethylformamide to obtain 3.56 g (yield: 77%) of the above-mentioned desired product.

The analysis and measurement results of the compound were as follows. Melting point 200
~202°C, I R (KBr, cm-') 1725,
1620°N M R (DzO+Na0Dl δ)
0.75-1.02 (m, 4) 1).

2.68 (s, 6H), 3.68-3.80 (m, I
II), 7.46 (dd, 1ll).

8, 23 (s, IH).

Examples 2 to 3 Compounds No. 2 and Nα4 in Table 1 were synthesized by the same method as in Example 1.

The respective melting points were as follows.

Compound No. 2: Melting point 154-156°C Compound NL
14: Melting point 237-239°C (hereinafter referred to as blank space) Reference Examples 1 to 2 In the same manner as in Example 1, the following compound (■) and compound (TV) were synthesized.

The respective melting points were as follows.

Compound (■): Melting point 223-224°C (decomposition) Compound (■): Melting point 261-262°C Test example! (Antibacterial activity test) Compounds NO, 1, No, 2, and N04 obtained in the above examples, the following representative compounds (■) described in the above-mentioned JP-A-59-212474, and commercially available quinolone antibacterial agents. The in vitro antibacterial activity of the following ofloxacin (■), the compounds 'I (I [[) and (IV)] synthesized in the above reference example, was determined using the Japanese Society of Chemotherapy standard method (chemotherapy,
29, p. 76, 1981) to determine the minimum inhibitory concentration (MIC). The results are shown in Table 2.

(Vl) Test Example 2 (Blood concentration 1 hour after oral administration) Compound NaI, compound (V) and compound (Vl) were administered to mice.
The drug 1) was orally administered at 1O2/kg, and blood was collected from a cruciate tube 1 hour later. The antibacterial activity of the serum obtained by centrifugation was measured by the thin layer cup method (Test bacterium I Schieriki 7coli NIIIJ JC-2), and from the calibration curve obtained by dissolving the drug in phosphate buffer, serum The amount of unbound protein was calculated. The results were as shown in Table 3 below.

Table 3 As is clear from the results, Compound No. 1 has reached approximately the same concentration as ofloxacin (Vl), which is said to have good oral absorption, whereas compound (V) has a concentration that is approximately the same as ofloxacin (Vl), which is said to have good oral absorption. The concentration was 4.

In addition, since compound (V) and ofloxacin (Vl) have a low serum protein binding rate, the amount of drug present in the blood is not much different from the concentration of serum protein-free form, but compound N
o. Since the serum pallor binding rate of mouse 1 was 95% as measured by a conventional method, it was found that the total serum concentration of the drug was more than 10 times that of ofloxacin.

In other words, compound Nα1 has a concentration of non-binding serum protein that exhibits antibacterial activity, which is almost the same as ofloxacin (Vl) and four times that of compound (V), and the total serum concentration is more than 10 times that of ofloxacin (Vl). Compound No. 1 is a combination of compound (V) and ofloxacin (Vl
) can be said to have completely different properties.

Test Example 3 (Test on changes in blood concentration) Compound 1 and Compound (V) were administered to mice at doses of 25 μ/kg
was orally administered, blood was collected after a predetermined period of time, the antibacterial activity was measured in the same manner as in Test Example 2, and from the calibration curve obtained by dissolving the drug in phosphate buffer and mouse serum, serum protein-free binding was determined. Body concentration and total amount in blood were calculated. The results are shown in Table 4 below.

For reference, please refer to the document ``30th Japanese Society of Chemotherapy, Western Japan Branch New Drug Symposium DL82''.
Table 5 below shows the changes in the blood concentration of ofloxacin, which is described in ``80.114 Page''.

(Hereinafter, blank spaces) As is clear from the above results, the quinolone derivative of the present invention has a longer half-life of blood concentration after oral administration than conventional quinolone derivatives.

〔Effect of the invention〕

The present invention is a novel quinolone derivative represented by the general formula (I) and its pharmaceutically acceptable salt, which exhibits high antibacterial activity against both Durum-negative bacteria and Durum-positive bacteria, and is an oral antibacterial agent. It is useful as

Moreover, the compound of the present invention has a high concentration in the surface after oral administration,
Moreover, since high concentrations can be maintained for a long period of time, the number of administrations can be reduced.

Claims (1)

[Claims] (1) A quinolone derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼……(I) (In the formula, X represents a halogen atom, R^1 and R^2
each independently represents a hydrogen atom or an alkyl group, and at least one of R^1 and R^2 represents an alkyl group. )