JPS62255482A - 6-alkoxyquinolonecarboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R is lower alkyl; R<1> is 3-6C cycloalkyl, lower alkyl, haloalkyl, (substituted) phenyl, etc.; X is halogen; Z is group of formula II, III (n is 1 or 2; R<3> is H, lower alkyl, lower acyl, etc.; R<4> and R<5> are H, lower alkyl, aminoalkyl, etc.; k and l are 0-2; m is 0 or 1; R<6> is H, halogen, etc.; R<7> is H, haloalkyl, etc.; R<8> is H, benzyl, etc.), azetidino, pyrrolidino, piperidino, etc.]. EXAMPLE:7-( 3-Amino-1-pyrrolidinyl )-8-chloro-1-cyclopropyl-1, 4-dihydro-6-metho xy-4-oxo-3-quinolinecarboxylic acid. USE:An antibacterial agent exhibiting high peroral absorptivity and free from troubling toxicity. PREPARATION:For example, a compound of formula IV (R<3> is H or lower alkyl; Y is halogen) is made to react with an alcoholate of formula MOR (M is alkali metal).

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a novel quinolone carboxyl conductor which is extremely excellent as an antibacterial agent, a method for producing the same, and an antibacterial agent containing the new compound as an active ingredient.

(Comparison with conventional technology) In detail, general formula (I) [wherein R represents a branched or straight-chain lower alkyl group, R1
is a cycloalkyl group having 3 to 6 carbon atoms; a bibranched or straight-chain lower alkyl group;

A haloalkyl group, an alkenyl group, a hydroxyalkyl group, a lower alkylamino group, a substituted or unsubstituted phenyl group, and X represents a halogen atom.

(Here, n is 1 or 2, R3 is a hydrogen atom, a lower alkyl group, a lower acyl group, an alkoxycarbonyl group, or a benzyl group, and R4A and R5 are each independently a hydrogen atom, a lower alkyl group, (Indicates an aminoalkyl group, hydroxyalkyl group or phenyl group.) Or (where k is 0.1 or 2.1 is 0.1 or 2, m
is O or 1, and R5 is a hydrogen atom.

A halogen atom, lower alkyl group or hydroxyl group, R7
represents a hydrogen atom, a lower alkyl group, a haloalkyl group, or a hydroxyalkyl group, and R8 represents a hydrogen atom, a lower alkyl group, or a lower acyl group.

group, alkoxycarbonyl group, or benzyl group. ) or abitidino group, pyrrolidino group, piperidino group 1
Indicates a morpholino group or a thiomorpholino group. ] The present invention relates to a 6-alkoxy-8-halogenoquinolonecarboxylic acid derivative represented by the following, a pharmacologically acceptable salt thereof, and a hydrate thereof.

The quinolone carboxylic acid antibacterial agents called new quinolones since norfloxacin all have a fluorine atom at the 6th position, including ciprofloxacin, which is currently under development.
This fluorine atom is considered to be essential for enhancing the antibacterial activity of quinolone carboxylic acid.

The compound of the present invention is characterized by having an alkoxy group at the 6-position of quinolonecarboxylic acid, and has antibacterial activity comparable to or stronger than that of 6-fluoroquinolonecarboxylic acid derivatives, as well as good oral absorption and pharmacokinetics. show. In addition, it is advantageous in terms of manufacturing cost.

[Means for solving problems]

The method for producing the compound of the present invention is shown below.

(II) (III) (I) (In the formula, M is an alkali metal, Y is a halogen atom, R
5 represents a hydrogen atom or a lower alkyl group. R1, X and Z are the same as above. ) That is, a compound represented by formula (n) is reacted with an alkali metal alcoholade represented by formula (In), and if necessary, hydrolyzed to produce a compound represented by formula [E].

Compounds represented by formula (n) and formula (III).

The reaction with the compound to be mixed can be carried out without a solvent or in a solvent such as water, alcohols, acetonitrile, dimethyl sulfoxide, dimethylformamide, dioxane, benzene, etc. However, when alcohols are used as a solvent, Alcolade and It is preferred and necessary to use alcohols having the same alkyl group. As the alkali metal alcoholade represented by the formula (1), for example, sodium, potassium, lithium, etc. alcoholades can be used, which are synthesized by reacting an alkali metal, an alkali metal hydride, etc. with the alcohol, and then directly subjected to the reaction. You can also serve it. In addition, t-
Compound (n) and the alcohol can also be reacted under a base catalyst such as potassium butoxy or alkali fluoride. More specifically, the compound represented by formula (II) and at least an equivalent mole of the alcoholade represented by compound (I[I) are mixed in 1 to 50 times the volume of the catalyst at room temperature to 2.
It is preferable to carry out the reaction at 00°C for 1 to 100 hours, and it is desirable to carry out the reaction at a high temperature in a sealed tube in order to shorten the reaction time.

Next, in general formula CI), when the 7th base contains a lower acyl group or an alkoxycarbonyl group, that is, X-f/) or (where RIG and R11 are lower acyl groups, alkoxycarbonyl groups, or ru represents a benzyl group, k, i,
m, n, R4, R5, R5 and R7 are the same as above. ) In the case of a compound represented by the following, the substituents of RIG and R11 can be converted into hydrogen atoms by commonly known methods such as hydrolysis and catalytic reduction.

Also, compounds represented by general formula (I).

When the group Z contains a primary or secondary amino group, the amino group can be alkylated by acting on it with a suitable alkylating agent, such as Gλ dealyl halide or formic acid and aldehyde. can. For example, when Z is a piperazinyl group, the compound can be converted to a 4-methylpiperazinyl group by reacting formaldehyde in formic acid.

The compound of the present invention can also be H-formed by reacting a compound represented by general formula (IV) with an amine represented by general formula (V) and, if necessary, hydrolyzing the compound.

H: (IV) m(I) (In the formula, l-1al represents a halogen atom, and R.

R', R9, Y and Z are the same as above. ) then formula CI)
The compound represented by can be converted into its salt according to a conventional method, if desired. Examples of salts include hydrochloric acid, 5A
Acids, salts with non-a acids such as phosphoric acid, methanesulfonic acid, lactic acid, oxalic acid.

Salts with acidic acids such as acetic acid, or sodium.

Potassium, magnesium, calcium, a! Reminium, cerium, chromium, cobalt, copper, iron.

Examples include salts of zinc, platinum, silver, etc.

Furthermore, the compounds of the present invention can be administered to animals or plants.

When this is done, conventional and well-known geometries and routes apply. For example, one powder tablet, capsule, ointment,
Injections, syrups, and solutions.

It is used orally or parenterally with eye drops, external scraping, etc.

〔Effect of the invention〕

The novel mono-alkoxy 8-octalogenoquinolone carbon M derivatives represented by the general formula (I), salts thereof and hydrates thereof produced by this process can be used to treat Gram-positive aerobic bacteria, Gram-positive aerobic bacteria, and It has a wide range of antibacterial effects, including against anaerobic bacteria, and not only shows extremely good absorption even when administered orally to animals, but also shows no toxic effects when administered orally or parenterally. Therefore, it is very useful as a medicine, veterinary medicine, and even as a soba.

(Example) Next, the compound of the present invention and the method for producing the same will be explained in detail using examples.

<Example 1> 7-(3-amino-1-pyrrolidinyl)-8-chloro-
1-Cyclopropyl-1,4-dihydro-6-me-1-xy-4-oxo-3-quinolinecarboxylic acid 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6- Add 10.59 fluoro-1,4-dihydro-4-oxo-3-quinolinecarvone to a sodium methylate/methanol solution (metallic sodium 0.29, anhydrous methanol 9d), seal the tube, and heat in an oil bath at 140 to 150°C. After cooling, the solvent was distilled off, water from the raw mother was added, and the pH was adjusted to 7 with acetic acid.The solvent was distilled off again, and the resulting residue was subjected to silica gel column chromatography [developing solvent]. Separated with chloroform-methanol-Fuchi aqueous ammonia (10: 10: 2>) and recrystallized from methanol to obtain the target object as pale yellow prism crystals 0.149
I got it.

Melting point 137°C (decomposition) Elemental analysis value: C+e N20 CI N304 ・N
20 total sieve value: C: 54.61, H: 5.60
．． N: 10.61 Actual value: C; 54.36
, H; 5.48. N; 10.65 trade mother analysis (
m/e) 377 (M+), 378 (M+ +i>
, 379 (M+ +2)H-NMR (δ in
D20. Na0D>4.0~4.2<1H,
m, <1>.

7.52 (1H, S, 5th position H).

8.53 (1H, S, H at 2-position) <Example 2> 8-chloro-1-cyclopropyl-1,4-dihydro-
6-medoxy7-(3-methyl-1-piperazinyl)
-4-oxo-3-quinolinecarboxylic acid 8-chloro-1
-cyclopropyl-6-fluoro-1,4-dihydro-
7-(3-methyl-1-piperazinyl)-4-oxo-
3.03 3-quinolinecarboxylic acid was added to a sodium methylate/methanol solution (metallic sodium 0.8 L3, anhydrous methanol 5 (7)) and reacted for 224.5 hours in an oil bath at 140 to 150°C. Allowed to cool. After that, the solvent was distilled off, ice water 5 (7) was added, and the pH was adjusted to 7 with acetic acid. aqueous ammonia (10:10:1)]. A part of it was recrystallized from methanol to obtain 37 m3 of the target product in the form of light orange prism crystals.

Melting point 224-24B, 5°C (decomposition) elemental analysis value (
%): C10HzC1N30+・1/2H20 Tightening value: C: 56.93, H: 5.78.
N: 10.48 Actual value: C; 57.0B,
H; 5.71. N; 10.38 <Example 3> 8-chloro-1-cyclopropyl-1,4-dihydro-
6-medoxy7-(3-methyl-1-piperazinyl)
-4-oxo-3-quinolinecarboxylic acid sulfate Example 2
The remainder of the fraction separated by silica gel column chromatography and used for recrystallization from methanol was used in Example 3.

The remainder was dissolved by adding 20 mA ice water, 50% sulfuric acid aqueous solution was added to adjust the pH to <1, and ethanol was further added and left to stand. The precipitated crystals were collected and washed with aqueous ethanol to obtain 40.87 g of sulfur i in the form of pale yellow needle-like crystals.

Melting point 243-246℃ (decomposition) Elemental analysis value (%): C19H22C1N304・H2
S O4・l-120 Calculated value: C: 44.93, H: 5.16. N
:8.27 Actual value: C: 45.14, H; 4
．． 86. N; 8.384.1 to 4.4 (1 to 1.
m, -to'').

6.90 (1H, S, 5th place 1).

8.47 (1H,S, 2-position 1-1) Reference example 1> 7-(3-amino-1-pyrrolidinyl)-8-chloro-
Synthesis of 1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid 8-chloro-1-cyclopropyl-6,7-difluoro-1,4
-dihydro-4-oxo-3-quinolinecarvone r! 1
0.6 No phoacetonitrile in L3! , 0.359 g of 3-aminopyrrolidine, and 31 g of DBUo were sequentially added and centrifuged for 1 hour. Here, 3-aminopyrrolidine 0
．． 2 g was added and centrifuged for 2 hours. After cooling, the precipitate was collected by filtration, and the crystals were dissolved in an aqueous solution 9 containing 0.12 g of sodium hydroxide.
ml and neutralized with acetic acid. Collect the precipitated crystals by filtration, wash with water, and rinse with acetonitrile to remove the desired product as a colorless powder.
I got 29.

Melting point 237-238℃ (decomposition) Elemental analysis value (%): CI7 f-1+7CI FN
303 HzO calculated value: C: 53.20, H: 4.99.
N: 10.95 Actual value: C: 52°97, H:
4.62. N: 10.83 Reference Example 2> 8-chloro-1-cyclopropyl-6-fluoro-1°4-dihydro-7-(3-methyl-1-piperazinyl)
-Synthesis of 4-oxoquinoline-3-carboxylic acid 0MS013d was added to 2.679 2-methylpiperazine and dissolved, and 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro 4 -Oxoquinoline-3-
12.0 L3 of carvone was added and stirred at 60-65°C for 1 hour. After concentrating the reaction solution, 25 ml of water was added to the residue,
Next, add 1N NaOH water) and add pl-(9 to 1
Adjusted to 0. After the reaction solution was heated and completely dissolved, acetic acid was added to adjust the pt to 7. After cooling, the precipitated crystals were collected by filtration, and further mixed with 200 ml of chloroform-methanol (1:1).
) and recrystallization was performed to obtain the desired product 1,189 in the form of light brown prism crystals.

Melting point 246-248℃ (decomposition) Elemental analysis value (%): CIB HI3 CI FN3
03.1/2HzO Calculated value: C: 55.60, H: 5.18.
N: 10.81 Actual value: C: 55.39,
H: 4.83. N; 10.72 Test Example 1> Antibacterial spectrum The antibacterial test was conducted according to the method specified by the Japanese Society of Chemotherapy. The results are shown in Table 1.

Claims (2)

[Claims] (1) General formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R is a branched or straight-chain lower alkyl group, R^
1 is a cycloalkyl group having 3 to 6 carbon atoms, a branched or straight-chain lower alkyl group, a haloalkyl group, an alkenyl group, a hydroxyalkyl group, a lower alkylamino group, a substituted or unsubstituted phenyl group, and X is a Indicates a halogen atom. Z is ▲Mathematical formula, chemical formula, table, etc.▼ (Here, n is 1 or 2, R^3 is a hydrogen atom, lower alkyl group, lower acyl group, alkoxycarbonyl group, or benzyl group, R^4 and R^5 each independently represent a hydrogen atom, a lower alkyl group, an aminoalkyl group,
Indicates a hydroxyalkyl group or a phenyl group. ) Or, there are ▲mathematical formulas, chemical formulas, tables, etc.▼ (where k is 0, 1 or 2, l is 0, 1 or 2, m
is 0 or 1, R^5 is a hydrogen atom, halogen atom, lower alkyl group or hydroxyl group, R^7 is a hydrogen atom, lower alkyl group, haloalkyl group or hydroxyalkyl group, R^8 is a hydrogen atom, Indicates a lower alkyl group, lower acyl group, alkoxycarbonyl group or benzyl group. ) or azetidino group, pyrrolidino group, piperidino group,
Indicates a morpholino group or a thiomorpholino group. ] Quinolone carboxylic acid derivatives, salts thereof, and hydrates thereof. (2) An antibacterial agent containing at least one of the compounds described in claim 1 as an active ingredient.