JPH01165584A - Novel 1,8-naphtylidine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I{X is H or halogen: R1 is lower alkyl, lower alkenyl or lower cycloalkyl; R2 is formula II or formula III [R3 is H, acetyl, formyl or (OH-substituted) lower alkyl; A is (substituted) 3-4C alkylene]}. EXAMPLE:1-Ethyl-1,4-dihydro-4-oxo-7-pyrazolidinyl-1,8-naphtylidine-3-c arboxylic acid. USE:An antibacterial agent against gram-negative bacterium and gram-positive bacterium. The agent has excellent absorption and is useful as 1 remedy for urinary tract infectious disease. PREPARATION:A carboxylic acid expressed by formula IV (Y is group capable of replacing with pyrazolidines, 1-aminopyrrolidine, etc.) or ester thereof is reacted with pyrazolidines expressed by formula V or 1-aminopyrrolidines expressed by formula VI or hydrochloride thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION 1) Industrial Application Field The present invention relates to novel 1,8-naphthyridine derivatives and pharmacologically acceptable salts thereof.

More specifically, the present invention refers to a hydrogen atom or a halogen atom, especially fluorine, R1 is a lower alkyl group, a lower alkenyl group or a lower cycloalkyl group, and R2 is a group of the formula In the formula, R3 is a hydrogen atom, an acetyl group, a formyl group, or a lower alkyl group optionally substituted with a hydroxyl group, and A is an optionally substituted alkylene chain having 3 to 4 carbon atoms. The present invention relates to a 1,8-naphthyridine derivative represented by the following formula, and a pharmacologically acceptable salt thereof.

Here, R2 includes a pyrazolidinyl group, a hexahydropyridazinyl group, a pyridinylamino group, and the like.

Examples of lower alkyl groups and lower alkenyl groups include methyl, ethyl, n-propyl, isopropyl, and 2-propenyl groups, and examples of lower cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclopentyl groups. Specific examples of the salt include salts with inorganic acids such as hydrochloric acid, sulfuric acid, and methanesulfonic acid, or salts with organic acids such as gluconic acid and tartaric acid, and sodium, potassium, and ammonium salts of carboxylic acids.

2) Prior art At present, nalidisucic acid (US Pat. No. 3,590,036) or pipemide NI (West German Pat. No. 2,341,146) are widely used as synthetic antibacterial agents for treating infections caused by Durham-negative bacteria. However, these methods are ineffective against Pseudomonas aeruginosa infection, which is one of the intractable diseases that has been increasing in recent years.

On the other hand, in order to solve these drawbacks, antibacterial agents called norfloxacin and ciprofloxacin have been developed and put into clinical use in recent years. However, although it certainly has excellent antibacterial activity in vitro, unlike nalidisucic acid and pipemidic acid, it has been pointed out that it has poor bioavailability and does not work effectively in vivo.

3) Problems to be solved by the invention As described above, conventional antibacterial agents have little activity but poor absorption.
In addition, absorption is good, but activity is low, which is unsatisfactory. Therefore, in order for a synthetic antibacterial agent to act effectively on living organisms, it is necessary to have both excellent antibacterial activity and bioavailability, and the present invention solves these problems.

4) Means to solve the problem We have already started developing an antibacterial agent with excellent antibacterial activity and high bioavailability. Heterocycles with nitrogen-nitrogen bonds, such as pyrazolidines, have low toxicity;
In addition, we have discovered that they have an appropriate balance of hydrophilicity and oiliness, and have developed many compounds in which pyrazolidines are introduced at the 7-position of quinolinecarboxylic acid, which is the core of existing synthetic antibacterial agents, and 1,8-naphthyridinecarboxylic acid. was synthesized. As a result, we found that these compounds have strong antibacterial activity not only against Durham-negative bacteria such as Pseudomonas aeruginosa but also against Durham-positive bacteria, and have excellent bioavailability (especially Gansho 6l-214258). The present invention provides a novel 1,8-naphthyridine derivative having excellent antibacterial activity as a ring.

5) Effect The compound represented by the above-mentioned Tsuzuriyo (I) can be produced by various methods, but a preferred example thereof is, for example, the following known method [J, Ed, Chem, 27
, 292 (1984)].

Carboxylic acid or its ester represented by general formula (11) (wherein, X and R are the same as above, and Y means a group that can be substituted with pyrazolidines, 1-aminopyrrolidines, etc.) and pyrazolidines, 1-aminopyrrolidines, or their hydrochloride represented by the following formula (in the formula, R3 and A mean the same as above), and the product is isolated by a conventional method. It can be manufactured by

In formula (II), specific examples of the functional group represented by Y include a halogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfonyloxy group, and the like.

This reaction uses ethanol, acetonitrile, dioxane,
In an inert solvent such as dimethylformamide, dimethyl sulfoxide, pyridine, toluene, xylene, room temperature to 2
Compound (I) at 00 degrees, preferably room temperature to 150 degrees
This can be carried out by mixing and stirring I) with the above pyrazolidines and 1-aminopyrrolidines at 0° for 25 to 24 hours, usually for 0.5 to 5 hours. Pyrazolidines used, 1
The amount of -aminopyrrolizidine is preferably slightly excess (1.1 to 5 equivalents) relative to compound (II). In addition, when using a hydrochloride, a base 1 such as [Chem, B
er, 91, 1982 (1958).

Depending on the selection of Y in compound (II), an acid may be produced as a by-product as a result of the reaction, so in such cases, a base is also used as the acid acceptor, but in this case, an excess of free pyrazolidines is used to It is convenient to have it also serve as the role of

In addition, for compounds in which R3 is an acetyl group, formyl group, or a lower alkyl group which may be substituted with a hydroxyl group, corresponding compounds in which R1 is a hydrogen atom may be substituted with acetic anhydride or formic acid.

It can also be obtained by reacting with alkyl halides, aldehydes, etc.

The objective compound (1) and its salts thus obtained exhibit excellent antibacterial activity against a wide range of Durham-negative and -positive bacteria, and have excellent absorbability, making them useful as therapeutic agents for urinary tract infections and the like.

6) Examples Next, the compounds of the present invention will be explained in more detail with reference to Examples.

Example 1 1-ethyl-1,4-dihydro-4-oxo-7-virazolidinyl-1,8-naphthyridine-3-carboxylic acid.

7-chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 1.85
g (7.3 mmol), pyrazolidine 0.56 g
(7°8 mmol) was added to 20 ml of ethanol and refluxed for 1 hour.

After the reaction, the precipitated crystals are collected by filtration, washed with ethanol, and then recrystallized from ethanol (yield: 1.7 g).

Melting point: 279-81℃ Elemental analysis: C engineering 4H, GN, 03 (MW=288
．． 307) Theoretical value H5, 59%, C58, 32%,
N 19.43% Actual value H5, 68%, C58,
52%, N 19.59% Example 2゜1-ethyl-1,4-dihydro-4-oxo-7-(2
-pyrazolin-1-yl)-1,8-naphthyridine-3
-Carboxylic acid.

7-chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carvone fio, 3a
g (1,3 01), pyrazolidine 0.1g (1
,4mn+ol), and anhydrous potassium carbonate 0.28
8g (2,11IIIlo1) in DMF10a+1
and heat at 95°C for 2 hours.

The reaction mixture was concentrated under reduced pressure, the residue was dissolved in a small amount of water, and the residue was dissolved in a small amount of water.
-After neutralization with hydrochloric acid, the precipitated crystals are collected by filtration, washed with water, dried and DM
Obtained by recrystallization from F (yield: 0.18 g).

Melting point = 289°C Elemental analysis: C,, H,, N, 03.1/4 H, 0 theoretical value H5,03%, C57,83%, N 19.
27% actual value H4, 75%, C57, 92%, N
19.30% Example 3゜1,4-dihydro-1-methyl-4-oxo-7-virazolidinyl-1,8-naphthyridine-3-carboxylic acid.

Example 1. Similarly, 7-chloro-1,4-dihydro-
1-Methyl-4-oxo-1,8-naphthyridine-3-
Synthesized from carboxylic acid and pyrazolidine, ethanol/D
Obtained by recrystallization from a mixed solvent of MF (yield 58%).

Melting point: 300℃ or higher Elemental analysis 2 〇□3H engineering 4N403 (MW=274
．． 28) Theoretical value H5, 15%, C56, 93%,
N 20.43% Actual 21M value H5, 12%, C56,
83%, N 20.31%Example 4゜1,4-dihydro-4-oxo-1-(2-propenyl)-7-virazolidinyl-1,8-naphthyridine-3-
carboxylic acid.

Example 1. Similarly, 7-chloro-1,4-dihydro-
It is synthesized from 4-oxo-1-(2-propenyl)-1,8-naphthyridine-3-carboxylic acid and pyrazolidine and recrystallized from ethanol (yield 71%).

Melting point: 233-5°C Elemental analysis: C, 5ILGN, O, (MW=300.
318 theoretical value H5, 37%, C59, 99%, N
18.66% actual value H5, 13%, C59,92
L N 18.5]% Example 5゜6-chloro-1-ethyl-1,4-dihydro-4-oxo-7-virazolidinyl-1,8-naphthyridine-3-
carboxylic acid.

Example 1. Similarly, 6,7-cyclo-1-ethyl-
1,4-dihydro-4-oxo-7-pyrazolidinyl 1
, F3-ff') Jin-3-h report:/ao, Ig
(0°35 mn+ol) and 0.05 g of pyrazolidine
(0.7 mmol), ethanol/DMF
Obtained by recrystallization from a mixed solvent of
22.752) Theoretical value H4, 68%, C52, 10%, N 17
．． 36% actual value H4, 54%, C52, 53%,
N 17.17% Example 6゜1-ethyl-1,4-dihydro-7-(2-methylpyrazolidinyl)-4-oxo-1,8-naphthyridine-3
-Carboxylic acid.

Example 1. Similarly, 7-chloro-1-ethyl-1゜4
-dihydro-4-oxo-1,8-naphthyridine-3-
Synthesized from 0.253g (1mmol) of carboxylic acid and 0.2'58g (3mmol) of 1-methylpyrazolidine, and obtained by recrystallizing from ethanol (yield: 0.17g)
.

Melting point: 235-6°C Elemental analysis: C1, Hl, N, O, (MW=302.
334 theoretical value 86.00%, C59,59%, N
18.53% actual value H5,90%, C511,5
4%, N 18.71%Example 7゜1-ethyl-1,4-dihydro-7-[2-(2-hydroxyethyl)pyrazolidinyl]-4-oxo-1,8
-naphthyridine-3-carboxylic acid.

Example 1. l-ethyl-1,4-dihydro-4- obtained in
Oxo-7-virazolidinyl-1,8-naphthyridine-
3-carboxylic acid 0.144g (0.5mmol)
, ethylene bromohydrin 0.313 g (2,5
mmol) and 50% sodium hydroxide in dry DM
Add to 2 ml of F and heat at 95°C for 3 hours. After the reaction, insoluble matters were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate (yield: 0.07 g) Melting point: 181-3°C Elemental analysis: Cxs Hia N404 (MW=3
32.36) Theoretical value H6,07%, C57,82%
, N 16.86% actual value H6, 11%, C57
,42%, N 16.75%Example 8゜1-ethyl-7-(2-formylpyrazolidinyl]-1
゜4-dihydro-4-oxo-1,8-naphthyridine-
3-carboxylic acid.

Example 1. 1-ethyl-1,4-dihydro-4- obtained in
Oxo-7-virazolidinyl-1,8-naphthyridine-
0.07 g (0.24 mmol) of 3-carboxylic acid and 0.3111 g of formic acid are heated at 95° C. for 30 minutes. The reaction mixture is concentrated under reduced pressure, ethanol is added to the residue, insoluble materials are filtered off, the residue is concentrated, and the residue is recrystallized from a mixed solvent of ethanol and DMF (yield: 0.07 g).

Melting point: 256-8°C Elemental analysis: C1, H, GN, O, (MW=316.
317 theoretical value H5, 10 Nu, C56, 96%, N
17.71% actual value Hs, u%, C56, 69%
, N 17.98% Example 9゜1-ethyl-7-(2-acetylpyrazolidinyl)-1
゜4-dihydro-4-oxo-1,8-naphthyridine-
3-carboxylic acid.

Example 1. 1-ethyl-1,4-dihydro-4- obtained in
Oxo-7-virazolidinyl-1,8-naphthyridine-
4 g (1.4 mmol) of 3-carboxylic acid Q is added to 5 ml of acetic anhydride and refluxed for 1 hour. The reaction mixture is concentrated under reduced pressure, ethanol is added to the residue, insoluble materials are filtered off, concentrated, and recrystallized from ethanol (yield: 0.4
g).

Melting point: 280-1°C Elemental analysis: C1, Hl, N40. (MW=33
0.344 theoretical value H5,49%, C58,17,
N 16.96% actual value H5, 62%, C58,
26%, N 16.83% Example 10゜7-hexahydropyridazinyl-1,4-dihydro-1
-Methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid.

7-chloro-1,4-dihydro-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid 0.47
7 g (2 mmol), hexahydropyridazine
Add 0.516 g (6 batches) to ethanol 2011 and reflux for 3 hours. After the reaction, the precipitated crystals are collected by filtration and recrystallized from a mixed solvent of ethanol and DMF (yield: 0.37
g).

Melting point: 275-7℃ Elemental analysis: C14H,, N403 (MW=288
．． 307 theoretical value H5,59L C5g, 32%, N
19.43% Actual value H5, 69%, C58, 43%
, N LD, 33% Example 11゜1-ethyl-7-hexahydropyridazinyl-1,4-
Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

Example 10. Similarly, 7-chloro-1-ethyl-1°4-dihydro-4-oxo-1,8-naphthyridine-3
- Synthesized from carboxylic acid and hexahydropyridazine and recrystallized from ethanol (yield 56%).

Melting point = 260℃ Elemental analysis: Cyu d-1□, N403 (MW = 302
,334 theoretical value H6,00%, C59,59%,
N 18.53% Actual value H6.05%, C59.5
3%, N 18.40%Example 12゜7-hexahydropyridazinyl-1,4-dihydro-4
-oxo-1-(2-propenyl)-1,8-naphthyridine-3-carboxylic acid.

Example 10. Similarly, it was synthesized from 7-chloro-1,4-dihydro-4-oxo-1-(2-propenyl)-1,8-naphthyridine-3-carboxylic acid and hexahydropyridazine, and recrystallized from ethanol. (yield 70%)
).

Melting point: 226-9℃ Elemental analysis: C1, Hl, N, 03 (MW=31
4.345 Theoretical value H5, 77%, C61, 14%,
N 17.82% actual value H5, 97%, C61,
31%, N 17.71% Example 13゜7-(2-acetylhexahydropyridazinyl)-1-
Ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

Example 11. Obtained 1-ethyl-7-hexahydropyridazinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 0.4 g (1,32 mm
. (2) was added to acetic anhydride 5 ml and refluxed for 1 hour. The reaction mixture is concentrated under reduced pressure, ethanol is added to the residue, insoluble materials are filtered off, concentrated, and recrystallized from ethanol to obtain
to, 39g).

Melting point = 286℃ Elemental analysis: C1□H,,N,04 (MW=344
．． 371 theoretical value H5, 85%, C59, 29%,
N 16.27% Actual value H5,05L C5! ], 1
1%, N 16.43%Example 14°1-Ethyl-6-fluorofhexahydrobyridazinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

3.0 ml of hexahydropyridazine was added to 1 g (3.7 mmol) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, and 60 The reaction mixture is concentrated under reduced pressure, water is added to the residue, and the precipitated crystals are collected by filtration, washed with water, dried, and recrystallized from ethanol (yield: 0.53 g).

Melting point: 200-1℃ Elemental analysis: CxsHitFN403 (MW=320
．． 324) Theoretical value H5, 35%, C56, 24m, N 17
．． 49% actual value H5, 31%, C56, 24%,
N 17.38% Example 15゜1-cyclopropyl-6-fluoro-7-hexahydropyridazinyl-1,4-dihydro-4-oxo-1,8
-naphthyridine-3-carboxylic acid.

7-chloro-1-cyclopropyl-6-fluoro-1゜4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic acid 1.1g (4,0⅜o1), hexahydropyridazine 2.5ml ethanol 20IIl
1 and heat at 60°C for 1 hour. The reaction mixture is concentrated under reduced pressure, water is added to the residue, the precipitated crystals are collected by filtration, washed with water, dried, and recrystallized from ethanol (yield: 0.6 g).
.

Melting point: 220-1℃ Elemental analysis: c, , engineering i, , FN4o.

(MW=332.335) Theoretical value H5, 16m, C57, 83%, N 16
．． 86% actual value H5, 17%, C5g, 02%,
N 16.78% Example 16°1-ethyl-6-fluoro-7-(3-iminopyrazolidinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid 0.5 g (1.8 mmol), 3-iminopyrazolidine hydrochloride 1 ．． Qg (8.2 mmol)
and anhydrous potassium carbonate 1.0g (7.2mmol
) was added to 25 ml of ethanol and heated at 50°C for 4 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, the pH was adjusted to 6 with diluted hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water and dried.I)
Obtained by recrystallization from MF (yield: 0.38 g).

Melting point = 300℃ or higher Elemental analysis: C1,1-114FN, 03 (MW = 3
．． 19.296) Theoretical value H4, 42%, C52, 66%, N 21
．． 93% actual value H4, 42%, C52, 71%,
N 21.89% Example 17゜1-cyclopropyl-6-fluoro-7-(3-iminopyrazolidinyl)-1,4-dihydro-4-oxo-1
゜8-Naphthyridine-3-carboxylic acid.

Example 16. Similarly, 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1
, 8-naphthyridine-3-carboxylic acid 1.13g (4
,0111Iol) and 3-iminopyrazolidine hydrochloride
It was synthesized from 2.19 g (18 dragon o1) and recrystallized from DMF (yield: 0.59 g).

Melting point = 300℃ or higher Elemental analysis: C; sHx4FNsO3 (MW = 331
．． 307) Theoretical value H4, 26%, C54, 38%, N 21
．． 14% actual value H4, 32%, C54, 46%,
N 21.22% Example 18° 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-pyrrolidinylamino)-1,8-naphthyridine-3-carboxylic acid.

Add 0.41 g (1.5 mmol) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid to 50 ml of ethanol and stir overnight at room temperature. Stir. The reaction mixture is concentrated under reduced pressure, the residue is subjected to silica gel column chromatography (chloroform: carbon tetrachloride = 10:1-+lo:O), the desired fractions are collected, concentrated, and recrystallized from ethanol to obtain (
Yield R0.1g).

Melting point: 238-40℃ (decomposition) Elemental analysis:
C1, Hl, FN, O.

(MW=320.324) Theoretical value H5, 35%, C5(i, 24%, N 1
7. /19% Actual value H5,50%, C56,06%
, N 17.35% Example 19゜1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-pyrrolidinylamino)-1゜8-naphthyridine-3-carboxylic acid .

Example 18. Similarly, 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1
, 8-naphthyridine-3-carboxylic acid 1.4g (5
mmol) and 1.3 g (15 mmol) of 1-aminopyrrolidine
mol), produced using silica gel column chromatography (chloroform: carbon tetrachloride = 4:l → 4:0),
Obtained by recrystallization from ethanol (yield: 0.2 g).

Melting point: 250℃ (decomposition) Elemental analysis: C15HttFN40x'l/4HzO
Theoretical value H5.24%, C57.05%, N16
．． 63% actual value H5,07%, C57,23L N
16.57% 7) Effect of the Invention The usefulness of the compound of the present invention as an antibacterial agent was proven by the following biological test. In vitro antibacterial testing is a method specified by the Japanese Society of Chemotherapy [Journal of the Japanese Society of Chemotherapy, 29. (1) 76 (1981)],
As control drugs, nalidisucic acid and norfloxacin were used. Among the compounds of the present invention, the test results for the compounds of Examples 4 and 15 are shown in Table 1. Shown below.

Table 1 Procedural amendment (voluntary) 1. Description of the case 1986 Patent Application No. 326411 2 Title of the invention New 1,8-naphthyridine derivative 3 Person making the amendment: Patent applicant 4 Agent address 2-2-39 Jingumae, Shibuya-ku, Tokyo 417 Detailed Description of the Invention Column 6, Statement of Amendment, page 3, line 1, F pyridinylamino group'' was changed to ``pyrrolidinylamino group'', line 12, line 20 of the same page, ``nalidisucic acid'' was changed to ``nalidix''. Corrected to "acid".

On page 5, line 3, "manufactured by a method" is corrected to "manufactured by a method."

On page 6, line 7, ``dimethylformamide,'' was corrected to ``dimethylformamide (DMF), J.'' Line 15 of the same page, ``For example,'' was followed by ``It is common to use alkali carbonates, alkali metal alcoholades, triethylamine, etc.'' In addition, the phrase "For example, pyrazolidines and hexahydropyridazines" is inserted.

``50% sodium hydroxide'' in line 1 of page 12 is changed to ``50% sodium hydride'', line 18 of page 12 and line 6 of page 14 [
Correct ethanol DMFJ to [ethanol/DMF].

On page 20, line 6, next to ``In addition,'' add the phrase ``Add 0.38 g (4.5 mmol) of 1-aminopyrrolidine there.''

On page 21, line 4, "produce," is changed to "purify," and in line 3 from the bottom, "nalidixic acid" is changed to "nalidixic acid."

In the table on page 22, "nalidixic acid" is replaced with "nalidixic acid".
"Staphylococcus aureus ATTCC653
8PJ [Staphylococcus aureus ATCC
Corrected to 6538PJ.

Claims (1)

[Claims] General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X means a hydrogen atom or a halogen atom,
R_1 is a lower alkyl group, lower alkenyl group, or lower cycloalkyl group, R_2 is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R_3 is a hydrogen atom, an acetyl group , a formyl group, or a lower alkyl group which may be substituted with a hydroxyl group, and A is an optionally substituted alkylene chain having 3 to 4 carbon atoms. ) A 1,8-naphthyridine derivative represented by: and a pharmacologically acceptable salt thereof.