JPS59137481A - 7-diazabicycloalkane-substituted-4-oxo-1,4-dihydro- quinoline-3-carboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A 7-diazabicycloalkane-substituted-4-oxo-1,4-dihydroquinoline-3- carboxylic acid derivative shown by the formula I (R is methyl, ethyl, or propyl; k and m are 1 or 2; n is 2 or 3). EXAMPLE:( - )-1-Ethyl-6-fluoro-7-{ octahydropyrrolo [1,2-a]pyrazine-2-yl}-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid. USE:Useful as an antibacterial agent. Having high antibacterial action on Gram- positive and Gram-negative bacteria. PROCESS:A 7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative shown by the formula II is reacted with a diazabicycloalkane derivative shown by the formula III in the absence or presence of a solvent, to give a compound shown by the formula I . Water, butanol, etc. may be cited as the solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 7-diazapicycloalkane substituted-4-
This invention relates to oxo-1,4-dihydroquinoline-3-carzanoic acid derivatives and pharmacologically acceptable salts thereof.

More specifically, the present invention relates to the general formula (1) (wherein R is a methyl, ethyl or propyl group, k is an integer of 1 or 2, m is an integer of 1 or 2, and n is a group of 2 or 2). 7-diazabicycloalkane ff substituted 4-oxo-1,4-dihydroquinoline-6-carboxylic acid derivatives represented by be.

Examples of pharmacologically acceptable salts of the compound represented by the general formula (1) include acid addition salts and alkali salts; examples of acid addition salts include hydrochloric acid, nitric acid, Mineral acid salts such as sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid,
Or acetic acid, maleic acid, fumaric acid, citric acid,
The organic acid salt of iFJ Taric Acid'S is an alkali salt, for example, an inorganic alkali salt such as sodium, potassium, calcium, or ammonium salt, or a salt of an organic base such as ethanolamine, N,N-dialkylethanolamine, etc. etc.

A novel 7-cyazavinchloroalkane-substituted-4-7xo-1,4-dihydroquinoline-6-carboxylic acid derivative represented by the general formula (1) of the present invention ('i, produced by the following method e) can do.

That is, the compound represented by the general formula (1) according to the present invention has the following general formula (I+) (wherein R represents the same meaning as above.
Chloro-4-oxo-1,'4-dihydrogynoline-6
-carboxylic acid derivative and a diazavinchloroalkane derivative represented by the following general formula (III) (wherein k, m and n represent the same meanings as above) without a solvent or under a solvent ( It can be produced by reacting in this process.

Examples of the solvent used in this reaction include water, alcohols such as butyl, 3-methquine butanol, and isoamyl alcohol, ethylene glycol dimethyl ether (monoglyme), diethylene glycol dimethyl ether (cedarime), l-diethylene glycol dimethyl ether ( ethers such as triglyme], aprotic polar solvents such as dimethylformamide, dimethylsulfoquinde, hexamethylphosphine, and benzene.

Examples include organic bases such as bilin, picoline, lutidine, colicin, 1, and ethylamine.

Also, the reaction is carried out at a temperature ranging from room temperature to 200°C, preferably at 10°C.
It is appropriately selected within the range of 0 to 180°.

7-chloro-4-ogine-1,4 represented by the general formula -(11) which is the starting material in the production method of the present invention
-dihydroquinoline-6 to carboxylic acid derivatives, for example, JP-A-53-147286, JP-A-55-476
This is a known substance already disclosed in No. 58.

Raw material compound used in the production method of the present invention, 1
1[The diazavinchloroalkane derivative represented by general formula (11) is octahydropyrrolo[]12-8
] Pyrazine, octahythro-IH-bioc+[1+
2-a) [11,4,]diazepine, octahydro-2
1(-pyrido[1,2-a]pyrazine and decahydropyrido[1,2-a)[1,4)diazepine, octahydro-1H-pyrrolo[1,2-d][1,4]diazepine, decahydropyrido[1 ,2-a,:][1°4,]diazepine and the like.

These diazabicycloalkane derivatives are, for example,
OhemiScheBeri
Chte) Volume 92, p. 240 (1959), The Journal of Organic Chemistry (Th
e Journal 1 of Organic
Chemistry) Volume 2 5 2108'R
(1960), Journal of Heterocyclic Chemistry
It is a known substance already disclosed in vol. 6, p. 181 (1969), JP-A-52-12188, JP-A-52-151188, and the like.

In addition, the above general formula (III) which is a raw material compound of the present invention
The diazabicycloalkane derivative represented by has an asymmetric carbon, and the existence of optical isomers is considered. However, a mixture of optical isomers or a separated optically active diazabicycloalkane derivative can be used as a raw material compound. Go 111
It can be obtained as a product.

The novel 7-cyazavinchloroalkane-substituted-4-oxo- represented by the general formula (1) produced in this way
1,4-dihydroxy/phosphorus-6-carboxylic acid derivatives and their pharmacologically acceptable salts have strong antibacterial activity against Durham-positive bacteria and Durham-negative bacteria, and are extremely useful as medicines.

Hereinafter, the present invention will be explained by examples.

“ (-)-1-ethyl-6-fluoro-7-[octahydropyrrolo[1,2-a,:l pyrazin-2-yl]
-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1-ethyl-6-fluoro-2chloro-4-oxo-
1,4-dihydroquinoline-6-carphon i1.11
g, octahydropyrrolo [1°0 2-a] flyer: y([a) +1.8°(C=L
A mixture of 1.55 g of pyridine and 1.55 g of pyridine is heated under reflux for 25 hours. After the reaction, add methanol,
Count the precipitates. The P residue was recrystallized from methanol-chloroform to obtain 072 g of pale yellow needles with a melting point of 260-261° (decomposed).

[α] ]14-17.1° (C=1. Chloroform) Elemental analysis value 019H22FN303 Theoretical value c, 63.50; H, 6,17; N, 1
1.69 Experimental value c, 63.30; H, 6,21;
N, 11.94 Example 2 (±)-1-ethyl-6-fluoro-7-(-Akukuhydro-2-fluoride [1,2-8) hyacin-2
1-ethyl-6-fluoro-7-chloro0-4-oxo-1,4-dihydroquinoline-6-carboxylate@1. 72g
, (±)-octahydro-211-pyrido C1,2-a
] A mixture of 268 g of pyrazine and 7 ml of pyridine,
Heat to reflux for 62 hours. After the reaction, add methanol and collect the precipitate. The precipitate was recrystallized from methanol-chloroborum to obtain 1.02 g of yellow Φ1 crystals with a melting point of 274-276° (minute w1).

Elemental analysis value 020824FN303 Theoretical value a, 64.33; L 6.4B,; N
, 11.25 Experimental value 0.64.25; L 6.56
:N, 11.29 Example 6 (+)-1-ethyl-6-fluoro-7-(octahydro-1H-pyrrolo(1,2-a:](1,4]diazepin-2-yl)-4 -oxo-1+4-dihydroquinoline-6-carboxylic acid 1-ethyl-6-fluoro-7-chloro -4-oxo-1,4-dihydroquinoline-localphone i 1.26g1 octahydro-1H-pyro4 0[ 11,2-a] [1,4) A mixture of 1.91 g of diazepine ([α]01.1° (0=1, ethanol)) and 7 ml of pyridine is heated under reflux for 42 hours. After the reaction, The solvent is distilled off. The residue is treated with water and extracted with chloroform. The chloroform layer is washed with water and dehydrated. The solvent is distilled off, and the resulting residue is recrystallized from ethyl acetate to give a solution with a melting point of 158-16]0 027 g of yellow prism crystals were obtained.

[α:] +84.7° (0=1. Chloroform) Elemental analysis value 020 H24FN303 theoretical value C264,33; H,6,48; N, 11.2
5 Experimental value c, 64.14; H, 6,56; N
, 11.26 Example 4 (1-ethyl-6-fluoro-7-tecahytroviride [1,2-d)[1.4]diazepin-6-yl)
-4-oxo-1,4-7hydroginoline-6-carboxylic acid 1-ethyl-6-fluoro-7-chloro0-4-oxo-
1.4-dihydroquinoline 1.7 4
g, (±]-decahydrohydryl 1-nod[1,2-a)
[1,4) A mixture of 298 g of diazepine and 7 ml of pyridine is heated under reflux for 42 hours. After the reaction, the solvent is distilled off. Add methanol to the residue and collect the precipitate at t5. Recrystallize the precipitate from methanol to obtain a melting point of 226~
225.

0.86 g of pale yellow needle crystals of (decomposition) are obtained.

Elemental analysis value C21H26FN303 Theoretical value c, 65.10; H, 6.76; N. 1
0.85 experimental value C. 64.77 ; H, 6.79
; IIJ, 1 0.68 Patent applicant Hokuriku Pharmaceutical Co., Ltd. 2-5-15 Asahi-cho, Katsuyama-shi Procedural amendment (voluntary) 1981 Otsuki N. Commissioner of the Patent Office Kazuo Wakasugi 1 Description of the case 1982 Patent Application No. 9874 2 Title of the invention 7-diazapicycloalkane-substituted-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative 8 Person making the amendment 4 Date of amendment order Initiator 5 Number of inventions to be increased by the amendment Subject of the amendment Contents of the amendment in column 7 of "Detailed Description of the Invention" in the specification (1) Between the 17th line on page 11 of the specification and the applicant's name, the following Add the text.

"Example 5 (-)-]-]methyl-6-fluoro7-octahydropyrrolo[1,2-a]pyrazin-2-yl)-4-oxo-1,4-dihydroxy/phosphorus-3 -Carboxylic acid・
Hydrochloride 1-Methyl-6-fluoro-twochloro-4-oquine-1,4-dihydroquinoline-3-carphonic acid 1. 4
0 if , octahydropyrrolo[1.2-a]pyrazine (Cd':].

A mixture of +2.2° (0=1, ethanol) 2.071 and pyridine 10/ml is heated under reflux for 30 hours. From now on, the precipitate is collected and the collected product is washed with methanol. After dissolving the P residue in chloroform, ethanolic hydrochloric acid is added. After concentrating the solution, collect a lot of precipitate. The residue was recrystallized from methanol to obtain 0.57 g of colorless needle crystals with a melting point of 278-283° (decomposed).

[σ) 22-5o, oo (C=0.25 Water) Elemental analysis value CIB) I20FN303/IICLH20 Science 3
& Ifi C, 54, 07; n, 5.8
0; N, 10.51 experimental value 0.54.19
, H,5,51iN+ 10.46 Example 6 (-)-1-propyl-6-fluoro-7-1 octahydropyrrolo[1,2-a)pyrazin-2-yl)-4-
Oxo-1゜4-dihydroquinoline-3-carboxylic acid 1
-propyl-6-fluoro-twochloro-4-oxo-
1,4-dihydroquinoline-3-carbon 1 ml 1.
70 g, octahydropyrrolo C1,2-a] pyrazine ([α scale + 24° (C' = 1. ethanol))
A mixture of 2.251 and 5 wl of pyridine was added to 16,5
Heat to reflux for an hour. After the reaction, the solvent is distilled off.

Ethanol is added to the residue, and the precipitate is recrystallized from the collected OF ethanol to obtain colorless Φ1 crystals 072f with a melting point of 181 to 1825°.

C") D -28,00 (c=0.5. riooform) Elemental analysis value c2oH24F'N5o3 theoretical value C,
64,3B, L(, 6,48iN+ 11.25 experimental value C, 64,57; II, 6.47.N, 11.
37 Example 7 (±)-r-ethyl-6-fluoro-7-(octahydropyrroloCI, 2.-..)]pyrazin-2-yl-4
-Oquine-l+ 4-dihydroquinoline-3-carboxylic acid 1-ethyl-6-fluoro-twochloro-4-oquine-1,4-dihydroquinoline-3-carboxylic acid 2.049
, (±)-octahydropyrrolo[11,2a']pyrazine 287! A mixture of 12+wl of pyridine and pyridine is heated to reflux for 25 hours. After the reaction, methanol is added and one portion of the precipitate is taken. The powder was recrystallized from methanol-chloroform to give 1.589 pale yellow needles with a melting point of 249-261' (decomposition).

Elemental analysis value 01gTl22FN303 Theoretical value C,6
8,50; H, 6,17iN+ 11.69 Experimental value 0
．． 6&68.11.6.22 iN+ 11.76 Example 8 (±)-1-ethyl-6-fluoro-7-1 decahydropyrido CI, 2-a][1°4] diazepin-2-yl 1-4- I-ethyl-6-fluoro-2-chloro-4-oxo-1,4-dihydroxy/phosphorus-3-carboxylate
1,4-dihydroxy/phosphorus-3-carboxylic acid 1.979
, decahydropyrido [:1,2-][+, 4:
] A mixture of 337 g of diazepine and 7 ml of pyridine is heated to reflux for 32 hours. After the reaction, the solvent is distilled off. Add methanol to the residue and plrl the precipitate. F scatter? Recrystallized from meta/-chloroform, melting point 21
124 g of pale yellow needles having an angle of 1-213° (decomposition) are obtained.

Elemental analysis value C21H26FN303 Theoretical value C,65,10;I(,6,76iN,10
．． 85 experimental value 0.65.06; 4L 6.98 i
N, 10.84.

Claims (1)

[Claims] (In the formula, R is a methyl, ethyl or propyl group, and k is 1
or an integer of 2, m represents an integer of 1 or 2, and n represents an integer of 2 or 6. ) A 7-diazapicloalkane-substituted-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative represented by the following, and a pharmacologically acceptable salt thereof.