Quinolizine carboxylic acid derivatives

Details Quinolizine carboxylic acid derivatives Quinolizine carboxylic acid derivatives

2000-02-08

2001-05-22

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S138000

Reexamination Certificate

active

06235751

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to 4-oxo-quinolizine carboxylic acid derivatives and pharmaceutically acceptable salts thereof having an excellent antibacterial activity, a process for preparing same, and an antibacterial composition containing same as an active ingredient.
BACKGROUND OF THE INVENTION
Quinolizine derivatives are known to exhibit excellent antibacterial activities(see PCT publication No. WO 95/10519) However, some of the conventional quinolizine compounds have limited activities against Gram-positive bacteria, while other quinolizine derivatives exhibit the problem of poor water-solubility or side effects such as high cytotoxicity.
The present inventors have, therefore, endeavored to develop non-toxic compounds having a higher potency against a wide spectrum of bacteria; and have unexpectedly found that certain quinolizine carboxylic acid derivatives having an amine moiety at the 8-position of the 4-oxo-quinolizine nucleus exhibit a broad spectrum antibacterial activity and reduced cytotoxicity.
SUMMARY OF THE INVENTION
It is, therefore, a primary object of the present invention to provide novel 4-oxo-quinolizine carboxylic acid derivatives, and pharmaceutically acceptable salts thereof, having a potent antibacterial activity, especially against Gram-positive bacteria, with a low cytotoxicity.
It is another object of the present invention to provide an antibacterial composition containing the inventive compounds as an active ingredient.
It is a further object of the present invention to provide a process for the preparation of the inventive novel compounds.
In accordance with the present invention, there is provided a 4-oxo-quinolizine carboxylic acid derivative of formula (I) or a pharmaceutically acceptable salt thereof:
wherein
R
1
is a C
1-4
alkyl group optionally substituted with one ore more halogens, or a C
1-4
alkoxy group;
R
2
is
R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
and R
14
are each independently H or a C
1-4
alkyl group optionally substituted with a pyridyl, arylalkyl or aryl group.
DETAILED DESCRIPTION OF THE INVENTION
Among the compounds of the present invention, preferred are those wherein: R
1
is CH
3
or OCH
3
; R
2
is
R
3
, R
5
, R
6
, R
8,
R
11
and R
12
are each independently H or CH
3
; R
4
is H or a methyl group optionally substituted with a pyridyl or benzyl group; R
7
, R
9
, R
10
and R
13
are H or CH
3
; R
14
is CH
3
.
Particularly preferred compounds of formula (I) of the present invention are:
8-{[(R)-2,8-diazabicyclo[4.3.0]non-5-en]-8-yl}-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-{[(S)-2,8-diazabicyclo[4.3.0]non-5-en]-8-yl}-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-{[(R)-5-methyl-2,8-diazabicyclo[4.3.0]non-5-en]-8-yl}-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-[(1-aminomethyl-3-azabicyclo[2.1.1]hex)-3-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-[(1-amino-3-azabicyclo[2.1.1]hex)-3-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-[(1-amino-3-azabicyclo[3.1.1]hept)-3-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-[(1-aminomethyl-3-azabicyclo[3.1.1]hept)-3-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-[(1-N-methylaminomethyl-3-azabicyclo[3.1.1]-hept)-3-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-[(1-N-methylamino-3-azabicyclo[3.1.1]hept)-3-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-[(3-amino-3-carbamoylpyrrolidine)-1-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-[(3-N-methylaminomethyl-4-N-methylaminopyrrolidine)-1-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-[(3-amino-4-aminomethylpyrrolidine)-1-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-[(3-aminomethyl-4-N-methoxyaminopyrrolidine)-1-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-[(3-amino-4-N-methoxyaminopyrrolidine)-1-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-[(3-N-methoxyamino-4-N-methylaminomethylpyrrolidine]-1-yl}-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-{[3-(3-pyridylmethyl)oxy-4-aminomethylpyrrolidine]-1-yl}-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-{[3-(2-pyridylmethyl)oxy-4-aminomethylpyrrolidine]-1-yl}-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-{[3-(4-pyridylmethyl)oxy-4-aminomethylpyrrolidine]-1-yl}-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-{[3-N-(3-pyridylmethyl)amino-4-aminomethylpyrrolidine]-1-yl}-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-[(3-N-benzylamino-4-aminomethylpyrrolidine)-1-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid;
8-{[(R)-2,8-diazabicyclo[4.3.0]non-5-en]-8-yl}-1-cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3-carboxylic acid;
8-{[(S)-2,8-diazabicyclo[4.3.0]non-5-en]-8-yl}-1-cyclopropyl-7-fluoro-9-methoxy-4-oxo-4H-quinolizine-3-carboxylic acid;
8-[(3-N-methoxyimino-4-aminomethylpyrrolidine)-1-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; and pharmaceutically acceptable salts thereof.
The present invention further includes, within its scope, pharmaceutically acceptable salts of the compounds of formula (I). The non-toxic salts which fall within the scope of the present invention may include inorganic acid salts such as hydrochloride, sulfate, phosphate and nitrate, and organic acid salts such as tartrate, fumarate, citrate, mesylate and acetate.
The pharmaceutically acceptable salt of the present invention may be prepared in accordance with a known method, e.g., by reacting the compounds of formula (I) with a suitable acid in the presence of a solvent, e.g., methanol, ethanol, dichloromethane, ethyl acetate or diethyl ether.
The compound of formula (I) may be prepared by a process which comprises reacting a 4-oxoquinolizine-3-carboxylic acid derivative of formula (II) with an amine of formula (III) in a suitable solvent in the presence of a base.
wherein, R
1
and R
2
have the same meanings as defined above; and X is halogen such as F and Cl, or sulfonyl group.
The condensation reaction of compounds (II) and (III) may be conducted at a temperature ranging from 20 to 120° C.
Exemplary solvents which may be suitably used in the process of the present invention include acetonitrile, dimethylformamide, dimethylsulfoxide and pyridine.
The base which can be used in practicing the present invention may be an inorganic base, or an organic base such as triethylamine, pyridine, diazabicyclo[5.4.0]undec-7-ene and diisopropylamine.
The compound of formula (II) may be prepared in accordance with the method disclosed in PCT Publication No. WO 95/10519.
The compound of formula (III) may be prepared in accordance with the procedure disclosed in U.S. Pat. No. 5,631,266 and 35th ICAAC, San Francisco, 1995, Abstract No. F204.
The compounds of the present invention may be administered, either orally or intraperitoneally, in an effective amount ranging from 0.01 mg/kg to 100 mg/kg, preferably from 0.01 mg/kg to 50 mg/kg to a subject patient per day.
The present invention also includes within its scope an antibacterial composition comprising one or more of the inventive compounds as an active ingredient, in association with a pharmaceutically acceptable carrier, excipient and/or other additives, if necess

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