Optically active quinoline carboxylic acid derivatives with...

Details Optically active quinoline carboxylic acid derivatives with... Optically active quinoline carboxylic acid derivatives with...

2003-06-20

2004-06-22

Seaman, D. Margaret (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S122000

Reexamination Certificate

active

06753430

ABSTRACT:

TECHNICAL FIELD
The present invention relates to optically active quinoline carboxylic acid derivatives represented by following formula 1, their pharmaceutically acceptable salts, their solvates, and a process for the preparation thereof. More specifically, the present invention relates to optically active quinoline carboxylic acid derivatives containing 4-aminomethyl-4-methyl-3-(Z)-alkoxyimino pyrrolidine substituents at 7-position of the quinolone nuclei.
Wherein
Q is C—H, C—F, C—Cl,or N;
Y is H, or NH
2
;
R is a straight or branched alkyl group of C
1
-C
4
, an allyl group, or a benzyl group; and
* represents optically pure chiral carbon atom.
BACKGROUND ART
Quinolone antibacterial agents show high therapeutic efficacy even when being administered orally as well as can be made available for parenteral dosage forms. At present, quinolone antibacterial agents are prevalently used to treat the diseases caused by bacterial infection. In general, quinolone antibacterial agents are classified into three generations according to chemical structure, activity and pharmacokinetics (David C. Hooper and John S. Wolfson. Quinolone Antibacterial Agents; American Society for Microbiology: Washington D.C., 1993: pp 1-2). The first-generation quinolone antibacterial agents were usually used for the treatment of urinary tract infection and were restricted to the treatment of the diseases caused by Gram-negative bacteria. It was riot until the second-generation emerged that quinolone antibacterial agents could be come to exert their activities against some Gram-positive pathogens as well as Gram-negative pathogens. The second-generation quinolone antibacterial agents were also greatly improved in the pharmacokinetics of absorption and distribution. The third-generation quinolones, which have been recently developed, can be administered as once daily dosing form because of long half life in case of lomefloxacin and fleroxacin, and show excellent pharmacokinetics and highly potent activity against Gram-positive bacteria in case of sparfloxacin, trovafloxacin, moxifloxacin and gatifloxacin. However, these conventional quinolone antibacterial agents are still weakly potent against the repression of streptococci and enterococci and quinolone-resistant strains are increasingly generated.
Most of conventional quinolone antibacterial agents have piperazine derivatives substituted at the 7-position but it was known that pyrrolidine derivatives were introduced into the 7-position in order to enhance the antibacterial activity against Gram-positive strains (Sanchez, J. P., et al.,
J. Med. Chem.,
31, 983 (1988)). The quinolone antibacterial agents in which pyrrolidine derivatives are substituted at the 7-position were certainly improved in the antibacterial activity against Gram-positive strains, but suffered from a problem in that the in vivo antibacterial activity did not correspondently reflected in vitro activity because of their poor water solubility and pharmacokinetic profiles.
Introduction of halogens into quinolone antibacterial agents at the 8-position is known to increase their antibacterial activity, but also to generate phototoxicity (Sanchez, J., et al.,
J. Med. Chem.,
35, 361-367 (1992)).
Korean Pat. No. 174,373 discloses a racemate which corresponds to the compound to be targeted in the present invention. However, its optical isomers, that is, isomers with pure (+) or (−) optical activity are not described. Nowhere are mentioned preparation or separation methods of the optical isomers. Neither are pharmacological effects of each isomer taken into account, nor is a description given of the relation between the racemate and its optical isomers.
Generally, two optically pure compounds which are in mirror image relationship to one another possess the same physical properties, except one-optical activity. In detail, the two enantiomers are completely or almost identical in, for example, melting point, boiling point, solubility, density and refractive index, but completely opposite in optical rotation. Since the two enantiomers rotate the plane of polarized light in equal but opposite directions, no net optical rotation is observed when they are mixed. In other words, the optical rotation of a racemate is zero in theory and near zero in practicality.
The difference in optical rotation, that is, in the spatial arrangement of four groups connected to the chiral atom, i.e., configuration, frequently causes a significant distinction between one enantiomer and its racemate in physiological activity and toxicity. However, since there is no consistent relationship between configurational difference and its influences, it is actually impossible to deduce them from the prior arts. For instance, levofloxacin, a (−) optical isomer, is known to show two-fold higher antibacterial activity than ofloxacin, a racemate, and 8-128 fold higher than the other enantiomer, (+)-ofloxacin (
Drugs of the future,
17(7): 559-563 (1992)). An example of a relation between configuration and toxicity may be referred to cisapride (Stephen C. Stinson,
Chemical
&
Engineering News,
76(3), 3 (1998)). Stephen C. Stinson revealed that the racemate (±)-cisapride, when used in combination with other drugs, may, cause a toxic effect whereas (+)-norcisapride does not, concluding that (−)-cisapride is causative of the toxicity of the racemate. Korean Pat. No. 179,65 describes 1-(5-hydroxyhexyl)-3-methyl-7-propylxanthine, showing that its R-(−) isomer is at least three-fold more potent in cerebral blood flow-stimulating action and three-fold longer in the duration time of activity than the S-(+) isomer. However, in the case of temafloxacin, its racemate and its enantiomers show no differences in antibacterial activity and pharmacokinetics (Daniel T. W. Chu, et al.,
J. Med. Chem.,
34, 168-174 (1991)).
As aforementioned, due to unexpected physiological differences, between a racemate and its optically pure enantiomers (i.e. activity, P.K., toxicity, etc.), a racemate must be resolved into its corresponding enantiomers. As can be recognized from the above, the use of a racemate, as it is, can be problematic though its one enantiomer shows excellent pharmacological effects and no toxicity, if the other enantiomer has any toxicity. This phenomenon can be frequently found in many pharmacologically effective compounds. In addition, when a pharmacologically effective racemate is used as it is, the two enantiomers are administered at the same dose. Which If one enantiomer is pharmacologically inactive, only results in imposing a load, on the body. Therefore, it is very important to resolve a racemate into pure compounds for better pharmacological effects and lower toxicity.
On the basis of aforementioned prior arts, through the intensive and thorough research on quinolone antibacterial agents, repeated by the present inventors found that 4-aminomethyl-4-methyl-3-(Z)-alkoxyimino pyrrolidine derivatives causing optical activity, when being attached to 7-positions of quinclone nuclei, endows optically active quinoline carboxylic acid derivatives with highly potent antibacterial activity and excellent pharmacokinetic properties.
Hence, the optically active quinoline carboxylic acid derivatives according to the present invention show greatly improved antibacterial activity against Gram-positive bacteria, especially against methicilline-resistant staphylococci and increasing quinolone-resistant strains, compared with their racemates, their counterpart enantiomers and the using quinolones. Also, according to the present invention the compounds are excellent in pharmacokinetic profiles and hardly cause phototoxicity in spite of bearing halogen atoms at 8-position.
DISCLOSURE OF INVENTION
The present invention provides optically active quinoline carboxylic acid derivatives with 4-aminomethyl-4-methyl-3-(Z)-alkoxyiminopyrrolidine substitutents at the 7-position of the quinolone nuclei, represented by the following formula 1, their pharmaceutically acceptable salts, and their solvates:
wherei

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