GB2062627A - Benzo[ij]quinolizine-2- carboxylic acid compounds and therapeutic compositions containing them - Google Patents

Abstract

Benzo[ij]quinolizine-2-carboxylic acids of the formula:- <IMAGE> wherein R<1> represents a hydrogen atom or a lower alkyl group; R<2> represents a hydrogen atom or a halogen atom; R<3> represents a lower alkyl group substituted with one or more of a halogen atom and a hydroxy group, a lower alkanoyl group substituted with one or more halogen atoms, a phenylalkyl group substituted with one or more lower alkoxy groups on the phenyl ring, a lower alkanesulfonyl group substituted with one or more halogen atoms, a lower alkenyl group or a lower alkynyl group; or pharmaceutically acceptable salts thereof, have antimicrobial activity. They are particularly effective on those bacteria resistant to conventional antibiotics and can be maintained at high concentration levels in blood for extended periods of time.

Description

SPECIFICATION Benzo[ij]quinolizine-2-carboxylic acid compounds, therapeutic composition containing same and processes for producing same This invention relates to certain benzo[ijjquinolizine-2-carboxylic acid compounds and pharmaceutically acceptable salts thereof which are useful as antimicrobial agents, processes for preparing the same, and pharmaceutical compositions containing the benzo[ij]quinolizine-2-carboxylic acid compound or a salt thereof.

It is known that certain types of polyheterocyclic compounds exhibit antimicrobial activities. For example U.S. Patent 3,917,609 to Gerster et al. discloses substituted derivatives of 1 ,2-dihydro-6-oxo- 6H-pyrrolo[3,2,1 -ij]quinoline which are useful as antimicrobial agents or as intermediates for the preparation of antimicrobial agents.

Also U.S. Patents 3,896,131,3,985,882, 3,969,463,4,001,243 and 4,014,877 to Gersteret al.

and British Patent Application GB 2020279A disclose 6,7-dihydro-1 -oxo-1 H,5H-benzo[ijjquinolizine derivatives having antimicrobial activities.

As a result of extensive research it has now been found that some benzo[ij]quinolizine-2- carboxylic acid derivatives have a potent antimicrobial activity and low toxicity, that they show no decrease in activity in the presence of serum, and that they are effective against bacteria which are resistant to conventional antibiotics such as penicillin, ampicillin, streptomycin, etc.

This invention is based on the above finding and provides a benzo[ijjquinolizine-2-carboxylic acid compound represented by the formula (I)

wherein R1 represents a hydrogen atom or a lower alkyl group; R2 represents a hydrogen atom or a halogen atom; R3 represents a lower alkyl group substituted with one or more of a halogen atom and a hydroxy group, a lower alkanoyl group substituted with one or more halogen atoms, a phenylalkyl group substituted with one or more lower alkoxy groups on the phenyl ring, a lower alkanesulfonyl group substituted with one or more halogen atoms, a lower alkenyl group or a lower alkynyl group; and pharmaceu'tically acceptable salts thereof.

In another aspect this invention provides a pharmaceutical composition containing the compounds of the formula (I) or a pharmaceutically acceptable salt thereof in an antimicrobially effective amount.

Further, this invention provides processes for preparing compounds of formula (I) and pharmaceutically acceptable salts thereof.

The term "halogen" as used herein includes a chlorine atom, a bromine atom, an iodine atom and a fluorine atom.

The term "lower alkyl" as used herein refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group and the like.

The term "lower alkanoyl" as used herein refers to a straight or branched alkanoyl group having 2 to 4 carbon atoms such as an acetyl group, a propanoyl group, a butanoyl group, an isobutanoyl group and the like.

The term "lower alkanesulfonyl" as used herein refers to a straight or branched alkanesulfonyl group having 1 to 4 carbon atoms such as a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, an isopropanesulfonyl group, a butanesulfonyl group, a tert-butanesulfonyl group and the like.

The term "arylsulfonyl" as used herein refers to a benzenesulfonyl group, a naphthalenesulfonyl group and the like. The aryl ring included in the arylsulfonyl group may be substituted with one or more of a halogen atom, a lower alkyl group, a hydroxy group, a nitro group and the like.

The term "Phenylalkyl" as used herein refers to a phenylalkyl group consisting of a phenyl group and a straight or branched alkylene group having 1 to 4 carbon atoms such as a benzyl group, a 2phenylethyl group, a 3-phenylpropyl group, a 4-phenyíbutyí group, a 1-phenylethyl group, a 1,1dimethyl-2-phenylethyl group and the like.

Examples of the lower alkyl group substituted with one or more of a halogen atom and a hydroxy group as used herein include a trifluoromethyl group, a trichioromethyl group, a dichloromethyl group, a tribromomethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichioroethyl group, a 2-chloroethyl group, a 1,2-dichloroethyl group, a 3,3,3-trichioropropyl group, a 3-fluoropropyl group, a 4-chíorobutyí group, a 3-chloro-2-methylethyl group, a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group, a 4-hydroxybutyl group, a 2-hydroxypropyl group, etc.

Examples of the lower alkanoyl group substituted with one or more halogen atoms as used herein include a trifluoroacetyl group, a trichloroacetyl group, a tribromoacetyl group, a 2,2-dichloropropionyl group, a monochloroacetyl group, a 2-chlorobutyryl group, a pentafluoropropionyl group, a heptafluorobutyryl group, etc.

Examples of the phenylalkyl group susbtituted with one or more alkoxy groups containing, e.g., from 1 to 3 carbon atoms, on the phenyl ring thereof include a 4-methoxybenzyl group, a 2isopropoxybenzyl group, a 3,4-dimethoxybenzyl group, a p3,4-dimethoxyphenethyl group, an a-3,4- dimethoxyphenethyl group, a ,B-2,3,4-trimethoxyphenethyl group, a 3-(4-ethoxyphenyl)propyl group, a 4-(4-methoxyphenyl)butyl group, etc.

Examples of the lower alkanesulfonyl group substituted with one or more halogen atoms include a trifluoromethanesulfonyl group, a trichloromethanesulfonyl group, a tribromomethanesulfonyl group, a dichloromethanesulfonyl group, a 2,2,2-trifluornethanesulfonyl group, a 2,2,2-trichloroethanesulfonyl group, a 2-chloroethanesulfonyl group, a 1 ,2-dichloroethanesulfonyl group, a 3,3,3 trifluoropropanesulfonyl group, a 3,3,3-trichloropropanesulfonyl group, a 3-fluoropropanesulfonyl group, a 4-chiorobutanesulfonyl group, a 3-chloro-2-methylethanesulfonyl group, etc.

Examples of the lower alkenyl group containing, e.g., from 2 to 4 carbon atoms, as used herein include a vinyl group, an allyl group, a crotyl group, a 1-methylallyl group, etc.

Examples of the lower alkynyl group containing e.g., from 2 to 4 carbon atoms, as used herein include an ethynyl group, a 2-propynyl group, a 2-butynyl group, a 1 -methyl-2-propynyl group, etc.

The compounds of this invention of the formula (I) and the salts thereof exhibit excellent antimicrobial activity broadly on gram-positive and negative bacteria at low concentrations. They are useful compounds which show particularly potent antibacterial activity on Streptococcus, Pseudomonas, Enterobacter, Proteus, etc., on which conventional synthetic antibacterial agents are not effective or only slightly effective. In addition, they show a high antibacterial activity on coliform bacilli, staphylococci, etc., which are major causes of infectious diseases and are also effective on Serratia, Klebsiella, etc., which also cause infectious diseases that have recently attracted wide attention of many workers in the field, and therefore they are very useful clinically.

As stated above, the compounds of this invention are advantageous not only because they are characterized by a broad antimicrobial spectrum and potent activity, but also because they not only show no decrease in antimicrobial activity in the presence of a serum, but rather show a tendency towards increased activity. This phenomenon is surprising to one skilled in the art since it has hitherto been observed that conventional pharmaceuticals having antimicrobial activity show decreased activity in the presence of a serum. This strongly suggests that the compound of this invention can exhibit potent antimicrobial activity in the blood.

The oral toxicity of the compounds of this invention is very low as compared with the effective oral dosage thereof.

The compounds of this invention have excellent antimicrobial activity on those bacteria which are resistant or have acquired resistance to conventional antibiotics such as penicillin, cephalosporin, ampicillin, streptomycin, erythromycin, Kanamycin, nalidixic acid, etc.

When administered orally the compounds of this invention are absorbed readily and their blood level or activity in the blood level is maintained at high levels so that they can exhibit potent antimicrobial activity also in this respect.

Representative examples of the compound of this invention include the following compounds. This list is provided for illustration only and is not intended to limit to scope of this invention.

(1) 8-(4-trifluoroacetyl-1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ijjquinolizine-2-carboxylic acid (2) 8-(4-trifluoroacetyl-1 -piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid (3) 8-(4-trifluoroacetyl-1 -piperazinyl)-1 0-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid (4) 8-(4-trichloroacetyl-1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid (5) 8-(4-trifluoroacetyl-1 -piperazinyl)-9-chloro-5-ethyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ijjquinolizine-2-carboxylic acid (6) 8-(4-trifluoroacetyl-1 -piperazinyl)-9-chloro-5-butyl-6,7-dihydro-1 -oxo- 1 H,5Hbenzo[ij]quinolizine-2-carboxylic acid (7) 8-(4-monochloroacetyl-1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid (8) 8-(4-trifl uoromethanesulfonyl-1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid (9) 8-(4-trifluoromethanesulfonyl-1 -piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H- benzo[ijjquinolizine-2-carboxylic acid (10) 8-[4-(2,2,2-trifluoroethanesulfonyl)-1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1 -oxo 1 H,SH-benzo[ijlquinolizine-2-carboxylic acid (11) 8-[4-(2-chloroethyl)-1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydrn- 1 -oxo-1 H,5Hbenzo[ij]quinolizine-2-carboxylic acid (12) 8-(4-tribromoacetyl- 1 -piperazinyl)-9-bromo-5-methyl-6,7-dihydro-1 -oxo-1 H,5Hbenzo[ij]quinol izine-2-carboxylic acid (13) 8-[4-82-chlorobutyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro- 1 -oxo- 1 H,5H benzo[ij]quinolizine-2-carboxylic acid (14) 8-(4-trifluoroacetyl- 1 -piperazinyl)-5-methyl-6,7-dihydro-1 -oxo-1 H ,5H-benzo[ij]quinolizine-2carboxylic acid (15) 8-(4-trifl uoroacetyl-1 -piperazinyl)-9-chloro-6,7-dihydro- 1 -oxo-1 H ,5H-benzo[ij]quinolizine-2carboxylic acid (16) 8-(4-allyl- 1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro- 1 -oxo- 1 H,5H-benzo[ij]quinolizine-2carboxylic acid (17) 8-(4-crotyl- 1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H-benzo[ij]quinolizine- 2-carboxylic acid (18) 8-(4-a llyl- 1 -piperazinyl)-5-methyl-6,7-dihydro-1 -oxo-1 H, 5H-benzo[ij] quinolizine-2-carboxylic acid (19) 8-(4-allyl- 1 -piperazinyl)-9-chloro-6,7-dihydro- 1 -oxo-1 H-benzo[ij]quinolizine-2-carboxylic acid (20) 8-(4-allyl- 1 -piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1 -oxo-1 H,5 H-benzo[ij]quinolizine-2carboxylic acid (21) 8-(4-trifl uoromethyl- 1 -piperazinyl)-1 0-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid (22) 8-(4-trifl uoromethyl- 1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid (23) 8-(4-trichloromethyl-1 -piperazinyl )-9-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid (24) 8-[4-(2,2,2-trifl uoroethyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5Hbenzo[ij]quinol izine-2-carboxylic acid (25) 8-[4-(4-chlorobutyl )- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro- 1 -oxo- 1 H,5H benzo[ij]quinolizine-2-carboxylic acid (26) 8-(4-trifl uoromethyl- 1 -piperazinyl)-9-fl uoro-5-methyl-6,7-dihydro-1 -oxo-1 H,5Hbenzo[ij]quinol izine-2-carboxylic acid (27) 8-(4-trifl uoromethyl-1 -piperazinyl)-5-methyl-6,7-dihydro-1 -oxo-1 H,5H-benzo[ij]quinolizine- 2-carboxylic acid (28) 8-[4-(2,2,2-trifl uoroethyl-1 -piperazinyl]-9-chloro-6,7-dihydro- 1 -oxo- 1 H,5H benzo[ijjqu inol izine-2-carboxylic acid (29) 8-(4-trifl uoromethyl- 1 -piperazinyl)-9-chloro-5-ethyl-6,7-dihydro- 1 -oxo-1 H,5H benzo[ijjquinolizine-2-carboxylic acid (30) 8-[4-(2-hydroxyethyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1 -oxo- 1 H,5H benzo[ij]quinolizine-2-carboxylic acid (31) 8-[4-(2-hydroxyethyl)- 1 -piperazinyl]-9-fluoro-5-methyl-6,7-di hydro- 1 -oxo- 1 H,5H benzo[ij]quinolizine-2-carboxylic acid (32) 8-[4-(2-hydroxyethyl)- 1 -piperazinyl]- 10-chloro-5-methyl-6,7-dihydro- 1 -oxo- 1 H,5H benzo[ij]quinolizine-2-carboxylic acid (33) 8-[4-(2-hydroxyethyl)- 1 -piperazinyl]-5-methyl-6,7-dihydro-1 -oxo- 1 H,5H benzo[ij]quinolizine-2-carboxylic acid (34) 8-[4-(2-hydroxyethyl)- 1 -piperazinyl]-9-chloro-6,7-di hydro- 1 -oxo- 1 H,5 H-benzo[ij]quinolizine2-carboxylic acid (35) 8-[4-(2,3-dihydroxylpropyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid (36) 8-[4-(4-hydroxybutyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1 -oxo- 1 H,5H benzo[ij]quinolizine-2-carboxylic acid (37) 8-[4-(2-propynyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H benzo[ijjquinolizine-2-carboxylic acid (38) 8-[4-(2-propynyl)-1 -piperazinyl]-9-fluoro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5Hbenzo [ijjquinolizine-2-carboxylic acid (39) 8-[4-(2-propynyl)- 1 -piperazinyl]-5-methyl-6,7-dihydro-1 -oxo-1 H,5H-benzo[ij]quinolizine-2carboxylic acid (40) 8-[4-(2-propynyl)- 1 -piperazinyl]-9-fluoro-6,7-dihydro- 1 -oxo-1 H,5H-benzo[ij]quinolizine-2carboxylic acid (41) 8-[4-(1 -methyl-2-propynyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid (42) 8-[4-(2-propynyl)-1 -piperazinyl]-1 0-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H- benzo[ij]quinolizine-2-carboxylic acid (43) 8-[4-(4-methoxybenzyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro- 1 -oxo- 1 H,5H benzo[i1]quinolizine-2-carboxylic acid (44) 8-[4-(4-methoxybenzyl)- 1 -piperazinyl]-9-fluoro-5-methyl-6,7-dihydro-1 -oxo- 1 H,5Hbenzo[ij]quinolizine-2-carboxylic acid (45) 8-[4-(4-methoxybenzyl)- 1 -piperazinyl]-9-chloro-6,7-dihydro- 1 -oxo-1 H,5 H benzo[i1]quinolizine-2-carboxylic acid (46) 8-[4-(4-methoxybenzyl)- 1 -piperazinyl]-5-methyl-6,7-dihydro- 1 -oxo-1 H,5Hbenzo[ij]quinolizine-2-carboxylic acid (47) 8-[4-(4-methoxybenzyl)- 1 -piperazinyl]-1 0-fluoro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5 H benzo[ij]quinolizine-2-carboxylic acid (48) 8-[4-(3,4-dimethoxybenzyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1 -oxo- 1 H,5Hbenzo[ij]quinolizine-2-carboxylic acid (49) 8-j4-(P-3,4-di methoxyphenethyl)-l -piperazinyl]-9-chloro-5-methyl-6 ,7-di hydro-l -oxo- 1 H,5H-benzo[ij]quinolizine-2-carboxylic acid (50) 8-4-[3-(4-ethoxyphenyl)prnpylj- 1 -piperazinyl I-9-chloro-5-methyl-6,7-di hydro-1 -oxo1 H,5H-benzo[ij]quinolizine-2-carboxylic acid (51) 8-[4-(ss-2,3,4-trimethoxyphenethyl) -1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo1H, 5H-benzo [ij] quinolizine02-carboxylic acid (52) 8-(4-trifl uoroacetyl-1 piperazinyl)-9-bromo-5-methyl-6,7-dihydro- 1 -oxo-1 H,5 H benzo[ij]quinolizine-2-carboxylic acid (53) 8-(4-trifl uoromethyl-1 -piperazinyl)-9-bromo-5-methyl-6,7-dihydro-1 -oxo-1 H,5Hbenzo[ij]quinolizine-2-carboxylic acid (54) 8-(4-allyl- 1 -piperazinyl)-9-bromo-5-methyl-6,7-dihydro-1 -oxo-1 H ,5H-benzo[ij]quinolizine-2- carboxylic acid (55) 8-(4-pentafluoropropionyl-1 -piperazinyl)-5-methyl-6,7-dihydro- 1 -oxo- 1 H,5 H benzo[ij]qu inolizine-2-carboxylic acid (56) 8-[4-heptafluarobutyryl-1-piperazinyl)-9-chloro-6,7-dihydro-1-oxo-1H, 5H benzo[ij]qu inolizine-2-carboxylic acid (57) 8-(4-pentafluoropropionyl-1 -piperazinyl)- 1 0-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid (58) 8-(4-heptafluorobutyryl-1 -piperazinyl)-5-methyl-6,7-dihydro-1 -oxo-1 H,5Hbenzo[ij]quinol izine-2-carboxylic acid (59) 8-(4-trifluoromethanesulfonyl-1 -piperazinyl)-9-chloro-6,7-dihydro- 1 -oxo-1 H,5H benzo[ijjquinolizine-2-carboxylic acid (60) 8-(4-pentafluoropropionyl- 1 -piperazinyl]-9-chloro-6,7-dihydro-1 -oxo-1 H,5 H benzo[i1]quinolizine-2-carboxylic acid (61) 8-(4-heptafluorobutyryl-1 -piperazinyl)- 1 0-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H benzo[ijjquinolizine-2-carboxylic acid (62) 8-(4-trifl uoromethanesulfonyl-1 -piperazinyl)-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H benzo[ijjquinolizine-2-carboxylic acid (63) 8-(4-trifluoromethyl-1 -piperazinyl)-6,7-dihydro- 1 -oxo- 1 H,5H-benzo[ij]quinolizine-2carboxylic acid The compounds of this invention of the formula (I) can be prepared by various alternative procedures, for example, by reacting a benzo[ij] quinolizine-2-carboxcylic acid compound of the formula (II)

wherein R4 represents a halogen atom, a lower alkanesulfonyloxy group or an arylsulfonyloxy group, and R' and R2 have the same meaning as defined above, with a piperazine compound of the formula (III)

wherein R3 has the same meaning as defined above.

The term "lower alkanesulfonyloxy" represented by R4 refers to a straight or branched alkanesulfonyloxy group having 1 to 4 carbon atoms such as a methanesulfonyloxy group, an ethanesulfonyloxy group, a propanesulfonyloxy group, an isopropanesulfonyloxy group, a butanesulfonyloxy group, a tert-butanesulfonyloxy group and the like.

The term "arylsulfonyloxy" as used herein includes a benzenesulfonyloxy group, a naphthalenesulfonyloxy group and the like. The aryl ring included in the aryl sulfonyloxy group may be substituted with one or more, and preferably from one to three, of a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, a nitro group and the like.

With respect to the compounds of the formula (II) which can be used as the starting material for preparing the compounds of this invention represented by the formula (I), some of those in which R4 represents a halogen atom are known compounds as described in U.S. Patents 3,917,609, 3,896,131, 3,985,882,3,969,463, 4,001,243 and 4,014,877 and others can be easily prepared by appropriate selection of starting materials according to known processes as described in Japanese Patent Publication No. 6156/76 and U.S. Patent 4,014,877. They can also be prepared by Reaction Scheme-2 hereinbelow.On the other hand, the compounds of the formula (II) in which R4 represents a lower alkanesulfonyloxy group or an arylsulfonyloxy group, i.e., compounds of the formula (ill) are novel and can be prepared, for example, by the Reaction Scheme-1 below.

Reaction Scheme-l

In the Reaction Scheme-1 above, R7 represents a lower alkanesulfonyl group or an arylsulfonyl group; R8 represents a lower alkyl group; X represents a halogen atom; and R1 and R2 have the same meaning as -defined above.

Thus, the compounds of the formula (Ila) can be prepared by reacting a compound of the formula (IV) with a compound of the formula (VI) to form a compound of the formula (VIII), further reacting this compound with a compound of the formula (IX) to obtain a compound of the formula (X), and cyclizing the compound of the formula (X) to form a compound of the formula (XI), which is then subjected to hydrolysis.

Of the compounds of the formula (VIII) those in which R1 represents a hydrogen atom can also be prepared by reacting a compound of the formula (V) with a compound of the formula (VI) to form a compound of the formula (VII) and reducing this compound.

In Reaction Scheme-1 above, a suitable amount of the compound of the formula (Vl) to be reacted with the compound of the formula (IV) is at least an approximately equimolar amount. Preferably 1 to 2 mols of the compound of the formula (VI) are reacted per mol of the compound of the formula (IV).

The reaction proceeds usually in an inert solvent in the presence of a deoxidizing agent in an amount of at least an approximately equimolar amount, and preferably 1 to 2 mols of the deoxidizing agent per mol of the compound of the formula (IV) at a temperature of about 0 to about 1000C, preferably at room temperature for about 0.5 to about 6 hours, thereby yielding the compound of the formula (VIII).

Examples of suitable deoxidizing agents include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., inorganic carbonates such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydrogen carbonate, etc., tertiary amines such as pyridine, quinoline, triethylamine, etc.

Examples of suitable inert solvents include lower alcohols such as methanol, ethanol, isopropanol, etc., ethers such as dioxane, tetrahydrofuran (THF), diglyme, etc., aromatic hydrocarbons such as benzene, toluene, etc., dimethyl sulfoxide (DMSO), dimethylformamide (DMF), hexamethylphosphoric triamide (HMPTA), pyridine, etc.

More particularly, in Reaction Scheme-l,the reaction between the compound of the formula (VIII) and the compound of the formula (IX) can be effected in the absence of solvents or in the presence of solvents such as the above-described lower alcohols, DMF, DMSO, and HMPTA and acetonitrile and the like. Preferably the reaction is conducted in the absence of solvents.

The compound of the formula (IX) can be used in excess amounts over the equimolar amount relative to the compounds of the formula (VEIL), preferably in an equimolar amount in the absence of solvents and in an amount of from about 1.1 to 1.5 mols per mol of the compound of the formula (VIII) in the presence of solvents. The reaction can generally be carried out at a temperature of from room temperature (from about 1 5 to 300 C) to about 1 500 C, and preferably from 100 to 1 300C, for a period of from about 0.5 to about 6 hours thereby easily yielding the compound represented by the formula (X).

The subsequent cyclization reaction of the thus obtained compound of the formula (X) can be effected in accordance with conventional cyclization reactions, for example, by heating the compound of the formula (X) or by using an acidic substance such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, polyphosphoric acid and the like. When the cyclization is effected by heating, it is preferred to heat the compound of the formula (X) in a solvent such as high boiling point hydrocarbons or high boiling point ethers, for example, diphenyl ether tetraphosphoric acid, diethylene glycol dimethyl ether, etc., at a temperature of from about 100 to about 2500C, and preferably from 150 to 2000C for a period of from about 0.5 to about 6 hours.When the cyclization is effected using an acidic substance, the cyclization can be conducted in the presence of the acid substance in an approximately equimolar amount to a large excess amount, preferably 10 to 20 molar excess acid, relative to the amount of the compound of the formula (X) at a temperature of about 100 to about 1 500C for a period of about 0.5 to about 6 hours, whereby the desired compounds of the formula (Xl) can be produced advantageously.

In the above Reaction Scheme-l, the hydrolysis of the compound of the formula (XI) into the compound of the formula (Ila) can be achieved by a conventional hydrolysis procedure in the presence of a typical hydrolyzation catalyst, for example, a basic compound such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, or an inorganic acid such as sulfuric acid, hydrochloric acid, nitric acid and the like or organic acid such as acetic acid, an aromatic sulfonic acid and the like.The hydrolysis can be carried out in a solvent such as water, the above-described alcohols, ethers, and ketones such as acetone, methyl ethyl ketone, dioxane, ethylene glycol, etc., and acetic acid and the like at a temperature of from room temperature to about 2000C, preferably 50 to 1 500C for a period of about 0.5 to about 6 hours, thereby easily yielding the compound represented by the formula (lea).

The reaction between the compound of the formula (V) and the compounds of the formula (VI) can be conducted in the same manner as the reaction of the compound of the formula (IV) with the compound of the formula (VI), thus yielding a compound of the formula (VII).

In Reaction Scheme-l above, the reduction of the compounds of the formula (VII) can be conducted catalytically or using a conventional hydrogenating agent such as a combination of sodium borohydride or lithium aluminum hydride and a lower fatty acid, e.g., acetic acid, trifluoroacetic acid, propionic acid, etc.

Suitable amounts of sodium borohydride or lithium aluminum hydride and the lower fatty acid are from an approximately equimolar amount to a large excess amount, preferably from 3 to 5 mols per mol of the compound of the formula (VII).

The reduction reaction using a hydrogenating agent can proceed advantageously in an inert solvent such as the above-described ethers, aromatic hydrocarbons, lower fatty acids, e.g., acetic acid, trifluoroacetic acid, propionic acid, etc., at a temperature of from room temperature to about 1 COoC, preferably from 50 to 1000C for about 1 to about 6 hours, thus yielding the compound of the formula (VIII) in which R1 represents a hydrogen atom.

Reaction Scheme-2

In the above formulae, Rg, R8 and X have the same meaning as defined above.

In the Reaction Scheme-2 above, nitration of the compound of the formula (XII) can proceed under conventional conditions for nitration of aromatic compounds, e.g., in the absence of solvents or in the presence of a suitable inert solvent using a nitration agent.

Suitable examples of the inert solvent include acetic acid, acetic anhydride, concentrated sulfuric acid, etc.

Suitable examples of nitration agent include fuming nitric acid, concentrated nitric acid, a mixed acid (a mixture of nitric acid and sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride), alkali metal nitrates such as potassium nitrate and sodium nitrate, and sulfuric acid, etc.

The reaction proceeds advantageously in the presence of at least equimolar amount, preferably excess amount, of the nitration agent with respect to the starting compound at a temperature of preferably 0 to 1 50C for 1 to 4 hours.

Reduction of the nitro group of the compound of the formula (XIII) obtained in the above nitration can be conducted in an inert solvent in the presence of a reducing agent such as a mixture of iron, zinc, tin, stannous chloride and an acid (e.g., hydrochloric acid and sulfuric acid) or a mixture of iron, iron sulfite, zinc or tin and hydroxide, sulfate, sulfite, etc., of an alkali metal. Alternatively, the reduction can be carried out catalytically using a reducing catalyst such as palladium on carbon in an inert solvent.

Examples of suitable inert solvents include water, acetic acid, methanol, ethanol, dioxane, etc.

The conditions under which the above reduction of nitro group is carried out can be suitably selected. For example, the reduction using a mixture of stannous chloride and hydrochloric acid as a reducing agent can proceed advantageously at a temperature of from 70 to 1 000C for from 0.5 to 1 hour using at least equimolar amount, and preferably from 1 to 2 mols of the reducing agent per mol of the starting compound. When the reduction is carried out catalytically, it can proceed advantageously at room temperature for from 0.5 to several hours.

The amino group of the compound of the formula (XIV) thus obtained can be replaced by halogen by the application of the Sandmeyer reaction involving dia=otation. Diazotation of the compound of the formula (XIV) can proceed advantageously in a solvent such as water, hydrochloric acid, sulfuric acid, etc., in the presence of a diazotation agent such as a mixture of sodium sulfite or potassium nitrogen and hydrochloric acid or sulfuric acid at a temperature of -300C to room temperature for 0.5 to 2 hours.Subsequently, the diazonium salt of the compound of the formula (XV) thus obtained, without isolation, can be reacted, with a halogenating agent such as cuprous chloride, cuprous bromide, etc., in an amount of at least equimolar amount, preferably 1 to 2 mols of the halogenating agent per mol of the starting compound at a temperature of O to 500C for 0.5 to 2 hours to form a compound of the formula (XV).

Reduction of the pyridine ring of the compound of the formula (XV) can be carried out catalytically in an inert solvent such as dioxane, tetrahydrofuran, acetic acid, water, etc., under acetic conditions using various acids capable of forming a quinolinium salt such as acetic acid, hydrochloric acid, sulfuric acid, etc., in the presence of a catalytic reduction agent such as platinum-carbon, palladium-carbon, rhodium-carbon, ruthenium-carbon, etc., at a temperature of room temperature to 50 C for 1 to 10 hours, thus yielding a compound of the formula (XVI).

Alternatively, the compound of the formula (XVI) can also be prepared by reducing the pyridine ring of the compound of the formula (XIV) to form a compound of the formula (XVII) and then replacing the amino group of the compound of the formula (XVII) by halogen atoms. The reduction of the pyridine ring of the compound of the formula (XIV) can be carried out in the same manner as the reduction of the pyridine ring of the compound of the formula (XV). Also, the replacement of the amino group of the compound of the formula (XVII) by a halogen atom can be conducted in the same manner as the replacement of the amino group of the compound of the formula (XIV) by a halogen atom.

Further, the compound of the formula (XVII) can be prepared by reducing the compound of the formula (XII I) in the same manner as the reduction of the pyridine ring of the compound of the formula (XIV).

Reaction between the compound of the formula (XVI) thus-obtained and the compound of the formula (IX) can be carried out under the same conditions as the reaction between the compound of the formula (VIII) and that of the formula (IX).

Cyclization of the compound (XVIII) which is formed in the above reaction and hydrolysis of the cyclized compound of the formula (XIX) can proceed in the same manner as the cyclization of the compound of the formula (X) and the hydrolysis of the compound of the formula (Xl), respectively, thus yielding the compound of the formula (llb).

Some of the compounds of the formula (III), another starting compound used in this invention, are known compounds and others can be prepared with ease according to known processes.

In the reaction between the compound of the formula (II) and the compound of the formula (III) in the Reaction Scheme-1 the proportion of the latter to the former is usually at least equimolar, and preferably from 1 to 5 mols of the latter per mol of the former, and the reaction can generally proceed in an inert solvent such as water, the above-described lower alcohols, aromatic hydrocarbons, ethers, DMSO, DMF, HMPTA, etc., with DMSO, DMF and HMPTA being preferred. In the reaction, the abovedescribed deoxidising agent can be used.

The reaction can proceed advantageously at a pressure of from 1 to 20 atms, and preferably from 1 to 10 atms, and at a temperature of 100 to 25O0C, and preferably from 140 to 2000C, for from 5 to 20 hours, thus yielding the compound of the formula (I) of this invention.

Further, the compound of the formula (I) of this invention can be prepared by reacting a compound of the formula (XX) with a compound of the formula (XXI) in the presence of the above-described deoxidizing agent as shown in Reaction Scheme-3 below.

Reaction Scheme-3

In the above formulae, R1, R2, R3 and X have the same meaning as defined above.

The compounds of the formula (XX) used in the above reaction are novel compounds and can be prepared, for example, by reacting a compound of the formula (II) with piperazine under the same conditions under which the compounds of the formula (II) is reacted with the compound of the formula (Ill).

More particularly, the reaction between the compounds of the formula (XX) and the compound of the formula (XXI) can be carried out by one of the processes described hereinbelow depending on the definition of R3 of the compound of the formula (XXI).

i) When R3 represents a lower alkanoyl group substituted with one or more halogen atoms: In this case, the reaction proceeds under conventional conditions for acylation, e.g., without any solvent or in an inert solvent such as the above-described ethers, aromatic hydrocarbons, DMSO, DMF, HMPTA, pyridine and halogenated hydrocarbons such as chloroform, methylene chloride, etc., in the presence of the above-described deoxidising agent at a temperature of O to 1000C, preferably at a vicinity of room temperature, from about 0.5 to 6 hours.

With respect to the proportion of the starting compounds, the compound of the formula (XXI) can be used in at least equimolar amount, preferably 1 to 2 mols per mol of the compound of the formula (XX) in the presence of solvents and in excess amounts over the equimolar amount relative to the compound of the formula (XX) in the absence of solvents.

ii) When R3 represents a group other than the halogen substituted lower alkanoyl group: The reaction can proceed under conventional conditions for alkylation or aralkylation without solvents or in an inert solvent using at least equimolar amount, preferably 1 to 2 mols, of the compound of the formula (XXI) per mol of the compound of the formula (XX) at a temperature of room temperature to 1 500C, preferably 50 to 1000C, for 1 to 10 hours. The reaction can also be carried out using the above-described deoxidizing agent.

Examples of suitable inert solvent include water, alcohols such as methanol, ethanol, isopropanol, butanol, amyl alcohol, isoamyl alcohol, etc., the above-described aromatic hydrocarbons, ethers, DMSO, DMF, HMPTA, etc with DMSO, DMF AND HMPTA being preferred.

Futhermore, the compound of the formula (I) of this invention can be prepared according to the process shown in Reaction Scheme-4 below.

Reaction Scheme-4

In the above formulae, R1, R2, R3 and R4 have the same meaning as defined above; R5 and Re each represents a hydrogen atom or a lower alkyl group; R8 represents a lower alkyl group; Ys represents a tertiary nitrogen atom containing aromatic heterocyclic residue being bonded through the nitrogen atom or a trialkyl ammonium group; and Z9 represents an anion.

In the Reaction Scheme-4, the compounds of the formulae (XXIV). (XXV) and (XXVI) can be prepared under the same conditions as the reactions in which the compounds of the formulae (X) and (Xl) are prepared and the reaction between the compound of the formula (II) and the compound of the formula (III), respectively.

The compound of the formula (XXVII) can be prepared by reacting the compound of the formula (XXVI) with a tertiary nitrogen atom containing aromatic heterocyclic compound or a trialkylamine in the presence of an anion donating compound.

Examples of suitable tertiary nitrogen atom containing aromatic heterocyclic compound include pyridine, alkyl substituted pyridines such as picoline, lutidine, etc., quinoline, alkyl substitute quinolines such as quinaldine, lepidine, etc.

Examples of suitable trialkylamine include those having 1 to 6 carbon atoms, for each alkyl moiety, e.g., trimethylamine, triethylamine, tripropylamine, triiospropylamine, etc.

Examples of suitable anion donating compound include compounds capable of releasing a halogen ion and compounds capable of releasing sulfate, phosphate, perchlorate ions, e.g., iodine, bromine, chlorine, sulfuric acid, phosphoric acid, perchloric acid, etc.

The tertiary nitrogen atom containing aromatic heterocyclic compound of the trialkylamine described above and the anion donating compound can be used in at least equimolar amount, preferably 1 to 2 mols per mol of the compound of the formula (XXVI), respectively.

The reaction can proceed in an inert solvent such as the above-described lower alcohols, aromatic hydrocarbons, ethers, DMSO, DMF, HMPTA, pyridine, etc., at a temperature of from room temperature to 1 200C, preferably 50 to 1000C, for about 0.5 to 6 hours. The compound of the formula (XXVI I) thus obtained can be used in the subsequent hydrolysis after isolation from the reaction mixture and purification or without isolation.

Hydrolysis of the compound of the formula (XXVI I) can be carried out in a suitable solvent in the absence or presence of an acid or an alkali, preferably in the presence of an alkali. Examples of the alkali include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., alkaline earth metal hydroxides such as calcium hydroxide, etc., ammonium hydroxide or carbonates of these metals or ammonium.

As for the solvents the above-described lower alcohols, aromatic hydrocarbons, ethers, water, pyridine, DMF, DMSO, HMPTA, etc., can be used. The hydrolysis can also proceed in an aqueous medium in which a trialkylamine such as trimethylamine, triethylamine, etc., is present. In the above hydrolysis, the reaction is accelerated by the addition of a lower alcohol.

The reaction proceed advantageously at a temperature of 20 to 1 500C preferably 80 to 1 200C for about 0.5 to 6 hours, thus yielding the desired compound of the formula (I).

The compounds of this invention of the formula (I) prepred as described above can form pharmaceutically acceptable salts with acids when the compound of the formula (I) has a basic group, and this invention also includes within its scope such pharmaceutically acceptable salts. The pharmaceutically acceptable acids which can be used for the salt formation can be various organic or inorganic acids, for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, mandelic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like.

The compounds of the formula (I) can be converted into a corresponding carboxylate by reacting the carboxylic acid with a pharmaceutically acceptable basic compound. Examples of basic compounds are inorganic basic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, sodium hydrogen carbonate and the like and organic basic compounds such as morpholine, piperazine, pyridine, piperidine, ethyl amine, dimethylamine, triethylamine, aniline and the like.

The compounds of the formula (I) and the salts thereof obtained as described above can be isolated from the respective reaction mixtures upon completion of the reaction and purified by conventional procedures, for example, by solvent extraction, dilution, precipitation, recrystallization, column chromatography and the like.

As is apparent to those skilled in the art, the compounds of the formula (I) can exist in optically active forms and this invention includes such optical isomers within its scope.

In using the benzo[ij]quinolizine-2-carboxylic acid compounds of this invention of the formula (I) and the salts thereof as antimicrobial agents these compounds can be formulated into pharmaceutical compositions together with ordinary pharmaceutically acceptable carriers. Suitable carriers which can be used are, for example, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surface active agents and lubricants which are usually employed to prepare such drugs depending on the type of dosage forms.

Various dosage forms of the therapeutic agents as an antimicrobial agent can be selected according to the purpose of the therapy. Typical dosage forms which can be used are tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, injectable preparations (solutions, suspensions, etc.), ointments, etc.

In molding a pharmaceutical composition containing the compounds of the formula (I) or the pharmaceutically acceptable salt thereof as an active ingredient into a tablet form, a wide range of carriers known in the art can be used. Examples of suitable carriers include excipients such as lactose, white sugar, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, binders such as water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and polyvinyl pyrrolidone, disintegrants such as dried starch, sodium alginate, agar powder, laminaria powder, sodium hydrogen carbonate, calcium carbonate, Tween, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose, disintegration inhibitors such as white sugar, stearic acid glyceryl ester, cacao butter and hydrogenated oils, absorption promotors such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerol and starch, adsorbents such as starch, lactose, kaolin, bentolite and colloidal silicic acid, and lubricants such as purified talc, stearic acid salts, boric acid powder, Macrogol (trade name for a polyethylene glycol produced by Shinetsu Chemical Industry Co., Ltd.) and solid polyethylene glycol.

The tablets, if desired, can be coated, and made into sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or tablets comprising two or more layers.

In molding the pharmaceutical composition into pills, a wide variety of conventional carriers known in the art can be used. Examples of suitable carriers are excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oils, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaria and agar.

In molding the pharmaceutical composition into a suppository form, a wide variety of carriers known in the art can be used. Examples of suitable carriers include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides.

When the pharmaceutical composition is formulated into an injectable preparation, the resulting solution and suspension are preferably sterilized, and are isotonic with respect to the blood. In formulating the pharmaceutical composition into the form of a solution or suspension, all diluents customarily used in the art can be used. Examples of suitable diluents are water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters. Sodium chloride, glucose or glycerol may be incorporated into a therapeutic agent, e.g., as a nephritis treating agent in an amount sufficient to prepare isotonic solutions. The therapeutic agent may further contain ordinary dissolving aids, buffers, pain-alleviating agents, and preservatives, and optionally coloring agents, perfumes, flavors, sweeteners, and other drugs.

When the pharmaceutical composition is formulated into a paste, a cream and a gel, white vaseline, paraffin, glycerol, cellulose drivatives, polyethylene glycol, silicone, etc., can be used as a diluent.

The amount of the compound of the formula (I) and the pharmaceutically acceptable salts thereof of this invention as an active ingredient to be incorporated into a pharmaceutical composition useful as an antimicrobial agent is not particularly limited, and can vary over a wide range. A suitable therapeutically effective amount of the compound of the general formula (I) and the pharmaceutically acceptable salts thereof of this invention is usually from about 1 to 70% by weight, preferably 5 to 50% by weight, based on the total weight of the composition.

There is no particular restriction on the manner of using the therapeutic agent and the therapeutic agent can be administered by routes suitable for the particular forms of the therapeutic agent. For example, the tablets, pills, liquid preparations, suspensions, emulsions, granules, and capsules are orally administered. The injectable preparations are intraveneously administered either alone or together with ordinary auxiliary agents such as glucose and amino acids. Furthermore, as required, the injectable preparation can be administered intramuscularly, intracutaneously, subcutaneously, or intraperitoneally.

The suppository is administered intrarectally and the ointment is coated on the skin.

The dosage of the antimicrobial agent is suitably selected according to the purpose of use, the symptons, etc. Usually, a preferred dosage of the compound of thisinvention is about 10 mg to 5 g/kg body per day in 3 to 4 multiple doses.

I. Antimicrobial Activity Test Method The antimicrobial activity of the following test compounds on various test organisms listed below was determined by the serial dilution method on agar plate (Heart Infusion agar produced by Difco Co.) (See CHEMOTHERAPY, 22, pp. 1126-1128 (1974)) and the minimum inhibitory concentrations (mcg/ml) obtained were determined.

A sample of each test organism was prepared so that the population of the organism was about 1 x 108 cells/ml (O.D. 660 mitt = 0.13 to 0.14).

Compound of Invention Tested 1. 8-(4-Trifluoroacetyl-1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro- 1 -oxo- 1 H,5H benzo[ijjquinolizine-2-carboxylic acid 2. 8-[4-(2-Trifluoroethyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5 H benzo[ij]quinolizine-2-carboxylic acid 3.8-(4-Pentafluoropropionyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1- oxo-1H, 5Henzo[ij] quinolizine-2-carboxylic acid 4. 8-(4-Pentafl uorobutyryl-l -piperazinyl)-9-chloro-5-methyl-6,7-dihydro- 1 -oxo- 1 H,5H benzo[ij]qu inolizine-2-carboxylic acid 5,8-[4-(2-Hydroxyethyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H benzo[ij]quinolizine-2-carboxylic acid 6. 8-[4-(4-Methoxybenzyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H benzo[ijjquinolizine-2-carboxylic acid 7, 8-(4-Allyl- 1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro- 1 -oxo- 1 H,5H-benzo[ij]quinolizine-2carboxylic acid 8. 8-[4-(2-Propynyl)-1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1 -oxo- 1 H,5H benzo[ij]quinolizine-2-carboxylic acid Comparison Compounds A. 1 -Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridene-3-carboxylic acid (nalidixic acid) 8.9-Fluoro=5methyl-6,7-dihydro-1-oxo-1H, 5H-benzo[ij] quinolizine-2-carboxylic acid (flumequlne) Microorganisms Tested S.a Staphylococcus aureaus FDA 209 P S.p Streptococcus pyrogenes IID S-23 E.c Escherichia coll NHHJ JC-2 (IFO 12734) K.p Klebsiella pneumoniae P.r Proteus rettgeri NIH 96 S.t Salmonella typhi 0-901 (NCTC 8393) S.s Shigella sonnei EW 33 S.m Serratia marcescens IFO 12648 P.a 1 Pseudomonas aeruginosa E-2 P.a2 Pseudomonas aeruginosa NCTC 10490 P.a3 Pseudomonas aeruginosa ATCC 10145 The results obtained are shown ih Table 1.

TABLE 1 Minimum Inhibitory Concentration Test Test Organism Compound S.a S.p. E. o. K.p. P.r. S.t. S.s. S.m. P.a1 P.a2 P.a3 1 3.13 6.25 0.39 0.39 1.56 0.2 0.39 1.56 3.13 1.56 3.13 2 0.1 1.56 0.39 0.39 0.39 0.39 0.2 1.58 6.25 0.78 3.13 3 1.56 12.5 0.39 0.39 0.2 0.2 0.1 0.78 6.25 3.13 1.56 4 3.13 5.25 0.39 0.39 02. 0.2 0.2 0.78 6.25 3.13 1.56 5 0.78 3.13 0.39 0.78 0.39 0.2 0.39 0.78 12.5 12.5 6.25 6 0.78 3.13 0.78 0.78 0.39 0.1 0.78 1.56 12.5 12.5 6.25 7 0.78 3.13 0.78 0.78 0.78 0.2 0.78 1.56 12.5 12.5 12.5 8 0.39 1.56 1.56 0.78 0.78 0.2 0.78 1.56 25 12.5 12.5 A 50 > 100 3.1 3.1 1.6 3.1 3.1 3.1 > 100 > 100 > 100 B 3.1 > 100 0.8 0.8 0.2 0.2 0.8 0.8 50 25 25 From the results shown in Table 1 above it can be seen that the compound of this invention exhibited potent antibacterial activity as compared with nalidixic acid and flumequine.

II. Acute Toxicity The acute toxicity of the compounds of this invention having the formula (I) was determined by intravenous administration (i.v.) in mice which had not been fed for 12 hours prior to the test. LDW values (50% lethal dose) obtained for all the compounds were at least 500 mg/kg.

The present invention is further illustrated by the following Reference Examples, Examples and Preparation Examples, but they are not to be construed as limiting the scope of this invention. Unless otherwise indicated, all parts, percents and ratios are by weight.

Unless otherwise indicated, Elemental Analysis was carried out at a temperature of 70 to 800C at reduced pressure (1 to 2 mmHg) for 6 hours using P205 as a dessicant.

REFERENCE EXAMPLE 1 5-Hydroxy-3,4-dihydrocarbostyril (10 g) was added to 100 ml of methanol having dissolved therein 3.8 g of potassium hydroxide and the mixture was stirred at room temperature for 30 minutes followed by removing methanol under reduced pressure. Benzene was added to the residue to form crystals and then benzene was removed by distillation. The residue thus obtained was suspended in 50 ml of dimethylformamide and 10.6 g of methanesulfonyl chloride was added dropwise to the suspension while ice-cooling with stirring. After adding 3.5 g of methanesulfonyl chloride and resulting mixture was stirred at room temperature for 4 hours.After the completion of the reaction the solvent was removed under reduced pressure and the residue was purified through silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform). Recrystallization of the elute from water-containing ethanol gave 5.7 g of 5methanesulfonyloxy-3,4-dihydrocarbostyril as colorless prismatic crystals having a melting point of 227 to2310C.

REFERENCE EXAMPLE 2 In an analogous manner as in Reference Example 1, 5-(p-toluenesulfonyloxy)-3,4- dihydrocarbostyril having a melting point of 215 to 21 60C was obtained.

REFERENCE EXAMPLE 3 5-Methanesulfonyloxy-3,4-dihydrocarbostyril (4.5 g) was suspended in 90 ml of dioxane and 35 g of NaBH4 was added to the suspension. Then, 5.3 ml of acetic acid was added dropwise to the mixture.

After heat-refluxing the resulting mixture for 1 hour the solvent was removed under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue to form precipitates which were filtered and washed with chloroform. The filtrate was extracted with chloroform and the chloroform layer was dried over Na2SO4 followed by removing the solvent. The residue was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform) and the eluate thus obtained was crystallized from petroleum ether. Recrystallization of the crystals thus obtained from methanol gave 1.9 g of 5 methanesulfonyloxy-1 ,2,3,4-tetrahydroquinoline as colorless prisms having a melting point of 74 to 760C.

REFERENCE EXAMPLE 4 In an analogous manner as in Reference Example 3, 5-(p-toluenesulfonyloxy)-1 ,2,3,4- tetrahydroquinoline having a melting point of 112 to 11 30C was obtained.

REFERENCE EXAMPLE 5 Ethyl ethoxymethylenemalonate (21.6 g) was added to 22.4 g of 5-methanesulfonyloxy-1 2,3,4- tetrahydroquinoline and the mixture was heated at 11 00C on an oil bath for 30 minutes while stirring, during which time distillation of ethanol was observed. After heating, 240 g of polyphosphoric acid prepared from 120 g of phosphoric acid and 120 g of phosphorus pentoxide was added to the mixture and the mixture was allowed to react on an oil bath at 1 400C for 45 minutes. After completion of the reaction, the mixture was allowed to cool to room temperature and poured into 400 ml of water, followed by rendering the mixture neutral with a 40% aqueous sodium hydroxide solution to precipitate crystals.The crystals thus obtained were mixed with 150 ml of a 10% aqueous sodium hydroxide solution and the mixture was heat refluxed for 40 minutes during which time the crystals were dissolved to form a uniform solution. The solution was treated with activated carbon while hot and filtered. The filtrate was allowed to cool and adjusted to a pH of 2 to precipitate crystals which were filtered.

Recrystallization of the crude crystals thus obtained from dimethyl formamide gave 21.3 g of 8 methanesulfonyloxy-6,7-dihydro- 1 -oxo-1 H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 270 to 2750C.

REFERENCE EXAMPLE 6 In an analogous manner as in Reference Example 5, 8-(p-toluenesulfonyloxy-6,7-dihydro-1 -oxo1 H,5H-benzo[ij]quinolizine-2-carboxylic acid having a melting point of 3000C or more was obtained.

REFERENCE EXAMPLE 7 8-Chloro-6,7-dihydro-1-oxo-1 H,5H-benzo[ij]quinolizine-2-carboxylic acid (19.2 g) and 35.5 g of anhydrous piperazine were added to 350 ml of anhydrous dimethyl sulfoxide and the mixture was heated on an oil bath at 1 70 to 1 800C for 6 hours while stirring. After completion of the reaction, the solvent was removed under reduced pressure. 500 ml of water was added to the residue and the pH of the mixture was adjusted to a pH of 2 followed by filtering water-insoluble materials. The filtrate was concentrated to 100 ml under reduced pressure and rendered alkaline (pH=9) with a 10% aqueous sodium hydroxide solution. After extraction the aqueous alkali solution with chloroform-soluble materials, the aqueous alkali solution layer was allowed to stand to precipitate crystals which were filtered.The crude crystals thus obtained were dissolved in 10 ml of a 10% aqueous sodium hydroxide solution and the solution was treated with activated carbon and adjusted to a pH of 8 with a 10% aqueous hydrochloric acid solution to precipitate crystals which were filtered and washed with water sufficiently. Recrystallization of the crystals from dimethylformamide gave 6.5 g of 8-(1-piperazinyl)- 6,7-dihydro-1 -oxo-1 H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 267 to2680C.

8-( 1 -Piperazinyl)-6,7-dihydro- 1 -oxo-1 H,5H-benzo[ijjquinolizine-2-carboxylic acid (6.4 g) thus obtained was suspended in 50 ml of water and 15 ml of a 10% aqueous hydrochloric acid solution was added to the resulting solution. After removing the insoluble materials by filtration, water was distilled off to obtain 5.7 g of 8-(1 -piperazinyl)-6,7-dihydro-1 -oxo-1 H,5H-benzo[ij}quinolizine-2-carboxylic acid hydrochloride as white amorphous crystals having a melting point of 3000C or more.

REFERENCE EXAMPLES 8-11 In an analogous manner as in Reference Example 7, the following compounds were obtained: Reference Example 8 8-( 1 -Piperazinyl)-5-methyl-6,7-dihydro-1 -oxo-1 H,5H-benzo[ij]quinolizine-2-carboxylic acid as colorless needles having a melting point of 264 to 2650C.

Reference Example 9 8-(1 -Piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 246 to 2470C.

Reference Example 10 8-( 1 -Piperazinyl)- 1 0-chloro-6,7-dihydro-1 -oxo- 1 H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride as white amorphous crystals having a melting point of 3000C or more.

Reference Example ii 8-( 1 -Piperazinyl)-9-chloro-6,7-dihydro-1 -oxo-1 H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride as white amorphous crystals having a melting point of 3000C or more.

REFERENCE EXAMPLE 12 Chloroquinaldine (11 g) was dissolved in 15 ml of concentrated sulfuric acid and the solution was ice-cooled. Then, a solution of 7.1 g of potassium nitrate dissolved in 20 ml of concentrated sulfuric acid was added to the solution dropwise, during which operation the reaction temperature was maintained at 1 00C or less. After completion of addition the mixture was agitated at the same temperature as above for 1 hour and then poured onto 200 g of ice. Subsequently, the mixture was rendered alkaline with 10% sodium hydroxide taking care that the internal temperature should not be raised to above 200 C, thus forming pale yellow precipitates.The precipitates were collected by filtration, washed with water and recrystallized from ethanol to obtain 12.3 g of 5-nitro-6 hloroquinaldine as pale yellow rhombic crystals having a melting point of 123 to 1 240C.

REFERENCE EXAMPLE 13 To 50 ml of concentrated hydrochloric acid having dissolved therein 25 g of stannous chloride was added 6.7 g of 5-nitro-6-chloroquinaldine and the mixture was allowed to react on a water bath at a temperature of 80 to 900C for 30 minutes. The reaction mixture was ice-cooled, rendered alkaline (pH 10)-with 30% sodium hydroxide and filtered and extracted with 500 ml of chloroform and Celite (diatomaceous earth). After drying over anhydrous sodium sulfate the chloroform fraction was concentrated and recrystallized from a mixture of benzene and hexane to obtain 4.5 g of 5-amino-6chloroquinaldine as colorless plates having a melting point of 196 to 1 970C.

REFERENCE EXAMPLE 14 5-Amino-6-chloroquinaldine (4 g) was dissolved in 40 ml of concentrated hydrochloric acid and the resulting solution was cooled with ice. Then, a solution of 2.1 g of sodium nitrite dissolved in 5 ml of water was added thereto dropwise while ice-cooling. After continuing the reaction at the same temperature as above, the reaction mixture was added to a solution of 7 g of cuprous chloride dissolved in 1 5 ml of concentrated hydrochloric acid and the resulting mixture was allowed to react on a water bath at a temperature of 500C for 1 hour, during which time vigorous formation of nitrogen gas was observed. Subsequently, the reaction mixture was cooled, rendered alkaline with 30% sodium hydroxide, and filtered and extracted using 300 ml of chloroform and Celite (diatomaceous earth).After drying over anhydrous sodium sulfate the chloroform fraction was concentrated and recrystallized from a mixture of isopropanol and water to give 3.5 g of 5,6-dichloroquinaldine as white needles having a melting point of 84 to 850C.

REFERENCE EXAMPLE 1 5 5,6-Dichloroquinaldine (5.5 g) was dissolved in 50 ml of acetic acid and 0.1 g of 5% platinumcarbon was added to the solution, which was then subjected to Parr's hydrogenation method to reduce the compound catalytically at a hydrogen gas pressure of 4 kg/cm2. After theoretical amount of hydrogen was absorbed the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After rendering it alkaline with 50 ml of water and 20% sodium hydroxide, the residue was extracted with 100 ml of chloroform. The extract was dried by the addition of anhydrous potassium carbonate and concentrated to give 4.4 g of 5,6-dichloro-1 ,2,3,4-tetrahydroquinaldine as oily product.

NMR analysis data (in CDCI3) v: 1.23 (d, 3H, J=6HZ), 1.7 (m, 2H), 2.72 (m, 2H), 3.28 (m, 1 H), 3.75 (m, 1 H, 6.62 (q, J=9Hz) REFERENCE EXAMPLE 16 A mixture of 3.2 g of 5,6-dichloro-1 ,2,3,4-tetrahydroquinaldine and 3.2 g of diethyl ethoxymethylenemalonate was allowed to react by heating at 1 600C for 30 minutes. Then, 13 g of polyphosphoric acid prepared from 6.5 g of phosphorus pentoxide and 6.5 g of phosphoric acid was added to the mixture and the resulting mixture was allowed to react by heating at 140 to 1 5000 for 1 hour.After completion of the reaction, the mixture was poured onto 100 g of ice, followed by rendering the mixture to pH 4 to 5 with a 40% aqueous sodium hydroxide solution to precipitate crystals. The crystals were collected by filtration, dried and mixed with 50 ml of a 10% aqueous sodium hydroxide solution. The mixture was allowed to react at 100 to 11000 for 1 hour. After cooling, the reaction mixture was rendered acidic with concentrated hydrochloric acid to precipitate crystals.

Recrystallization of the crystals thus obtained from ethanol gave 2.3 g of 8,9-dichloro-5-methyl-6,7 dihydro-1-oxo-1 H,5H-benzo[ij]quinoline-2-carboxylic acid having a melting point of 269 to 271 00.

REFERENCE EXAMPLE 17 Hexamethylphosphoryl triamide (20 ml) was added to mixture of 3 g of 8,9-dichloro-5-methyl 6,7-dihydro-1 -oxo-1 H,5H-benzo[ij]quinolizine-2-carboxylic acid and 5 g of anhydrous piperazine and the mixture was heated with stirring at 1 50 to 1 6QOC for 3 hours. After the completion of the reaction, the solvent was removed therefrom under reduced pressure and the residue was washed with 10 ml of ethyl acetate. The crystals obtained were dissolved in 100 ml of water and the solution was adjusted to pH 4 with acetic acid. Insoluble substances were removed by filtration and the filtrate was treated with activated carbon.The aqueous solution thus obtained was concentrated under reduced pressure and the residue was recrystallized from a mixture of isopropanol and water to give 1.8 g 8-( 1 -piperazinyl)-9- chloro-5-methyl-6,7-dihydro-l -oxo-l H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride having a melting point of 3000C or more.

The hydrochloride salt was dissolved in water with adding a 2% aqueous sodium hydroxide solution and adjusted to pH 9 with 1 N hydrochloric acid to obtain white crystals having a melting point of 246 to 2470C.

EXAMPLE 1 A mixture of 2.5 g of 8-( 1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H-benzo[ij]- quinolizine-2-carboxylic acid and 50 ml of trifluoroacetic anhydride was heated under reflux for 3 hours.

After completion of heating, excessive trifluoroacetic anhydride was distilled off under reduced pressure and 50 ml of water was added to the residue followed by stirring to precipitate white crystals.

Recrystallization of the crystals from dimethylformamide gave 2.3 g of 8-(4-trifluoroacetyl-1 piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H-benzo[ijjquinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 3000C or more.

Elemental Analysis for C20H19CIF3N3O4 (molecular weight: 457.5) C H N Calc'd (%): 52.31 4.11 9.22 Found (%): 52.46 4.15 9.18 EXAMPLE 2 A mixture of 1 g of 8-(1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid, 15 ml of dimethylformamide, 1.2 ml of 2,2,2-trifluoroethyl iodide and 2 ml of triethylamine was heated at 800C for 5 hours. After cooling, insoluble substances were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was mixed with 30 ml of water and insoluble substances were removed by filtration.After concentrating it under reduced pressure, the filtrate was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform-methanol (9:1 by volume)) to obtain 0.5 g of 8-[4-(2,2,2-trifluoroethyl)-1 -piperazinylj-9-chloro-5-methyl-6,7-dihydro-1 - oxo-1 H,5H-benzo[ij]quinolizine-2-carboxylic acid iodide' monohydrate as white rhombic crystals having a melting point of 298 to 2990C.

EXAMPLE 3 A mixture of 0.8 g of 8-(1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ijlquinolizine hydrochloride monohydrate, 0.4 ml of propargyl bromide, 0.8 ml of triethylamine and 10 ml of dimethylformamide was allowed to react by heating at 900C for 5 hours. After completion of the reaction insoluble substances were removed by filtration.After concentration under reduced pressure the filtrate was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform-methanol (8:1 by volume)) to obtain 0.3 g of 8-[4-(2-propynyl)-1 -piperazinylj-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H-benzo[ij]- quinolizine as pale yellow rhombic crystals having a melting point of 1 to 213 or.

EXAMPLE 4 A mixture of 1 g of 8-(1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid, 0.6 ml of triethylamine, 0.6 ml of trifluoromethanesulfonyl chloride and 15 ml of dimethylformamide was stirred at room temperature for 3 hours. After completion of stirring, the solvent was removed under reduced pressure to concentrate the reaction mixture. By the addition of 30 ml of water to the concentrate pale yellow crystals precipitated. Recrystallization of the crystals from a mixture of dimethylformamide and water gave 0.7 g of 8-(4-trifluoromethanesulfonyl 1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H-benzo[ij]quinolizine-2-carboxylic acid as pale yellow powder having a melting point of 232 to 2350C.

EXAMPLES 5-10 In an analogous manner as in Example 4, the following compounds were prepared: Example 5 8-(4-Allyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H-benzo[ij]quinolizine-2 carboxylic acid Melting point: 226 to 2270C Example 6 8-[4-(2-Chloroethyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[0]quinolizine-2-carboxylic acid, Melting point: 284 to 2850C Example 7 8-[4-(4-Methoxybenxyl)-1 -piperazinylj-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid Melting point: 270 to 2720C Example 8 8-[4-(2-Hydroxyethyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ijjquinolizine-2-carboxylic acid Melting point: 228 to 2300C.

Example 9 8-(4-Pentafluoropropionyl-1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid Melting point: 296 to 2970C Example 10 8-(4-Heptafluorobutyryl- 1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H- benzo[ij]quinolizine-2-carboxylic acid Melting point: 269.5 to 270.50C Example 11 8-j4-(2-Hydroxyethyl)- 1 -piperazinyl]-9-fluoro-5-methyl-6,7-dihydro- 1 -oxo- 1 H,5H- benzo[ij]quinolizine-2-carboxylic acid Melting point: 288 to 2900C EXAMPLE 12 A mixture of 3.1 g of 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-1 H,SH-benzo[ij]quinolizine-2carboxylic acid, 9.1 g of 1-trifluoroacetylpiperazine and 50 ml of HMPTA was heated at 1 600C for 4 hours under atmosphere of argon. After completion of the reaction, the solvent was removed by distillation under reduced pressure and the residue was washed with water. Recrystallization of the residue from dimethylformamide gave 2.3 g of 8-(4-trifluoroacetyl-1 -piperazinyl)-9-chloro-5-methyl6,7-dihydro-1-oxo-1 H,5H-benzo[ijlquinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 3000C or more.

EXAMPLE 13 A mixture of 1.6 g of 8,9-dichloro-6,7-dihydro-5-methyl-1-oxo-1 H,SH-benzo[ijlquinolizine-2carboxylic acid, 3.2 g of 1 -propargylpiperazine and 25 ml of HMPTA was heated with stirring at 1 600C for 5 hours under atmosphere of argon. After completion of the reaction, the solvent was removed by distillation and the residue was washed with water. The residue was dissolved in 100 ml of water and insoluble substances were removed by filtration. The aqueous fraction was extracted with 200 ml of chloroform and the chloroform fraction was dried over anhydrous sodium sulfate.After concentration, the concentrate was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform-methanol (9:1 by volume)) to obtain 1.2 g of 8-[4-(2-propynyl)-1 -piperazinylj-9-chloro-5-methyl-6,7-:lihydro-1 -oxo-1 H,5Hbenzo[ij]quinolizine-2-carboxylic acid having a melting point of 211 to 21 30C.

EXAMPLES 14-21 In an analogous manner as in Example 13, the following compounds were attained: Example 14 8-(4-Allyl-1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,SH-benzo[ij]quinolizine-2carboxylic acid Melting point: 226 to 2270C Example 15 8-[4-(4-Methoxybenzyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5Hbenzo[ij]quinolizine-2-carboxylic acid Melting point: 270 to 2720C Example 16 8-[4-(2-hydroxyethyl)-1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H- benzo[ij]quinolizine-2-carboxylic acid Melting point: 228 to 2300C Example 17 8-[4-(2-chloroethyl)-1 -piperazinylj-9-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,SH- benzo[ij]quinolizine-2-carboxylic acid Melting point: 284 to 2850C Example 18 8-(4-Pentafluoropropionyl-1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5Hbenzo[ij]quinolizine-2-carboxylic acid Melting point: 296 to 2970C Example 19 8-(4-Heptafluorobutyryl-1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid Melting point: 269.5 to 270.50C Example 20 8-(4-Trifluoromethanesulfonyl- 1 -piperazinyl)-9-chloro-6,7-dihydro-1 -oxo-1 H,5 H benzo[ij]quinolizine-2-carboxylic acid Melting point: 232 to 2350C Example 21 8-[4-(2-Hydroxyethyl)- 1 -piperazinyl]-9-fluoro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid Melting point: 288 to 2900C EXAMPLE 22 A mixture of 2.75 g of 8-(4-trifluoroacetyl-1 -piperazinyl)-9-chloro-5-methyl-2-acetyl-6,7-dihydro- 1-oxo-1 H,5H-benzo[ij]quinolizine, 3 g of iodine and 20 ml of pyridine was heated at 1000C for 1 hour.

After completion of the reaction, crystals precipitated were collected by filtration and washed with 10 ml of cool pyridine and with 10 ml of methanol to obtain 8-(4-trifluoroacetyl-1 -piperazinyl)-9-chioro-5methyl-6,7-dihydro- 1 -oxo-1 H ,5H-benzo[ij]quinolizine-2-carbonylmethylpyridinium iodide. This compound was mixed with 50 ml of methanol and 50 ml of a 10% aqueous sodium hydroxide solution and the resulting mixture was refluxed for 1 hour. After completion of the reaction methanol was removed by distillation and the reaction mixture was adjusted to pH 7 with N hydrochloric acid to give 1.8 g of 8-(4-trifluoroacetyl-1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5Hbenzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 3000C or more.

EXAMPLES 23-32 In an analogous manner as in Example 22, the following compounds were prepared: Example 23 8-[4-(2,2,2-Trifluoroethyl)-1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid Melting point: 298 to 2990C Example 24 8-[4-(2-Hydroxyethyl)-1 -piperazinyll-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5Hbenzo[ij]quinolizine-2-carboxylic acid Melting point: 228 to 2300C Example 25 8-[4-(2-Chloroethyl)-1 -pipernzinyl]-9-chlorn-5-methyl-6,7-dihydrn-1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid Melting point: 284 to 2850C Example 26 8-(4-Allyl-1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H.SH-benzo[ij]quinolizine-2- carboxylic acid Melting point: 226 to 2270C Example 27 8-[4-(4-Methoxybenzyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid Melting point: 270 to 2720C Example 28 8-[4-(2-Propynyl)-1 -piperazinylj-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5Hbenzo[ij]quinolizine-2-carboxylic acid Melting point: 211 to 2130C Example 29 8-(4-Pentafluoropropionyl-1 -piperazinnyl)-9-chloro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H benzo[ij]quinolizine-2-carboxylic acid Melting point: 296 to 297 OC Example 30 8-(4-Heptafluorobutyryl-1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo- 1 H,5H benzo[ij]quinolizine-2-carboxylic acid Melting point: 269.5 to 270.50C Example 31 8-(4-Trifluoromethanesulfonyl- 1 -piperazinyl)-5-methyl-6,7-dihydro-1 -oxo-1 H 5 H- benzo[ijjquinolizine-2-carboxylic acid Melting point: 232 to 2350C Example 32 8-[4-(2-Hydroxyethyl )- 1 -piperazinyl]-9-fluoro-5-methyl-6,7-dihydro-1 -oxo-1 H,5 H benzo[ijjquinolizine-2-carboxylic acid Melting point: 288 to 2900C EXAMPLE 33 A mixture of 3.4 g of 8-(p-tol uenesulfonyloxy)-6,7-dihydro- 1 -oxo- 1 H,5 H-benzo[ij]quinolizine-2carboxylic acid, 9.1 g of 1 -(trifluoromethyl)piperazine and 200 ml of anhydrous dimethyl sulfoxide was heated with stirring in an autoclave at 1 50 to 1 600C for 1 8 hours under nitrogen gas flow at a pressure of 10 atms. After completion of the reaction, the solvent and excessive piperazine compound were removed by distillation under reduced pressure and a mixture of methanol and ethanol was added to the residue. The precipitates formed were collected by filtration and washed with ether. The crystals obtained were suspended in a mixture of 200 ml of water and 40 ml of a 10% aqueous hydrochloric acid solution and insoluble substances were removed by filtration.The filtrate was rendered neutral with saturated aqueous solution of sodium bicarbonate and purified through column chromatography using Amberlite LH-20 (a trade name for a product of Tokyo Organic Chemical Industries Ltd.) (eluent: water, ethanol). Recrystallization of the eluate from dimethylformamide gave 1.7 g of 8-(4-trifluoromethyl-1 - piperazinyl)-6,7-dihydro-1 -oxo-1 H,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 3000C or more.

EXAMPLE 34 A mixture of 4.5 g of 8-(p-toluenesulfonyloxy)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ijjquinolizine-2-carboxylic acid, 9.1 g of 1-(trifluoroacetyl)piperazine and 200 ml of anhydrous dimethyl sulfoxide was heated with stirring in an autoclave at 1 50 to 1 600C for 1 7 hours under nitrogen gas flow at a pressure of 10 atms. The reaction mixture was treated in the same manner as Example 33 to obtain 2.3 g of 8-(4-trifluoroacetyl-1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo- 1 H,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 3000C or more.

EXAMPLE 35 A mixture of 3.37 g of 8-methanesulfonyloxy-6,7-dihydro-1 -oxo-1 H,5H-benzo[ij]quinolizine-2carboxylic acid, 9.1 g of 1-(trifluoromethyl)piperazine and 200 ml of anhydrous dimethyl sulfoxide was heated with stirring in an autoclave at 1 70 to 1 800C for 20 hours under nitrogen gas flow at a pressure of 8 atms. The reaction mixture was treated in the same manner as Example 33 and further treated with concentrated hydrochloric acid to obtain 1.7 g of 8-(4-trifluoromethyl-1 -piperazinyl)-6,7-dihydro- 1 -oxo- 1 H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride as white rhombic crystals having a melting point of 3000C or more.

PREPARATION EXAMPLE 1 8-(4-Trifluoroacetyl- 1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro- 1 -oxo- 1 H,5H benzo[ijjquinolizine-2-carboxylic acid hydrochloride 200 mg Glucose 250 mg Distilled water for injection q.s. to make 5 ml The active compound and glucose were dissolved in distilled water for injection, and the solution was poured into a 5 ml ampoule. The air was purged with nitrogen, and the ampoule was sealed and sterilized at 121 OC for 1 5 minutes to obtain an injectable preparation.

PREPARATION EXAMPLE 2 8-(4-Trifl uoroacetyl- 1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro- 1 -oxo- 1 H,5 Hbenzo[ij]quinolizine-2-carboxylic acid 100g Avicel (trade name for a product of Asahi Kasei Kogyo Kabushiki Kaisha) 40 g Corn Starch 30 g Magnesium stearate 29 TC-5 (trade name for hydroxypropylmethyl cellulose, produced by Shinetsu Chemical Industry Co., Ltd.) 109 Polyethylene Glycol-6000 (molecular weight, 6000) 39 Castor oil 40 Methanol 40 g The active compound, Avicel, corn starch and magnesium stearate were mixed and ground, and then tableted using a conventional pounder (R 10 mm) for sugar coating (produced by Kikusui Seisakusho Co., Ltd.).The resulting tablets were coated with a film coating agent composed of TC-5, polyethylene glycol-6000, castor oil and methanol to produce film-coated tablets.

PREPARATION EXAMPLE 3 8-(4-Trifluoroacetyl-1 -piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1 -oxo-1 H,5H benzo[ijjquinolizine-2-carboxylic acid 29 Purified hydrous lanolin 59 Japan wax 5g White petrolatum 88g Total: 100g Japan wax was heat-molten and the active compound, purified hydrous lanolin and white petrolatum were added thereto followed by heat-melting. The mixture was stirred until it began to solidify to prepare an ointment.

While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims (18)

1. A benzo[ij]quinolizine-2-carboxylic acid compound represented by the formula (I)

wherein R1 represents a hydrogen atom or a lower alkyl group; R2 represents a hydrogen atom or a halogen atom; R3 represents a lower alkyl group substituted with oBe or more of a halogen atom and a hydroxy group, a lower alkanoyl group substituted with one or more halogen atoms, a phenylalkyl group substituted with one or more lower alkoxy groups on the phenyl ring a lower alkanesulfonyl group substituted with one or more halogen atoms, a lower alkenyl group or a lower alkynyl group; or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in Claim 1, wherein R2 represents a halogen atom.

3. A compound as claimed in Claim 2, wherein R2 represents chlorine or fluorine.

4. 8-(4-trifluoroacetyl-l -piperazinyl)-9-chloro-5-methyl-6,7-dihydro-l -oxo-1 H,5Hbenzo[ij]quinolizine-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

5. 8-[4-(2,2,2-trifluoroethyl)- 1 -piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1 -oxo- 1 H,5H benzo[ijjquinolizine-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

6. 8-[4-(2-hydroxyethyl)-1 -piperazinyl]-9-fluoro-5-methyl-6,7-dihydro- 1 -oxo-1 H,5H benzo[ijjquinolizine-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

7. A compound as claimed in Claim 1, substantially as hereinbefore described in any one of Examples 2 to 10 and 33.

8. A process for preparing a compound as claimed in Claim 1, which comprises reacting a benzo[ij]quinolizine-2-carboxylic acid compound of the formula (II)

wherein R4 represents a halogen atom, a lower alkanesulfonyloxy group or an arylsulfonyloxy group, and R1 and R2 are as defined in Claim 1, with a piperazine compound of the formula (III)

wherein R3 is as defined in Claim 1.

9. A process for preparing a compound as claimed in Claim 1, which comprises reacting compound of the formula (XX)

wherein R1 and R2 are as defined in Claim 1 with a compound of the formula (XXI) R3X (XXI) wherein R3 is as defined in Claim 1.

10. A process for preparing a compound as claimed in claim 1, which comprises reacting a compound of the formula (XXVI)

wherein R1, R2 and R3 are as defined in Claim 1, and R5 and R8 each represents a hydrogen atom or a lower alkyl group, with a tertiary nitrogen atom containing aromatic heterocyclic compound or a trialkylamine in the presence of an anion donating compound to form a compound of the formula (XXVII)

wherein R1, R2, R3, R5 and Rss have the same meaning as defined above; Y&commat; represents a tertiary nitrogen atom containing atom or a trialkyl ammonium group; and ze represents an anion, and then hydrolyzing this compound.

11. A process as claimed in claim 8, 9 or 10, substantially as hereinbefore described in any one of Examples 1 to 35.

12. A compound when prepared by a process as claimed in any one of claims 8 to 11.

13. An antimicrobial composition comprising antimicrobially effective amount of a compound as claimed in any one of claims 1 to 7 and 12, and a carrier.

14. A composition as claimed in claim 13, susbtantially as hereinbefore described in Preparation Example 1,2 or 3.

15. A method for controlling bacteria which comprises applying to bacteria a compound as claimed in any one of claims 1 to 7 and 12 or a composition as claimed in claim 13 or 14, in an antimicrobially effective amount.

16. A method for treating bacteria infection having industrial application, which comprises administering to a mammal a therapeutically effective amount of a compound as claimed in any one of claims 1 to 7 and 12 or a composition as claimed in claims 14 or 1 5.

17. A method as claimed'in claim 16, wherein the compound as claimed in claim 1 is administered in an amount of about 10 mg to 5 g/kg body weight/day.

18. A method as claimed in claim 17, wherein said compound is administered in 3 ro 4 multiple doses.