CA1153374A - Piperazinylbenzoheterocyclic compounds - Google Patents

Piperazinylbenzoheterocyclic compounds

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Publication number
CA1153374A
CA1153374A CA000325376A CA325376A CA1153374A CA 1153374 A CA1153374 A CA 1153374A CA 000325376 A CA000325376 A CA 000325376A CA 325376 A CA325376 A CA 325376A CA 1153374 A CA1153374 A CA 1153374A
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CA
Canada
Prior art keywords
oxo
dihydro
carboxylic acid
methyl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
CA000325376A
Other languages
French (fr)
Inventor
Hiroshi Ishikawa
Fujio Tabusa
Kazuyuki Nakagawa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Otsuka Pharmaceutical Co Ltd
Original Assignee
Otsuka Pharmaceutical Co Ltd
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Filing date
Publication date
Priority claimed from JP53043624A external-priority patent/JPS6034957B2/en
Priority claimed from JP10738778A external-priority patent/JPS5576875A/en
Priority claimed from JP53110464A external-priority patent/JPS6037118B2/en
Priority claimed from JP13715778A external-priority patent/JPS5564588A/en
Priority claimed from JP53141785A external-priority patent/JPS6037119B2/en
Priority claimed from JP14273178A external-priority patent/JPS5569583A/en
Priority claimed from JP53145638A external-priority patent/JPS5951959B2/en
Application filed by Otsuka Pharmaceutical Co Ltd filed Critical Otsuka Pharmaceutical Co Ltd
Application granted granted Critical
Publication of CA1153374A publication Critical patent/CA1153374A/en
Expired legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE
A piperazinylbenzoheterocyclic compound represented by the formula (I) (I) wherein R1 represents a hydrogen atom or a lower alkyl group;
R2 represents a hydrogen atom; R3 represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a lower alkane-sulfonyl group,a phenylaklyl group, a benzoyl group, a p-toluene-sulfonyl group or a group represented by the formula R4 represents a hydrogen atom or a halogen group; n is an integer of 0 or 1; and R1 and R2 may combine to form a cyclo-hexane ring together with the carbon atoms to which they are attached when n is 0; and pharmaceutically acceptable salts thereof as well as a method for preparing the same are disclosed.
These compounds have antimicrobial activity.

Description

1~!.,5 ~.37~
1 BACKGROUND OF TH~ INVENTION
.. ~
1. Field of the Invention This invention relates to piperazinylbenzoheteroeyclie compounds represented by the formula (I~ hereinafter defined and to pharmaceutieally aceeptable salts thereof which are useful as antimicrobial agents, a proeess for preparing the same and a pharmaceutieal eomposition eontaining the piperazinylbenzo-heteroeyelic compound or salt thereof.
2. ~escription of the Prior Art ; 10 It is known that certain types of polyheterocyelie eompounds exhibit antimicrobial aetivities. For example, U.S.
Patent 3,917,609 to Gerster et al diseloses substituted deriva-tives of 1,2-dihydro-6-oxo-6H-pyrrolo[3,2,1ij]quinoline which are useful as antimierobial agents or as intermediates for the pre-paration of antimierobial agents.
Also, U.S. Patents 3,896,131; 3,985,882; 3,969,463;
4,001,243 and 4,014,877 to Gerster et al disclose 6,7-dihydro-l-oxo-lH, 5H-benzo[ij]quinolizine derivatives having anti-microbial activities.

However, the piperazinylbenzoheteroeyclic compounds of the present invention are structurally different from these quinoline and quinolizine eompounds.
SUMMARY OF THE INVENTION
Aeeordingly, one objeet of the present invention is to provide a piperazinylbenzoheteroeyelic compound having anti-mierobial activity and low toxicity.
A more particular object of the present invention is to provide a piperazinylbenzoheterocyclic compound having low oral toxicity by comparison to the effective oral dosage thereof~

Another object of the present invention is to provide an ;' ..

. .

~, ~, r,~ ~ 3374 1 antibacterial ag~nt which shows no decrease in activity in the presence of serum.
Still another object of the present invention is to provide an antimicrobial agent which is effective ag~inst bacteria which are resistant to conventional antibiotics such as penicillin, ampicillin, streptomycin, etc.
A further object of the present invention is to provide a pharmaceutical composition containing the aforesaid anti-microbial agent or a pharmaceutically acceptable salt thereof in a therapeutically effective amount.
Still a further object of the present invention is to provide a process for preparing a piperazinylbenzoheterocyclic compound.
Accordingly, the present invention provides a piperazinylbenzoheterocyclic compound represented by the formula (I) ~ ~ CO~H (I) ; R -N ~ R2 ~H2)n~ Rl ;

..
wherein Rl represents a hydrogen atom or a lower alkyl group;
R2 represents a hydrogen atom; R3 represents a hydrogen atom, a - lower alkyl group, a lower alkanoyl group, a lower alkanesulfonyl group, a phenylalkyl group, a benzoyl group, a p-toluenesulfonyl group or a group represented by the formula OH
"' ~CO-,.~

.', ` ~l5, ~37~
1 R~ represents a hydrogen atom or a halogen group; n is an integer of O or l; and Rl and R2 may combine to form a cyclo-hexane ring together with the carbon atoms to which they are attached when n is O; and pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
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 tertbutyl group and the like.
The term "lower alkanoyl" as used herein refers to a straight or branched alkanoyl group having 1 to 4 carbon atoms - such as a formyl group, 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 "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 2-phenylethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, a l-phenylethyl group, a 1,1-dimethyl-2-- phenylethyl group and the like.

In the above formula (I), the group of the formula QH
CO-i:.'.

, .
';~

7,37~
represented by R3 is present as a, i.e., as tautomer, an enol type group (A), i.e., a 4-hydroxy-1,5-naphthyridine-3-carbonyl group and a keto type group (B), i.e., a 4-oxo-1,4-dihydro-1,S-naphthyridine-3-carbonyl group. This invention includes both enol and keto type tautomers.
The compounds of this invention are particularly effective against bacteria belonging to the genera Streptococcus, Pseudomanas, Enterobacter, etc. and exhibit potent antibacterial activity on those bacteria which are resistant to streptomycin, ampicillin and/or tetracyclin.
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 thescope of this invention.
8-(1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid 10-chloro-8-(1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 9-chloro-8-(1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 9-fluoro-8-(1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzolij]quinolizine-2-carboxylic acid ;; 8-(1-piperazinyl)-5-ethyl-6,7-dihydro-1-oxo-lH,5H-; benzo~ij]quinolizine-2-carboxylic acid 8-(1-piperazinyl)-5-butyl-6,7-dihydro-1-oxo-lH,5H-. . .
benzo[ij]quinolizine-2-carboxylic acid 8-(4-methyl-1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-: ., benzo[ij]quinolizine-2-carboxylic acid :``

37~
1 ~-(4-butyl-1-piperaz.inyl)-5-me-thyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 8-(4-acetyl-1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzolij]quinolizine-2-carboxylic acid 8-(4-isobutyl-1-piperazinyl)-5-me~hyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 8-(4-formyl-1-piperazinyl)-9-~luoro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij~quinolizine-2-carboxylic acid 8-(4-benzoyl-1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 8-(4-benzoyl-1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid ~: 8-(4-methanesulfonyl-1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 8-(4-tert-butanesulfonyl-1-piperazinyl)-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 8-(4-benzyl-1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 8-[4-(2-phenylethyl)-1-piperazinyl]-5-methyl-6,7-,:
dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 8-[4-(4-phenylbutyl)-1-piperazinyl]-10-chloro-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 8-(1-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-: oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 8-[4-(4-hydroxy-1,5-naphthyridine-3-carbonyl)-1-`:
!; piperazinyl]-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid . 8-[4-(4-hydroxy-1,5-naphthyridine-3-carbonyl)-1-`~ . piperazinyl]-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinoli-30 zine-2-carboxylic acid ' . -5-..~, .

q37~
1 ~-[~-~4-oxo~ -dihydro-1,5-naphthyridine-3-carbonyl)-l-piperazinyl]-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid
3-(4-ethyl-1-piperazinyl)-10-~luoro-6,7-dihydro-1-; oxo-lH,5H-benzo[ij]quinolizine-2-carbo~ylic acid 8-(4-propionyl-1-piperazinyl)-9-bromo-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 8-(1-piperazinyl)-10-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 8-(4-benzoyl-1-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij~quinolizine-2-carboxylic acid 8-[4-(p-toluenesul~onyl)-1-piperazinyl]-5-methyl-6,7-dihy~ro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 9-(1-piperazinyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid 9-(1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-ij]quinoline-5-carboxylic acid 9-(1-piperazinyl)-2-ethyl-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-ij]quinoline-5-carboxylic acid 9-(1-piperazinyl)-2-isopropyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid 9-(1-piperazinyl)-2-butyl-6-oxo-1,2-dihydro-6H-pyrrolo . [3,2,1-ij]quinoline-5-carboxylic acid 7-chloro-9-(1-piperazinyl)-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-ij]quinoline-5-carboxylic acid 8-fluoro-9-(1-piperazinyl)-6-oxo-1,2-dihydro-6H-pyrrolo [3,2,1-ij]quinoline-5-carboxylic acid 9-(~-methyl-1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid 9-(4-isopropyl-1-piperazinyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid . ~ .

, ~.5,~3~7~
1 9-(4-ace~yl-1-p.iperaæ.inyl)-~-metllyl-6-oxo-1,2-d.ihyclro-6H-pyrrolo[3,2,1-ij]quinoline-S-carhoxylie acid 9-(4-butyryl-1-piperazinyl)-6-oxo-1,2-dihydro-6~-pyrrolo[3,2,1-ij]quinoline-S-carboxylie acid - 9-(4-formyl-1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carbo~ylic acid 9-(4-benzoyl-1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-earbo~ylie aeid 9-(4-methanesulfonyl-1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-earboxylie acid 9-t4-propanesulfonyl-1-piperazinyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxYlie acid 9-(4-benzyl-1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolol3,2,1-ij]quinoline-5-carboxylie aeid 9-[4-(4-phenylbutyl)-1-piperazinyl]-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-earboxylic acid ,. 8-~luoro-9-(1-piperazinyl)- -metnyl-5-oxo-1,2-dihydro-; 6H-pyrrolo[3,2,1-ij]quinoline-5-earboxylic acid 8-chloro-9-(4-acetyl-1-piperazinyl)-2-methyl-6-o~o-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-earboxylic acid 9-[4-(4-hydro~y-1,5-naphthyridine-3-carbonyl)-1-~ piperazinyl]-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij~-quinoline-5-carboxylie aeid 9-[4-(4-oxo-1,4-dihydro-1,5-naphthyridine-3-carbonyl)-i l-piperazinyl]-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]-quinoline-5-carboXY~ie aeid 9-(4-ethyl-1-piperazinyl)-8-bromo-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid l-(l-piperazinyl)-7a,8,9,10,11, lla-hexahydro-4-o~o-4H-pyrido[3,2,1-jk]carbazole-5-carboxylic acid ~-7-'' ~

~.3 ~.~37~
1 3-chloro-1-(piperazinyl)-7a,8,9,10,11, lla-hexahydro-
4-oxo-4H-pyrido[3,2,1-jk]carbazole -S-carboxylic acid 2-fluoro-1-(piperazinyl)-7a,8,9.10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-S-carboxylic acid 1-(4-acetyl-1-piperazinyl)-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-S-carboxylic acid 1-(4-benzyl-l-piperazinyl)-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-5-carboXylic acid 1-(4-methanesulfonyl-1-piperazinyl)-7a,8,9,10,11,11a-10hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-5-carboxylic acid 1-(4-benzyl-1-piperazinyl)-7a,8,9,10, 11, lla-hexa-hydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-5-carboxylic acid 1-(4-methyl-1-piperazinyl)-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-5-carbo~ylic acid 1-[4-(4-hydroxy-l,S-naphthyridine-3-carhonyl)-1-piperazinyl]-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-5-carboxylic acid 1-(4-ethyl-1-piperazinyl)-2-chloro-7a,8,9,10,11,11a-.. hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-S-carboxylic acid 1-(4-acetyl-1-piperazinyl)-3-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-5-carboxylic acid The compounds of this invention represented by the j~ formula (I) can be prepared by various alternative procedures, : for example, by reacting a benzoheterocyclic compound of the .` formula (II) .' R4 ~ .
COOH (II) S - ~ N

H2~n~
.~

~ ~.5''~3~f~
1 wherein Rl, R , R~ and n hav~ the ~amo mc~rling as deined above, and R repr~s~nts a ha]ogen a-tom, a lower alkanesulfonyloxy group or an arylsulfonyloxy group; with a piperazine compound of the formula (III).

~ 3 HN N-R (III) wherein R has the same meaning as above.

The term "lower alkanesulfonyloxy" as used herein re-fers to a straight or branched alkanesulfonyloxy group having 1 to 4 carbon atoms such as a methanesulfonyloxy group, an ethane-sulfonyloxy group, a propanesulfonyloxy group, an isopropane-sulfonyloxy group, a butanesulfonyloxy group, a tert-butane-sulfonyloxy group and the like.
The term "arylsufonyloxy" as used herein includes a benzenesulfonyloxy group, a naphthalenesulfonyloxy group and the ... .
like. The aryl ring included in the arenesulfonyloxy 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.

More particularly, the reaction of the compound of the formula (II) with the compound of the formula (III~ can be carried out in an inert solvent under pressurized conditions, i.e., at a pressure of about l to about 20 atms, preferably l to lO atms at a temperature of about lO0 to about 250C, preferably at 140 to 200 C for a period of about 5 to about 20 hours.

In the above reaction the proportion of the compound ~,~ of the formula (III) to the compound of the formula (II) is not particularly limited and can be varied broadly~ Usually the re-action can be carried out using at least an equimolar amount, preferably l to 5 mols, of the compound of the formula (III) per ;~ "
r?.i379L
I mol of the compound oE the formula tII).
Suitable examples of the inert solvent include water, lower alcohols such as methanol, ethanol, isopropanol, etc.
aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane, diglyme (diethylene glycol dimethyl ether), etc., dimethyl sulfoxide, dimethyl formamide, hexamethylphosphoric triamide and the like, with di- -methyl sulfoxide, dimethylformamide and hexamethylphosphoric triamide being preferred.
The above reaction may be conducted in the presence of a deoxidizing agent in an amount of at leas~ an approximately equimolar amount, preferably 1 to 2 mols, of the oxidizing agent per mol of the compound of the formula (II).
Examples of suitable deoxidizing agent include alkaki ,~ metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., inorganic carbonates such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbon-ate, etc., tertiary amines such as pyridine, quinoline, triethyl-amine, etc.
With respect to the benzoheteroc~clic compounds of the formula (II) which can be used as the starting material for pre-paring the compounds of this invention represented by the formula (I), some of them 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 are novel and can be prepared by Re-action Scheme - 1 hereinbelow.
On the other hand, the compounds of the formula (III), another starting material of the compounds of this invention re-presented by the formula (I), are knGwn and commercially available.

5337~
1 Reaction Sch~me - 1 CH2)n 6 /CoOR7 ~ ~ ~ Cll ) I 1 1 + R OCH=C ~-~) l 1 2 n - ] ~ H \ CoOR7 ~ : \ N ~ Rl ~ RCH--C(COOR )2 '~
; (IV) (V) (VI) .,~ 10 Cyclization ~ ~ CaOR7 ~ COQH
) I ~ ~\ ~ ~ /
` R5 / ~ ~ ~J Hyd~olysis ~ N

2 ~ ( -2 Rl R2 ~ CH2) ~ R

:.,'.
,~- (VII) (II) ,s, In the above formulae (II), (IV), (V), (VI) and (VII), ; 20 R , R , R , R and n have the same meaning as defined above, and R6, R7, which may be same or different, each represents a lower ' alkyl group.
In Reaction Scheme - 1 above, of the compounds of the formula (IV) which are used as a starting material those in which R represents a halogen atom are known compounds as des-cribed in the above-mentioned U.S. Patents to Gerster et al, Bayer; Annalen, 278, 105 (1894), Schmidt and Sitwart; Berichte, 45, 1779 (1912), etc. or can be easily prepared by known process-es described therein; while those in which R represents a lower alkanesulfonyloxy group or an arylsulfonylo~y group are novel 3r 3 ~
1 cempounds and c~n be prepared easily in accordance with the process shown in Reaction Scheme -2 shown hereinbelow.
On the other hand, the compounds of the formula (V), another starting material, are known compounds and commercially available.
Further, the compounds of the formula (IV) in whi.ch R represents a halogen atom can also be prepared easily in accordance with the process shown in Reaction Scheme - 2 below.

.
Reaction Scheme - 2 .:, , aH R OH
(CH2)n f ~ (CH2)n R ~ N ,lRl l~N 0 H R H
. ., (VIII) (IX) ,~, .' R8 X R8 .,.~' (X) (X) ~ ~ i `:
X ~5 R2 oR8 1 Reduction ~ ~ Reduction ~
f - ~ CH2)n ~ (CIH2)n ~ 2)n ~N ~Rl (XI) (IV) (XII) .

~.S~3~
1 In the above Eormulae, Rl, R2, R~, R and n have the ; same meaning as defined above, and R represents a lower alkane-sulfonyl group or an arylsulfonyl group and x represents a halogen atom.
The term "arylsulfonyl" as used herein re~ers to a benzenesulfonyl group, a naphthalenesulfonyl group and the like.
The aryl ring included in the arylsulfonyl group may be sub-stituted with one or more of a halogen atom, a lower alkyl group, a hydroxY group, a nitro group and the like.
More particularly, in the Reaction Scheme - l the re-action between the compound of the formula (IV) and the compound i f the formula (V) can be effected in the absence of solvents or ' in the presence of solvents such as methanol, ethanol, isopro-panol, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide and the like. Preferably the re-; action is performed in the absence of solvents.
' The compound of the formula (V) can be used in excess ~, .
amounts over the equimolar amount relative to the compounds of the formula (IV), preferably in an equimolar amount in theabsence of solvents and in an amount of from about l.l to 1.5 mol per mol of the compound of the formula (III) in the presence of solvents.
The reaction can generally be carried out at a temperature of : from room temperature (about 15 to 30 C) to about 150C, pre-ferably 100 to 130 C, for a period of from about 0.5 to about 6 hours thereby easily yielding the compound represented by the formula (VI).
The subsequent cyclization reaction of the thus obtained compound of the formula (VI) can be effected in accordance ~^~ith conventional cyclization reactions, for example, by heating the compound of the formula (VI) or by using an acidic substance ;

,37f~ 1 such as phosphorus oxychloride, phosphoru~ pentachlor.ide, phosphorus trichloride, thionyl chloride, concentrated sul.~uric acid, polyphosphoric acid and the like. ~hen the cyclization ;. if effected by heating, it is preferred to heat the compound of the formula tVI) in a solvent such as high boilin~ point hyclro-carbons or high boiling point ethers, for example, tetralin diphenyl ether, diethylene glycol dimethyl ether, etc. at a , temperature of about 100 to about 250 C, preferably 150 to 200 C
.~ for a period of about 0.5 to about 6 hours. When the cycli- ; lO zation is effected using an acidic substance, the cyclization can be effected in the presence of the acid substance in an : approximately equimolar amount to a large excess amount, pre-ferably 10 to 20 molar excess acid, relative to the amount of the compound of the formula (VI) at a temperature of about 100 to about 150C for a period of about 0.5 to about 6 hours, whereby the desired compounds of the formula (VII) can be i;~; , .
~i produced advantageously.
.
- In the above Reaction Scheme - 1, the hydrolysis of ; the compound of the formula (VII) into the compound of the form-20 ula (II) can be achieved by a conventional hydrolysis procedure in the presence of a typical hydrolysis usual catalyst, for example, a basic compound such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, or an inorganic or organic acid such as sulfuric acid, hydrochloric acid, nitric acid, acetic acid, an aromatic sulfonic acid and the like. The hydrolysis can be carried out in a solvent such as water, methan-ol, ethanol, isopropanol, acetone, methyl ethyl ketone,dioxane, ethylene glycol, acetic acid and the like at temperature of from room temperature to about 200C, preferably 50 to 150C for a period of about 0.5 -to about 6 hours, thereby easily yielding .

~, :

~.5~37~
1 the compound represented by the ~ormula (II).

In Reactlon Scheme - 2 above, a suitable amount of the compound of the formula (X) to be reacted with the compound of the formula (XIII) or (IX) is at least an approximatcly equi-molar amount, preferably 1 to 2 moles of the compound of the formula (X) are reacted per mol of the compound of the formula (VIII) or (IX).
The reaction proceeds usually in an inert solvent in the presence of a deoxidizing agent in an amount of at least an i 10 approximately equimolar amount, preferably 1 to 2 mols, of the ; oxidizing agent per mol of the compound of the formula (VIII) or (IX) at a temperature of about 0 to about 100 C, preferably at room temperature for about 0.5 to about 6 hours, thereby yielding the compound of the formula (IV) or (XII).
Examples of suitable deoxidizing agents include alkal metal hydroxides such as sodium hydroxide, potassium hydroxide, ... .
etc., inorganic carbonates such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate sodium hydrogen carbon-ate, 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, diglyme, etc., a'^omatic hydro-carbons such as benzene, toluene, etc., dimethyl sulfoxide, di-methylformamide, hexamethylphoshoric triamide, pyridine, etc.
In reaction Scheme - 2 above, the reduction of the com-pounds of the formula (XI) or (XII) can be conducted catalytic-ally 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, ; -15-.

37~
I propionic acid, etc.

Suitable amounts of sodium borohydride or lithium aluminum hydride and the lower fatty acid are an approximately equimolar amount to a large excess amount, preferably 3 to 5 mols per mol of the compound of the formula (XI) or (XII), res-pectively.
The reduction reaction using a hydrogenating agent can proceed advantageously in an inert solvent such as ethers e.g., dioxane, tetrahydrofuran, diglyme, etc., aromatic hydrocarbons, e.g., benzene, toluene, etc., lower fatty acids, e.g., trifluro-acetic acid, propionic acid, etc. at a temperature of room tem-perature to about 100 C, preferably 50 to 100C for about 1 to about 6 hours.
The compounds of this invention represented by the formula (I) can be prepared also by the following Reaction Scheme - 2a.

Reaction Scheme - 2a R4~ ~JN~Rl ~ R60CH=C~ ~R

(IV) (V' ) R ~ ~Rl CH=C \ ,R
COCH

(VI') 3~
1 Reaction Schem~ -2a continued Reduction R5 ~ - ; COCH

' ~ (CH2) (VII'?

~ ~3N ~ -R3 .. (III) O R
R3 N ~ / ~ COCH

2 CH2~ Rl R3-N ~N / ~ \ R' 2/ 2 ~ R

1 (I") ~17-:;

: ~.. 5~3~
1 Reaction Scheme - 2a continucd ¦ Hydrolysis ' / I I

` 2 / 2 ~ R
`. 10 : (I

wherein R and R' represent a hydrogen atom or a lower alkyl group; Y represents an aromatic heterocyclic ring con~aining a tertiary nitrogen atom through which it is connected or a tri-alkylamino group; Z represents an anionic ion; and R , R , R ,R , R , R6, R7 and n have the same meaning as defined above.
In the above Reaction Scheme - 2a, the reaction be~ween the compound of the formula (IV) and the compound of the formula (V') can be conducted in the same manner as the reaction between the compound of the formula (IV) and the compound of the formula (V) described above. The cyclization of the compound of the formula (VI') can be carried out in the same manner as the cycli-zation of the compound of the formula (VI) described above. The ` reaction between the compound of the formula (VII') and the com-pound of the formula (III) can be carried out in the same manner as the reaction between the compound of the formual (II) and the compound of the formula (III).
The preparation of the compounds of the formula (I) from the compound of the formula (I') can be effected by reacting 337~
the compound of the ~ormula (I') with a ~ertiary nitrogen atom containing aromatic heterocyclic compound or a trialkylamine and an anion donating compound in an appropriate inert solvent to obtain a compound of the formula (II") and hydrolyzing the compound of the formula (I") thus obtained after isolation or without isolation thereof.
In the above reaction, examples of suitable tertiary nitrogen atom containing aromatic heterocyclic compound include unsubstituted pyridine and alkyl substituted pyridine compounds such as picolines, lutidines etc., quinoline and alkyl substitut-ed quinolines such as quinaldine, lepidine, etc.
Examples of suitable trialkylamine include trialkyl-amines having 1 to 6 carbon atoms in each alkyl moiety, such as trimethylamine, triethylamine, tripropylamine, triisopropylamine, etc.
Examples of suitable anion donating compound include those compounds which can donate a halogen ion such as an iodine ion, a bromine ion, a chlorine ion, etc., for example, iodine, bromine, chlorine, or those compounds which can donate a sulfate residue, a phosphate residue, a perchlorate residue, etc., for example, sulfuric acid, phosphoric acid, perchloric acid, etc.
Examples of suitable inert solvent which can be used in the above reaction include lower alcohols such as methanol, ethanol, isopropanol, etc., aromatic hydrocarbons such as benzene, toluene, etc., ethers such as tetrahydrofuran, dioxane, diglyme, etc., dimethyl sulfcxide, dimethylformamide, hexamethylphosphoric triamide, pyridine, etc.
The tertiary nitrogen containing aromatic heterocyclic compound or trialkylamine, and anion donating compound can be used in excess amounts over th~ equimolar amount relative to the .
5.~ 7~

1 compounds of th~ formula (I'), pre~o~ably in an amoun-t of from ; l to 2 mols per mol of the compound of the formula (I').
The reaction can usually be carried out at room tem-~` perature to about 120 C, preferably 50 to 100C for 30 minutes to 6 hours.
The hydrolysis of the compound of the formula (I")thus obtained can be conducted in an appropriate solvent in the absence or presence of an acid hydrolyzing agent or an alkaline hydrolyzing agent, preferably in the presence of such agent.
Examples of sultable alkaline hydrolyzing agent which can be used in the above hydrolysis reaction include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., alkaline earth metal hydroxides such as calcium hydroxide, etc., ammonium hydroxide, and carbonates of these metals and ammonium.
The hydrolysis of the compound of the formula (II") can also be conducted in an aqueous medium in the presence of a trialkylamine such as a lower trialkylamine, e.g., trimethyl-amine, triethylamine, etc.

Examples of sutable solvent which can be used includelower alcohols such as methanol, ethanol, isopropanol, etc., aromatic hydrocarbons such as benzene, toluene, etc., ethers such as tetrahydrofuran, dioxane, diglyme, etc., water, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric tri-:
amide, etc.
The hydrolysis can usually be effected at about 20 toabout 150 C, preferably 80 to 120 C for 30 minutes to 6 hours.

The above hydrolysis can be accelerated by the addition of a lower alcohol.

' .

1~5,~3~
1 Of th~ compounds oE thi.s invention ropres~nted by the ormula (I) those compounds .in which R3 represents a lower alkyl ` group, a lower alkanoyl group, a benzoyl group, a lower alkane-sulonyl group, a p-toluenesulfonyl yroup, a phenylalkyl group, or a group represented by the following formula:
OH
~CO- .

:~ ~compounds of the formula (Ib) below] can also be prepared by reacting compounds in which R represents a hydrogen atom [com-pounds of the formula IIa) below] with a compound of the formula . (XIII) below in the presence of a deoxidizing agent.

.

~ ~ CO~II R4\~X~CooH

20 HN ~ ¦ (XIII) R N N
CH2) ~ ~ ~ 2~ C 2~n~ l , (Ia) (Ib) ,s~
In the above formulae, Rl, R2, R4, n and X have the : same meaning as defined above, and R represents a lower alkyl : group, a lower alkanoyl group, a benzoyl group, a lower alkane-sulfonyl group, a p-toluenesulfonyl group, a phenylalkyl group or a group represented by the following formula:

` 1 OH
CO--The compounds of this invention represented by the formula (I) prepared as described above can form pharmaceutical-ly 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 pharma-ceutically acceptable acids which can be used for the salt forma-tion 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, eth-anesulfonic acid, p-toluenesulfonic acid and the like.
The benzoheterocyclic compounds of the Lormula (I) can be converted into a corresponding carboxylate by reacting the carboxylic acid with a pharmaceutically acceptable basic com-pound. Examples o~ basic compounds are inorganic basic compounds such as sodium hydroxide, potassium hydroxide, calclum hydroxide, aluminum hydroxide, sodium bicarbonate and the like and organic basic compounds such as morpholine, piperazine, pyridine, piper-idine, ethylamine, 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 and purified by con~-entional procedures, for example, by solvent extraction, dilution, pre-cipitation, recrystallization column chromatography and the like.

' .':

~S33'7~
1 The compounds o~ this invcntion of the formula (I) and the salts thereof exhibit excellent antimicrobial activity broadly on gram positive and negative bacteria at low concentra-tions. They are useful compounds which show particularly potent antibacterial activity on Streptococcus, Pseudomonas, Enterobacter, etc. on which conventional synthetic antibacterial agents are not effective or only slightly effective. In add-ition, they show a high antibacterial activity on coliform bacilli, staphylococci, etc. which are major causes of infec-tions diseases and are also effective on Serratia, Krebsiella, etc. which also cause infectious diseases that have recently attracted wide attention of many workers in the field, and there-fore 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 show no decrease in antimicrobial activity but rather show a tendency of an increase in such activity even in the presence of a serum. This phenomenon is surprising to one skilled in the art since it is hitherto observed that conventional pharmaceuti-cals having antimicrobial activity show decreased activity inthe presence of a serum. This strongly suggests that the com-pound of this invention can exhibit potent antimicrobial acitiv-ity in the blood.
The oral toxicity of the compounds of this invention is by far low as compared with effective oral dosage thereof.
The compounds of this invention have excellent anit-microbial activity on those bacteria which are resistant or have acquired resistance to conventional antibiotics such as penicil-3 lin, cephalosporin, ampicillin, streptomycin, erythromycin, ~' l~X.,~37~
1 Kanamycin, nalidixic ac.id, etc.
The compounds of this invention represented by the formula (I) can be converted into penicillanic acid derivatives represented by the formula ~XIV) below which exhibit excellent antimicrobial activity on gram positive and negative bacteria, especially on Pseudomonas and Streptococcus, in accordance with the process shown in Reaction Scheme - 3 below and as exempli-fied in Reference Examples 16 to 18.

.Reaction Scheme - _ R ~ ~ C O OH

1 3 ~ ~ ~ N
R -i ~ N (CH2) ~ R

O (I) Rl OCX /

3 A~
.~ R --N N
\--/ 2/L(CH2)~ 1 O

N

~ ~3~Co~ o~H 5 ~H3 \~ R2 ( H2)~l\R1 ~ 0~/ N \`COOH
,` (XIV) ~.~ S~ `74 1 In the above ormulae, Rl~ represents a lower alkyl group,`X represents a halogen atom, R represents a hydrogen atom and a hydroxy group, ~I represents a hydrogen atom or an alkali metal and R , R , R , R and n have the same meaning as defined above.
The reaction scheme is explained in detail in copend-ing application Serial No. 325,375 filed on even date with this application and corresponding to Japanese Application No. 43624/

1978 filed in Japan April 12, 1978.
As is apparent to those skilled in the art, the com-pounds of the formula (1) can exist in optically active forms and this invention includes such optical isomers within its scope.
' In using the compounds of this invention of the form-ula (1) and the salts thereof as therapeutic agents, these com-pounds can be formulated into pharmaceutical compositions to-gether with ordinary pharmaceutically acceptable carriers. Suit-able 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 are used;
r tablets, pills powders, liquid preparations, suspensions, emul-sions, granules, capsules, suppositories, and injectable pre-parations (solutions, suspensions, etc.).
In molding a pharmaceutical composition containing the compounds of the formula (I) or the pharmaceutically acceptable 1 salt thereo~ as an activ~ ingr~dient into ~ tablet form, a wide range o~ c~rriers 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, lC 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, bentonite and colloidal silicic acid, and lubricants such as purified talc, stearic acid salts, boric acid powder, Macrogol*
(trademark 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 lami-naria and agar.
' ~
*Trade Marks -26-~ 3 ':

3~
; 1 In molding the pha~maceutical composition into a suppository form, a wide variety of carriers known in the art can be used. Examples o~ suitable carriers include polyethylene glycol, cacao butter, higher alcohols, esters oE hicJher 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 i' , 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, polyoxyethylene sorbitol, and sorbitan esters. Sodium chloride, glucose or glycerol may be incorporated into a thera-peutic 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.

; 20 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 therapeutic-` ally effective amount of the compound of the general formula (I) and the pharmaceutically acceptable salts thereof of this invention is usually about l to about 70% by weight, preferably 5 to 50% by weight, based on the entire 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 1 the therapeu~ic agent. For example, the tablcts, pills, liquid preparations, suspensions, emulsions, granules, and capsules are orally administered. The injectable preparations are intravenously administered either alone or tocJether witl ordinary auxiliary agents such as qlucose and amino acids.
Furthermore, as required, the therapeutic agent can be singly ` administered intramuscularly, intracutaneously, subcutaneously, or intraperitoneally. The suppository is administered intra-rectally and the ointment is coated on the skin.
The dosage of the antimicrobial agent is suitably , selected according to the purpose of use, the symptoms, etc.
- Usually, a preferred dosage of the compound of this invention is about 10 mg to 5 g/kg body per day in 3 to 4 multiple doses.

I. Antimicrobial Activity 1. Test Method The antimicrobial activity of the following test com-pounds on various test organisms listed below was determined by the serial dilution method on agar plate (Heart Infusion agar produced by Difco Co.)- (See CHE~OTHERAPY 22, p. 1126 - 1128 (1974), and the minimum inhibitory concentrations (mcg/mQ) obtained are shown in Table 1 below.
A sample of each test organism was prepared so that the population of the organism was 1 x 10 cells/mQ
(O.D. 660 mll = 0.07 to 0.16) and 1 x 10 cells/mQ (~hich was obtained by diluting the above 1 x 10 cells/mQ preparation).

:

~''' . .
; -28-.

. .

~ 3~ `7~
12- Test OrcJanisms 1. Escherichia Coli NIHJ
2. Eseherichia Coli NIHJ JC-2(IFO 12734) 3. Klebsiella pneumoniae ~ 4. Klebsiella pneumoniae ST-101 '~ 5. Proteus rettgeri NIH 96
6. Proteus morganii IID Kono
7. Proteus vulgaris IID OX-l9
8. Enterobacter aerogenes IFO 12979
9. Enterobaeter eloacae
10. Yersinia enteroeolitiea 0-3
11. Yersinia enterocolitica 0-5
12. Hafnia alvei IFO 3731
13. Pseudomonas aeruginosa E-2
14. Pseudomonas aeruginosa NCTC 10490
15. Pseudomonas aeruginosa ATCC 10145
16. Pseudomonas maltophilia IFO 12592 , 17. Pseudomonas putida IFO 13696 18. Salmonella typhi 0-901 (NCTC 8393) 20 19. Shigella Sonnei E~ 33 20. Serattia marcescens IFO 12648 21. Bacillus subtilis PCI 219 22. Staphyloeoceus aureus FDA 209 P
23. Streptoeoccus pyogenes IID S-23 24. Streptococcus pyogenes IID Cook 25. Streptococcus pneumoniae Type I
26. Streptococcus pneumoniae Type II
27. Streptococcus pneumoniae Type III
28. Corinebacterium diphteriae :' .

: :.

r~3 ~ 37 ~
. 1 3. Tcst C mpound ; ~ n- ~ l-Piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH, (Invention) 5H-benzo[ij]quinolizine-2-carboxylic acid hydro-chloride B 8-tl-Piperazinyl)-6,7-dihydro-1-oxv-111,5~-benzo ~Invention) [ij]quinolizine-2-carboxylic ~cid hy~rochloride C ~ Piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-(Invention) pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid hydrochloride D l-(l-Piperazinyl)-7a,8,9,10,11,11a-hexahydro-4-. (Invention) oxo-4H-pyrido[3,2,1-jk]carbazole-5-carboxy~ic acid hydrochloride E l-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyri-(Comparison) dene-3-carboxylic acid (nalidixic acid) ; F 9-Fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo ....
(Comparison) [ij]quinolizine-2-carboxylic acid (flumequine) ,~ 5 Sodium 9-chloro-2-methyl-6-oxo-1,2-dihydro-6H-~.~ (Comparison) pyrrolo[3,2,1-ij]quinoline-5-carboxylate ~,, H 6-~2-[8-(4-acetyl-1-piperazinyl)-6,7-dihydro-1-~ (Comparison) oxo-lH,5H-benzo[ij]quinolizine-2-carboxamide]-: 2-phenylacetamido3-3,3-dimethyl-7-oxo-4-thia-1-: azabicyclo[3,2,0]heptane-2-carboxylic acid I 6-{2-[8-(1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-~: (Comparison) benzo[ij]quinolizine-2-carboxamido]-2-phenylacet-: amido}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3, 2,0]heptane-2-carboxylic acid .,' J 6-~2-[8-(4-methanesulfonyl-1-piperazinyl)-6,7-di-(Comparison) hydro-l-oxo-lH,5~-benzo[ij]quinolizine-2-carbox-~ 30 amido]-2-phenylacetamido~-3,3-dimethyl-7-oxo-4-: ~hia-l-azabicyclo[3,2,0~heptane-2-carboxylic acid ,~, :~. ;,.
,, j~ -30-,~ , .

g- ~L r~ 7 ~
, 1 K 6- 2-[l.0-chloro-8tl-piperazinyl]~6,7-dihydro-1-~ (Comparison) oxo-lH,5H-benzo[ij]quinolizine-2-(carboxamido]-2-phenylacetamido -3,3-dimethyl-7-oxo-4-thia-1-- azabicyclo[3,2,0]heptane-2-carboxylic acid :,.

`i ',`

','`
:.

. r~ ~ 37 ~3~
T A B L E
Minimum Inhibitory Concentration Test - Test Organism Compound 12 3 4 5 6 7 _ 910 lx108 0.81.61.60.40.46.31.60.80.83.1 ; Alx106 0.41.61.60.20.43.10.80.80.81.6 lx108 1.63.16.31.61.612.512.5 - - 12.5 Blx106 0.83.11.61.61.66.31.6 - - 3.1 lx10a 0.81.60.80.80.83.13.10.80.81.6 lx106 0.41.60.80.20.83.10.80.40.41.6 lx108 D lxlo6 lx108 3.13.13.11.61.66.33.16.33.112.5 Elx106 1.63.13.11.60.83.13.13.13.11.6 i~ lx108 0.20.80.80.20.20.8 - 0-40.40.8 , lx106 0.10.40.40.10.10.4 - 0.20.20.4 ; lx108 0.8 - 3.1 - 0.4 -Glx106 0.4 _ 1.6 - 0.2 lx108 6.3 - 12.5 - 25 - - - - -lXlo6 _ _ _ _ _ _ _ _ -- --lx108 1.6 - 0.8 - 0.4 Ilxl06 8 3.1 - 6.3 - 12.5 ,: JlXlo6 lx108 6.3 - 6.3 - 12.5 KlXlo6 . . .
, .................................................................... .
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.

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T A B L E 1 (C~t~d) Minimum Inhibitory Concentration Test Test Organism Compound 11 12 13 14 I5 16 17 18 19 20 lxl08 0.86.312.56.3 6.3 12.5 3.1 0.4 0.8 3.1 lx106 0.83.16.3 3.1 6.3 12.5 1.6 0.2 0.4 1.6 lx108 - - _ _ 12.5 _ _ 0. 81 66 . 3 lx106 -- - -- -- 6.3 -- - 0.8 1.6 3.1 lx108 1.61.66.3 6.3 6.3 6.3 3.1 0.4 1.6 3.1 ^ C lxl06 1.60.83.1 3.1 6.3 6.3 3.1 0.2 1.6 1.6 lX108 D lx106 lxl08 3. 1 100>100>100 >100 >100 1003. 1 3. 1 3. 1 E lxl06 1. 6 50 >100>100 >100 >100 50 3.1 3.1 3.1 lxl08 0. 4 25 50 25 25 25 25 0.20. 8 0. 8 F lx106 0.412550 12.512.5 25 125 0.2 0.8 0.4 lxlo 8 _ 100 25 50 - - 0. 81. 63 . 1 lx106 - - 50 12.5 25 - - 0.8 1.6 1.6 8 _ - 25 3 . 112.5 - - 6 . 3 12.5 50 lxlO 6 lx108 - 25 6.3 25 - - 0.2 3.112.5 I lYlo6 lx108 - - 25 3.112.5 - - 3.1 6.3 50 ' J lxl06 - - - - - - ~ ~ ~ ~
8 _ - 25 3 . 112.5 - - 3.13. 112 . 5 K lxl06 - - - ~ ~ ~ ~ ~ ~ ~

., ., .

: .

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, ' ~ ' ' 3 ~ ~
T A B L E 1 (Cont'd) Minimum Inhibitory Concentration Test Test Organism Compound 21 22 23 24 25 26 27 28 lxlOa0.8 6.3 25 25 12.5 25 25 1.6 A lx1060.8 3.112.512.5 3.1 6.312.5 1.6 lxlOa12.52.5 - - - - - -B lx10612.512.5 - - - - - -lxlOa3.1 25 10050 100 100100 25 C lxlO~3.1 25 50 25 50 50 50 6.3 lxlOa D lx106 lxlOa6.3 50 >100>100>100>100>100>100 E lx1063.1 50 >100>100>100>100>100>100 lxlOa0.4 3.1>100>100>100>100>100 >25 F lx1060.2 1.6>100>100>100>100>100>6.3 " lxlOa - 3.1>100 G lx106 _ 3.1>100 lxlOa- 1.6 - - - - - -lX106 lxlOa- 0.1 - - - - - -i I lxl06 lx109 - 0.8 , I
lx106 lxlOa - 0.8 lXlo6 _ _ _ _ _. _ _ -, . .

, ., .

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1 In the same manner as above, the antimicroblal activity of the follo~ing compounds on various test organisms which cause infectious diseases in fish was determined. The results obtained are shown in Table 2 below.

Table 2 Antimicr~bial Activity on Bacteria Which Cause Infectious Diseases in Fish Minimum Inhibitory Concentration (,ug JmQ) Test Compound B A C E
Test Organism 10 10 ~ ~ 10 lOb lOb lOb Aeromonas hydrophila IFO 12658 1.6 0.8 0.2 0.1 0.4 0.2 0.8 0.8 Aeromonas hydrophila IFO 12981 0.8 0.4 0.2 0.2 0.4 0.2 0.4 0.2 Aeromonas salmonicida IFO 12659 1.6 0.8 0.4 0.2 0.4 0.2 0.8 0.8 Aeromonas salmonicida ; IFO ]2718 0.8 0.4 0.4 0.2 0.4 0.4 0.8 0.8 Pseudomonas fluorescens ' 20 IFO 121806.3 6.3 3.1 3.1 3.1 3.1 >50 50 Pseudomonas fluorescens IFO 1256850 25 25 12,5 50 25 ~50 50 Vibrio anguillarum IFO 12710 12.5 3.1 3.1 3.1 3.1 1.6 1.6 0.8 Vibrio anguillarum ~;? IFO 13266 0.8 0.4 0.2 0.1 0.4 0.2 1.6 0.8 ~ .
Influence of the Addition of Horse Serum on the Minimum Inhibitory Concentration of Quinoline Derivatives ` Minimum inhibitory concentration of test compounds A, C

~, and F on various test organisms shown in Table 3 was determined.
:
:, .

5 r ~37 4 The determination w~s conducted by evalua-ting minimum inhibitory . concentration of each test compound by serial dilution plate method using a culture medium of ~Ieart Infusion Agar (a product of Difco Co.) containing horse serum at a final concentra-tion of 0, 10, 20 or 40% by volume with inoculum size of the test organ-ism being 10 cells/mQ (CHEMOTHER~PY, 22, p. 1126 - 1128 (1974)).
: The results are shown in table 3 below.
~:;
Table 3 - Influence of the Addition of Horse Serum .~ on the MIC of Quinoline Derivatives Test Serum Minimum Inhibitory Concentration (mcg/mQ) ~: Com- Conc. Test Orqanism pound(~6) ~ ~~~~---~~ 2 17 16 21 27 .. _ ~, lo8 lo6 lo8 lo6 lOs lo6lOs lo6 lo8 lo6 lo8 10~
~ r 0 1.6 1.6 0.8 0.8 0.2 0.10.8 0.8 0.8 0.8 50 50 . 10 3.1 3.1 0.8 0.8 0.4 0.20.8 0.4 0.8 0.8 >50 50 .~. 20 6.3 3.1 0.8 0.8 0.2 0.20.8 1.6 0.8 0.8 ~50 50 40 12.5 12.5 1.6 1.6 0.2 ().2 1.6 1.6 1.6 1.6 >50 50 "! .. ~
~,. 20 0 12.5 12,5 1.61.6 0.8 0.4 1.6 1.6 3.1 1.6 6.3 3.1 : 10 12.5 6.3 1.6 1.6 0.~0.4 1.6 1.6 1.6 1.6 6.3 3.1 :~. C
:j . 20 12.5 5.3 0.81.6 0.8 0.4 0~8 0.4 1.6 1.6 3.1 3.1 ,~
'. 40 12.5 6.3 0.40.4 0.4 0.4 0.4 0.4 0.4 0.4 3.1 1.6 ' ;.,, 1~ 6.36.3 1.6 1.60.4 0.2 3.1 1.6 6.3 3.1 '~5 6.3 ~ 10 6.3 3.1 0.8 0.8 0.2 0.21.6 1.6 3.1 3.1 6.3 6.3 ,:. A
-~ 20 3.1 3.1 0.8 0.8 0.2 0.20.8 0.8 1.6 0.8 6.3 6.3 ~ 40 3.1 3.1 0.4 0.4 0.2 0.20.8 0.4 0.8 0.8 6.3 3.1 i .
~ :-.

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1 (III) Inactivation Ratio by Human Serum Protein A 1/15 mol/Q phosphate buffer was added to powders ofMoni-Trol 1 (dehydrated preparation of human serum, a product of - Midori Juji Co. Ltd.) to prepare a composition having the same serum protein concentration as natural human serum and this pre-paration was labeled "100~ human serum", an aliquot of the "100 human serum" preparation was mixed with the same volume of the above buffer to prepare "50~ human serum" and another aliquot was mixed with 4 times as much as its volume of the buffer to prepare "20~ human serum".

Each of test compounds A and E was dissolved in an ~ appropriate amount of the above serum preparations such that the ,~ final concentrations were 12.5 ~g/mQ and 3.1 ~g/mQ. After in-cubating the resulting preparations at 37 C for 2 hours, the ~" amount of active component was evaluated by determining the . .
activity of the test compound in the human serum on Escherichia , coli As-l9 (Inoculum size: 10 cells/mQ).

The Inactivation Ratio of test compounds A and E in ., human serum was calculated in accordance with the following ' 20 equation.

; ' .. Co -- C
Inactivation Ratio = x 100 "` Co ;, wherein Co indicates the concentration of test compound in the , absence of the serum, and C the concentration of active component ~ in the serum.

";
; The results obtained are shown in Table 4 below.
`:`

r~ 37 ~
1 Table 4 Inactivation by Human Serum Protein Inactivation ratio (~
` TestConcen-Compounds traction Serum Concentration (mcg/mQ) 100(%) 50(%) 20(%) 10(%) A12.5 -2.5 -17.9 -2.5 -2.5 `~ 3.1 0 -26.5 0 8.2 .

.. . _ _ . .. . . .
~;~ E 12.5 76 62.4 39.2 47.2 '- 10 ` 3.1 61.3 61.3 43.5 41.3 '' ' ~ Acut~ Toxicity ., ~ The acute toxicity of the compounds of this invention ~;.
,~ having the formula (I) was determined by intravenous administra-tion (i.v. ? in mice which had been fasted for 12 hours prior to the test. LD50 values (50~ lethal dose) obtained are as ~t' . follows.
,~.~;

Acute Toxicity Test Compound LD50 (i.v.) , . .
,~ (mg/kg) B 1,100 - In the same manner as above were obtained LD50 values of the other test comp~unds which amounted to 500 mg/kg or more.
-~ The present invention is further illustrated by the following Reference Examples and Examples, but they are not to be construed as limiting the scope of this invention. The :
' -.

~5~3~
1 antimicrobial activity of typical compounds of the prcsentinvention is also shown in Examples. 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 80 C at reduced pressure (1 to 2 mmHg) for 6 hours using P2O5 as a desiccant.
Reference Example 1 10 g of 5-hydroxy-3,4-dihydrocarbostyril was added to 100 mQ of methanol having dissolved therein 3.8 g of potassium hydroxide and the mixture was stirred at room tempera-, ture 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 evaporation. The residue thus obtained was suspended in 50 mQ of dimethylformamide and 10.6 g of methanesulfonyl chloride was added drop~ise to the suspension ,i~
while ice-cooling with stirring. After adding 3.5 g of methane-sulfonyl chloride the resulting mixture was stirred at room temperature for 4 hours. After the completion of the reaction ,i the solvent was removed under reduced pressure and the residue was purified through silica gel column chromatography (silica gel: Wako C-200, a tradename for a product of T~ako Junyaku Co., . Ltd.; eluent: chloroform). Recrystallization of the elute from water-containing ethanol gave 5.7 g of 5-methane-sulfonyloxy~3, 4-dihydrocarbostyril as colorless prismatic crystals having a melting point of 227 to 231 C.

Reference Example 2 In the same manner as in Reference Example 1, 5-(p-toluenesulfonyloxy~-3,4-dihydrocarbostyril having a melting point of 215 to 216 C was o~tained.

~1 S;~37~
1 Reference Example 3 ; 45 g oE 5-amino-3,4-dihydrocarbostyril was suspended in 250 mQ of a 15~ hydrochloric acid and 250 mQ of water having dissolved therein 20 g of sodium nitrite was added dropwise to the mixture followed by stirring at room temperature for 1 hour.
` The resulting solution was added dropwise to a solution prepared by dissolving 41.2 g of cuprous chloride in 120 mQ of concen-trated hydrochloric acid at room temperature while stirring.
.~
After completion of the addition, the mixture was heated on a water bath at 50 to 60 C for 1 hour while stirring. After allow-ing the mixture to cool to precipitate crystals, they were collected by filtration and washed with water. The wet crystals were dissolved in chloroform and insoluble materials were re-moved by filtration. The residue was dried over anhydrous sodium sulfate. After removal of the solvent the residue was dissolved with heating and the solution was treated with activ-,"
ated carbon while hot. The ethanolic solution thus treated wasconcentrated under reduced pressure. Recrystallization of the concentrate from ethanol gave 3I.5 g of 5-chloro-3,4-dihydro-carbostyril having a melting point of 193 to 194 C.

Reference Example 4 - 42.5 g of 5-chloro-3,4-dihydrocarbostyril was suspend-ed in 250 mQ of dioxane and 44.3 g of NaBH4 was added to the suspension. Then 67 mQ of acetic acid (d=1.05) was added drop-wise to the mixture at room temperature. After heat-refluxing the resulting mixture for 2 hours the solvent was removed under reduced pressure. Water was added to the residue and insoluable materials were removed by filtration followed by washing with diethyl ether. The residue was extracted with diethyl ether, dried over anhydrous sodium sulfate and distilled under reduced : .

~ ?~37~
1 pressure to obtain 36.0 ~ of 5-chloro-1,2,3,~-tetrahydroquino-line having a boiling point oE 116 to 12oCjO.2mmHg.
Reference Ex_mple 5 4.5 g of 5-methanesulfonyloxy-3,4-dihydrocarbostyril was suspended in 90 mQ of dioxane and 35 g of NaB~l4 was added to the suspension then 5.3 mQ of acetic acid was added drop-~' wise 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 ~unyaku 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-tetrhydro-i quinoline, colorless prisms having a melting point of 74 to 76C~
Reference Example 6 In the same manner as in reference Example 5, 5-(p-toluenesulfonyloxy)-1,2,3,4-tetrahydroquinoline having a melting ! point of 112 to 113C.
Reference Example 7 5.5 g of 4-chlorooxindole was dissolved in 80 mQ of dioxane and 6.2 g of sodium borohydride was suspended in the resulting solution and 12.7 mQ of trifluoro acetic acid (d=1.48) was added thereto dropwise at room temperature while stirring.
After heat-refluxing the mixture for 4.5 hours the solvent was ., .

;' ".

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1 removed thereErom under reduced pressurc. ~ater was added to -the residue and water insoluble materials were removed by filtra-tion and washed with diethyl ether. The filtrate was extracted with diethyl ether and the ether layer was dried over anhydrous ~ sodium sulfate followed by removing the solvent. The residue `~ was distilled under reduced pressure to obtain 3.9 g of 4-chloroindoline as a colorless oily product having a boiling point of 135 C at 10 mmHg.
Reference Example 8 5 g of sodium borohydride was added to 66 mQ of ` pyridine having dissolved therein 4.4 g of 2-methyl-4-chloro-indole. To the mixture were added gradually 10.6 g of fine powders of aluminum chloride while ice-cooling with stirring.
After completion of addition the mixture was stirred and allowed to react at room temperature for 27 hours, the solvent was re-; moved therefrom under reduced pressure. Water was added to the residue and the mixture was extracted with 100 mQ of benzene.
The benzene layer was washed with a saturated aqueous sodium chloride solution followed by concentration. To the residue was added a 10% aqueous hydrochloric acid which caused foaming.
After foaming ceased the mixture was rendered neutral with an aqueous sodium carbonate solution followed by extracting the mixture with 100 mQ of benzene. The benzene layer was dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure the extract was purified through a silica gel column chromatography (eluent:chloroform) to obtain 3.4 g of 2-methyl-4-chloroindoline which was confirmed by N~IR.
Reference Example 9 21.6 g of ethyl ethoxymethylenemalonate was added to 22.4 g of 5-methanesulfonyloxy-1,2,3,4-tetrahydroquinoline and ~' ,.~
:' i: ~ il 5,~3~
1 the mixture was heated at 110C 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 140 C for 45 minutes. After completion of the reaction, the mixture was allowed to cool to room tempera-ture and poured into 400 m~ 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 mQ 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 solu-tion 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 dimethylformamide gave 21.3 g of 8-methanesulfonyloxy-6,7-dihydro-1-oxo-lH,5H-benzo ~ij]quinolizine-2-carboxylic acid as white needles having a melting point of 270 to 275C.

Reference Example 10 21.6 g of ethyl ethoxymethylenemalonate was added to 30.0 g of 5-(p-toluenesulfonyloxy)-1,2,3,4-tetrahydroquinoline and the mixture was heated at 110 C on an oil bath for 30 minutes while stirring, during which time distillation of ethanol was observed. After heating, 240 g of polyphGsphoric acid prepared from 120 g of phosphoric acid and 120 g of phos-phorus pentoxide was added to the mixture and the mixture was ; allowed to react on an oil bath at 140 C for 40 minutes. After completion of the reaction, the mixture was allowed to cool to , 1 room temperatura and poured in-to 400 mQ of water, followed by rendering the mixture neutral with a 40~ aqueous sodium hydr-oxide to precipitate crystals. The crystals thus obtained ; were mixed with 150 m~ of a 10% aqueous sodium hydroxide solution and the mixture was heat refluxed for 40 minutes dur-ing which time the crystals were dissolved to form a uniform solution. The solution was filtered and the filtrate was allowed to cool and adjusted to a pH of 2 to precipitate - crystals which were collected by filtration. Recrystallization of the crude crystals thus obtained from dimethylformamide gave 27.4 g of a 8-(p-toluenesulfonyloxy)-6,7-dihydro-1-oxo-lH,5H-..j benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of not lower than 300C.
- Reference Example 11 To 4.4 g of diethyl ethoxymethylenemalonate was added 3 g of 4-chloroindoline and the mixture was heated on an oil bath at 110 to 120 C during which time liberation of ethanol -~ was observed 20 g of polyphosphoric acid prepared from 10 g of phosphoric acid and lO g of phosphorus pentoxide was added thereto and the mixture was heated on an oil bath at 130 to 140 C for 40 minutes. After completion of the reaction, the mixture was allowed to cool to 60 C, poured into water and rendered neutral with a 10% aqueous sodium hydroxide solution.
The crystals precipitated were collected by filtration and wash-ed with water. The crystals thus treated were mixed with 50 m~
of a 10~ aqueous sodium hydroxide solution and the mixture was heat-refluxed on an oil bath for 1 hour. As the reaction pro-ceeded the mixture changed to a uniform solution. The solution - was treated with activated carbon while hot followed by filtra tion. The filtrate was rendered acidic with concentrated . .

1 hydrochloric acid to precipitate crystals. Recryst~llization of the crystals from dimethylformamide gave 3.5 g of 9-chloro-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid as white needles having a melting point of 307,5 C (decomposi-tion).
Reference Example 12 . 4.4 g of diethyl ethoxymethylenemalonate was added to `. 3.4 g of 2-methyl-4-chloroindoline and the mixture was heated on an oil bath at 110 to 120 C for 40 minutes. 20 g of poly-phosphoric acid prepared from 10 g of phosphoric acid and 10 g of phosphorus pentoxide was added thereto and the mixture was heated on an oil bath at 130 to 140 C for 1 hour. After com-pletion of the reaction, the mixture was allowed to cool to 60C, poured into ice water and rendered neutral with a 10%

aqueous sodium hydroxide solution. The crystals precipitated were collected by filtration and washed with water. The crystals thus treated were mixed with 50 mQ of a 10% aqueous sodium hydroxide solution and the mixture was heat-refluxed on an oil bath for 1 hour. As the reaction proceeded the mixture changed to a uniform solution. The solution was treated with activated carbon while hot followed by filtration. The filtrate was rendered acidic with concentrated hydrochloric acid to precipitate crystals. Recrystalli~ation of the product from dimethylformamide gave 3.8 g of 9-chloro-2-methyl-6-oxo-1,2-di-hydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid as white needles having a melting point of 288 to 290 C.
; Reference Example 13 25 g of ethyl ethoxymethylenemalonate was aaded to 21g of 5-chloro-2-methyl-1,2,3,4-tetrahydroquinoline and the mixture was heated on an oil bath at 110 to 120C during which time 3'~(~
~ 1 distillation o~ e-thanol was observed. ~eter he~ting the mixture ;; at the same temperature as above for 30 minutes 160 g of poly-phosphoric acid prepared from 80 g of phosphoric acid and 80 g of phosphorus pentoxide was added thereto followed by heating on an oil bath at 130 to 140 C for 1 hour. After completion of ,~ .
; the reaction the reaction mixture was poured into 600 mQ of i~
water and the resulting mixture was rendered neutral with a 10%
aqueous sodium hydroxide solution to precipitate crystals, which were collected by filtration and mixed with 200 mQ of a 10%
aqueous sodium hydroxide solution and the mixture was heat-re-fluxed for 1 hour 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 pH was adjusted with concentrated hydro-chloric acid to a pH of 2 to precipitate crystals. Recrystal-lization of the crude crystals thus obtained from dimethylform-amide gave 22 g of 8-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as colorless rhombic crystals having a melting point of 290 to 291C-Reference Example 14 In the same manner as in Reference Example 13, 8-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as colorless needles having a melting point of not lower , .
than 300 C was obtained.
Reference Example lS
9 g of diethyl ethoxymethylenemalonate was added to 9 g of 5-chloro-1,2,3,4,-tetrahydrocarbazole and the mixture was heated without solvent at 110 C on an oil bath for 30 minutes while stirring; during which time distillation of ethanol was observed. After heating, 100 g of polyphosphoric ?,3~
1 acid prepared ~rom 50 g oE phosphoric aci~ and 50 g of phos-phorus pentoxide was added to the mixture and the mixture was ` allowed to react on an oil bath at 140 C for 40 minutes. After completion of the reaction, the mixture was allowe~ to cool to 60 C and poured into 500 mQ of ice water to precipitate light yellow crystals. The crystals thus formed were filtered and washed with water sufficiently followed by refluxing with 100 mQ of a 10% aqueous NaOH solution for 1 hour. The crystals were dissolved to give a uniform solution which was then treat-ed with activated carbon while hot and the pH of the solution was adjusted to a pH of 2 with concentrated hydrochloric acid to obtain 9.3 g of 1-chloro-7a,8,9,10,11,11a-hexahydro-4H-pyrrido[3,2,1-jk]carbazole-4-oxo-5-carboxylic acid as light yellow crystals having a melting point of 273 to 275 C.
Reference Example 16 0.78 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid was suspended in 25 mQ
of anhydrous dimethylformamide and 0.42 mQ of triethylamine was added to the mixture while ice cooling and stirred for 15 minutes. Then 0~4 mQ of isobutyl chloroformate was added there-to dropwise and stirred for 45 minutes at the same temperature as above. On the other hand, 1.3 g of ampicillin ~as suspended in 15 mQ of anhydrous dimethylformamide and 0.7 mQ of triethyl-amine and 0.5 g of anhydrous magnesium sulfate were added to the suspension while ice cooling and the mixture was stirred at the same temperature as above for 30 minutes and insoluble materials ' were removed by filtration. The triethylamine salt of ampicil-lin thus obtained was added to the former reaction mixture and stirred for 2 hours while ice cooling. After completion of the reaction, insoluble materials were removed by filtration and ' '', , l~r~?~7 ~
.~
2.5 mQ of a 20% n-butanol solution oE potassium 2-ethylhexano-at~ and then 300 m~ o~ dièthyl ether were added to the filtrate to precipitate crystals to obtain 0.97 g of potassium-6-{2[8-(piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxamido]-2-phenylacetamido}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0]heptane-2-carboxylate as light yellow amor-- phous crystals having a melting point of 218 to 225C (redden-ing); 245 to 250 C (decomposition).
Reference Example 17 0.7 g of 3-(4-ac~tyl-1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid was suspended in 20 mQ of dimethylformamide and 0.34 mQ of triethylamine was added to the mixture while ice-cooling and stirred for 15 minutes. Then 0.32 mQ of isobutyl chloroformate was added thereto dropwise and stirred for 45 minutes at the same tempera-ture as above. On the other hand, 1 g of ampicillin was suspended in 10 mQ of anhydrous dimethylformamide and 0.56 mQ
of triethylamine and 0.4 g of anhydrous magnesium sulfate were - added to the suspension while ice cooling and the mixture was stirred at the same temperature as above for 30 minutes and ' insoluble materials were removed by filtration. The triethyl-;' ' amine salt of ampicillin thus obtained was added to the former reaction mixture and stirred for 2 hours while ice cooling.
After completion of the reaction, insoluble materials were re-moved by filtration and 2.5 mQ of a 20% n-butanol solution of potassium 2-ethyl hexanoate and then 300 mQ of diethyl ether were added to the filtrate to precipitate crystals. The crystals were collected by filtration and dissolved in 100 mQ

of water and the solution was rendered acidic pH=3 to form precipitates, which were washed with water and dried at room ~l~Sr ~ 3~ ~

temperature under reduce~ pressure. r~hO product was treated in the same manner as Reference Example 1 to obtain 0.75g of 6-{2-[8-(4-acetyl-1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxamido]-2-(4-hydroxy)phenylacetamido¦-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0]heptane-2-carboxylic acid as white amorphous crystals having a melting point oE 214 to 219C (decomposition).
Reference Example 18 0.81 g of 8-(4-methanesulfonyl-1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo~ij]quinolizine-2-carboxylic acid was suspended in 25 mQ of dimethylformamide and 0.42 mQ of triethyl-amine was added to the mixture while ice cooling and stirred for 15 minutes. Then 0.4 mQ of isobutyl chloroformate was added thereto dropwise and stirred for 45 minutes at the same temp-- erature as above. On the other hand, 1.3 g of ampicillin was suspended in 15 mQ of anhydrous dimethylformamide and 0.7 mQ of ; triethylamine and 0.5 g of anhydrous magnesium sulfate were added to the suspension while ice cooling and the mixture was stirred at the same temperature as above for 30 minutes and insoluble materials were removed by filtration. The triethyl-amine salt of ampicillin thus obtained was added to the former reaction mixture and stirred for 2 hours while ice cooling followed by treating the resulting mixture in the same manner as in Reference Example 17 to obtain 1.25 g of 6-r2-[8-(4-methane-sulfonyl-l-piperazinyl~-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quino-lizine-2-carboxamido]-2-phenylacetamido~-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3,2,0]heptane-2-carboxylic acid as white amorphous crystals having a melting point of 182 to 187C
(decomposition).
Reference Example 19 21.6 g of ethyl ethoxymethyleneacetoacetate was added ~' .'~

.5~ 7 ~
1 to 18 g of S-chloro~2-methyl-1,2,3,4-tetrahydroquinoline and the mixture was heated on an oil bath at 120C for ~0 minutes during which time distillation of ethanol was observed. Then, 100 g of polyphosphoric acid prepared from 50 g of phosphoric acid and 50 g of phosphorus pentoxide was added thereto follow-ed by heating the mixture on an oil bath at 140C for 30 minutes for reaction. After completion of the reaction, the reaction mixture was allowed to cool to 60 C and poured into 200 mQ of water followed by adjusting the mixture to pH 7 with IO a 40~ aqueous sodium hydroxide solution to precipitate crystals.

Recrystallization of the crystals thus obtained from ethanol-water gave 15 g of 8-chloro-5-methyl-2-acetyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine having a melting point of C.
Reference Example 20 8 g of anhydrous piperazine was added to 5 g of 8-chloro-5-methyl-2-acetyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quino-,lizine. 70 mQ of hexamethylphosphoric triamide was added there-to and the mixture was allowed to react at 140 C on an oil bath ; for 6 hours. After completion of the reaction any excess solvent and piperazine were removed by distillation under re-duced pressure and 100 mQ of ethyl acetate was added to the residue to precipitate light yellow crystals. The crystals thus obtained were separated by filtration and 300 mQ of water was added thereto followed by adjusting the resulting solution to a pH of 2 with lN hydrochloric acid. The solution was heated and filtered. The filtrate was concentrated to 50 mQ and rendered ; alkaline with a 10% aqueous sodium hydroxide solution to obtain 3.2 g of 8-(1-piperazinyl)-5-methyl-2-acetyl-6,7-dihydro-dr l-oxo-lH,SH-benzo[ij]quinolizine.

~5~3711~
_xample 1 19.2 g of 8-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid and 35.5 ~ of piperazine were added to 350 mQ of anhydrous dimethyl sul~oxide and ~he mixture was heated on an oil bath at 170 to 180 C for 6 hours whlle stirring. After completion of the reaction, the solvent was removed under reduced pressure. 500 mQ of water was added to ; the residue and the pH value of the mixture was adjusted to a pH of 2 followed by filtering water-insoluble materials. The filtrate was concentrated to 100 mQ under reduced pressure and rendered alkaline (pH=9) with a 10% aqueous sodium hydroxide solution. After extracting the aqueous alkali solution with chloroform to thereby remove chloroform-soluble materials, the aqueous alkali solution layer was allowed to stand to pre-cipitate crystals which were filtered. The crude crystals thus obtained were dissolved in 10 mQ of a 10% aqueous sodium hydr-oxide solution and the solution was treated with activated i 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-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 267 to 268C-Elemental Analysis for C17H1903N3.4H20 C H N
(%~ (%) (~) Calculated: 52.94 7.00 10.90 Found : 52.91 6.78 10.73 6.4 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-1~.5 ~7ll 1 benzo[ij]quinolizine-2-carbo,yylic acid thus obtained was suspended in S0 mQ of water and 15 mQ of a 10% aqueous hydro-chloric 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-l-oxo-lH,5H-benzo[ij]quinoline-2-carboxylic acid hydrochloride as white amorphous crystals having a melting point of 300 C or more.
Elemental Analysis for C17Hl903N3-HcQ H2o C H N
(~) (~) (~) ~ Calculated: 55.51 6.02 11.42 !j; Found : 55.43 6.00 10.57 The above Elemental Analysis was conducted at room temperature under reduced pressure (1 to 2 mmHg) for 6 hours using P205 as a desiccant.
Example 2 19.5 g of 8-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid and 35.5 g of piperazine were added to 350 mQ of anhydrous dimethyl sulfoxide and the mixture was heated on an oil bath at 170 to 180 C for 6 hours ; while stirring. Treatment of the reaction mixture in the same manner as in Example 1 gave 5.3 g of 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride as white amorphous crystals having a melting point of 300 C or more.

7- ~
1 El~men-tal Analysis for C18il2103N3.HCQ.H20 C H N
(%) (%) (~) Calculated: 56.62 6.33 11.00 Found : 56.71 6.33 11.00 3.8 g of 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij~quinolizine-2-carboxylic acid hydrochlGride was added to 100 mQ of water and lN aqueous sodium hydroxide solution was added thereto followed by heating the mixture to form a uniform solution. The solution was rendered alkaline (pH=8) with dilute hydrochloric acid to obtain 3.1 g of 8-(1-piperazinyl)-5-methyl-6,7-dihydr~ oxo-lH,5H-benzo[ij]quinoli-; zine-2-carboxylic acid as colorless needles having a melting point of 264 to 26sC.

Elemental Analysis for C18H2103N3 C H N
(%) (%) (%) Calculated:66.03 6.47 12.84 Found : 65.90 6.41 12.89 '' Example 3 In the same manner as in Example 2,8~ piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid was prepared.
Example 4 ., ~
' 4.0 g of 8-chlor~ 6,7-dihydro-1-oxo-lH,5H-benzo[ij]-5~ quinolizine-2-carboxylic acid and 4.6 g of N-methylpiperazine was added to 10 mQ of anhydrous dimethylsulfoxide and the mix-3 ture was heated on an oil bath at 150 to 160 C for 8 hours :

:
"' l:~.S~7~
1 ~hile s~i~ring. AEt~r completion o tha reaction, the solvcnt and excessive methylpiperazine were removed under reduced pressure and a mixture of methanol and diethyl ether was added to form precipitates which were separated by Eiltra~ion and washed with diethyl ether. The crystals thus obtained were suspended in 20 mQ of a 10% aqueous hydrochloric acid solution and insoluble materials were removed by filtration. The filtrate was purified through column chromatography using Amberlite LH-20 (a tradename for a product of Tokyo Organic Chemical Industries Ltd.)(eluent:water, ethanol). Recrystal-lization of the eluate from dimethylformamide gave 1.0 g of 8-(4-methyl-1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij] -quinolizine-2-carboxylic acid light yellow plates having a melting point of 278 to 280.5C.

Elemental analysis for C18H2103N3 C H N
(%) (%) (%) Calculated: 66.03 6.47 12.84 Found : 66.03 6.42 12.85 Example 5 4.4 g of 8,10-dichloro-6,7-dihydro-1-oxo-lH,5H-benzo-[ij]quinolizine-2-carboxylic acid and 4.5 g of piperazine were added to 10 mQ of anhydrous dimethylsulfoxide and the mixture was heated on an oil bath at 160 to 170 C for 7 hours while ; stirring. Treatment of the reaction mixture in the same manner as in Example 4 gave 0.9 g of 8-(1-piperazinyl)-10-chloro-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride as white amorphous crystals having a melting point of 300C or more.

. .
., r~ ? ~7 ~

El~ment~l ~nalysis ~or C17H1803N3CQ.IICQ.H20 C H N
(%) (%~
Calculated: 50.76 5.26 10.45 Found : 50.68 5.24 10.53 Exam~les 6 - 14 In the same manner as described in Examples 1 to S, the following compounds having various substituents shown in Table 5 were prepared. The melting point and the crystal form of the resulting products are also shown iD Table S belo~l.

.

:

'' ., ` 20 ,..:

: ^

' ' .; 30 ~.

. .
;`,' ..

?j~ 4 Table 5 O

R2-N~ ~COOH ~IA

Example 2 3 Color and Form Melting No. R R of CrystalHA Point(C) 6 ll H White Needle - Above 3 O O
. HC-7 1¦ H ~- 285 - 287 8 ~ C- H "- Above 3 O O
A

9 CH3S2- H .,- Above 3 O O

: OH
lO ~ CO- H Brown ~eedle - ~oove 300 11 ~ _ CH2- Sca~- 274 - 278 12 CH3-~so2_ H White Needle - Above 300 13 H Cl White (9-position) Amorphous HCl Above 300 14 CH3 Cl " HCl 297 ~: (lO-position) (Decom-position) .:

:
':`

1 Elemental ~nalyses o e the compounds prepared in accordance with Examples 6 to 14 are shown in Table 6 below.

Table 6 Elemental Analysis Example Molecular Calcul lted Fo ~nd No. FormulaeC I H N I C H I N
. .
6 ClgHlgO4N3 63.33 5.61 12.31163.27 5.49'12.18 7 ClgH2104N3 64.21 5.96 11.83 64.13 5.95 11.81 24 23 4 3 69.05 5.55 10.07 68.88 5.43 10.01 9C18 21 5 3 55.24 5.41 10.74i55.07 5.39jlO.62 10C26H235 5 64.32 4.78 14.43 64.09 4.61'14.27 11C24H2503N3 71.44 6.25 10.42l71.23 6.15,10.31 ; 12C24 25 5 3 61.6615.39 8.99 51.58 5.35 8.81 13Cl7Hl803N3cl HCl 250.76 5.26 10.45 50.70 5.23 10.33 14 Cl8H20o3N3cl HCl H2 51.93 5.57 ll 09 ;1 71 5 42 ' 35 ~ .

Example 15 19.1 g of 8~(p-toluenesulfonyloxy)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid and 12.9 g of piper-azine were added to 200 mQ of anhydrous dimethyl sulfoxide and the mixture was heated in an autoclave under flow of nitrogen at 10 atm at a temperature of 150 to 160 C for 18 hours while stirring. After completion of the reaction, the solvent and excess piperazine were removed under reduced pressure and a mix-ture of methanol and ethanol was added to the residue. The ~,~ precipitates formed were separated by filtration and washed with .":
`:

i37~
1 diethyl e-ther. Th~ crystals thus obtaincd w~re susp~nded in a mixture of 200 mQ of water and ~0 mQ of a 10~ aqueous hydro-chloric acid solution and insolu~le materials 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 tradename for a product of Tokyo Organic Chemical Industries Ltd.) (Eluent:
water, ethanol). Recrystallization of the eluate from dimethyl-formamide gave 2.7 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-; lO lH,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 267 to 268 C.

- Exam~le 16 ~`:
20.0 g of 8-(p-nitrobenzenesulfonyloxy)-6,7-dihydro-- l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 mQ of anhydrous dimethyl sulfoxide and the mixture was heated in an autoclave under flow of nitrogen at 10 atm at a temperature of 150 to 160C for 17 hours while stirring. Treatment in the same manner in Example 15 gave 2.1 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 267 to 268C.
Example 17 - 15.4 g of 8-methanesulfonyloxy-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid and piper-azine 12.9 g were added to 200 mQ of anhydrous dimethyl sulfox-' ide and the mixture was heated in an autoclave under flow of ~; nitrogen at 8 atm at a temperature of 170 to 180 C for 20 hours , while stirring. Treatment in the same manner as in Example 15 gave 1.7 g of 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride as ~ .

7 ~
1 white amorphous crystals havirlg a malting point of not lower than 300~C.
Example 18 18.5 g of 8-benzenesulfonyloxy-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid and 12.9 y of piperazine were added to 200 mQ of anhydrous dimethyl sulfoxide and the mixture was heated in an autoclave under flow of - nitrogen at 10 atm at a temperature of 160 to 170C for 20 hours while stirring. Treatment in the same manner as in Example 15 gave 1.5 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 267 to 268C-Example 19 , 20.7 g of 8-(o-methoxybenzenesulfonyloxy)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 mQ of anhydrous dimethyl sulfoxide and the mixture was heated in-an autoclave under flow of nitrogen at 10 atm at a temperature of 150 to 160C for 18 hours while stirring. Treatment in the same manner in Example 17 gave 2.5 g of 8-(1-piperazinyl)-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as white amorphous crystals having a melting point of not lower than 300C.
Examples 20 - 26 In the same manner as described in Examples 15 to 19 the following compounds having various substituents shown in ` Table 7 below were prepared. The melting point and the crystal ; form of the resulting products are also shown in Table 7.

. ::

. . .

~.5~37~
1 Table 7 O
~3 ~ / COOH

-N N / ~ N HA
,, /
~.

Example 2 3 Color and Form Melting No. R R of Crystal HA Point(C) :. , -- _ _ ~ 1 0 ~ 20 CH3 H Light Yellow - 278 -280.5 : Plate 21 H Cl White HCl Above 300 (9-position) Amorphous O :.
22 ll H White Needle - 285 - 287 23 fi~ H Light Brown - 274 - 278 CH2- Scale ' _S02_ H White Needle - Above 300 , . 25 CH3S02- H I' _ Above 30Q

. :, . .
26 CH3- C1 White HCl 297 (10-position) Amorphous (Decom-position) ':~ 30 '','''~' .
~i , ,~
. ~

~5~ 7~
1 Example 27 2.0 g of 8~ piperazinyl)-6,7-dihydro-1-oxo-lH,5~-benzo[ij~quinolizine-2-carboxylic acid and 1.2 g of sodium hydrogen carbonate were added to 30 mQ of water and the mixture was stirred at room temperature for 30 minutes. 5 mQ of acetone having dissolved therein 1.0 g of benzoyl chloride was added dropwise to the mixture while ice cooling followed by stirring at the same temperature as above for 30 minutes and then at room temperat4re for 1.5 hours to precipitate crystals, which were separated by filtration and washed with water. Recrystal-lization of the crystals thus treated from dimethylformamide -~ gave 2.4 g of 8-(4-benzoyl-1-piperazinyl)-6,7-dihydro-1-oxo-; H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of not lower than 300 C.
Example 28 ! 2.0 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-~.
benzo[ij]quinolizine-2-carboxylic acid was dissolved in 20 mQ
of water having dissolved therein 0.8 g of potassium hydroxide ; and 0.8 g of methanesulfonyl ch~oride was added dropwise to the solution. The resulting mixture was allowed to stand overnight at the same temperature as above while stirring. The crystals precipitated were separated by filtration and washed with water.
` The crystals thus treated were dissolved in lN aqueous sodium hydroxide solution and the solution was treated with activated ;~ carbon and rendered neutral with a 10% aqueous hydrochloric ; acid solution to precipitate crystals, which were separated by filtration and washed with water. Recrystallization of the ` crystals thus obtained from dimethylformamide gave 1.0 g of 8-(4-methanesulfonyl-1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij~quinolizine-2-carboxylic acid as white needles having '. .
'':

:`

1~5~37~

1 a melting poin-t o~ not lower than 300C.
; Example 29 2.0 g o~ 8-(1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid was added -to 20 mQ of water having dissolved therein 2.0 g of potassium carbonate ` and the mixture was stirred at room temperature for 30 minutes.
- After dissolving insoluble materi~ls complete~y with the addi-- tion of 3 mQ of lN aqueous sodium hydroxide solution, 10 mQ
of methanol having dissolved therein 0.9 g of benzyl chloride was added dropwise to the mixture while ice cooling. After -~ completion of the addition, the resulting mixture was heat-re-fluxed for 3 hours to form a uniform solution. The solution obtained was treated with activated carbon while hot and render-. .
ed neutral with a 10% aqueous hydrochloric acid to precipitate crystals, which were separated by filtration and washed with ' water. Recrystallization of the crystals thus treated from di-methylformamide gave 0.25 g of 8-(4-benzyl-1-piperazinyl)-6,7--dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid , having a melting point of 274 to 278 C.

. 20 Example 30 20 mQ of dimethyl sulfoxide was added to a mixture of 5` - 3 g of 9-chloro-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ijlquinoline-5-carboxylic acid and 6 g of anhydrous piperazine and the mix-ture was heated on an oil bath at 140 to lS0 C for 6 hours.
After completion of reaction the solvent was removed therefrom , .
~; under reduced pressure and 50 mQ of water was added to the residue to dissolve it. The solution was shaken with 100 mQ of ;j chloroform and the water layer was separated and treated with ~` activated carbon. The aqueous solution was rendered acidic with a 10% aqueous hydrochloric acid and filtered. The filtrate was r' ~ j `.~ .

~I~S~37~
1 again treated with activated carbon followed by concentration.

The addition of ethanol to the concentrate gave rise to crystals ~ which were recrystallized from ethanol-water to obtain 1.5 g of .~' 9-(1-piperazinyl)-6-oxo-1,2-dihydro-6H-pyrrolot3,2,1-ij]quino-line-5-carboxylic acid hydrochloride as light yellow needles having a melting point of 300C or more.

Elemental Analysis for C16H1703N3 HCQ 4H20 C H N
~, . (%) (%) (~) Calculated:47.12 6.38 10.31 Found : 47.23 6.09 10.10 .i~
Example 31 20 mQ of dimethyl sulfoxide was added to a mixture of 1.6 g of 9-chloro-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-- ij]quinoline-5-carboxylic acid and 3 g of anhydrous piperazine and the mixture was heated on an oil bath at 140 to 150 C for ;:,, ~; 6 hours. After completion of reaction the solvent was removed .~,.
therefrom under reduced pressure and 50 mQ of water was added i 20 to the residue to dissolve it. The solution was shaken with -100 mQ of chloroform and the water layer was separated and ~s~.g~ .
treated with activated carbon. The aqueous solution was render-ed acidic with a 10% aqueous hydrochloric acid solution and filtered. The filtrate was again treated with activated carbon ' followed by concentration. The addition of ethanol to the ~, concentrate gave rise to crystals which were recrystallized from ethanol-water to obtain 0.9 g of 9~ piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carb-o~ylic acid hydrochloride as light yellow needles having a ~,; melting point of 269 to 273 C (decomposition).

7 ~
1 Elemell~al ~nalysis for C17II1903N3~EICQ-~l20 C H N
t%) (%) (~) Calculated: 55.51 6.02 11.42 Found : 55.47 5.98 11.29 Example 32 3.1 g of 1-chloro-7a,8,9,10,11,11a-hexahydro-4H-pyrido[3,2,1-jkIcarbazole-4-oxo-5-carboxylic acid was mixed - 10 with 5 g of anhydrous piperazine and 50 mQ of dimethyl sulfoxide and the mixture was heated at 140 to 150 C on an oil bath for 4 hours with stirring. After completion of the reaction the solvent was removed under reduced pressure. 200 m~ of water and 200 mQ of chloroform were added to the residue and after shaking the water layer was separated. After adjusting the pH
value thereof to a pH of 3 the water layer was filtered. The filtrate was treated with activated carbon and concentrated to obtain light yellow precipitates. The precipitates were washed with a small amount of water and dried to give 1.3 g of 1-(1-piperazinyl)-7a,8,9,10,11,11a-hexahydro-4H-pyrido[3,2,1-jk]-carbazole-4-oxo-5-carboxylic acid hydrochloride having a melt-; ing point of 289 to 294 C (decomposition).
Elemental Analysis for C2oH23N3o3 HcQ 3H2o C H N
( % ) ( % ) ( % ) Calculated: 54.12 6.76 9.47 Found : 53.77 6.95 9.18 ' Example 33 a) 3 g iodine and 20 mQ of pyridine were added to 2.75 g 1 o~ 8-(l-pip~razinyl)-S-m~-thyl-2-acetyl-6,7-dihydro-1-oxo-1~-~,51l-benzo[ij]quinolizine and the mixture was heated at 100C for 1 hour. After completion of the reaction, the crystals pre-cipitated were separated by filtration and washed with 10 m~ of ; cold pyridine and lO mQ of methanol to obtain 8-(l-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carbon-ylmethylpyridinium iodide.
b) The product obtained in (a) above was added in 50 m~
of methanol and 50 mQ of a 10% aqueous sodium hydroxide was 1Q added to thereto and the mixture was refluxed for 1 hour. ~fter completion of the reaction, methanol was removed by distillation ; under reduced pressure followed by adjusting the concentrate to pH 7 with 1 N hydrochloric acid to obtain 1.8 g of 8-(1-~; piperzinyl)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quino-lizine-2-carboxylic acid as colorless needles having a melting point of 264 to 265C.
The compound thus obtained was converted into corres-ponding acid salt with hydrochloric acid to obtain 8-(1-pipera-zinyl)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzolij]quinolizine-2-carboxylic acid hydrochloride as white amorphous crystals having a melting point of 300C.
Example 34 In the same manner as Example 33 was obtained 8-(1-` piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 267 to 268C.
Example 35 In the same manner as Example 33 was obtained 8-(4-.' methyl-l-piperazinyl)-6,7-dihydro-1-oxo-lII,5H-benzoEij]quinoli-zine-2-carboxylic acid as light yellow plates having a melting point o~ 278 to 280.5C.

Example 36 In the same manner as Example 33 was obtained 8-(l-piperazinyl~-lO-chloro-6,7-dihydro-l-oxo-l11,511-benzo[ij]quino-lizine-2-carboxylic acid hydrocloride as white amorphous crystals having a melting point of not lower than 300 C.
;~ Example 37 In the same manner as Example 33 was obta.ined 8-(4-benzoyl-l-piperazinyl)-6,7-dihydro-l-oxo-lH,5H-benzo[ij~quinoli-. lO zine-2-carboxylic acid as white needles having a melting point of not lower than 300 C.
. Example 38 i: In the same manner as Example 33 was obtained 8-(4-. benzyl-l-piperazinyl)-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinoli-zine-2-carboxylic acid as light yellow scales having a melting .. o .;. point of 274 to 278 C.
Example 39 In the same manner as Example 33 was obtained 9-(l-piperazinyl)-2-methyl-6-oxo-l,2-dihydro-6H-pyrrolo[3,2,l-ij]-quinoline-5-carboxylic acid hydrochloride as light yellow needles having a melting point of 269 to 273 C. (decomposition) Example 40 . In the same manner as Example 33 was obtained 9-(l-piperazinyl)-6-oxo-l,2-dihydro-6H-pyrrolo[3,2,l-ij]quinoline-5-carboxylic acid hydrochloride as light yellow needles having a melting point of not lower than 300C.
Example 4l In the same manner as Example 33 was obtained l-(l-piperazinyl)-7a~8r9llorll~lla-hexahydro-4H-pyrido[3~2~ };]

carbazole-4-oxo-5-carboxylic acid hydrochloride having a melting 7~
~I point of 239 to 29~C. (decomposition) Preparation Example 1 8-(1-Piperazinyl)-6,7-dihydro-1-oxo-lH,5~-:
ben~o[ij]quinolizine-2-carboxylic acid hydrochloride 200 mg Glucose 250 mg Distilled Water for Injection q.s. to make 5 mQ

The active compound and glucose were dissolved in ' lO distilled water for injection, and the solution was poured into a 5 mQ ampoule. The air was purged with nitrogen, and the ,~ ampoule was sealed and sterilized at 121 C for 15 minutes to obtain an injectable preparation.
Preparation Example 2 ,~
8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride 100 g ~,~ Avicel (trademark for a product of Asahi Kasei Kogyo Kabushiki Kaisha)0 g Corn Starch 30 g Magnesium Stearate 2 g TC-5*(trademark for hydroxypropylmethyl cellulose, produced by Shinetsu Chemical Industry Co., Ltd.) 10 g Polyethylene glycol-6000 (molecular weight, 600) 3 g Castor Oil 40 g Methanol 40 g The active compound, avicel, corn starch and magnesium - 30 stearate were mixed and ground, and then tableted using a *Trade Marks -66-? 37 9L
1 conventional pounder (R 10 mm) for suyar coatiny (produced by Kikusui Seisakusho Co., Ltd.). The resulting tablets were coated with a film coating agent composed of TC-5, polyethylene ylycol-6000, castor oil and methanol to produce film-coated tablets.
; Preparation Example 3 8-(1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid 2 g Purified hydrous lanolin 5 g Japan wax 5 g White petrolatum 88 g 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.
-:
Preparation Example 4 ,:;
,~ 9-(1-Piperazinyl)-6-oxo-1,2-dihydro-6H-~; pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid hydrochloride 200 mg Glucose 250 mg Distilled Water for Injection q.s. to make 5 m~

The active compound and glucose were dissolved in distilled water for injection, and the solution was poured into a 5 mQ ampoule. The air was purged with nitrogen, and the ampoule was sealed and sterilized at 121 C for 15 minutes to obtain an injectable preparation.
Preparation Example 5 9-(1-Piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij3quinoline-1 -5-carboxylic acid hydrochloridel00 g Avicel (tradename for a product of Asahi Kasei Kogyo Kabushiki Kaisha) 40 g Corn Starch 30 g Magnesium Stearate 2 g . TC-5 (tradename for hydroxypropylmethyl : cellulose, produced by Shinetsu Chemical ; Industry Co., Ltd.) l0 g Polyethylene Glycol-6000 (molecular ; 10 weight, 6000) 3 g Castor Oil 40 g : Methanol 40 g ,...
i The active compound, avicel, corn starch and magnesiu~
;~ stearate were mixed and ground, and then tableted using a conventional pounder (r l0 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 20 . tablets~

Preparation Example 6 l-(l-Piperazinyl)-7a,8,9,l0,ll,lla-hexahydro-4-oxo-4H-pyrido~3,2,l-jk]carbazole-5-carboxylic acid hydrochloride l00 g Avicel (tradename for a product of Asahi Kasei Kogyo Kabushiki Kaisha) 40 g Corn Starch 30 g Magnesium Stearate 2 g TC-5 (tradename for hydroxypropylmethyl cellulose, produced by Shinetsu Chemical Industry Co., Ltd.) l0 g .
~ -68-`~
:

37 ~
1 Polye-thylene Glycol-6000 (molccular weight, 6000) 3 g Castor Oil 40 g Methanol 40 g "`
n 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.

: -69-':`
:;` 1 SUPPI.~E~T~Y DISCLOSURE
`'`:
`; The inventors have conducted further tests to determine - the antimicrobial activity of further test compounds and the~e `. tests were identical to the test described hereinbefore.
The following test compounds were used:
Compound L 8-(4-Methyl-l-piperazinyl)-6,7-dihydro-1-(Invention) oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid ~i Compound M 8-(4-Formyl-l-piperazinyl)-6,7-dihydro-1-~ 10 (Invention) oxo-lH,5H-benzolij~quinolizine-2-carboxylic acid Compound N `8-(4-Benzoyl-l-piperazinyl)-6,7-dihydro-1 (Invention) oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Compound 0 8-(4-Methanesulfonyl-l-piperazinyl)-6,7-(Invention) dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Compound P 9-Chloro-8-(1-piperazinyl)-6,7-dihydro-1-(Invention) oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic.
acid hydrochloride Compound Q 9-(1-Piperazinyl)-6-oxo-1,2-dihydro-6H-(Invention) pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid hydrochloride Compound R 8-(4-Benzyl-l-piperazinyl)-6,7-dihydro-1-(Invention) oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Compound S ~-(4-p-Toluenesulfonyl-l-piperazinyl)-6,7-(Invention) dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid ~: 30 Compound T 8-(1-Piperazinyl)-9-chloro-5-methyl-6,7-,.....

~.~.5,~ ,74 1 (Invention) d.ihydro-l-oxo-l11,5~1-benzo[ij]~uinoli~.ine-2-carboxylic acid hydrochloride hydrate Compound U 8-(4-Methyl-l-piperazinyl)-9-chloro-5-methyl-; (Invention) 6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Compound V 8-(4-Formyl-l-piperazinyl)-9-chloro-5-methyl-..~
(Invention) 6,7-dihydro-l-oxo-lH,5H-benzo[ij]-quinolizine-.~ 2-carboxylic acid ;` Compound W 8-(4-Methyl-l-piperazinyl)-9-fluoro-5-methyl-(Invention) 6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Compound X 8-(l-Piperazinyl)-9-fluoro-5-methyl-6,7-(Invention) dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrobromide Compound Y 8-Chloro-9-(4-methyl-l-piperazinyl)-2-methyl-(Invention) 6-oxo-l,2-dihydro-6H-pyrrolo[3,2,l-ij]quinoline-;
5-carboxylic acid Compound Z 8-Fluoro-9-(4-methyl-l-piperazinyl)-2-methyl-(Invention) 6-oxo-l,2-dihydro-6H-pyrrolo[3,2,l-ij]quinoline-2C~ 5-carboxylic acid Compound a 8-Fluoro-9-(4-methyl-l-piperazinyl)-2-methyl-(Invention) 6-oxo-l,2-dihydro-6H-pyrrolol3,2,l-ij]quinoline-5-carboxylic acid The following results were obtained.

. .

~;
~ ~I rj~ ~3 74 T A B L E 1A.
Minimum Inhibitory Concentration . . .
Test Or~anism Test ~,Compound 2 3 5 13 14 15 18 19 20 22 23 `~` lX108 1.66.33.1 S0 50 50 3.13.1 6.3 6.3 . L :Lx106 - - - - - _ _ _ _ _ _ 108 1.63.11.6 25 12.5 250.8 1.6 3.1 3.1 ` ~ M lXlo6 lxlOa 6.36.36.3100 25 50 1.63.112.5 3.1 12C106 - - - - - - - - _ _ _ lX108 6.36.36.3100 25 100 1.6 6.3 12.5 3.1 lXl o 6 _ _ _ _ _ _ _ _ _ _ _ -~ lx108 1.6 0.8 0.4 6.36.36.30.81.61.66.3 lXlo6 1X108 25 12.5 25 50 25 50 6.3 3.1 6.3100 Q 1x106 lx108 1.63.11.6 25 12.5 25 1.61.63.1 12.5 lX106 12C108 1.63.13.1 50 12.5 25 1.63.16.36.3 ` lX108 0.4 0.4 0.2 3.11.63.1 0.2 0.2 1.61.66.3 T 1X106 0.4 0.4 0.2 3.11.61.60.1 0.2 1.61.63.1 lx108 0.2 0.2 0.4 6.31.6 3.1 ~0.05 0.2 0.4 0.8 3.1 U 1:~106 0.2 0.2 0.4 6.31.6 3.1 ~0.05 0.1 0.40.43.1 lX108 0.80.80.8 12.5 3.1 12.5 0.2 0.83.1 0.2 3.1 ~ lX106 0.80.80.86.31.6 12.5 0.2 0.4 3.1 0.2 1.6 '~ lx108 0.4 0.4 0.4 6.31.63.10.1 0.2 0.4 0.4 1.6 v W1~106 0.4 0.2 0.4 3.11.61.6 ~O.OS 0.2 0.4 0.4 1.6 :.

, : --72--;.

--. ~
.7~
T A B L E lA (Corlt ' cl~

Test Test Organi~m Compound 2 3 5 13 14 15 18 19 20 22 23 lx108 0.4 0.4 0.1 1.6 1.6 1.6 0.1 0.20.8 0.8 3.1 X lX10 6 ~
lX108 0.2 0.4 0.2 3.1 1.6 1.6 0.1 0.10.8 3.1 12.5 Y lX106 0.2 0.2 0.1 3.1 1.6 1.6 ~;0.05 ~0.05 0.4 3.1 6.3 lx109 0.2 0.2 0.4 6.3 3.1 3.1 0.1 0.20.4 0.8 12.5 Z .lx106 0.2 0.2 0.2 3.1 3.1 3.1 0.10.2 0.4 0.4 6.3 lx108 0.1 0.2 0.2 1.6 1.6 1.6 ~0.05 0.1 0.2 0.8 6.3 a lx106 0.1 0.2 0.1 1.6 1.6 1.6 _0.05 0.1 0.2 0.4 3.1 ' 3l~ J7'~
1 The present invention is s-till Eurther illus-trated by the following examples which are not limiting but are merely illustrative in nature. Unless otherwise indicated, all parts, percents and ratios are by weight.

In example 3 hereinbefore disclosed, the prepared ; compound was obtained as white rho~bic crystals having a melting point of from 260C to 261C.

EXA~LE 42 In the same manner as in Example 1, 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-l~I,5H-benzo[ij]quinolizine-2-carboxylic acid was reacted with piperazine, l-methyl-piperazine, l-ethylpiperazine or 4-formylpiperazine to form the following compounds~
8-(1-Piperazinyl)-9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5~-benzo~ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 246 to 247C.
; 8-(1-Piperazinyl)-9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid mono-hydrochloride monohydrate as white amorphous crystals having i a melting pointof 306 to 307C (decomposed after blackening).
,'.:
8-(4-Methyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a meltingpoint of 292 to 293 C.
8-(4-Ethyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid monohydroiodide monohydrate as white rhombic crystals having a melting point of 271 to 272C.

8-(4-Formyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ijlquinolizine-2-carboxylic acid as ' ~

r~ 37 ~

1 white rhombic crystals having a melting point of 262 to 265C.

In the same manner as in ~xample 1, 8-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid was reacted with l-formylpiperazine to form 8-(4-formyl-1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 300C or more.

` 10 A mixture of 1.8 g of 9-fluoro-8-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid, 36 mQ of N-methyl-piperazine and 15 mQ of hexamethylphosphoric triamide was heated at 150 to 160C for 4 hours. After com-pletion of the reaction the solvent was removed by distillation under rèduced pressure and the residue was washed with 10 mQ
of ethyl acetate. The crude crystals thus obtained was mixed with 100 mQ of water and adjusted to a pH of 4 with acetic acid. Insoluble materials were removed by filtration and the filtrate was treated with activated carbon followed by concentration under reduced pressure. The residue was mixed with 20 mQ of water and the solution was adjusted to a pH of 9 with a 10% aqueous sodium hydroxide solution and extracted with 80 mQ of chloroform. After the extract was dried over anhydrous sodium sulfate and concentrated it was purified through a silica gel column chromatography [silica gel: Wako C-200*, a trademark for product of Wako Junyaku Co., Ltd.; eluent:
chloroform-methanol (9:1 by volume)] to obtain 0.8 g of 8-(4-methyl-l-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-- benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 262 to 263C.

*Trade Mark ~`~ - 75 -;` ` ~.~l.5.~ ,,7-~
I EXA~IPLE 45 A mixture of 3 g of 9-fluoro-8-bromo-5-methyl-6,7-~ dihydro-l-oxo-lH,SH-benzo[ij]quinolizine-2-carboxylic acid, 3.8 g ; of anhydrous piperazine and 30 ml of hexamethylphosphoric triamide was heated at 150 to 160C on a water bath for 5 hours in an argon stream. After completion of the reaction the solvent was removed under reduced pressure and 20 ml of ethyl acetate was added to the residue. The crystals preciptated were collected by filtration. The crystals thus obtained were dissolved in 300 ml of water and the solution was adjusted to a pH of 4 with acetic acid. After adding activated carbon to the solution and - filtering, the filtrate was concentrated under reduced pressure.
Recrystallization of the crude crystals precipitated from isopropanol-water (2:1 by volume) gave 2.7 g of 8-(1-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-benæo[ij]quinolizine-2-carboxylic acid hydrobromide as rhombic crystals having a melting ,~ point of 300C or more.
Elemental Analysis Values for C18H20N3O3F.HBr.H2O

C H N
Calc'd (%): 48.65 5.18 9.46 Found (%): 48.53 5.11 9.32 8-(4-Methyl-l-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid obtained in Example 44 was added to 48 % hydrobromic acid and the solvent was removed by distillation under reduced pressure.
; Recrystallization of the residue from isopropanol-water (2:1 by ; volume) gave 8-(4-methyl-1-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrobromide monohydrate as white rhombic crystals having a melting point of 298 to 299C (decomposed).

.- ~ .

37 ~?~
1 ~X~MP~E ~7 In the same manner as in Example 30, 8,9-dichloro-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid was reacted with piperazine, l-methyl-piperazine, l-formylpiperazine or l-acetylpiperazine to form the following compounds.
8-Chloro-9-(1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-- 6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid as pale yellow rhombic crystals having a melting point of 258 to 260 C.
10 - 8-Chloro-9-(4-methyl-1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6~-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid as pale yellow rhombic crystals having a melting point of 273 to 276C.
8-Chloro-9-(4-methyl-1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid.
8-Chloro-9-(4-acetyl-1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid.

! In the same manner as in Example 30, 8-fluoro-9-iodo-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ii]quinoline-5-carboxylic acid was reacted with piperazine, l-methyl-piperazine or l-formylpiperazine to obtain the following compounds.
8-Fluoro-9-(1-piperazinyI)--2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid.
; 8-Fluoro-9-(4-methyl-1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid as white rhombic crystals having a melting point of 242 to 244C.
8-Fluoro-9-(4-formyl-1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid.

' ,'' 5 7~37~
~XAMPLE ~9 In the same manner as in Example 1, 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid was reacted with l-formylpiperazine, l-acetylpiperazine, l-propionylpiperazine or l-ethylpiperazine to obtain the followin~
compounds.
8-(4-Formyl-l-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 300C or more.

8-(4-Acetyl-l-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-l-oxo-1~,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 247 .o 249C.
8-(4-Propionyl-l-piperazinyl)-9-fluoro-5-methyl-` 6,7-dihydro-1-oxobenzo[ij]quinolizine-2-carboxylic acid as ~hite rhombic crystals having a melting point of 272 to ~74C.
8-(4-Ethyl-l-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-l-oxobenzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 253 to 255C.

20 ` 8-(4-Methyl-l-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride 100 g Avicel (tradename for a product of Asahi Xasei Kogyo Kabushiki Raisha) 40 g Corn Starch 30 g Magnesium Stearate 2 g TC-5 (tradename for hydroxypropylmethyl - cellulose, produced by Shinetsu Chemical Industry Co., ~td.) 10 g Polyethylene glycol-6000 (molecular . .

. .

J37/~
1 ~Y~i~ht, 6000) 3 g Castor Oil 40 g Methanol 40 g The active compound, avicel, corn starch and magnesium stearate were mixed and ground, and then tabl~ted 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.

~-Fluoro-9-(4-methyl-piperazinyl)-2-methyl 6-oxo-1,2-dihydro-6~ yrroloL3,2,1-ij]quinoline-; 5 carboxylic acid 100 g Avicel (tradename for a product of Asahi Kasei Kogyo Kabushiki Kaisha) 40 g Corn Starch 30 g Magnesium Stearate 2 g TC-5 (tradename for hydroxypropylmethyl cellulose, produced by Shinetsu Ch~mical Industry Co., Ltd.) 10 g Polyethylene glycol-6000 (molecular weight, 6000) 3 g ; Castor Oil 40 g Methanol ~0 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 table-ts.

:` ~

.

Claims (69)

    The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

    1. A process for preparing piperazinylbenzoheterocyclic compound represented by the general formula (I) (I) wherein R1 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R2 represents a hydrogen atom; R3 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkanoyl group having 1 to 4 carbon atoms; an alkanesulfonyl group having 1 to 4 carbon atoms, a phenylalkyl group consisting of a phenyl group and an alkylene group having 1 to 4 carbon atoms, a benzoyl group, a p-toluenesulfonyl group or a group represented by the formula R4 represents a hydrogen atom or a halogen atom; n is an integer of O or l; and R1 and R2 may combine to form a cyclohexane ring together with the carbon atoms to which they are attached when n is O; or pharmaceutically acceptable salt thereof, which comprises selecting a process from the group of processes consisting of:
    (A) reacting a piperazinylbenzoheterocyclic compound of the general formula (II) Claim 1 continued (II) wherein R1, R2, R4 and n have the same meaning as defined above, and R5 represents a halogen atom, a lower alkanesulonyloxy group or an arylsulfonyloxy group; with a piperazine compound of the general formula (III) (III) wherein R3 has the same meaning as above;

    (B) reacting a compound of the general formula (I') wherein R1, R2, R3, R4 and n have the same meaning as defined above and R and R' 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 general formula (II') (II') Claim 1 continued wherein R1, R2, R3, R4, n, R and R1 have the same meaning as defined above; Y? represents a tertiary nitrogen atom containing aromatic heterocyclic residue being bonded through said nitrogen atom or a trialkyl ammonium group; and Z? represents an anion, and then hydrolyzing this compound; and (C) for the preparation of a piperazinylbenzoheterocyclic compound represented by the general formula (Ib) (Ib) wherein R1 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R2 represents a hydrogen atom; R9 represents an alkyl group having 1 to 4 carbon atoms, an alkanoyl group having 1 to 4 carbon atoms, an alkanesulfonyl group having 1 to 4 carbon atoms, a phenylalkyl group consisting of a phenyl group and an alkylene group having 1 to 4 carbon atoms, a benzoyl group, a p-toluenesulfonyl group or a group represented by the formula R4 represents a hydrogen atom or a halogen atom; n is an integer of 0 to 1; and R1 and R2 may combine to form a cyclohexane ring together with the carbon atoms to which they are attached when n is 0, or pharmaceutically acceptable salt thereof, with the proviso that R3 is not a halogen atom, reacting a compound of the general formula (Ia)
  1. Claim 1 continued wherein R1, R2, R4 and n have the same meaning as defined above, with a compound of the general formula (XIII) R9X (XIII) wherein R9 has the same meaning as defined above, and X is a halogen atom.
  2. 2. A process as claimed in claim l(A), wherein the propor-tion of the compound of the formula (III) to the compound of the formula (II) is at least equimolar.
  3. 3. A process as claimed in claim 2, wherein the molar proportion of the compound of the formula (III) to the compound of the formula (II) is 1 : 1 to 5 : 1.
  4. 4. A process as claimed in claim l(A), wherein the reaction is carried out in the presence of deoxidizing agent.
  5. 5. A process as claimed in claim l(A) wherein the reaction is carried out at a temperature of 100 to 250°C for 5 to 20 hours.
  6. 6. A process as claimed in claim 5, wherein the reaction is carried out at a temperature of 140 to 200°C.
  7. 7. A process as claimed in claim l(A), wherein the reaction is carried out at a pressure of 1 to 10 atoms.
  8. 8. A process as claimed in claim l(B), wherein said tertiary nitrogen atom containing aromatic heterocyclic com-pound or trialkylamine and said anion donating compound are used in at least an equimolar amount with respect to the com-pound of the formula (I'), respectively.
  9. 9. A process as claimed in claim 8, wherein said tertiary nitrogen atom containing aromatic heterocyclic compound or trialkylamine and said anion donating compound are used in an amount of 1 to 2 mols per mol of the compound of the formula (I'), respectively.
  10. 10. A process as claimed in claim 8, wherein said first reaction step is carried out at a temperature of from about room temperature to about 120°C for 0.5 to 6 hours.
  11. 11. A process as claimed in claim 10, wherein said first reaction step is carried out at a temperature of 50 to 100°C.
  12. 12. A process as claimed in claim 8, wherein said hydrolysis is carried out in the presence of an acid or an alkali.
  13. 13. A process as claimed in claim 8 wherein said hydrolysis is carried out in an inert solvent.
  14. 14. A process as claimed in claim 8, wherein said hydrolysis is carried out in an aqueous medium containing a trialkylamine.
  15. 15. A process as claimed in claim 8, wherein said hydrolysis is carried out in the presence of a lower alcohol.
  16. 16. A process as claimed in claim 8, wherein said hydrolysis is carried out at a temperature of 20 to 150°C for 0.5 to 6 hours.
  17. 17. A process as claimed in claim 16, wherein said hydrolysis is carred out at a temperature of 80 to 120°C.
  18. 18. A process as claimed in claim l(A), wherein the proportion of the compound of the formula (III) to the compound of the formula (II) is 1:1 to 5:1, and the reaction is carried out at a temperature of 140 to 200°C for 5 to 20 hours and at a pressure of 1 to 10 atoms.
  19. 19. A process as claimed in claim l(A).
  20. 20. A process as claimed in claim l(B).
  21. 21. A process as claimed in claim l(C).
  22. 22. A compound of the general formula (I) as defined in claim 1 whenever prepared by a process as claimed in claim 1 or an obvious chemical equivalent thereof.
  23. 23. A compound of the general formula (I) as defined in claim 1 whenever prepared by a process as claimed in claim 19 or an obvious chemical equivalent thereof.
  24. 24. A compound of the general formula (I) as defined in claim whenever prepared by a process as claimed in claim 20 or an obvious chemical equivalent thereof.
  25. 25. A compound of the general formula l(b) as defined in claim l(C) whenever prepared by a process as claimed in claim 21 or an obvious chemical equivalent thereof.
  26. 26. A process as claimed in claim 1 which comprises react-ing 8-chloro-5-methyl-6, 7-dihydro-1-oxo-lH, 5H-benzo[ij]
    quinolizine-2-carboxylic acid with piperazine.
  27. 27. 8-(1-Piperazinyl)-5-methyl-6, 7-dihydro-1-oxo-1H, 5H-benzo[ij]-quinolizine-2-carboxylic acid whenever prepared by a process as claimed in claim 26 or an obvious chemical equivalent thereof.
  28. 28. A process as claimed in claim 1 which comprises reacting 9-chloro-2-methyl-6-oxo-1, 2-dihydro-6H-pyrrolo [3, 2, l-ij] quinoline-5-carboxylic acid with piperazine.
  29. 29. 9-(l-Piperazinyl)-2-methyl-6-oxo-1, 2-dihydro-6H-pyrrolo [3, 2, 1-ij]quinoline-5-carboxylic acid whenever prepared by a process as claimed in claim 28 or an obvious chemical equivalent thereof.
  30. 30. A process as claimed in claim 1 which comprises reacting 8-(p-toluenesulfonyloxy)-6, 7-dihydro-1-oxo-lH, 5H-benzo[ij]quinolizine-2-carboxylic acid with piperazine.
  31. 31. 8-(1-Piperazinyl)-6, 7-dihydro-1-oxo-lH, 5H-benzo [ij]quinolizine-2-carboxylic acid whenever prepared by a process as claimed in claim 30 or an obvious chemical equivalent thereof.
  32. 32. A process as claimed in claim 1 which comprises react-ing 9-chloro-6-oxo-1, 2-dihydro-6H-pyrrolo[3, 2, l-ij]quinoline-5-carboxylic acid with piperazine.
  33. 33. 9-(1-Piperazinyl)-6-oxo-1, 2-dihydro-6H-pyrrolo [3, 2, 1-ij]quinoline-5-carboxylic acid whenever prepared by a process as claimed in claim 32 or an obvious chemical equivalent thereof.
  34. 34. A process as claimed in claim 1 which comprises react-ing l-chloro-7a, 8, 9, 10, 11, 11a-hexahydro-4H-pyrido[3, 2, l-jk]
    carbazole-4-oxo-5-carboxylic acid with piperazine.
  35. 35. l-(1-Piperazinyl)-7a, 8, 9, 10, 11, 11a-hexahydro-4H-pyrido[3, 2, 1-jh]-carbazole-4-oxo-5-carboxylic acid whenever prepared by a process as claimed in claim 34 or an obvious chemical equivalent thereof.
  36. 36. A process as claimed in claim 1 which comprises reacting 8-chloro-9-fluoro-5-methyl-6, 7-dihydro-1-oxo-lH, 5H-benzo[ij]
    quinolizine-2-carboxylic acid with piperazine.
  37. 37. 8-(1-Piperazinyl)-9-fluoro-5-methyl-6, 7-dihydro-1-oxo-lH, 5H-benzo[ij]quinolizine-2-carboxylic acid whenever pre-pared by a process as claimed in claim 36 or an obvious chemical equivalent thereof.

    38. A process for preparing a compound of the formula wherein A is hydrogen or lower alkyl B is hydrogen or lower alkyl and X is halogen which comprises reacting a compound of the formula
  38. Claim 38 continued wherein X1 is a halogen, X and B are as hereinabove defined, with a piperazine of the formula wherein A is as hereinabove defined.
  39. 39. A compound of the formula wherein A, B and X are as defined in claim 38 whenever pre-pared by the process of claim 38 or an obvious chemical equivalent.
  40. 40. A process for preparing 8-(1-piperazinyl)-9-fluoro-5-methyl-6, 7-dihydro-1-oxo-lH, 5H-benzo [ij] quinolizine-2-carboxylic acid which comprises reacting 8-halo-9-fluoro-5-methyl-6, 7-dihydro-1-oxo-lH, 5H-benzo [ij].quinolizine-2-carboxylic acid with piperazine.
  41. 41. 8-(1-piperazinyl)-9-fluoro-5-methyl-6, 7-dihydro-1-oxo-lH, 5H-benzo [ij] quinolizine-2-carboxylic acid whenever prepared by the process of claim 40 or an obvious chemical equivalent.

    .
  42. 42. A process for preparing a compound of the formula wherein A is hydrogen or lower alkyl B is hydrogen or lower alkyl and X is halogen which comprises reacting a compound of the formula wherein X1 is a halogen, X and B are defined hereinbefore, with a piperazine of the formula wherein A is defined hereinbefore.
  43. 43. A compound of the formula wherein A, B and X are defined in claim 42, whenever pre-pared by a process as claimed in claim 42 or an obvious chemical equivalent thereof.

    CLAIMS SUPPORTED BY SUPPLEMENTARY DISCLOSURE
  44. 44. A process as claimed in claim 1 which comprises react-ing 8, 9-dichloro-5-methyl-6, 7-dihydro-1-oxo-lH, 5H-benzo [ij]quinolizine-2-carboxylic acid with piperazine.
  45. 45. 8-(1-Piperazinyl)-9-chloro-5-methyl-6, 7 dihydro-l-oxo-lH, 5H-benzo[ij]quinolizine-2-carboxylic acid, whenever prepared by a process as claimed in claim 44 or an obvious chemical equivalent thereof.
  46. 46. A process as claimed in claim 1 which comprises react-ing 8, 9-dichloro-5-methyl-6, 7-dihydro-1-oxo-lH, 5H-benzo [ij]quinolizine-2-carboxylic acid with l-methyl-piperazine.
  47. 47. 8-(4-Methyl-l-piperazinyl)-9-chloro-5-methyl-6, 7-dihydro-l-oxo-lH, 5H-benzo[ij]quinolizine-2-carboxylic acid whenever prepared by a process as claimed in claim 46 or an obvious chemical equivalent thereof.
  48. 48. A process as claimed in claim 1 which comprises react-ing 8, 9-dichloro-5-methyl-6, 7-dihydro-1-oxo-lH, 5H-benzo [ij]quinolizine-2-carboxylic acid with 4-formylpiperazine.
  49. 49. 8-(4-Formyl-l-piperazinyl)-9-chloro-5-methyl-6, 7-dihydro-l-oxo-lH, 5H-benzo[ij]quinolizine-2-carboxylic acid when-ever prepared by a process as claimed in claim 48 or an obvious chemical equivalent thereof.
  50. 50. A process as claimed in claim 1 which comprises react-ing 9-fluoro-8-chloro-5-methyl-6, 7-dihydro-1-oxo-lH, 5H-benzo [ij]quinolizine-2-carboxylic acid with N-methylpiperazine.
  51. 51. 8-(4-Methyl-l-piporazinyl)-9-fluoro-5-methyl-6, 7-dihydro-l-oxo-lH, 5H-benzo[ij]quinolizine-2-carboxylic acid whenever prepared by a process as claimed in claim 50 or an obvious chemical equivalent thereof.
  52. 52. A process as claimed in claim 1 which comprises reacting 9-fluoro-8-bromo-5-methyl-6, 7-dihydro-l-oxo-lH, 5H-benzo [ij]quinolizine-2-carboxylic acid with l formylpiperazine
  53. 53. 8-(4-Formyl-l-piperazinyll-9-fluoro-5-methyl-6, 7-di-hydro-l-oxo-lH, 5H-benzo[ij]quinolizine-2-carboxylic acid when-ever prepared by a process as claimed in claim 52 or an obvious chemical equivalent thereof.
  54. 54. A process as claimed in claim l which comprises react-ing 9-fluoro-8-bromo-5-methyl-6, 7-dihydro-l-oxo lH, 5H-benzo [ij]quinolizine-2-carboxylic acid with l-acetyl piperazine.
  55. 55. 8-(4-Acetyl-l-piperazinyl)-9-fluoro-5-methyl-6, 7-dihydro-l-oxo-lH, 5H-benzo[ij]quinolizine-2-carboxylic acid whenever prepared by a process as claimed in claim 54 or an obvious chemical equivalent thereof.
  56. 56. A process as claimed in claim l which comprises reacting 9-fluoro-8-bromo-5-methyl-6, 7-dihydro-l-oxo-lH, 5H-benzo[ij]
    quinolizine-2-carboxylic acid with l-ethylpiperazine.
  57. 57. 8-(4-Ethyl-l-piperazinyl)-9-fluoro-5-methyl-6, 7-dihydro-l-oxo-lH, 5H-benzo[ij]quinolizine-2-carboxylic acid whenever pre-pared by a process as claimed in claim 56 or an obvious chemical equivalent thereof.
  58. 58. A process as claimed in claim l which comprises reacting 8, 9-dichloro-2-methyl-6-oxo-l, 2-dihydro-6H-pyrrolo[3, 2, l-ij]
    quinoline-5-carboxylic acid with piperazine.
  59. 59. 8-Chloro-9-(1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3, 2, l-ij]quinoline-5-carboxylic acid whenever prepared by a process as claimed in claim 58 or an obvious chemical equivalent thereof.
  60. 60. A process as claimed in claim l which comprises react-ing 8, 9-dichloro-2-methyl-6-oxo-l, 2-dihydro-611-pyrrolo[3, 2, l-ij]quinoline-5-carboxylic acid with l-methylpiperazine.
  61. 61. 8-Chloro-9-(4-methyl-l-piperazinyl)-2-methyl-6-oxo-l, 2-dihydro-6H-pyrrolo[3, 2, l-ij]quinoline-5-carboxylic acid whenever prepared by a process as claimed in claim 60 or an obvious chemical equivalent thereof.
  62. 62. A process as claimed in claim l which comprises reacting 8, 9-dichloro-2-methyl-6-oxo-l, 2-dihydro-6H-pyrrolo[3, 2, l-ij]
    quinoline-5-carboxylic acid with l-acetylpiperazine.
  63. 63. 8-Chloro-9-(4-acetyl-l-piperazinyl)-2-methyl-6-oxo-, 2-dihydro-6H-pyrrolo[3, 2, 1-ij]quinoline-5-carboxylic acid when-ever prepared by a process as claimed in claim 62 or an obvious chemical equivalent thereof.
  64. 64. A process as claimed in claim l which comprises reacting 8-fluoro-9-iodo-2-methyl-6-oxo-l, 2-dihydro-6H-pyrrolo[3, 2, l-ij]
    quinoline-5-carboxylic acid with piperazine.
  65. 65. 8-Fluoro-9-(piperazinyl)-2-methyl-6-oxo-l,2-dihydro-6H-pyrrolo[3, 2, l-ij]quinoline-5-carboxylic acid whenever pre-pared by a process as claimed in claim 64 or an obvious chemical equivalent thereof.
  66. 66. A process as claimed in claim 1 which comprises reacting 8-fluoro-9-iodo-2-methy]-6-oxo-1, 2-dihydro-6H-pyrrolo[3,2, 1-ij]
    quinoline-5-carboxylic acid with 1-formylpiperazine.
  67. 67. 8-Fluoro-9-(4-formyl-1-piperazinyl)-2-methyl-6-oxo-1, 2-dihydro-6H-pyrrolo[3, 2, 1-ij]quinoline-5-carboxylic acid whenever prepared by a process as claimed in claim 66 or an obvious chemical equivalent thereof.
  68. 68. A process as claimed in claim 1 which comprises reacting 8-fluoro-9-iodo-2-methyl-6-oxo-1, 2-dihydro-6H-pyrrolo[3, 2, 1-ij]quinoline-5-carboxylic acid with 1-methylpiperazine.
  69. 69. 8-Fluoro-9-(4-methyl-1-piperazinyl)-2-methyl-6-oxo-1, 2-dihydro-6H-pyrrolo[3, 2, 1-ij]quinoline-5-carboxylic acid whenever prepared by a process as claimed in claim 68 or another chemical equivalent thereof.
CA000325376A 1978-04-12 1979-04-11 Piperazinylbenzoheterocyclic compounds Expired CA1153374A (en)

Applications Claiming Priority (14)

Application Number Priority Date Filing Date Title
JP53043624A JPS6034957B2 (en) 1978-04-12 1978-04-12 penicillanic acid derivatives
JP43624/78 1978-04-12
JP10738778A JPS5576875A (en) 1978-08-31 1978-08-31 Benzo ij quinolizine-2-carboxylic acid derivative and its preparation
JP107387/78 1978-08-31
JP110464/78 1978-09-07
JP53110464A JPS6037118B2 (en) 1978-09-07 1978-09-07 penicillanic acid derivatives
JP137157/78 1978-11-06
JP13715778A JPS5564588A (en) 1978-11-06 1978-11-06 Pyrrolo (3, 2, 1-ij) quinoline-5-carboxylic acid derivative and its preparation
JP141785/78 1978-11-16
JP53141785A JPS6037119B2 (en) 1978-11-16 1978-11-16 penicillanic acid derivatives
JP14273178A JPS5569583A (en) 1978-11-17 1978-11-17 Pyrido 3,2,1-jk carbazole derivative
JP142731/78 1978-11-17
JP145638/78 1978-11-24
JP53145638A JPS5951959B2 (en) 1978-11-24 1978-11-24 penicillanic acid derivatives

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DE (3) DE2953973C2 (en)
FR (1) FR2422658A1 (en)
GB (2) GB2019844B (en)
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JPS5630964A (en) * 1979-08-22 1981-03-28 Kyorin Pharmaceut Co Ltd Novel substituted quinolinecarboxylic acid and its preparation
JPS5746986A (en) * 1980-09-02 1982-03-17 Dai Ichi Seiyaku Co Ltd Pyrido(1,2,3-de)(1,4)benzoxazine derivative
JPS57176987A (en) * 1981-04-24 1982-10-30 Otsuka Pharmaceut Co Ltd Pyrrolo(3,2,1-ij)quinoline-5-carboxylic acid derivative
NO156828C (en) * 1980-11-10 1987-12-02 Otsuka Pharma Co Ltd ANALOGY PROCEDURE FOR THE PREPARATION OF ANTIBACTERYLY EFFECTIVE BENZOHETEROCYCLIC COMPOUNDS.
AT380250B (en) * 1980-12-18 1986-04-25 Otsuka Pharma Co Ltd METHOD FOR PRODUCING BENZOHETEROCYCLIC COMPOUNDS
PH22140A (en) 1982-06-29 1988-06-01 Daiichi Seiyaku Co Tricyclic compounds
JPS59137482A (en) * 1983-01-26 1984-08-07 Otsuka Pharmaceut Co Ltd Pyrrolo(3,2,1,-ij)quinoline-5-carboxylic acid derivative
DE3517709A1 (en) * 1985-01-05 1986-07-10 Bayer Ag BASIC PREPARATIONS OF CHINOLON CARBON ACIDS
AU585981B2 (en) * 1985-05-24 1989-06-29 Tokyo Tanabe Company Limited Benzo (IJ) quinolizine-2-carboxylic acid derivatives, the salts and their hydrates, pharmaceutical compositions thereof, and processes for preparing the same
KR900014383A (en) * 1989-03-29 1990-10-23 원본미기재 Pyrroloquinoline derivatives, preparation method thereof and antibacterial agent using same
DE69102900T3 (en) * 1990-02-14 1998-04-09 Takeda Chemical Industries Ltd Shower mix, its production and use.
US6488961B1 (en) 1996-09-20 2002-12-03 Ethypharm, Inc. Effervescent granules and methods for their preparation

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BE793524A (en) * 1971-12-30 1973-06-29 Riker Laboratories Inc BENZOQUINOLIZINE-CARBOXYLIC ACIDS AND THEIR DERIVATIVES
US3985882A (en) * 1972-11-02 1976-10-12 Riker Laboratories, Inc. Substituted benzo[ij]quinolinzine-2-carboxylic acids and derivatives thereof as bactericidal agents

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IT1196531B (en) 1988-11-16
DE2914258A1 (en) 1979-10-25
DE2953973C2 (en) 1989-02-02
NL7902905A (en) 1979-10-16
DE2914258C2 (en) 1989-08-03
GB2020279A (en) 1979-11-14
NL180664B (en) 1986-11-03
FR2422658B1 (en) 1981-12-31
FR2422658A1 (en) 1979-11-09
AU4603779A (en) 1979-10-18
AU529330B2 (en) 1983-06-02
GB2019844A (en) 1979-11-07
IT7948690A0 (en) 1979-04-10
GB2020279B (en) 1983-02-02
GB2019844B (en) 1983-01-19
DE2953974C2 (en) 1992-06-25
DE2953973A1 (en) 1982-08-26
NL180664C (en) 1987-04-01
CH640853A5 (en) 1984-01-31

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