CA1156232A - Benzo(ij)quinolizine-2-carboxylic acid compounds, therapeutic composition containing same and process for producing same - Google Patents
Benzo(ij)quinolizine-2-carboxylic acid compounds, therapeutic composition containing same and process for producing sameInfo
- Publication number
- CA1156232A CA1156232A CA000362012A CA362012A CA1156232A CA 1156232 A CA1156232 A CA 1156232A CA 000362012 A CA000362012 A CA 000362012A CA 362012 A CA362012 A CA 362012A CA 1156232 A CA1156232 A CA 1156232A
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- Prior art keywords
- compound
- compounds
- formula
- pharmaceutically acceptable
- acceptable salts
- Prior art date
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Classifications
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
ABSTRACT OF THE DISCLOSURE
A benzo[ij]quinolizine-2-carboxylic acid compound, a composition containing the compound, and processes for production of the compound are described;
the compound is (I) wherein R1 represents a hydrogen atom or a lower alkyl group; R2 represents a hydrogen atom or a halogen atom;
R3 represents a lower alkyl group substituted with one or more of a halogen atom and a hydroxy group, a lower alkanoyl group substituted with one or more halogen atoms, a phenylalkyl group substituted with one or more lower alkoxy groups on the phenyl ring, a lower alkanesulfonyl group substituted with one or more halogen atoms, a lower alkenyl group or a lower alkynyl group; or a pharmaceu-tically acceptable salt thereof. The compounds have an antimicrobial activity, and are particularly effective on those bacteria resistant to conventional antibiotics and can be maintained at high concentration levels in blood for extended periods of time.
A benzo[ij]quinolizine-2-carboxylic acid compound, a composition containing the compound, and processes for production of the compound are described;
the compound is (I) wherein R1 represents a hydrogen atom or a lower alkyl group; R2 represents a hydrogen atom or a halogen atom;
R3 represents a lower alkyl group substituted with one or more of a halogen atom and a hydroxy group, a lower alkanoyl group substituted with one or more halogen atoms, a phenylalkyl group substituted with one or more lower alkoxy groups on the phenyl ring, a lower alkanesulfonyl group substituted with one or more halogen atoms, a lower alkenyl group or a lower alkynyl group; or a pharmaceu-tically acceptable salt thereof. The compounds have an antimicrobial activity, and are particularly effective on those bacteria resistant to conventional antibiotics and can be maintained at high concentration levels in blood for extended periods of time.
Description
1 15~232 BENZO[ij]QUINOLIZINE-2-CARBOXYLIC ACID COMPOUNDS, THERAPEUTIC COMPOSITION CONTAINING SAME
AND PROCESSES FOR PRODUCING SAME
BACKGROUND OF THE INVENTION
1. Field of the Invention This invention relates to certain ben20[ij]-quinolizine-2-carboxylic acid compounds and pharmaceu-tically acceptable salts thereof which are useful as antimicrobial agents, processes for preparing the same, and pharmaceutical compositions containing the benzo[ij]-quinolizine-2-carboxylic acid compound or a salt thereof.
AND PROCESSES FOR PRODUCING SAME
BACKGROUND OF THE INVENTION
1. Field of the Invention This invention relates to certain ben20[ij]-quinolizine-2-carboxylic acid compounds and pharmaceu-tically acceptable salts thereof which are useful as antimicrobial agents, processes for preparing the same, and pharmaceutical compositions containing the benzo[ij]-quinolizine-2-carboxylic acid compound or a salt thereof.
2. Description of the Prior Art It is known that certain types of polyhetero-cyclic compounds exhibit antimicrobial activities. For example, U.S. Patent 3,917,609 to Gerster et al. discloses substituted derivatives of l,2-dihydro-6-oxo-6H-pyrrolo-~3,2,1-ij]quinoline which are useful as antimicrobial agents or as intermediates for the preparation of anti-microbial agents.
Also, U.S. Patents 3,896,131, 3,985,882,
Also, U.S. Patents 3,896,131, 3,985,882,
3,969,463, 4,001,243 and 4,014,877 to Gerster et al. and British Patent Application GB 2020279A disclose 6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine derivatives having antimicrobial activities.
1 15~232 SUM~ARY OF T~IE INVENTION
As a result of extensive research it has now been found that some benzo[ij~quinolizine-2-carboxylic acid derivatives have a potent antimicrobial activity and low toxicity, that they show no desrease in activity in the presence of serum, and that they are effective against bacteria which are resistant to conventional antibiotics such as penicillin, ampicillin, streptomycin, etc.
This invention is based on the above finding and provides a benzo[ij]quinolizine-2-carboxylic acid compound represented by the formula ~I) R3-N N~COOH (I) ~ Rl wherein Rl represents a hydrogen atom or a lower alkyl group; R2 represents a hydrogen atom or a halogen atom;
R3 represents a lower alkyl group substituted with one or more of a halogen atom and a hydroxy group, a lower alkanoyl group substituted with one or more halogen atoms, a phenylalkyl group substituted with one or more lower : alkoxy groups on the phenyl ring, a lower alkanesulfonyl 1 15~232 1 group substituted with one or more halogen atoms, a lower alkenyl group or a lower alkynyl group; and pharmaceu-tically acceptable salts thereof.
In another aspect this invention provides a pharmaceutical composition containing the compound of the formula (I) or a pharmaceutically acceptable salt thereof in an antimicrobially effective amount.
Further, this invention provides processes for preparing compounds of formula (I) and pharmaceutically acceptable salts thereof.
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 tert-butyl group and the like.
The term "lower alkanoyl" as used herein refers to a straight or branched alkanoyl group having 2 to 4 carbon atoms such as an acetyl group, a propanoyl group, a butanoyl group, an isobutanoyl group and the like.
The term "lower alkanesulfonyl" as used herein refers to a straight or branched alkanesulfonyl group having 1 to 4 carbon atoms such as a methanesulfonyl group, 1 15~232
1 15~232 SUM~ARY OF T~IE INVENTION
As a result of extensive research it has now been found that some benzo[ij~quinolizine-2-carboxylic acid derivatives have a potent antimicrobial activity and low toxicity, that they show no desrease in activity in the presence of serum, and that they are effective against bacteria which are resistant to conventional antibiotics such as penicillin, ampicillin, streptomycin, etc.
This invention is based on the above finding and provides a benzo[ij]quinolizine-2-carboxylic acid compound represented by the formula ~I) R3-N N~COOH (I) ~ Rl wherein Rl represents a hydrogen atom or a lower alkyl group; R2 represents a hydrogen atom or a halogen atom;
R3 represents a lower alkyl group substituted with one or more of a halogen atom and a hydroxy group, a lower alkanoyl group substituted with one or more halogen atoms, a phenylalkyl group substituted with one or more lower : alkoxy groups on the phenyl ring, a lower alkanesulfonyl 1 15~232 1 group substituted with one or more halogen atoms, a lower alkenyl group or a lower alkynyl group; and pharmaceu-tically acceptable salts thereof.
In another aspect this invention provides a pharmaceutical composition containing the compound of the formula (I) or a pharmaceutically acceptable salt thereof in an antimicrobially effective amount.
Further, this invention provides processes for preparing compounds of formula (I) and pharmaceutically acceptable salts thereof.
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 tert-butyl group and the like.
The term "lower alkanoyl" as used herein refers to a straight or branched alkanoyl group having 2 to 4 carbon atoms such as an acetyl group, a propanoyl group, a butanoyl group, an isobutanoyl group and the like.
The term "lower alkanesulfonyl" as used herein refers to a straight or branched alkanesulfonyl group having 1 to 4 carbon atoms such as a methanesulfonyl group, 1 15~232
- 4 1 an ethanesulfonyl group, a propallesulfonyl group, an isopropanesulfonyl group, a butanesulfonyl group, a tert-butanesulfonyl group and the like.
The term "arylsulfonyl" as used herein refers to a benzenesulfonyl group, a naphthalenesulfonyl group and the like. The aryl ring included in the arylsulfonyl group may be substituted with one or more of a halogen atom, a lower alkyl group, a hydroxy group, a nitro group and the like.
The term "phenylalkyl" as used herein refers to a phenylalkyl group consisting of a phenyl group and a straight or branched alkylene group having 1 to 4 carbon atoms such as a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, a l-phenylethyl group, a l,l-dimethyl-2-phenylethyl group and the like.
Examples of the lower alkyl group substituted with one or more of a halogen atom and a hydroxy group as used herein include a trifluoromethyl group, a trichloro-methyl group, a dichloromethyl group, a tribromomethylgroup, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloro-ethyl group, a 2-chloroethyl group, a 1,2-dichloroethyl group, a 3,3,3-trichloropropyl group, a 3-fluoropropyl group, a 4-chlorobutyl group, a 3-chloro-2-methylethyl : group, a hydroxymethyl group, a 2-hydroxyethyl group, l 15~232
The term "arylsulfonyl" as used herein refers to a benzenesulfonyl group, a naphthalenesulfonyl group and the like. The aryl ring included in the arylsulfonyl group may be substituted with one or more of a halogen atom, a lower alkyl group, a hydroxy group, a nitro group and the like.
The term "phenylalkyl" as used herein refers to a phenylalkyl group consisting of a phenyl group and a straight or branched alkylene group having 1 to 4 carbon atoms such as a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, a l-phenylethyl group, a l,l-dimethyl-2-phenylethyl group and the like.
Examples of the lower alkyl group substituted with one or more of a halogen atom and a hydroxy group as used herein include a trifluoromethyl group, a trichloro-methyl group, a dichloromethyl group, a tribromomethylgroup, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloro-ethyl group, a 2-chloroethyl group, a 1,2-dichloroethyl group, a 3,3,3-trichloropropyl group, a 3-fluoropropyl group, a 4-chlorobutyl group, a 3-chloro-2-methylethyl : group, a hydroxymethyl group, a 2-hydroxyethyl group, l 15~232
- 5 1 a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group, a 4-hydroxybutyl group, a 2-hydroxypropyl group, etc.
Examples of the lower alkanoyl group substi-tuted with one or more halogen atoms as used herein include a trifluoroacetyl group, a trichloroacetyl group, a tribromoacetyl group, a 2,2-dichloropropionyl group, a monochloroacetyl group, a 2-chlorobutyryl group, a pentafluoropropionyl group, a heptafluorobutyryl group, etc.
Examples of the phenylalkyl group substituted with one or more alkoxy groups containing, e.g., from 1 to 3 carbon atoms, on the phenyl ring thereof include a 4-methoxybenzyl group, a 2-isopropoxybenzyl group, a 3,4-dimethoxybenzyl group, a ~-3,4-dimethoxyphenethyl group, an ~-3,4-dimethoxyphenethyl group, a ~-2,3,4-trimethoxyphenethyl group, a 3-(4-ethoxyphenyl)propyl group, a 4-(4-methoxyphenyl)butyl group, etc.
Examples of the lower alkanesulfonyl group substituted with one or more halogen atoms include a trifluoromethanesulfonyl group, a trichloromethanesulfonyl group, a tribromomethanesulfonyl group, a dichloromethane-sulfonyl group, a 2,2,2-trifluoroethanesulfonyl group, a 2,2,2-trichloroethanesulfonyl group, a 2-chloroethane-sulfonyl group, a 1,2-dichloroethanesulfonyl group, a 3,3,3-trifluoropropanesulfonyl group, a 3,3,3-trichloro 1 15~232
Examples of the lower alkanoyl group substi-tuted with one or more halogen atoms as used herein include a trifluoroacetyl group, a trichloroacetyl group, a tribromoacetyl group, a 2,2-dichloropropionyl group, a monochloroacetyl group, a 2-chlorobutyryl group, a pentafluoropropionyl group, a heptafluorobutyryl group, etc.
Examples of the phenylalkyl group substituted with one or more alkoxy groups containing, e.g., from 1 to 3 carbon atoms, on the phenyl ring thereof include a 4-methoxybenzyl group, a 2-isopropoxybenzyl group, a 3,4-dimethoxybenzyl group, a ~-3,4-dimethoxyphenethyl group, an ~-3,4-dimethoxyphenethyl group, a ~-2,3,4-trimethoxyphenethyl group, a 3-(4-ethoxyphenyl)propyl group, a 4-(4-methoxyphenyl)butyl group, etc.
Examples of the lower alkanesulfonyl group substituted with one or more halogen atoms include a trifluoromethanesulfonyl group, a trichloromethanesulfonyl group, a tribromomethanesulfonyl group, a dichloromethane-sulfonyl group, a 2,2,2-trifluoroethanesulfonyl group, a 2,2,2-trichloroethanesulfonyl group, a 2-chloroethane-sulfonyl group, a 1,2-dichloroethanesulfonyl group, a 3,3,3-trifluoropropanesulfonyl group, a 3,3,3-trichloro 1 15~232
- 6 1 propanesulfonyl group, a 3-fluoropropanesulfonyl group, a 4-chlorobutanesul~onyl group, a 3-chloro-2-methyl-ethanesulfonyl group, etc.
Examples of the lower alkenyl group containing, e.g., from 2 to 4 carbon atoms, as used herein include a vinyl group, an allyl group, a crotyl group, a l-methyl-allyl group, etc.
Examples of the lower alkynyl group containing, e.g., from 2 to ~ carbon atoms, as used herein include an ethynyl group, a 2-propynyl group, a 2-butynyl group, a l-methyl-2-propynyl group, etc.
The compounds of this invention of the formula (I) and the salts thereof exhibit excellent antimicrobial activity broadly on gram-positive and negative bacteria at low concentrations. They are useful compounds which show particularly potent antibacterial activity on Streptococcus, Pseudomonas, Enterobacter, Proteus, etc., on which conventional synthetic antibacterial agents are not effective or only slightly effective. In addition, they show a high antibacterial activity on coliform bacilli, staphylococci, etc., which are major causes of infectious diseases and are also effective on Serratia, Klebsiella, etc., which also cause infectious diseases that have recently attracted wide attention of many workers in the field, and therefore they are very useful clinically.
1 15~232 1 As stated above, the compounds of this invention are advantageous not only because they are characterized by a broad antimicrobial spectrum and potent activity, but also because they not only show no decrease in anti-microbial activity in the presence of a serum, but rather show a tendency towards increased activity. This phenom-enon is surprising to one skilled in the art since it has hitherto been observed that conventional pharmaceuticals having antimicrobial activity show decreased activity in the presence of a serum. This strongly suggests that the compound of this invention can exhibit potent antimicrobial activity in the blood.
The oral toxicity of the compounds of this invention is very low as compared with the effective oral dosage thereof.
The compounds of this invention have excellent antimicrobial activity on those bacteria which are resist-ant or have acquired resistance to conventional anti-biotics such as penicillin, cephalosporin, ampicillin, streptomycin, erythromycin, Kanamycin, nalidixic acid, etc.
~ Vhen administered orally the compounds of this invention are absorbed readily and their blood level or activity in the blood level is maintained at high levels so that they can exhibit potent antimicrobial activity also in this respect.
Examples of the lower alkenyl group containing, e.g., from 2 to 4 carbon atoms, as used herein include a vinyl group, an allyl group, a crotyl group, a l-methyl-allyl group, etc.
Examples of the lower alkynyl group containing, e.g., from 2 to ~ carbon atoms, as used herein include an ethynyl group, a 2-propynyl group, a 2-butynyl group, a l-methyl-2-propynyl group, etc.
The compounds of this invention of the formula (I) and the salts thereof exhibit excellent antimicrobial activity broadly on gram-positive and negative bacteria at low concentrations. They are useful compounds which show particularly potent antibacterial activity on Streptococcus, Pseudomonas, Enterobacter, Proteus, etc., on which conventional synthetic antibacterial agents are not effective or only slightly effective. In addition, they show a high antibacterial activity on coliform bacilli, staphylococci, etc., which are major causes of infectious diseases and are also effective on Serratia, Klebsiella, etc., which also cause infectious diseases that have recently attracted wide attention of many workers in the field, and therefore they are very useful clinically.
1 15~232 1 As stated above, the compounds of this invention are advantageous not only because they are characterized by a broad antimicrobial spectrum and potent activity, but also because they not only show no decrease in anti-microbial activity in the presence of a serum, but rather show a tendency towards increased activity. This phenom-enon is surprising to one skilled in the art since it has hitherto been observed that conventional pharmaceuticals having antimicrobial activity show decreased activity in the presence of a serum. This strongly suggests that the compound of this invention can exhibit potent antimicrobial activity in the blood.
The oral toxicity of the compounds of this invention is very low as compared with the effective oral dosage thereof.
The compounds of this invention have excellent antimicrobial activity on those bacteria which are resist-ant or have acquired resistance to conventional anti-biotics such as penicillin, cephalosporin, ampicillin, streptomycin, erythromycin, Kanamycin, nalidixic acid, etc.
~ Vhen administered orally the compounds of this invention are absorbed readily and their blood level or activity in the blood level is maintained at high levels so that they can exhibit potent antimicrobial activity also in this respect.
- 7 1 Representative examples of the compound of this invention include the following compounds. This list is provided for illustration only and is not intended to limit to scope of this invention.
(1) 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (2) 8-(4-trifluoroacetyl-1-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (3) 8-(4-trifluoroacetyl-1-piperazinyl)-10-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (4) 8-(4-trichloroacetyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-; carboxylic acid (5) 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-5-ethyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij~quinolizine-2-carboxylic acid (6) 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-5-butyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (7) 8-(4-monochloroacetyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid .
1 I5~232 1 (8) 8-(4-trifluoromethanesulfonyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid (9) 8-(4-trifluoromethanesul~onyl-1-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-1~-1,5H-benzoEij]-quinolizine-2-carboxylic acid (10) 8-[4-(2,2,2-trifluoroethanesulfonyl)-1-piperazinyl~-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (11) 8-[4-(2-chloroethyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quizolizine-2-carboxylic acid (12) 8-(4-tribromoacetyl-1-piperazinyl)-9-bromo-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (13) 8-[4-(2-chlorobutyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (14) 8-(4-trifluoroacetyl-1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH~5H-benzo[ij]quinolizine-2-carboxylic acid (lS) 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic ;~ acid 1 15~2~2 1 (16) 8-(4-allyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,511-benzo[ij]quinolizine-2-carboxylic acid (17) 8-(4-crotyl-1-piperazinyl)-9-chloro-S-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (18) 8-(4-allyl-1-piperazinyl)-S-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (19~ 8-(4-allyl-1-piperazinyl)-9-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (20) 8-(4-allyl-1-piperazinyl)-9-fluoro-5-methyl-: 6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (21) 8-(4-trifluoromethyl-1-piperazinyl)-10-chloro-! S-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]quinolizine-2-carboxylic acid (22) 8-(4-trifluoromethyl-1-piperazinyl)-9-chloro-S-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]quinolizine-2-carboxylic acid : 20 (23~ 8-(4-trichloromethyl-1-piperazinyl)-9-chloro-S-methyl-6~7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (24) 8-[4-(2,2,2-trifluoroethyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,51-1-benzo[ij]-quinolizine-2-carboxylic acid ~, 1 15~232 I (25) 8-[4-(~-chlorobutyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,51-1-benzo[ij]quinolizine-2-carboxylic acid ~ 26) 8-(4-tri~luoromethyl-1-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (27) 8-(4-trifluoromethyl-1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-earboxylic acld (28) 8-[4-~2,2,2-trifluoroethyl)-1-piperazinyl]-9-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (29) 8-(4-trifluoromethyl-1-piperazinyl)-9-chloro-5-ethyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (30) 8-[4-(2-hydroxyethyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (31) 8-[4-(2-hydroxyethyl)-1-piperazinyl]-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (32) 8-[4-(2-hydroxyethyl)-1-piperazinyl]-10-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid , .
1 15~232 - l2 -1 (33) 8-[4-(2-hydroxyethyl)-1-piperazinyl]-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (34) 8-[4-(2-hydroxyethyl)-1-piperazinyl]-9-chloro-6,7-dihydro-1-oxo-lH,S~-I-benzo[ij]quinolizine-2-carboxylic acid (35) 8-[4-(2,3-dihydroxylpropyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid ~36) 8-[4-(4-hydroxybutyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (37) 8-[4-(2-propynyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid ~ 38) 8-[4-(2-propynyl)-1-piperazinyl]-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (39) 8-~4-(2-propynyl)-1-piperazinyl]-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acld (40) 8-[4-(2-propynyl)-1-piperazinyl~-9-fluoro-6,7-dihydro-l-oxo-lH,5H-benzo~ij]quinolizine-2-carboxylic acid ' :
. .
1 15~232 - :13 -1 (41) 8-[4-(1-methyl-2-propynyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,511-benzo[ij]-quinolizine-2-carboxylic acid (42) 8-[4-(2-propynyl)-1-piperazinyl]-10-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (43) 8-[4-(4-methoxybenzyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 10 (44) 8-[4-(4-methoxybenzyl)-1-piperazinyl]-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (45) 8-[4-(4-methoxybenzyl)-1-piperazinyl]-9-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (46) 8-[4-(4-methoxybenzyl)-1-piperazinyl]-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (47) 8-[4-(4-methoxybenzyl)-1-piperazinyl]-10-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]-quinolizine-2-carboxylic acid (48) 8-[4-(3,4-dimethoxybenzyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid - l4 -1 (49) 8-[4~ 3,4-dimethoxyphenethyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid (50) 8-{4-[3-(4-ethoxyphenyl)propyl]-1-piperazinyl}-9-chloro-5-methyl-6,7-dihydro-1-oxo-111,5H-benzo[ij]-quinolizine-2-carboxylic acid ~ Sl) 8-[4-~-2,3,4-trimethoxyphenethyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinollzine-2-carboxylic acid (52) 8-(4-trifluoroacetyl-1-piperazinyl)-9-bromo-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (53) 8-(4-trifluoromethyl-1-piperazinyl)-9-bromo-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (54) 8-(4-allyl-1-piperazinyl)-9-bromo-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (55) 8-(4-pentafluoropropionyl-1-piperazinyl)-5-methyl-6~7-dihydro-l-oxo-lH~5t-l-benzo[ij]quinolizine-2 carboxylic acid (56) 8-(4-heptafluorobutyryl-1-piperazinyl)-9-chloro-6,7-dihydro-1-oxo-111,5h benzo~ij]quinolizine-2-ca~rboxylic acid ' ' 1 (57) 8-(4-pentafluoropropionyl-1-piperazinyl)-10-chloro-S-metllyl-6,7-(li}ly(lro-i-oxo-111,511-benzo[ij]quinolizine-2-carboxylic acid (58) 8-(4-heptafluorobutyryl-1-piperazinyl~-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (59) 8-(4-trifluoromethanesulfonyl-1-piperazinyl)-9-chloro-6,7-dihydro-1-oxo-111,5H-benzo[ij]quinolizine-2-carboxylic acid (60) 8-(4-pentafluoropropionyl-1-piperazinyl)-9-chloro-6,7-dihydro-1-oxo-lH,51~-benzo[ij~quinolizine-2-carboxylic acid (61) 8-(4-heptafluorobutyryl-1-piperazinyl)-10-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (62) 8-(4-trifluoromethanesulfonyl-1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (63) 8-(4-trifluoromethyl-1-piperazinyl)-6,7-dihydro-~: 20 1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid `:
~ - 15 -~:
1 The compounds of this invention of the formula (I) can be prepared by various alternative procedures, for example, by reacting a benzo[ij]quinolizine-2-carboxylic acid compound of the formula ~II) tll) Rl wherein R4 represents a halogen atom, a lower alkane-- sulfonyloxy group or an arylsulfonyloxy group, and Rl and R2 have the same meaning as defined above, with a piperazine compound of the formula ~III) \ 3 HN\___/N-R (III) ;
wherein R3 has the same meaning as defined above.
The term "lower alkanesulfonyloxy" represented by R4 refers to a straight or branched alkanesulfonyloxy group having 1 to 4 carbon atoms such as a methane-sulfonyloxy group, an ethanesulfonyloxy group, a propane-;~ sulfonyloxy group, an isopropanesulfonyloxy group, a ~ butanesulfonyloxy group, a tert-butanesulfonyloxy group : and the like.
. - 16 -1 The term "arylsulonyloxy" as used herein includes a benzenesulfonyloxy group, a naphthalene-sulfonyloxy group and the like. The aryl ring included in the arylsulfonyloxy group may be substituted with one or more, and preferably from one to three, of a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, a nitro group and the like.
With respect to the compounds of the formula (Il) which can be used as the starting material for preparing the compounds of this invention represented by the formula (I), some of those in which R4 represents a halogen atom are known compounds as described in U.S.
Patents 3,917,609, 3,896,131, 3,985,882, 3,969,463, 4,001,243 and 4,014,877 and others can be easily prepared by appropriate selection of starting materials according to known processes as described in Japanese Patent Publication No. 6156/76 and U.S. Patent 4,014~877.
They can also be prepared by Reaction Scheme-2 herein-; below. On the other hand, the compounds of the formula (II) in which R4 represents a lower alkanesulfonyloxygroup or an arylsulfonyloxy group, i.e., compounds oE the formula (IIa) are novel and can be prepared, for example, -by the Reaction Scheme-l below.
;~ ~
~; , ' l 15~232 Reaction Scheme-l OH OH
R2~ ~Rl ~ `~--~0 H ~l (IV) (V) ~ R X ~VI) ~ R7X (VI) oR7 oR7 R2 ~ Reduction R2 ~
N Rl ~ N O
H H
~VIII) (VII) , COORg C2H50CH C ~cooR8 (IX) oR7 R ~ Cyclization R2 0 ;!~,COOR8 CH=C~COOR8)2 R O ~ N~
.~ (X) l J~ 1 : " ~' R
(XI) COOH
Hydrolysis > R70 ~ N') ~Rl (IIa) ' 1 l~B232 l In the Reaction Scheme-l abo~e, R7 represents a lower alkanesulfonyl group or an arylsulfonyl group; R8 repre-sents a lower alkyl group; X represents a halogen atom;
and Rl and R2 have the same meaning as defined above.
Thus, the compounds of the formula (IIa~ can be prepared by reacting a compound of the formula (IV~ with a compound of the formula (VI) to form a compound of the formula (VIII), further reacting this compound with a compound of the formula ~IX) to obtain a compound of the formula (X), and cyclizing the compound of the formula (X) to form a compound of the formula (XI), which is then subjected to hydrolysis.
Of the compounds of the formula (VIII) those in which Rl represents a hydrogen atom can also be prepared by reacting a compound of the formula (V) wi~h a compound of the formula (VI) to form a compound of the formula (VII) and reducing this compound.
In Reaction Scheme-l above, a suitable amount of the compound of the formula (VI) to be reacted with the compound of the formula (IV) is at least an approxi-mately equimolar amount. Preferably l to 2 mols of the compound of the formula (VI) are reacted per mol of the compound of the formula (IV).
The reaction proceeds usually in an inert solvent in the presence of a deoxidizing agent in an amount of at least an approximately equimolar amount, 1 15~232 l and preferably 1 to 2 mols of the deoxiclizin~ agent per mol of the compound of the formula (IV) at a temperature of about 0 to about 100C, preferably at room temperature for about 0.5 to about 6 hours, thereby yielding the compound of the formula (VIII).
Examples of suitable deoxidizing agents include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., inorganic carbonates such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydrogen carbonate, etc., tertiary amines such as pyridine, quinoline, triethylamine, etc.
Examples of suitable inert solvents include lower alcohols such as methanol, ethanol, isopropanol, etc., ethers such as dioxane, tetrahydrofuran (THF), diglyme, etc., aromatic hydrocarbons such as benzene, toluene, etc., dimethyl sulfoxide ~DMSO), dimethylformamide (DMF~, hexamethylphosphoric triamide (HMPTA), pyridine, etc.
More particularly~ in Reaction Scheme-l, the reaction between the compound of the formula tVIII~ and the compound of the formula (IX) can be effected in the absence of solvents or in the presence of solvents such as the above-described lower alcohols, DMF, DMSO, and HMPTA and acetonitrile and the like. Preferably the reaction is conducted in the absence of solvents.
2~2 - Zl -1 The compound of the formula ~IX) can be used in excess amounts over the equimolar amount relative to the compounds of the formula (VIII), preferably in an equimolar amount in the absence of solvents and in an amount of from about 1.1 to 1.5 mols per mol of the compound of the formula (VIII) in the presence of solvents.
The reaction can generally be carried out at a temperature of from room temperature (from about 15 to 30C) to about 150C, and preferably from 100 to 130C, for a period of from about 0.5 to about 6 hours thereby easily yielding the compound represented by the formula (X).
The subsequent cyclization reaction of the thus-obtained compound of the formula (X) can be effected in accordance with conventional cyclization reactions, for example, by heating the compound of the formula (X) or by using an acidic substance such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, polyphosphoric acid and the like. When the cyclization is effected by heating, it is preferred to heat the compound of the formula (X) in a solvent such as high boiling point hydrocarbons or high boiling point ethers, for example, diphenyl ether tetraphosphoric acid, diethylene glycol dimethyl ether, etc., at a temperature of from about 100 to about 250C, and preferably from 150 to 200C for a period of from l 1S~232 1 about 0.5 to about 6 hours. lYhen the cyclization iseffected using an acidic substance, the cyclization can be conducted in the presence of the acid substance in an approximately equimolar amount to a large excess amount, preferably 10 to 20 molar excess acid, relative to the amount of the compound of the formula (X) at a temperature of about 100 to about 150C for a period of about 0.5 to about 6 hours, whereby the desired compounds of the formula (XI) can be produced advantageously.
In the above Reaction Scheme-l, the hydrolysis of the compound of the formula (XI) into the compound of the formula (IIa) can be achieved by a conventional hydrolysis procedure in the presence of a typical hydrolyzation catalyst, for example, a basic compound such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, or an inorganic acid such as sulfuric acid, hydrochloric acid, nitric acid and the like or organic acid such as acetic acid, an aromatic sulfonic acid and the like. The hydrolysis can be carried out in a solvent such as water, the above-described alcohols, ethers, and ketones such as acetone, methyl ethyl ketone, dioxane, ethylene glycol, etc., and acetic acid and the like at a temperature of from room tempera-ture to about 200C, preferably 5Q to 150C for a period of about 0.5 to about 6 hours, thereby easily yielding the compound represented by the formula ~IIa).
1 l~B2~2 1 The reaction between the compound of the formula (V) and the compounds of the formula ~VI) can be conducted in the same manner as the reaction of the compound of the formula (lV) with ~he compound of the formula (VI), thus yielding a compound of the formula (VII).
In Reaction Scheme-l above, the reduction of the compounds of the formula (VII) can be conducted catalytically or using a conventional hydrogenating agent such as a combination of sodium borohydride or lithium aluminum hydride and a lower fatty acid, e.g., acetic acid, trifluoroacetic acid, propionic acid, etc.
Suitable amounts of sodium borohydride or lithium aluminum hydride and the lower fatty acid are from an approximately equimolar amount to a large excess amount, preferably from 3 to 5 mols per mol of the ; compound of the formula (VII).
The reduction reaction using a hydrogenating agent can proceed advantageously in an inert solvent such as the above-described ethers, aromatic hydrocarbons, lower fatty acids, e.g., acetic acid, trifluoroacetic acid, propionic acid, etc., at a temperature of from room temperature to about 100C, preferably from 50 to 100C for about 1 to about 6 hours, thus yielding the compound of the formula ~VIII) in which Rl represents a hydrogen atom.
1 15~232 Reaction Scheme-2 Nitration X ~ R
(XIII) ~ Reduction N~12 ~ of Nitro Group X~'~Rl Reduction ~XIV) \ Reduction of \ Pyridine Replacement of \ing Amino Group by ~
Halogen NH2 X ~ H
N Rl (XVII~
~XV) ~`. Reduction of /Replacement of Pyridine Ring / Amino by Halogen ~ X \ / k/
X~ R
H
(XVI~
(XVI ) ~COOR8 ~ C2H50CHsC~ 8 ~IX) X O
X~ X~COOR8 lRl Cyclization J~N~J
CH=C (COOR8) 2 U~R1 ~XVI I I ) (XIX3 O
, l ~ ~COOH
Hydro ly s i s ~ R
(I Ib) ,: j .~ ;::
,:
~ ~, .
~`
l 156232 1 In the above formulae, R-, R8 and X have the same meaning as defined above.
In the Reac~ion Scheme-2 above, nitration of the compound of the formula (XII) can proceed under conven-tional conditions for nitration of aromatic compounds, e.g., in the absence of solvents or in the presence of a suitable inert solvent using a nitration agent.
Suitable examples of the inert solvent include acetic acid, acetic anhydride, concentrated sulfuric acid, etc.
Suitable examples of nitration agent include fuming nitric acid, concentrated nitric acid, a mixed acid (a mixture of nitric acid and sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride), alkali metal nitrates such as potassium nitrate and sodium nitrate, and sulfuric acid, etc.
The reaction proceeds advantageously in the presence of at least equimolar amount, preferably excess ; amount, of the nitration agent with respect to the 2Q starting compound at a temperature of preferably O to 15C for 1 to 4 hours.
Reduction of the nitro group of the compound of the formula (XIII) obtained in the above nitration can be conducted in an inert solvent in the presence of a reducing agent such as a mixture of iron, zinc, tin, 1 1 5B2~
1 stannous chloride and an acid (e.g., hydrochloric acidand sulfuric acid) or a mixture of iron, iron sulfite, zinc or tin and hydroxide, sulfate, sulfite, etc., of an alkali metal. Alternatively, the reduction can he carried out catalytically using a reducing catalyst such as palladium on carbon in an inert solvent.
~ xamples of suitable inert solvents include water, acetic acid, methanol, ethanol, dioxane, etc.
The conditions under which the above reduction of nitro group is carried out can be suitably selected.
For example, the reduction using a mixture of stannous chloride and hydrochloric acid as a reducing agent can proceed advantageously at a temperature of from 70 to lOO~C for from 0.5 to 1 hour using at least equimolar amount, and preferably from 1 to 2 mols of the reducing agent per mol of the starting compound. When the reduc-tion is carried out catalytically, it can proceed advanta-geously at room temperature for from 0.5 to several hours.
The amino group of the compound of the formula (XIV) thus obtained can be replaced by halogen by the application of the Sandmeyer reaction involving diazota-tion. Diazotation of the compound of the formula (XIV) can proceed advantageously in a solvent such as water, hydrochloric acid, sulfuric acid, etc., in the presence of a diazotation agent such as a mixture of sodium sulfite - 2~ -1 or potassium nitrite and hydrochloric acid or sulfuricacid at a temperature of -30C to room temperature for 0.5 to 2 hours. Subsequently, the diazonium salt of the compound of the formula (XV) thus obtained, without isolation, can be reacted, with a halogenating agent such as cuprous chloride, cuprous bromide, etc., in an amount of at least equimolar amount, preferably 1 to 2 mols of the halogenating agent per mol of the starting compound at a temperature of 0 to 50C for 0.5 to 2 hours to form a compound of the formula (XV).
Reduction of the pyridine ring of the compound of the formula (XV) can be carried out catalytically in an inert solvent such as dioxane, tetrahydrofuran, acetic acid, water, etc., under acidic condition using various acids capable of forming a quinolinium salt such as acetic acid, hydrochloric acid, sulfuric acid, etc., in the presence of a catalytic reduction agent such as platinum-carbon, palladium-carbon, r~odi~ll-carbon, ruthenium-carbon, etc., at a temperature of room temperature to 50C for 1 to 10 hours, thus yielding a compound of the formula (XVI).
Alternatively, the compound of the formula ~XVI~
can also be prepared by reducing the pyridine ring of the compound of the formula (XIV) to form a compound of the formula (XVII) and then replacing the amino group of the compound of the formula (XVII) by halogen atoms. The l 156232 1 reduction of the pyridine ring of the compound of the formula ~XIV) can be carried out in the same manner as the reduction of the pyridine ring of the compound of the formula (XV). Also, The replacement of the amino group of the compound of the formula (XVII) by a halogen atom can be conducted in the same manner as the replacement of the amino group of the compound of the formula (XIV) by a halogen atom.
~urther, the compound of the formula (XVII) can be prepared by reducing the compound of the formula (XIII) in the same manner as the reduction of the pyridine ring of the compound of the formula (XIV).
Reaction between the compound of the formula (XVI) thus-obtained and the compound of the formula (IX) can be carried out under the same conditions as the reac-tion between the compound of the formula (VIII) and that of the formula (IX).
Cyclization of the compound (XVIII) which is formed in the above reaction and hydrolysis of the cyclized compound of the formula (XIX) can proceed in the same manner as the cyclization of the compound of the formula (X) and the hydrolysis o the compound of the formula ~XI), respectively, thus yielding the compound of the formula (IIb).
1 Some of the compounds of the formula (III), another starting compound used in this invention, are known compounds and others can be prepared with ease according to known processes.
In the reaction between the compound of theformula (II) and the compound of the formula (III) in the Reaction Scheme-l the proportion of the latter to the former is usually at least equimolar, and preferably from 1 to 5 mols of the latter per mol of the former, and the reaction can generally proceed in an inert solvent such as water, the above-described lower alcohols, aromatic hydrocarbons, ethers, DMSO, DMF, HMPTA, etc., with DMSO, DMF and HMPTA being preferred. In the reaction, the above-described deoxidizing agent can be used.
The reaction can proceed advantageously at a pressure of from 1 to 20 atms, and preferably from 1 to 10 atms, and at a temperature of 100 to 250C, and prefer-ably from 140 to 2Q0C, for from 5 to 20 hours, thus yielding the compound of the formula (I) of this invention.
Further, the compound of the formula (I) of this invention can be prepared by reacting a compound of the formula (XX) with a compound of the formula (XXI) in the presence of the above-described deoxidizing agent as shown in Reaction Scheme-3 below.
_eaction Scheme-3 ~ COOH ~ COOH
HN N ~ N~ R3N N ~ N
~Rl ~R
(XX) (XXI) (I~
In the above formulae, Rl, R2, R3 and X have the same meaning as defined above.
The compounds of the formula (XX) used in the above reaction are novel compounds and can be prepared, for example, by reacting a compound of the formula (II) with piperazine under the same conditions under which the compounds of the formula (II) is reacted with the compound of the formula (III).
More particularly, the reaction between the compounds of the formula (XX) and the compound of the formula (XXI) can be carried out by one of the processes described hereinbelow depending on the definition of R3 of the compound of the formula (XXI).
i) l~hen R3 represents a lower alkanoyl group substituted with one or more halogen atoms:
In th;s case, the reaction proceeds under conventional conditions for acylation7 e.g., without any solvent or in an inert solvent such as the above-described l 15~232 1 ethers, aromatic hydrocarbons, DMSO, I)~F, HMPTA, pyridine and halogenated hydrocarbons such as chloroform, methylene chloride, etc., in the presence of the above-described deoxidizing agent at a temperature of 0 to 100C, prefer-ably at a vicinity of room temperature, for about 0.5 to 6 hours.
With respect to the proportion of the starting compounds, the compound of the formula (XXI) can be used in at least equimolar amount, preferably 1 to 2 mols per mol of the compound of the formula (XX) in the presence of solvents and in excess amounts over the equimolar amount relative to the compound of the formula (XX) in the absence of solvents.
ii) When ~3 represents a group other than the halogen substituted lower alkanoyl group:
The reaction can proceed under conventional conditions for alkylation or aralkylation without solvents or in an inert solvent using at least equimolar amount, preferably 1 to 2 mols, of the compound of the formula (XXI) per mol of the compound of the formula (XX~ at a temperature of room temperature to 150C, preferably 50 to 100C, for 1 to 10 hours. The reaction can also be carried out using the above-described deoxidizing agent.
l 1~6~32 1 Examples of su;table inert solvent include water, alcohols such as methanol, ethanol, isopropanol, butanol, amyl alcohol, isoamyl alcohol, etc., the above-described aromatic hydrocarbons, ethers, DMSO, DMF, HMPTA, etc., with DMSO, DMF and HMPTA being preferred.
Furthermore, the compound of the formula (I~ of this invention can be prepared according to the process shown in Reaction Scheme-4 below.
Re ac t i on Sch eme - 4 lRl 2 5\COCH
~XXII) (XXIII) R~ 1 Cyclization CH = C R5 \ COCH
R~
(XXIV) j~ R6 +HN N- R3 l (III) (XXV) l 1562~2 R ~ COCH
R -N N \ ~`N
\J
~Rl (XXVI) ~ COC/~ Z~
R3-N N ~ N ~ \ R6 Hydrolysis / I I
Rl (XXVII) R3-N N ~ COOH
~ ~Rl (I) 1 In the above formulae, Rl, R2, R3 and R4 have the same meaning as defined above; R5 and R6 each repre-sents a hydrogen atom or a lower alkyl group; R8 repre-sents a lower alkyl group; Y~ represents a tertiary nitrogen atom containing aromatic heterocyclic residue being bonded through the nitrogen atom or a trialkyl ammonium group; and Z~ represents an anion.
In the Reaction Scheme-4, the compounds of the formulae (XXIV), (XXV) and (XXVI) can be prepared under the same conditions as the reactions in which the compounds of the formulae (X) and (XI) are prepared and the reaction between the compound of the formula (II) and the compound of the formula ~III), respectively.
The compound of the formula (XXVII) can be prepared by reacting the compound of the formula (XXVI) with a tertiary nitrogen atom containing aromatic hetero-cyclic compound or a trialkylamine in the presence of an anion donating compound.
Examples of suitable tertiary nitrogen atom containing aromatic heterocyclic compound include pyridine, alkyl substituted pyridines such as picoline, lutidine, etc., quinoline, alkyl substituted quinolines such as quinaldine, lepidine, etc.
Examples of suitable trialkylamine include those having 1 to 6 carbon atoms, for each alkyl moiety, e.g., ll5~232 1 trimethylamine, triethylamine, tripropylamine, triiso-propylamine, etc.
Examples of suitable anion donating compound include compounds capable of releasing a halogen ion and compounds capable of releasing sulfate, phosphate, perchlorate ions, e.g., iodine, bromine, chlorine, sulfuric acid, phosphoric acid, perchloric acid, etc.
The tertiary nitrogen atom containing aromatic heterocyclic compound or the trialkylamine described above and the anion donating compound can be used in at least equimolar amount, preferably 1 to 2 mols per mol of the compound of the formula (XXVI~, respectively.
The reaction can proceed in an inert solvent such as the above-described lower alcohols, aromatic hydrocarbons, ethers, DMSO, DMF, HMPTA, pyridine, etc., at a temperature of from room temperature to 120C, preferably 50 to 100C, for about 0.5 to 6 hours. The compound of the formula ~XXVII) thus obtained can be used in the subsequent hydrolysis after isolation from the reaction mixture and purification or without isolation.
Hydrolysis of the compound of the formula ~XXVII~ can be carried out in a suitable solvent in the absence or presence of an acid or an alkali, preferably in the presence of an alkali. Examples of the alkali include alkali metal hydroxides such as sodium hydroxide, 1 15~232 1 potassium hydroxide, etc., alkaline earth metal hydroxidessuch as calcium hydroxide, etc., ammonium hydroxide or carbonates o~ these metals or ammonium.
As for the solvents the above-described lower alcohols, aromatic hydrocarbons, ethers, water, pyridine, DMF, DMS0, HMPTA, etc., can be used. The hydrolysis can also proceed in an aqueous medium in which a trialkylamine such as trimethylamine, triethylamine, etc., is present.
In the above hydrolysis, the reaction is accelerated by the addition of a lower alcohol.
The reaction proceed advantageously at a temper-ature of 20 to 150C, preferably 80 to 120C for about 0.5 to 6 hours, thus yielding the desired compound of the formula (I).
The compounds of this invention of the formula ~I) prepared as described above can form pharmaceutically acceptable salts with acids when the compound of the formula ~I) has a basic group, and this invention also includes within its scope such pharmaceutically acceptable salts. The pharmaceutically acceptable acids which can be ` ~ used for the salt formation can be various organic or inorganic acids, for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, mandelic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like.
1 15~2:32 - 3~ -1 The compounds of the formula (I) can be converted into a corresponding carboxylate by reacting the carboxylic acid with a pharmaceutically acceptable basic compound.
Examples of basic compounds are inorganic basic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, sodium hydrogen carbonate and the like and organic basic compounds such as morpholine, piperazine~ pyridine, piperidine, 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 of the reaction and purified by conventional procedures, for example, by solvent extraction, dilution, precipitation, recrystallization, column chromatography and the like.
As is apparent to those skilled in the art, thecompounds of the formula (I) can exist in optically active forms and this invention includes such optical isomers within its scope.
In using the benzo[ij]quinolizine-2-carboxylic acid compounds of this invention of the formula (I) and the salts thereof as antimicrobial agents these compounds can be formulated into pharmaceutical compositions together with ordinary pharmaceutically acceptable carriers.
Suitable carriers which can be used are, for example, dilucnLs or e.~;cil):ielltt; s~ ; fillcrs, cxten(lcrs, binders, ~et:tin~ agell~s, dis;lltc~rants, surface active agents and lubricall~s ~hich are usually cmployed to prepare such drugs dcpending on the type of dosage forms.
Various dosagc forms o the therapeutic agents as an antimicrobial agent can be sclected according to the purpose o the therapy. Typical dosage forms which can be used are tablets, pills, po~ders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, injectable preparations ~solutions, suspensions, etc.), ointments, etc.
In molding a pharmaceutical composition containing the compounds of the forrnula (I) or the pharmaceutically acceptable salt thereof as an active ingredient into a tablet form, a wide range of carriers known in the art can be used. Examples of suitable carriers include excipients ~, such as lactose, white sugar, sodium chloride, glucose solution~ urea, starch~ calcium carbonate, kaolin, crystal-line cellulose and silicic acid, binders such as water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methylcellulose, potassium phosphatc and polyvinyl pyrrolidone, disintegrants such as dried starch, sodium alginate, agaT
powder, laminaria powder, sodium hydrogen carbonate, calcium carbonate, Tween, sodium lauryl sulfate, stearic * Trade Mark 4 o 'A
1 15623~
1 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 ammoniwn 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 (trade name for a polyethylene glycol produced by Shinetsu Chemical Industry Co., Ltd.) and solid polyethylene glycol.
The table~s, 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 carTiers known in the art can be used. Examples of suitable carriers are excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oils, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaria and agar.
In molding the pharmaceutical composition into a suppository form, a wide variety of carriers known in the art can be used. Examples of suitable carriers include l 15B232 1 polyethylene glycol, cacao butter, higher alcohols, estersof higher alcohols, gelatin and semi-synthetic glycerides.
When the pharmaceutical composition is formulated into an injectable preparation, the resulting solution and suspension are preferably sterilized, and are isotonic with respect to the blood. In formulating the pharmaceutical composition into the form of a solution or suspension, all diluents customarily used in the art can be used.
Examples of suitable diluents are water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters. Sodium chloride, glucose ar glycerol may be incorporated into a therapeutic agent, e.g., as a nephritis treating agent in an amount sufficient to prepare isotonic solutions. The therapeutic agent may further contain ordinary dissolving aids, buffers, pain-alleviating agents, and preservatives, and optionally coloring agents~ perfumes, flavors, sweeteners, and other drugs.
l,~hen the pharmaceutical composition is formulated into a paste, a cream and a gel, white vaseline, paraffin, glycerol, cellulose derivatives, polyethylene glycol, silicone, etc., can be used as a diluent.
The amount of the compound of the formula (I) and the pharmaceutically acceptable salts thereof of this invention as an active ingredient to be incorporated into l 15~232 - ~3 -1 a pharmaceutical composition useful as an antimicrobial agent is not particularly limited, and can vary over a wide range. A suitable therapeutically effective amount of the compound of the general formula (I) and the pharmaceutically acceptable salts thereof of this inven-tion is usually from about 1 to about 70% by weight, preferably 5 to 50% by weight, based on the total weight of the composition.
There is no particular restriction on the manner of using the therapeutic agent and the therapeutic agent can be administered by routes suitable for the particular forms of the therapeutic agent. For example, the tablets, pills, liquid preparations, suspensions, emulsions, granules, and capsules are orally administered. The inject-able preparations are intravenously administered either alone or together with ordinary auxiliary agents such as glucose and amino acids. Furthermore, as required, the injectable preparation can be administered intramuscularly, intracutaneously, subcutaneously, or intraperitoneally.
The suppository is administered intrarectally and the ointment is coated on the skin.
The dosage of the antimicrobial agent is suitably selected according to the purpsoe of use, the symptons, 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.
l 1S~232- 44 -1 I. Antimicrobial Activ~
Test ~lethod The antimicrobial activity of the followingtest compounds on various test organisms listed below was determined by the serial dilution method on agar plate (lleart Infusion agar produced by Difco Co.) (See CHEMOTH~RAPY, 22, pp. 1126-1128 (1974))and the minimum inhibitory concentrations (mcg/mQ) obtained were determined.
A sample of each test organism was prepared so that the population of the or~anism was about 1 x 108 cells/mQ (O.D. 660 m~ = 0.13 to 0.14).
Compound of Invention Tested 1. 8-(4-Trifluoroacetyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]quinolizine-2-- carboxylic acid 2. 8-[4-(2-Trifluoroethyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid 3. 8-(4-Pentafluoropropionyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid 4. 8-~4-Pentafluorobutyryl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]-; quinolizine-2-carboxylic acid 11~6232 ~,5 5. 8-[4-(2-}-Iydroxyethyl)-l-piperazinyl~-9-fluoro-5-methyl-6,7-dihydro-l-oxo-111,5~1-benzo[ij]quinolizine-2-carboxylic acid 6. 8-[4-(4-Methoxybenzyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 7. 8-(4-Allyl-1 piperazinyl)-9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid
(1) 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (2) 8-(4-trifluoroacetyl-1-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (3) 8-(4-trifluoroacetyl-1-piperazinyl)-10-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (4) 8-(4-trichloroacetyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-; carboxylic acid (5) 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-5-ethyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij~quinolizine-2-carboxylic acid (6) 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-5-butyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (7) 8-(4-monochloroacetyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid .
1 I5~232 1 (8) 8-(4-trifluoromethanesulfonyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid (9) 8-(4-trifluoromethanesul~onyl-1-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-1~-1,5H-benzoEij]-quinolizine-2-carboxylic acid (10) 8-[4-(2,2,2-trifluoroethanesulfonyl)-1-piperazinyl~-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (11) 8-[4-(2-chloroethyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quizolizine-2-carboxylic acid (12) 8-(4-tribromoacetyl-1-piperazinyl)-9-bromo-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (13) 8-[4-(2-chlorobutyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (14) 8-(4-trifluoroacetyl-1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH~5H-benzo[ij]quinolizine-2-carboxylic acid (lS) 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic ;~ acid 1 15~2~2 1 (16) 8-(4-allyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,511-benzo[ij]quinolizine-2-carboxylic acid (17) 8-(4-crotyl-1-piperazinyl)-9-chloro-S-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (18) 8-(4-allyl-1-piperazinyl)-S-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (19~ 8-(4-allyl-1-piperazinyl)-9-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (20) 8-(4-allyl-1-piperazinyl)-9-fluoro-5-methyl-: 6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (21) 8-(4-trifluoromethyl-1-piperazinyl)-10-chloro-! S-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]quinolizine-2-carboxylic acid (22) 8-(4-trifluoromethyl-1-piperazinyl)-9-chloro-S-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]quinolizine-2-carboxylic acid : 20 (23~ 8-(4-trichloromethyl-1-piperazinyl)-9-chloro-S-methyl-6~7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (24) 8-[4-(2,2,2-trifluoroethyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,51-1-benzo[ij]-quinolizine-2-carboxylic acid ~, 1 15~232 I (25) 8-[4-(~-chlorobutyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,51-1-benzo[ij]quinolizine-2-carboxylic acid ~ 26) 8-(4-tri~luoromethyl-1-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (27) 8-(4-trifluoromethyl-1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-earboxylic acld (28) 8-[4-~2,2,2-trifluoroethyl)-1-piperazinyl]-9-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (29) 8-(4-trifluoromethyl-1-piperazinyl)-9-chloro-5-ethyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (30) 8-[4-(2-hydroxyethyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (31) 8-[4-(2-hydroxyethyl)-1-piperazinyl]-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (32) 8-[4-(2-hydroxyethyl)-1-piperazinyl]-10-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid , .
1 15~232 - l2 -1 (33) 8-[4-(2-hydroxyethyl)-1-piperazinyl]-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (34) 8-[4-(2-hydroxyethyl)-1-piperazinyl]-9-chloro-6,7-dihydro-1-oxo-lH,S~-I-benzo[ij]quinolizine-2-carboxylic acid (35) 8-[4-(2,3-dihydroxylpropyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid ~36) 8-[4-(4-hydroxybutyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (37) 8-[4-(2-propynyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid ~ 38) 8-[4-(2-propynyl)-1-piperazinyl]-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (39) 8-~4-(2-propynyl)-1-piperazinyl]-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acld (40) 8-[4-(2-propynyl)-1-piperazinyl~-9-fluoro-6,7-dihydro-l-oxo-lH,5H-benzo~ij]quinolizine-2-carboxylic acid ' :
. .
1 15~232 - :13 -1 (41) 8-[4-(1-methyl-2-propynyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,511-benzo[ij]-quinolizine-2-carboxylic acid (42) 8-[4-(2-propynyl)-1-piperazinyl]-10-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (43) 8-[4-(4-methoxybenzyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 10 (44) 8-[4-(4-methoxybenzyl)-1-piperazinyl]-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (45) 8-[4-(4-methoxybenzyl)-1-piperazinyl]-9-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (46) 8-[4-(4-methoxybenzyl)-1-piperazinyl]-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (47) 8-[4-(4-methoxybenzyl)-1-piperazinyl]-10-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]-quinolizine-2-carboxylic acid (48) 8-[4-(3,4-dimethoxybenzyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid - l4 -1 (49) 8-[4~ 3,4-dimethoxyphenethyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid (50) 8-{4-[3-(4-ethoxyphenyl)propyl]-1-piperazinyl}-9-chloro-5-methyl-6,7-dihydro-1-oxo-111,5H-benzo[ij]-quinolizine-2-carboxylic acid ~ Sl) 8-[4-~-2,3,4-trimethoxyphenethyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinollzine-2-carboxylic acid (52) 8-(4-trifluoroacetyl-1-piperazinyl)-9-bromo-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (53) 8-(4-trifluoromethyl-1-piperazinyl)-9-bromo-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (54) 8-(4-allyl-1-piperazinyl)-9-bromo-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (55) 8-(4-pentafluoropropionyl-1-piperazinyl)-5-methyl-6~7-dihydro-l-oxo-lH~5t-l-benzo[ij]quinolizine-2 carboxylic acid (56) 8-(4-heptafluorobutyryl-1-piperazinyl)-9-chloro-6,7-dihydro-1-oxo-111,5h benzo~ij]quinolizine-2-ca~rboxylic acid ' ' 1 (57) 8-(4-pentafluoropropionyl-1-piperazinyl)-10-chloro-S-metllyl-6,7-(li}ly(lro-i-oxo-111,511-benzo[ij]quinolizine-2-carboxylic acid (58) 8-(4-heptafluorobutyryl-1-piperazinyl~-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (59) 8-(4-trifluoromethanesulfonyl-1-piperazinyl)-9-chloro-6,7-dihydro-1-oxo-111,5H-benzo[ij]quinolizine-2-carboxylic acid (60) 8-(4-pentafluoropropionyl-1-piperazinyl)-9-chloro-6,7-dihydro-1-oxo-lH,51~-benzo[ij~quinolizine-2-carboxylic acid (61) 8-(4-heptafluorobutyryl-1-piperazinyl)-10-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (62) 8-(4-trifluoromethanesulfonyl-1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (63) 8-(4-trifluoromethyl-1-piperazinyl)-6,7-dihydro-~: 20 1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid `:
~ - 15 -~:
1 The compounds of this invention of the formula (I) can be prepared by various alternative procedures, for example, by reacting a benzo[ij]quinolizine-2-carboxylic acid compound of the formula ~II) tll) Rl wherein R4 represents a halogen atom, a lower alkane-- sulfonyloxy group or an arylsulfonyloxy group, and Rl and R2 have the same meaning as defined above, with a piperazine compound of the formula ~III) \ 3 HN\___/N-R (III) ;
wherein R3 has the same meaning as defined above.
The term "lower alkanesulfonyloxy" represented by R4 refers to a straight or branched alkanesulfonyloxy group having 1 to 4 carbon atoms such as a methane-sulfonyloxy group, an ethanesulfonyloxy group, a propane-;~ sulfonyloxy group, an isopropanesulfonyloxy group, a ~ butanesulfonyloxy group, a tert-butanesulfonyloxy group : and the like.
. - 16 -1 The term "arylsulonyloxy" as used herein includes a benzenesulfonyloxy group, a naphthalene-sulfonyloxy group and the like. The aryl ring included in the arylsulfonyloxy group may be substituted with one or more, and preferably from one to three, of a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, a nitro group and the like.
With respect to the compounds of the formula (Il) which can be used as the starting material for preparing the compounds of this invention represented by the formula (I), some of those in which R4 represents a halogen atom are known compounds as described in U.S.
Patents 3,917,609, 3,896,131, 3,985,882, 3,969,463, 4,001,243 and 4,014,877 and others can be easily prepared by appropriate selection of starting materials according to known processes as described in Japanese Patent Publication No. 6156/76 and U.S. Patent 4,014~877.
They can also be prepared by Reaction Scheme-2 herein-; below. On the other hand, the compounds of the formula (II) in which R4 represents a lower alkanesulfonyloxygroup or an arylsulfonyloxy group, i.e., compounds oE the formula (IIa) are novel and can be prepared, for example, -by the Reaction Scheme-l below.
;~ ~
~; , ' l 15~232 Reaction Scheme-l OH OH
R2~ ~Rl ~ `~--~0 H ~l (IV) (V) ~ R X ~VI) ~ R7X (VI) oR7 oR7 R2 ~ Reduction R2 ~
N Rl ~ N O
H H
~VIII) (VII) , COORg C2H50CH C ~cooR8 (IX) oR7 R ~ Cyclization R2 0 ;!~,COOR8 CH=C~COOR8)2 R O ~ N~
.~ (X) l J~ 1 : " ~' R
(XI) COOH
Hydrolysis > R70 ~ N') ~Rl (IIa) ' 1 l~B232 l In the Reaction Scheme-l abo~e, R7 represents a lower alkanesulfonyl group or an arylsulfonyl group; R8 repre-sents a lower alkyl group; X represents a halogen atom;
and Rl and R2 have the same meaning as defined above.
Thus, the compounds of the formula (IIa~ can be prepared by reacting a compound of the formula (IV~ with a compound of the formula (VI) to form a compound of the formula (VIII), further reacting this compound with a compound of the formula ~IX) to obtain a compound of the formula (X), and cyclizing the compound of the formula (X) to form a compound of the formula (XI), which is then subjected to hydrolysis.
Of the compounds of the formula (VIII) those in which Rl represents a hydrogen atom can also be prepared by reacting a compound of the formula (V) wi~h a compound of the formula (VI) to form a compound of the formula (VII) and reducing this compound.
In Reaction Scheme-l above, a suitable amount of the compound of the formula (VI) to be reacted with the compound of the formula (IV) is at least an approxi-mately equimolar amount. Preferably l to 2 mols of the compound of the formula (VI) are reacted per mol of the compound of the formula (IV).
The reaction proceeds usually in an inert solvent in the presence of a deoxidizing agent in an amount of at least an approximately equimolar amount, 1 15~232 l and preferably 1 to 2 mols of the deoxiclizin~ agent per mol of the compound of the formula (IV) at a temperature of about 0 to about 100C, preferably at room temperature for about 0.5 to about 6 hours, thereby yielding the compound of the formula (VIII).
Examples of suitable deoxidizing agents include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., inorganic carbonates such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydrogen carbonate, etc., tertiary amines such as pyridine, quinoline, triethylamine, etc.
Examples of suitable inert solvents include lower alcohols such as methanol, ethanol, isopropanol, etc., ethers such as dioxane, tetrahydrofuran (THF), diglyme, etc., aromatic hydrocarbons such as benzene, toluene, etc., dimethyl sulfoxide ~DMSO), dimethylformamide (DMF~, hexamethylphosphoric triamide (HMPTA), pyridine, etc.
More particularly~ in Reaction Scheme-l, the reaction between the compound of the formula tVIII~ and the compound of the formula (IX) can be effected in the absence of solvents or in the presence of solvents such as the above-described lower alcohols, DMF, DMSO, and HMPTA and acetonitrile and the like. Preferably the reaction is conducted in the absence of solvents.
2~2 - Zl -1 The compound of the formula ~IX) can be used in excess amounts over the equimolar amount relative to the compounds of the formula (VIII), preferably in an equimolar amount in the absence of solvents and in an amount of from about 1.1 to 1.5 mols per mol of the compound of the formula (VIII) in the presence of solvents.
The reaction can generally be carried out at a temperature of from room temperature (from about 15 to 30C) to about 150C, and preferably from 100 to 130C, for a period of from about 0.5 to about 6 hours thereby easily yielding the compound represented by the formula (X).
The subsequent cyclization reaction of the thus-obtained compound of the formula (X) can be effected in accordance with conventional cyclization reactions, for example, by heating the compound of the formula (X) or by using an acidic substance such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, polyphosphoric acid and the like. When the cyclization is effected by heating, it is preferred to heat the compound of the formula (X) in a solvent such as high boiling point hydrocarbons or high boiling point ethers, for example, diphenyl ether tetraphosphoric acid, diethylene glycol dimethyl ether, etc., at a temperature of from about 100 to about 250C, and preferably from 150 to 200C for a period of from l 1S~232 1 about 0.5 to about 6 hours. lYhen the cyclization iseffected using an acidic substance, the cyclization can be conducted in the presence of the acid substance in an approximately equimolar amount to a large excess amount, preferably 10 to 20 molar excess acid, relative to the amount of the compound of the formula (X) at a temperature of about 100 to about 150C for a period of about 0.5 to about 6 hours, whereby the desired compounds of the formula (XI) can be produced advantageously.
In the above Reaction Scheme-l, the hydrolysis of the compound of the formula (XI) into the compound of the formula (IIa) can be achieved by a conventional hydrolysis procedure in the presence of a typical hydrolyzation catalyst, for example, a basic compound such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, or an inorganic acid such as sulfuric acid, hydrochloric acid, nitric acid and the like or organic acid such as acetic acid, an aromatic sulfonic acid and the like. The hydrolysis can be carried out in a solvent such as water, the above-described alcohols, ethers, and ketones such as acetone, methyl ethyl ketone, dioxane, ethylene glycol, etc., and acetic acid and the like at a temperature of from room tempera-ture to about 200C, preferably 5Q to 150C for a period of about 0.5 to about 6 hours, thereby easily yielding the compound represented by the formula ~IIa).
1 l~B2~2 1 The reaction between the compound of the formula (V) and the compounds of the formula ~VI) can be conducted in the same manner as the reaction of the compound of the formula (lV) with ~he compound of the formula (VI), thus yielding a compound of the formula (VII).
In Reaction Scheme-l above, the reduction of the compounds of the formula (VII) can be conducted catalytically or using a conventional hydrogenating agent such as a combination of sodium borohydride or lithium aluminum hydride and a lower fatty acid, e.g., acetic acid, trifluoroacetic acid, propionic acid, etc.
Suitable amounts of sodium borohydride or lithium aluminum hydride and the lower fatty acid are from an approximately equimolar amount to a large excess amount, preferably from 3 to 5 mols per mol of the ; compound of the formula (VII).
The reduction reaction using a hydrogenating agent can proceed advantageously in an inert solvent such as the above-described ethers, aromatic hydrocarbons, lower fatty acids, e.g., acetic acid, trifluoroacetic acid, propionic acid, etc., at a temperature of from room temperature to about 100C, preferably from 50 to 100C for about 1 to about 6 hours, thus yielding the compound of the formula ~VIII) in which Rl represents a hydrogen atom.
1 15~232 Reaction Scheme-2 Nitration X ~ R
(XIII) ~ Reduction N~12 ~ of Nitro Group X~'~Rl Reduction ~XIV) \ Reduction of \ Pyridine Replacement of \ing Amino Group by ~
Halogen NH2 X ~ H
N Rl (XVII~
~XV) ~`. Reduction of /Replacement of Pyridine Ring / Amino by Halogen ~ X \ / k/
X~ R
H
(XVI~
(XVI ) ~COOR8 ~ C2H50CHsC~ 8 ~IX) X O
X~ X~COOR8 lRl Cyclization J~N~J
CH=C (COOR8) 2 U~R1 ~XVI I I ) (XIX3 O
, l ~ ~COOH
Hydro ly s i s ~ R
(I Ib) ,: j .~ ;::
,:
~ ~, .
~`
l 156232 1 In the above formulae, R-, R8 and X have the same meaning as defined above.
In the Reac~ion Scheme-2 above, nitration of the compound of the formula (XII) can proceed under conven-tional conditions for nitration of aromatic compounds, e.g., in the absence of solvents or in the presence of a suitable inert solvent using a nitration agent.
Suitable examples of the inert solvent include acetic acid, acetic anhydride, concentrated sulfuric acid, etc.
Suitable examples of nitration agent include fuming nitric acid, concentrated nitric acid, a mixed acid (a mixture of nitric acid and sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride), alkali metal nitrates such as potassium nitrate and sodium nitrate, and sulfuric acid, etc.
The reaction proceeds advantageously in the presence of at least equimolar amount, preferably excess ; amount, of the nitration agent with respect to the 2Q starting compound at a temperature of preferably O to 15C for 1 to 4 hours.
Reduction of the nitro group of the compound of the formula (XIII) obtained in the above nitration can be conducted in an inert solvent in the presence of a reducing agent such as a mixture of iron, zinc, tin, 1 1 5B2~
1 stannous chloride and an acid (e.g., hydrochloric acidand sulfuric acid) or a mixture of iron, iron sulfite, zinc or tin and hydroxide, sulfate, sulfite, etc., of an alkali metal. Alternatively, the reduction can he carried out catalytically using a reducing catalyst such as palladium on carbon in an inert solvent.
~ xamples of suitable inert solvents include water, acetic acid, methanol, ethanol, dioxane, etc.
The conditions under which the above reduction of nitro group is carried out can be suitably selected.
For example, the reduction using a mixture of stannous chloride and hydrochloric acid as a reducing agent can proceed advantageously at a temperature of from 70 to lOO~C for from 0.5 to 1 hour using at least equimolar amount, and preferably from 1 to 2 mols of the reducing agent per mol of the starting compound. When the reduc-tion is carried out catalytically, it can proceed advanta-geously at room temperature for from 0.5 to several hours.
The amino group of the compound of the formula (XIV) thus obtained can be replaced by halogen by the application of the Sandmeyer reaction involving diazota-tion. Diazotation of the compound of the formula (XIV) can proceed advantageously in a solvent such as water, hydrochloric acid, sulfuric acid, etc., in the presence of a diazotation agent such as a mixture of sodium sulfite - 2~ -1 or potassium nitrite and hydrochloric acid or sulfuricacid at a temperature of -30C to room temperature for 0.5 to 2 hours. Subsequently, the diazonium salt of the compound of the formula (XV) thus obtained, without isolation, can be reacted, with a halogenating agent such as cuprous chloride, cuprous bromide, etc., in an amount of at least equimolar amount, preferably 1 to 2 mols of the halogenating agent per mol of the starting compound at a temperature of 0 to 50C for 0.5 to 2 hours to form a compound of the formula (XV).
Reduction of the pyridine ring of the compound of the formula (XV) can be carried out catalytically in an inert solvent such as dioxane, tetrahydrofuran, acetic acid, water, etc., under acidic condition using various acids capable of forming a quinolinium salt such as acetic acid, hydrochloric acid, sulfuric acid, etc., in the presence of a catalytic reduction agent such as platinum-carbon, palladium-carbon, r~odi~ll-carbon, ruthenium-carbon, etc., at a temperature of room temperature to 50C for 1 to 10 hours, thus yielding a compound of the formula (XVI).
Alternatively, the compound of the formula ~XVI~
can also be prepared by reducing the pyridine ring of the compound of the formula (XIV) to form a compound of the formula (XVII) and then replacing the amino group of the compound of the formula (XVII) by halogen atoms. The l 156232 1 reduction of the pyridine ring of the compound of the formula ~XIV) can be carried out in the same manner as the reduction of the pyridine ring of the compound of the formula (XV). Also, The replacement of the amino group of the compound of the formula (XVII) by a halogen atom can be conducted in the same manner as the replacement of the amino group of the compound of the formula (XIV) by a halogen atom.
~urther, the compound of the formula (XVII) can be prepared by reducing the compound of the formula (XIII) in the same manner as the reduction of the pyridine ring of the compound of the formula (XIV).
Reaction between the compound of the formula (XVI) thus-obtained and the compound of the formula (IX) can be carried out under the same conditions as the reac-tion between the compound of the formula (VIII) and that of the formula (IX).
Cyclization of the compound (XVIII) which is formed in the above reaction and hydrolysis of the cyclized compound of the formula (XIX) can proceed in the same manner as the cyclization of the compound of the formula (X) and the hydrolysis o the compound of the formula ~XI), respectively, thus yielding the compound of the formula (IIb).
1 Some of the compounds of the formula (III), another starting compound used in this invention, are known compounds and others can be prepared with ease according to known processes.
In the reaction between the compound of theformula (II) and the compound of the formula (III) in the Reaction Scheme-l the proportion of the latter to the former is usually at least equimolar, and preferably from 1 to 5 mols of the latter per mol of the former, and the reaction can generally proceed in an inert solvent such as water, the above-described lower alcohols, aromatic hydrocarbons, ethers, DMSO, DMF, HMPTA, etc., with DMSO, DMF and HMPTA being preferred. In the reaction, the above-described deoxidizing agent can be used.
The reaction can proceed advantageously at a pressure of from 1 to 20 atms, and preferably from 1 to 10 atms, and at a temperature of 100 to 250C, and prefer-ably from 140 to 2Q0C, for from 5 to 20 hours, thus yielding the compound of the formula (I) of this invention.
Further, the compound of the formula (I) of this invention can be prepared by reacting a compound of the formula (XX) with a compound of the formula (XXI) in the presence of the above-described deoxidizing agent as shown in Reaction Scheme-3 below.
_eaction Scheme-3 ~ COOH ~ COOH
HN N ~ N~ R3N N ~ N
~Rl ~R
(XX) (XXI) (I~
In the above formulae, Rl, R2, R3 and X have the same meaning as defined above.
The compounds of the formula (XX) used in the above reaction are novel compounds and can be prepared, for example, by reacting a compound of the formula (II) with piperazine under the same conditions under which the compounds of the formula (II) is reacted with the compound of the formula (III).
More particularly, the reaction between the compounds of the formula (XX) and the compound of the formula (XXI) can be carried out by one of the processes described hereinbelow depending on the definition of R3 of the compound of the formula (XXI).
i) l~hen R3 represents a lower alkanoyl group substituted with one or more halogen atoms:
In th;s case, the reaction proceeds under conventional conditions for acylation7 e.g., without any solvent or in an inert solvent such as the above-described l 15~232 1 ethers, aromatic hydrocarbons, DMSO, I)~F, HMPTA, pyridine and halogenated hydrocarbons such as chloroform, methylene chloride, etc., in the presence of the above-described deoxidizing agent at a temperature of 0 to 100C, prefer-ably at a vicinity of room temperature, for about 0.5 to 6 hours.
With respect to the proportion of the starting compounds, the compound of the formula (XXI) can be used in at least equimolar amount, preferably 1 to 2 mols per mol of the compound of the formula (XX) in the presence of solvents and in excess amounts over the equimolar amount relative to the compound of the formula (XX) in the absence of solvents.
ii) When ~3 represents a group other than the halogen substituted lower alkanoyl group:
The reaction can proceed under conventional conditions for alkylation or aralkylation without solvents or in an inert solvent using at least equimolar amount, preferably 1 to 2 mols, of the compound of the formula (XXI) per mol of the compound of the formula (XX~ at a temperature of room temperature to 150C, preferably 50 to 100C, for 1 to 10 hours. The reaction can also be carried out using the above-described deoxidizing agent.
l 1~6~32 1 Examples of su;table inert solvent include water, alcohols such as methanol, ethanol, isopropanol, butanol, amyl alcohol, isoamyl alcohol, etc., the above-described aromatic hydrocarbons, ethers, DMSO, DMF, HMPTA, etc., with DMSO, DMF and HMPTA being preferred.
Furthermore, the compound of the formula (I~ of this invention can be prepared according to the process shown in Reaction Scheme-4 below.
Re ac t i on Sch eme - 4 lRl 2 5\COCH
~XXII) (XXIII) R~ 1 Cyclization CH = C R5 \ COCH
R~
(XXIV) j~ R6 +HN N- R3 l (III) (XXV) l 1562~2 R ~ COCH
R -N N \ ~`N
\J
~Rl (XXVI) ~ COC/~ Z~
R3-N N ~ N ~ \ R6 Hydrolysis / I I
Rl (XXVII) R3-N N ~ COOH
~ ~Rl (I) 1 In the above formulae, Rl, R2, R3 and R4 have the same meaning as defined above; R5 and R6 each repre-sents a hydrogen atom or a lower alkyl group; R8 repre-sents a lower alkyl group; Y~ represents a tertiary nitrogen atom containing aromatic heterocyclic residue being bonded through the nitrogen atom or a trialkyl ammonium group; and Z~ represents an anion.
In the Reaction Scheme-4, the compounds of the formulae (XXIV), (XXV) and (XXVI) can be prepared under the same conditions as the reactions in which the compounds of the formulae (X) and (XI) are prepared and the reaction between the compound of the formula (II) and the compound of the formula ~III), respectively.
The compound of the formula (XXVII) can be prepared by reacting the compound of the formula (XXVI) with a tertiary nitrogen atom containing aromatic hetero-cyclic compound or a trialkylamine in the presence of an anion donating compound.
Examples of suitable tertiary nitrogen atom containing aromatic heterocyclic compound include pyridine, alkyl substituted pyridines such as picoline, lutidine, etc., quinoline, alkyl substituted quinolines such as quinaldine, lepidine, etc.
Examples of suitable trialkylamine include those having 1 to 6 carbon atoms, for each alkyl moiety, e.g., ll5~232 1 trimethylamine, triethylamine, tripropylamine, triiso-propylamine, etc.
Examples of suitable anion donating compound include compounds capable of releasing a halogen ion and compounds capable of releasing sulfate, phosphate, perchlorate ions, e.g., iodine, bromine, chlorine, sulfuric acid, phosphoric acid, perchloric acid, etc.
The tertiary nitrogen atom containing aromatic heterocyclic compound or the trialkylamine described above and the anion donating compound can be used in at least equimolar amount, preferably 1 to 2 mols per mol of the compound of the formula (XXVI~, respectively.
The reaction can proceed in an inert solvent such as the above-described lower alcohols, aromatic hydrocarbons, ethers, DMSO, DMF, HMPTA, pyridine, etc., at a temperature of from room temperature to 120C, preferably 50 to 100C, for about 0.5 to 6 hours. The compound of the formula ~XXVII) thus obtained can be used in the subsequent hydrolysis after isolation from the reaction mixture and purification or without isolation.
Hydrolysis of the compound of the formula ~XXVII~ can be carried out in a suitable solvent in the absence or presence of an acid or an alkali, preferably in the presence of an alkali. Examples of the alkali include alkali metal hydroxides such as sodium hydroxide, 1 15~232 1 potassium hydroxide, etc., alkaline earth metal hydroxidessuch as calcium hydroxide, etc., ammonium hydroxide or carbonates o~ these metals or ammonium.
As for the solvents the above-described lower alcohols, aromatic hydrocarbons, ethers, water, pyridine, DMF, DMS0, HMPTA, etc., can be used. The hydrolysis can also proceed in an aqueous medium in which a trialkylamine such as trimethylamine, triethylamine, etc., is present.
In the above hydrolysis, the reaction is accelerated by the addition of a lower alcohol.
The reaction proceed advantageously at a temper-ature of 20 to 150C, preferably 80 to 120C for about 0.5 to 6 hours, thus yielding the desired compound of the formula (I).
The compounds of this invention of the formula ~I) prepared as described above can form pharmaceutically acceptable salts with acids when the compound of the formula ~I) has a basic group, and this invention also includes within its scope such pharmaceutically acceptable salts. The pharmaceutically acceptable acids which can be ` ~ used for the salt formation can be various organic or inorganic acids, for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, mandelic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like.
1 15~2:32 - 3~ -1 The compounds of the formula (I) can be converted into a corresponding carboxylate by reacting the carboxylic acid with a pharmaceutically acceptable basic compound.
Examples of basic compounds are inorganic basic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, sodium hydrogen carbonate and the like and organic basic compounds such as morpholine, piperazine~ pyridine, piperidine, 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 of the reaction and purified by conventional procedures, for example, by solvent extraction, dilution, precipitation, recrystallization, column chromatography and the like.
As is apparent to those skilled in the art, thecompounds of the formula (I) can exist in optically active forms and this invention includes such optical isomers within its scope.
In using the benzo[ij]quinolizine-2-carboxylic acid compounds of this invention of the formula (I) and the salts thereof as antimicrobial agents these compounds can be formulated into pharmaceutical compositions together with ordinary pharmaceutically acceptable carriers.
Suitable carriers which can be used are, for example, dilucnLs or e.~;cil):ielltt; s~ ; fillcrs, cxten(lcrs, binders, ~et:tin~ agell~s, dis;lltc~rants, surface active agents and lubricall~s ~hich are usually cmployed to prepare such drugs dcpending on the type of dosage forms.
Various dosagc forms o the therapeutic agents as an antimicrobial agent can be sclected according to the purpose o the therapy. Typical dosage forms which can be used are tablets, pills, po~ders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, injectable preparations ~solutions, suspensions, etc.), ointments, etc.
In molding a pharmaceutical composition containing the compounds of the forrnula (I) or the pharmaceutically acceptable salt thereof as an active ingredient into a tablet form, a wide range of carriers known in the art can be used. Examples of suitable carriers include excipients ~, such as lactose, white sugar, sodium chloride, glucose solution~ urea, starch~ calcium carbonate, kaolin, crystal-line cellulose and silicic acid, binders such as water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methylcellulose, potassium phosphatc and polyvinyl pyrrolidone, disintegrants such as dried starch, sodium alginate, agaT
powder, laminaria powder, sodium hydrogen carbonate, calcium carbonate, Tween, sodium lauryl sulfate, stearic * Trade Mark 4 o 'A
1 15623~
1 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 ammoniwn 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 (trade name for a polyethylene glycol produced by Shinetsu Chemical Industry Co., Ltd.) and solid polyethylene glycol.
The table~s, 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 carTiers known in the art can be used. Examples of suitable carriers are excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oils, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaria and agar.
In molding the pharmaceutical composition into a suppository form, a wide variety of carriers known in the art can be used. Examples of suitable carriers include l 15B232 1 polyethylene glycol, cacao butter, higher alcohols, estersof higher alcohols, gelatin and semi-synthetic glycerides.
When the pharmaceutical composition is formulated into an injectable preparation, the resulting solution and suspension are preferably sterilized, and are isotonic with respect to the blood. In formulating the pharmaceutical composition into the form of a solution or suspension, all diluents customarily used in the art can be used.
Examples of suitable diluents are water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters. Sodium chloride, glucose ar glycerol may be incorporated into a therapeutic agent, e.g., as a nephritis treating agent in an amount sufficient to prepare isotonic solutions. The therapeutic agent may further contain ordinary dissolving aids, buffers, pain-alleviating agents, and preservatives, and optionally coloring agents~ perfumes, flavors, sweeteners, and other drugs.
l,~hen the pharmaceutical composition is formulated into a paste, a cream and a gel, white vaseline, paraffin, glycerol, cellulose derivatives, polyethylene glycol, silicone, etc., can be used as a diluent.
The amount of the compound of the formula (I) and the pharmaceutically acceptable salts thereof of this invention as an active ingredient to be incorporated into l 15~232 - ~3 -1 a pharmaceutical composition useful as an antimicrobial agent is not particularly limited, and can vary over a wide range. A suitable therapeutically effective amount of the compound of the general formula (I) and the pharmaceutically acceptable salts thereof of this inven-tion is usually from about 1 to about 70% by weight, preferably 5 to 50% by weight, based on the total weight of the composition.
There is no particular restriction on the manner of using the therapeutic agent and the therapeutic agent can be administered by routes suitable for the particular forms of the therapeutic agent. For example, the tablets, pills, liquid preparations, suspensions, emulsions, granules, and capsules are orally administered. The inject-able preparations are intravenously administered either alone or together with ordinary auxiliary agents such as glucose and amino acids. Furthermore, as required, the injectable preparation can be administered intramuscularly, intracutaneously, subcutaneously, or intraperitoneally.
The suppository is administered intrarectally and the ointment is coated on the skin.
The dosage of the antimicrobial agent is suitably selected according to the purpsoe of use, the symptons, 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.
l 1S~232- 44 -1 I. Antimicrobial Activ~
Test ~lethod The antimicrobial activity of the followingtest compounds on various test organisms listed below was determined by the serial dilution method on agar plate (lleart Infusion agar produced by Difco Co.) (See CHEMOTH~RAPY, 22, pp. 1126-1128 (1974))and the minimum inhibitory concentrations (mcg/mQ) obtained were determined.
A sample of each test organism was prepared so that the population of the or~anism was about 1 x 108 cells/mQ (O.D. 660 m~ = 0.13 to 0.14).
Compound of Invention Tested 1. 8-(4-Trifluoroacetyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]quinolizine-2-- carboxylic acid 2. 8-[4-(2-Trifluoroethyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid 3. 8-(4-Pentafluoropropionyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid 4. 8-~4-Pentafluorobutyryl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]-; quinolizine-2-carboxylic acid 11~6232 ~,5 5. 8-[4-(2-}-Iydroxyethyl)-l-piperazinyl~-9-fluoro-5-methyl-6,7-dihydro-l-oxo-111,5~1-benzo[ij]quinolizine-2-carboxylic acid 6. 8-[4-(4-Methoxybenzyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 7. 8-(4-Allyl-1 piperazinyl)-9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid
8. 8-[4-(2-Propynyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,SH-benzo[ij]quinolizine-2-carboxylic acid Comparison Compounds A. l-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridene-3-carboxylic acid (nalidixic acid) B. 9-Fluoro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (flumequine) Microorganisms Tested S.a Staphylococcus aureus FDA 209 P
S.p Streptococcus pyogenes IID S-23 E.c Bscherichia coli NHHJ JC-2 (IFO 12734) K.p Klebsiella pneumoniae P.r Proteus rettgeri NIH 96 S.t Salmonella typhi 0-9Ol (NCTC 8393) S.s Shigella sonnei FW 33 - 46 ~
l S.m Serrat _ marcescens IFO 12648 P al Pseudomonas aeruginosa E-2 .
P.a2 Pseudomonas aeruginosa NCTC 10490 P a3 Pseudomonas aeruginosa ATCC 10145 The results obtained are shown in Table 1 below.
i O
~o ~ ~ ~
cd u~ ~ ~ O
. ,i o ~ ~ ~ ~ ~ C~
~1~ A ~I
C`~
r 1 --I ~ ~ N U~. . g Pl ~ ~o ~O
~ U~
t~ ~i ~i 0 0 0 ~ 1 ~ O
~ ~n ~ o~ ao co a~
~1 . ~
~ ~ tn Oooooooo~o ~ .
-~ ~
~3 C,) ~ U~ o o o o o o o o ~ o O E~
~ ~ _i O O OO O O O ~1 O
E-~ ~
~ ~ ~ c~ o ooooa) oo co ~ o o o o o o o o ~ o O~ CA ~ C~000~ 'D
r~ ,I cO
~ ~ o o o o o o o _i ~ o : u~ ~D u~ ~ ~ ~ ~
~ c~ O a ~ ~ V~
~ ~ ~ o~o~ X
d U~ ~ o ~i ~ o o o o o c --I ~ ~ ~;r u~ ~ r~ co 'C
C~
11~6232 1 From the results shown in Table 1 above it can be seen that the compound of this invention exhibited potent antibacterial activity as compared with nalidixic acid and flumequine.
II. Acute Toxicity The acute toxicity of the compounds of this invention having the formula (I) was determined by intravenous administration (i.v.) in mice which had not been fed for 12 hours prior to the test. LD50 values ~50% lethal dose) obtained for all the compounds were at least 500 mg/kg.
The present invention is further illustrated by the following Reference Examples, Examples and Preparation Examples, but they are not to be construed as limiting the scope of this invention. Unless otherwise indicated, all parts, percents and ratios are by weight.
Unless otherwise indicated, Elemental Analysis was carried out at a temperature of 70 to 80C at reduced pressure (1 to 2 mmHg) for 6 hours using P2O5 as a dessicant.
REFERENCE EXAMPLE
5-Hydroxy-3,4-dihydrocarbostyril ~10 g) was added to 100 mQ of methanol having dissolved therein 3.8 g of potassium hydroxide and the mixture was stirred at room temperature for 30 minutes followed by removing methanol 1 15~23~
1 under reduced pressure. Benzene was added to the residue to form crystals and then benzene was removed by distilla-tion. ~he residue thus obtained was suspended in 50 mQ
of dimethylformamide and 10.6 g of methanesulfonyl chloride was added dropwise to the suspension while ice-cooling with stirring. After adding 3.5 g of methanesulfonyl chloride and resulting mixture was stirred at room temper-ature for 4 hours. After the completion of the reaction the solvent was removed under reduced pressure and the residue was purified through silica gel column chromatog-raphy ~silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform). Recrystal-lization of the eluate from water-containing ethanol gave 5.7 g of S-methanesulfonyloxy-3,4-dihydrocarbostyril as colorless prismatic crystals having a melting point of 227 to 231C.
In an analogous manner as in Reference Example 1, 5-(p-toluenesulfonyloxy)-3,4-dihydrocarbos~yril having a melting point of 215 to 216C was obtained.
5-Methanesulfonyloxy-3,4-dihydrocarbostyril ~4.5 g~ was suspended in 90 mQ of dioxane and 35 g of NaB~4 was added to the suspension. Then, 5.3 mQ of acetic acid was added dropwise to the mixture. After heat-1 1 5~232 l 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. Ihe residue was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.;
eluent: chloroform) and the eluate thus obtained was crystallized from petroleum ether. Recrystallization of the crystals thus obtained from ~ethanol gave 1.9 g of 5-methanesulfonyloxy-1,2,3,4-tetrahydroquinoline as color-less prisms having a melting point of 74 to 76C.
In an analogous manner as in Reference Example 3, 5-(p-toluenesulfonyloxy)-1,2,3,4-tetrahydroquinoline having a melting point of 112 to 113C was obtained.
Ethyl ethoxymethylenemalonate (21.6 g) was added to 22.4 g of 5-methanesulfonyloxy-1,2,3,4-tetrahydro-quinoline and 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 1 l~B23X
1 pl-osphoric acid and 120 g of phosphorus pentoxide was added to the mixture and the mixture was allowed to react on an oil bath at 140C for 45 minutes. After completion of the reaction, the mixture was allowed to cool to room temperature and poured into 400 mQ 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 solution was treated with activated carbon while hot and filtered.
The filtrate was allowed to cool and adjusted to a pH of 2 to precipitate crystals which were filtered. Recrystal-lization of the crude crystals thus obtained from dimethyl-formamide gave 21.3 g of 8-methanesulfonyloxy-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 270 to 275C.
In an analogous manner as in Reference Example 5, 8-(p-toluenesulfonyloxy-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid having a melting point of 300C or more was obtained.
8-Chloro-6,7-dihydro-l-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid (19.2 g) and 35.5 g of 1 15~232 1 anhydrous piperazine were added to 350 m~ of anhydrous dimethyl sulfoxide and the mixture was heated on an oil bath at 170 to 180C for 6 hours while 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 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-soluble materials, the aqueous alkali solution layer was allowed to stand to precipitate crystals which were filtered. The crude crystals thus obtained were dissolved in 10 mQ of a 10% aqueous sodium hydroxide solution and the solution was treated with activated carbon and adjusted to a pH of 8 with a 10%
aqueous hydrochloric acid solution to precipitate crystals which were filtered and washed with water sufficiently. Recrystallization of the crystals from 20 dimethylformamide gave 6.5 g of 8-(1-piperazinyl)-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 267 to 268C.
8-(1-Piperazinyl)-6,7-dihydro-1-oxo-lH,SH-benzo-; [ij]quinolizine-2-carboxylic acid (6.4 g) thus obtained was suspended in 50 mQ of water and 15 mQ of a 10% aqueous 1 15~232 1 hydrochloric acid solution was added to the resulting solution. After removing the insoluble materials by filtration, water was distilled off to obtain 5.7 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid hydrochloride as white amorphous crystals having a melting point of 300C or more.
In an analogous manner as in Reference Example 7, the following compounds were obtained:
Reference Example 8 8-(1-Piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]quinolizine-2-carboxylic acid as colorless needles having a melting point of 264 to 265C.
Reference Example 9 8-(1-Piperazinyl)-9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 246 to 247C.
Reference Example 10 8-(1-Piperazinyl)-10-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride as white amorphous crystals having a melting point of 300C or more.
Reference Example 11 8-~1-Piperazinyl~-9-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride - 5~ -1 as white amorphous crystals having a melting point of 300C
or more.
6-Chloroquinaldine (11 g) was dissolved in 15 mQ
of concentrated sulfuric acid and the solution was ice-cooled. Then, a solution of 7.1 g of potassium nitrate dissolved in 20 mQ of concentrated sulfuric acid was added to the solution dropwise, during which operation the reaction temperature was maintained at 10C or less.
After completion of addition the mixture was agitated at the same temperature as above for 1 hour and then poured onto 200 g of ice. Subsequently, the mixture was rendered alkaline with 10% sodium hydroxide taking care that the internal temperature should not be raised to above 20C, thus forming pale yellow precipitates. The precipitates were collected by filtration, washed with water and recrystallized from ethanol to obtain 12.3 g of 5-nitro-6-chloroquinaldine as pale yellow rhombic crystals having a melting point of 123 to 124C.
To 50 m~ of concentrated hydrochloric acid having dissolved therein 25 g of stannous chloride was added 6.7 g of 5-nitro-6-chloroquinaldine and the mixture was allowed to react on a water bath at a temperature of ; 80 to 90C for 30 minutes. The reaction mixture was ice-.
1 1 5~23~
1 coole~ el~lele(l .~ e (~ll l.0) ~ith 30% sodium hydroxicle alld fi.ltercd ~lnd extractcd t~;tll 500 mQ o~
chl~lc-~orm all~ (`elite (di~tomaccous earth). After drying over ~Inhydrous sodium sulfatc the chloroform fraction ~;as concelltIatcd and recrystalli.zed from a m;xture of bcnzclle and hexclne to obt~lin 4.5 g of 5-amino-~-chloro-~uinaldine as colorless plates having a melting poin~ of 196 to 197C.
~EFERE~IC~ E~ArlPLE 14 5-~mino-6-chloroqui.naldine (~ g) was dissolved in 40 mQ of concentrated hydrochloric acid and the resulting solution was cooled with ice. Then, a solution of 2.1 g of sodium nitrite dissolved in 5 mQ of water was added thereto drop~ise while ice-cooling. After continuing the reaction at the same temperature as above, the reaction mixture was added to a solution of 7 g of cuprous chloride dissolved in 15 mQ of concentrated hydrochloric acid and the resulting mixture was allowed to react on a water bath at a temperature of 50C for 1 2~ hour, during which time vigorous formation of nitrogen gas was observed. Subsequently, the reaction mixture was cooled, rendered alkaline with 30% sodium hydroxide, ancl filtered and extracted using 300 mQ of chloroform and Celite (diatomaceous earth). After drying over anhydrous sodium sulfatc the chloro-form fraction was concentrated * Trade Mark 55 A
1 15~232 1 and recrystallized from a mixture of isopropanol and water to give 3.5 g of 5,6-dichloroquinaldine as white needles having a melting point of 84 to 85C.
REFERENCE EXAMPLE l 5 5,6-Dichloroquinaldine (5 . 5 g) was dissolved in 50 mQ of acetic acid and 0.1 g of 5% platinum-carbon was added to the solution, which was then subjected to Parr's llydrogenationr.lethod to reduce thc compound catalytically at a hydrogen gas pressure of 4 kg/cm . After theoretical amount of hydrogen was absorbed the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After rendering it alkaline with 50 mQ of water and 20% sodium hydroxide, the residue was extracted with 100 mQ of chloroform. The extract was dried by the addition of anhydrous potassium carbonate and concentrated to give 4.4 g of 5,6-dichloro-1,2,3,4-tetrahydroquinaldine as oily product.
NMR analysis data ~ln CDC~3) a: 1.23 (d, 3H, J=6Hz), 1.7 (m, 2H), 2.72 (m, 2H), 3.28 (m, lH), 3.75 (m, lH), 6.62 (q, 2H, J=9Hz) A mixture of 3.2 g of 5,6-dichloro-1,2,3,4-;~ tetrahydroquinaldine and 3.2 g of diethyl ethoxymethylene-f~ malonate was allowed to react by heating at 160C for 30 minutes. Then, 13 g of polyphosphoric acid prepared from ;:
~ - 56 -:
,. . .
1 15~23~
1 6.5 g of phosphorus pentoxide and 6.5 g of phosphoric acid was added to the mixture and the resulting mixture was allowed to react by heating at 140 to 150C for 1 hour. After completion of the reaction, the mixture was poured onto 100 g of ice, followed by rendering the mixture to pH 4 to 5 with a 40~ aqueous sodium hydroxide solution to precipitate crystals. The crystals were collected by filtration, dried and mixed with 50 mQ of a 10% aqueous sodium hydroxide solution. The mixture was allowed to react at 100 to 110C for 1 hour. After cool-ing, the reaction mixture was rendered acidic with concentrated hydrochloric acid to precipitate crystals.
Recrystallization of the crystals thus obtained from ethanol gave 2.3 g of 8,9-dichloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid having a melting point of 269 to 271C.
~ lexamethylphosphoryl triamide (20 mQ) was added to a mixture of 3 g of 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo~ij]quinolizine-2-carboxylic acid and 5 g of anhydrous piperazine and the mixture was heated with stirring at 150 to 160C for 3 hours. After the completion of the reaction, the solvent was removed there-from under reduced pressure and the residue was washed ~ with 10 mQ of ethyl acetate. The crystals obtained were .~
1 dissolved in 100 mQ of water and the solution was adjusted to pH 4 with acetic acid. Insoluble substances were removed by filtration and the filtrate was treated with activated carbon. The aqueous solution thus obtained was concentrated under reduced pressure and the residue was recrystallized from a mixture of isopropanol and water to give 1.8 g of 8-(1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride having a melting point of 300C or more.
The hydrochloride salt was dissolved in water with adding a 2% aqueous sodium hydroxide solution and adjusted to pH 9 with lN hydrochloric acid to obtain white crystals having a melting poir.t of 246 to 247C.
EXAMPLE
A mixture of 2.5 g of 8-~1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid and S0 mQ of trifluoroacetic anhydride was heated under reflux for 3 hours. After completion of heating, excessive trifluoroacetic anhydride was distilled off under reduced pressure and 50 mQ of water was added to the residue followed by stirring to precipitate white crystals. Recrystallization of the crystals from dimethylformamide gave 2.3 g of 8-(4-trifluoroacetyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 1 15~232 l as white rhombic crystals having a melting point of 300Cor more.
Elemental Analysis for C2UHlgCQF3N3O4 (molecular weight:
457.5) C H N
Calc'd (%): 52.31 4.11 9.22 Found (%): 52.464.15 9.18 A mixture of 1 g of 8-(l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij~quinolizine-2-carboxylic acid, 15 mQ of dimethylformamide, 1.2 mQ of 2,2,2-trifluoroethyl iodide and 2 mQ of triethylamine was ! heated at 80C for 5 hours. After cooling, insoluble substances were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was mixed with 30 mQ of water and insoluble substances were removed by filtration. After concentrating it under reduced pressure, the filtrate was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.;
eluent chloroform-methanol (9:1 by volume)) to obtain 0.5 g of 8-[4-~2,2,2-trifluoroethyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid-iodide-monohydrate as white ~- rhombic crystals having a melting point of 298 to 299C.
1 15~23~
EXAMPL~ 3 1 A mixture of 0.8 g of 8-(1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine hydrochloride monohydrate, 0.4 mQ of propargyl bromide, ~.8 mQ of triethylamine and 10 mQ of dimethyl-formamide was allowed to react by heating at 90C for 5 hours. After completion of the reaction insoluble substances were removed by filtration. After concentra-tion under reduced pressure the filtrate was purified through a silica gel column chromatography (silica gel:
Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform-methanol (8:1 by volume)) to obtain 0.3 g of 8-[4-(2-propynyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine as pale yellow rhombic crystals having a melting point of 211 to 213C.
A mixture of 1 g of 8-~1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid, 0.6 mQ of triethylamine, 0.6 mQ oftrifluoromethanesulfonyl chloride and 15 mQ of dimethyl-formamide was stirred at room temperature for 3 hours.
After completion of stirring, the solvent was removed under reduced pressure to concentrate the reaction mixture.
By the addition of 30 mQ of water to the concentrate pale ~' - 6l.
yellow crystals precipitated. Recrystallization of the crystals from a mixture of dimethyl:formamide and water gave 0.7 g of 8-(4-trifluoromethanesulfonyl-1-piperazinyl)-
S.p Streptococcus pyogenes IID S-23 E.c Bscherichia coli NHHJ JC-2 (IFO 12734) K.p Klebsiella pneumoniae P.r Proteus rettgeri NIH 96 S.t Salmonella typhi 0-9Ol (NCTC 8393) S.s Shigella sonnei FW 33 - 46 ~
l S.m Serrat _ marcescens IFO 12648 P al Pseudomonas aeruginosa E-2 .
P.a2 Pseudomonas aeruginosa NCTC 10490 P a3 Pseudomonas aeruginosa ATCC 10145 The results obtained are shown in Table 1 below.
i O
~o ~ ~ ~
cd u~ ~ ~ O
. ,i o ~ ~ ~ ~ ~ C~
~1~ A ~I
C`~
r 1 --I ~ ~ N U~. . g Pl ~ ~o ~O
~ U~
t~ ~i ~i 0 0 0 ~ 1 ~ O
~ ~n ~ o~ ao co a~
~1 . ~
~ ~ tn Oooooooo~o ~ .
-~ ~
~3 C,) ~ U~ o o o o o o o o ~ o O E~
~ ~ _i O O OO O O O ~1 O
E-~ ~
~ ~ ~ c~ o ooooa) oo co ~ o o o o o o o o ~ o O~ CA ~ C~000~ 'D
r~ ,I cO
~ ~ o o o o o o o _i ~ o : u~ ~D u~ ~ ~ ~ ~
~ c~ O a ~ ~ V~
~ ~ ~ o~o~ X
d U~ ~ o ~i ~ o o o o o c --I ~ ~ ~;r u~ ~ r~ co 'C
C~
11~6232 1 From the results shown in Table 1 above it can be seen that the compound of this invention exhibited potent antibacterial activity as compared with nalidixic acid and flumequine.
II. Acute Toxicity The acute toxicity of the compounds of this invention having the formula (I) was determined by intravenous administration (i.v.) in mice which had not been fed for 12 hours prior to the test. LD50 values ~50% lethal dose) obtained for all the compounds were at least 500 mg/kg.
The present invention is further illustrated by the following Reference Examples, Examples and Preparation Examples, but they are not to be construed as limiting the scope of this invention. Unless otherwise indicated, all parts, percents and ratios are by weight.
Unless otherwise indicated, Elemental Analysis was carried out at a temperature of 70 to 80C at reduced pressure (1 to 2 mmHg) for 6 hours using P2O5 as a dessicant.
REFERENCE EXAMPLE
5-Hydroxy-3,4-dihydrocarbostyril ~10 g) was added to 100 mQ of methanol having dissolved therein 3.8 g of potassium hydroxide and the mixture was stirred at room temperature for 30 minutes followed by removing methanol 1 15~23~
1 under reduced pressure. Benzene was added to the residue to form crystals and then benzene was removed by distilla-tion. ~he residue thus obtained was suspended in 50 mQ
of dimethylformamide and 10.6 g of methanesulfonyl chloride was added dropwise to the suspension while ice-cooling with stirring. After adding 3.5 g of methanesulfonyl chloride and resulting mixture was stirred at room temper-ature for 4 hours. After the completion of the reaction the solvent was removed under reduced pressure and the residue was purified through silica gel column chromatog-raphy ~silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform). Recrystal-lization of the eluate from water-containing ethanol gave 5.7 g of S-methanesulfonyloxy-3,4-dihydrocarbostyril as colorless prismatic crystals having a melting point of 227 to 231C.
In an analogous manner as in Reference Example 1, 5-(p-toluenesulfonyloxy)-3,4-dihydrocarbos~yril having a melting point of 215 to 216C was obtained.
5-Methanesulfonyloxy-3,4-dihydrocarbostyril ~4.5 g~ was suspended in 90 mQ of dioxane and 35 g of NaB~4 was added to the suspension. Then, 5.3 mQ of acetic acid was added dropwise to the mixture. After heat-1 1 5~232 l 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. Ihe residue was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.;
eluent: chloroform) and the eluate thus obtained was crystallized from petroleum ether. Recrystallization of the crystals thus obtained from ~ethanol gave 1.9 g of 5-methanesulfonyloxy-1,2,3,4-tetrahydroquinoline as color-less prisms having a melting point of 74 to 76C.
In an analogous manner as in Reference Example 3, 5-(p-toluenesulfonyloxy)-1,2,3,4-tetrahydroquinoline having a melting point of 112 to 113C was obtained.
Ethyl ethoxymethylenemalonate (21.6 g) was added to 22.4 g of 5-methanesulfonyloxy-1,2,3,4-tetrahydro-quinoline and 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 1 l~B23X
1 pl-osphoric acid and 120 g of phosphorus pentoxide was added to the mixture and the mixture was allowed to react on an oil bath at 140C for 45 minutes. After completion of the reaction, the mixture was allowed to cool to room temperature and poured into 400 mQ 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 solution was treated with activated carbon while hot and filtered.
The filtrate was allowed to cool and adjusted to a pH of 2 to precipitate crystals which were filtered. Recrystal-lization of the crude crystals thus obtained from dimethyl-formamide gave 21.3 g of 8-methanesulfonyloxy-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 270 to 275C.
In an analogous manner as in Reference Example 5, 8-(p-toluenesulfonyloxy-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid having a melting point of 300C or more was obtained.
8-Chloro-6,7-dihydro-l-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid (19.2 g) and 35.5 g of 1 15~232 1 anhydrous piperazine were added to 350 m~ of anhydrous dimethyl sulfoxide and the mixture was heated on an oil bath at 170 to 180C for 6 hours while 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 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-soluble materials, the aqueous alkali solution layer was allowed to stand to precipitate crystals which were filtered. The crude crystals thus obtained were dissolved in 10 mQ of a 10% aqueous sodium hydroxide solution and the solution was treated with activated carbon and adjusted to a pH of 8 with a 10%
aqueous hydrochloric acid solution to precipitate crystals which were filtered and washed with water sufficiently. Recrystallization of the crystals from 20 dimethylformamide gave 6.5 g of 8-(1-piperazinyl)-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 267 to 268C.
8-(1-Piperazinyl)-6,7-dihydro-1-oxo-lH,SH-benzo-; [ij]quinolizine-2-carboxylic acid (6.4 g) thus obtained was suspended in 50 mQ of water and 15 mQ of a 10% aqueous 1 15~232 1 hydrochloric acid solution was added to the resulting solution. After removing the insoluble materials by filtration, water was distilled off to obtain 5.7 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid hydrochloride as white amorphous crystals having a melting point of 300C or more.
In an analogous manner as in Reference Example 7, the following compounds were obtained:
Reference Example 8 8-(1-Piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]quinolizine-2-carboxylic acid as colorless needles having a melting point of 264 to 265C.
Reference Example 9 8-(1-Piperazinyl)-9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 246 to 247C.
Reference Example 10 8-(1-Piperazinyl)-10-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride as white amorphous crystals having a melting point of 300C or more.
Reference Example 11 8-~1-Piperazinyl~-9-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride - 5~ -1 as white amorphous crystals having a melting point of 300C
or more.
6-Chloroquinaldine (11 g) was dissolved in 15 mQ
of concentrated sulfuric acid and the solution was ice-cooled. Then, a solution of 7.1 g of potassium nitrate dissolved in 20 mQ of concentrated sulfuric acid was added to the solution dropwise, during which operation the reaction temperature was maintained at 10C or less.
After completion of addition the mixture was agitated at the same temperature as above for 1 hour and then poured onto 200 g of ice. Subsequently, the mixture was rendered alkaline with 10% sodium hydroxide taking care that the internal temperature should not be raised to above 20C, thus forming pale yellow precipitates. The precipitates were collected by filtration, washed with water and recrystallized from ethanol to obtain 12.3 g of 5-nitro-6-chloroquinaldine as pale yellow rhombic crystals having a melting point of 123 to 124C.
To 50 m~ of concentrated hydrochloric acid having dissolved therein 25 g of stannous chloride was added 6.7 g of 5-nitro-6-chloroquinaldine and the mixture was allowed to react on a water bath at a temperature of ; 80 to 90C for 30 minutes. The reaction mixture was ice-.
1 1 5~23~
1 coole~ el~lele(l .~ e (~ll l.0) ~ith 30% sodium hydroxicle alld fi.ltercd ~lnd extractcd t~;tll 500 mQ o~
chl~lc-~orm all~ (`elite (di~tomaccous earth). After drying over ~Inhydrous sodium sulfatc the chloroform fraction ~;as concelltIatcd and recrystalli.zed from a m;xture of bcnzclle and hexclne to obt~lin 4.5 g of 5-amino-~-chloro-~uinaldine as colorless plates having a melting poin~ of 196 to 197C.
~EFERE~IC~ E~ArlPLE 14 5-~mino-6-chloroqui.naldine (~ g) was dissolved in 40 mQ of concentrated hydrochloric acid and the resulting solution was cooled with ice. Then, a solution of 2.1 g of sodium nitrite dissolved in 5 mQ of water was added thereto drop~ise while ice-cooling. After continuing the reaction at the same temperature as above, the reaction mixture was added to a solution of 7 g of cuprous chloride dissolved in 15 mQ of concentrated hydrochloric acid and the resulting mixture was allowed to react on a water bath at a temperature of 50C for 1 2~ hour, during which time vigorous formation of nitrogen gas was observed. Subsequently, the reaction mixture was cooled, rendered alkaline with 30% sodium hydroxide, ancl filtered and extracted using 300 mQ of chloroform and Celite (diatomaceous earth). After drying over anhydrous sodium sulfatc the chloro-form fraction was concentrated * Trade Mark 55 A
1 15~232 1 and recrystallized from a mixture of isopropanol and water to give 3.5 g of 5,6-dichloroquinaldine as white needles having a melting point of 84 to 85C.
REFERENCE EXAMPLE l 5 5,6-Dichloroquinaldine (5 . 5 g) was dissolved in 50 mQ of acetic acid and 0.1 g of 5% platinum-carbon was added to the solution, which was then subjected to Parr's llydrogenationr.lethod to reduce thc compound catalytically at a hydrogen gas pressure of 4 kg/cm . After theoretical amount of hydrogen was absorbed the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After rendering it alkaline with 50 mQ of water and 20% sodium hydroxide, the residue was extracted with 100 mQ of chloroform. The extract was dried by the addition of anhydrous potassium carbonate and concentrated to give 4.4 g of 5,6-dichloro-1,2,3,4-tetrahydroquinaldine as oily product.
NMR analysis data ~ln CDC~3) a: 1.23 (d, 3H, J=6Hz), 1.7 (m, 2H), 2.72 (m, 2H), 3.28 (m, lH), 3.75 (m, lH), 6.62 (q, 2H, J=9Hz) A mixture of 3.2 g of 5,6-dichloro-1,2,3,4-;~ tetrahydroquinaldine and 3.2 g of diethyl ethoxymethylene-f~ malonate was allowed to react by heating at 160C for 30 minutes. Then, 13 g of polyphosphoric acid prepared from ;:
~ - 56 -:
,. . .
1 15~23~
1 6.5 g of phosphorus pentoxide and 6.5 g of phosphoric acid was added to the mixture and the resulting mixture was allowed to react by heating at 140 to 150C for 1 hour. After completion of the reaction, the mixture was poured onto 100 g of ice, followed by rendering the mixture to pH 4 to 5 with a 40~ aqueous sodium hydroxide solution to precipitate crystals. The crystals were collected by filtration, dried and mixed with 50 mQ of a 10% aqueous sodium hydroxide solution. The mixture was allowed to react at 100 to 110C for 1 hour. After cool-ing, the reaction mixture was rendered acidic with concentrated hydrochloric acid to precipitate crystals.
Recrystallization of the crystals thus obtained from ethanol gave 2.3 g of 8,9-dichloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid having a melting point of 269 to 271C.
~ lexamethylphosphoryl triamide (20 mQ) was added to a mixture of 3 g of 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo~ij]quinolizine-2-carboxylic acid and 5 g of anhydrous piperazine and the mixture was heated with stirring at 150 to 160C for 3 hours. After the completion of the reaction, the solvent was removed there-from under reduced pressure and the residue was washed ~ with 10 mQ of ethyl acetate. The crystals obtained were .~
1 dissolved in 100 mQ of water and the solution was adjusted to pH 4 with acetic acid. Insoluble substances were removed by filtration and the filtrate was treated with activated carbon. The aqueous solution thus obtained was concentrated under reduced pressure and the residue was recrystallized from a mixture of isopropanol and water to give 1.8 g of 8-(1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride having a melting point of 300C or more.
The hydrochloride salt was dissolved in water with adding a 2% aqueous sodium hydroxide solution and adjusted to pH 9 with lN hydrochloric acid to obtain white crystals having a melting poir.t of 246 to 247C.
EXAMPLE
A mixture of 2.5 g of 8-~1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid and S0 mQ of trifluoroacetic anhydride was heated under reflux for 3 hours. After completion of heating, excessive trifluoroacetic anhydride was distilled off under reduced pressure and 50 mQ of water was added to the residue followed by stirring to precipitate white crystals. Recrystallization of the crystals from dimethylformamide gave 2.3 g of 8-(4-trifluoroacetyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid 1 15~232 l as white rhombic crystals having a melting point of 300Cor more.
Elemental Analysis for C2UHlgCQF3N3O4 (molecular weight:
457.5) C H N
Calc'd (%): 52.31 4.11 9.22 Found (%): 52.464.15 9.18 A mixture of 1 g of 8-(l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij~quinolizine-2-carboxylic acid, 15 mQ of dimethylformamide, 1.2 mQ of 2,2,2-trifluoroethyl iodide and 2 mQ of triethylamine was ! heated at 80C for 5 hours. After cooling, insoluble substances were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was mixed with 30 mQ of water and insoluble substances were removed by filtration. After concentrating it under reduced pressure, the filtrate was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.;
eluent chloroform-methanol (9:1 by volume)) to obtain 0.5 g of 8-[4-~2,2,2-trifluoroethyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid-iodide-monohydrate as white ~- rhombic crystals having a melting point of 298 to 299C.
1 15~23~
EXAMPL~ 3 1 A mixture of 0.8 g of 8-(1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine hydrochloride monohydrate, 0.4 mQ of propargyl bromide, ~.8 mQ of triethylamine and 10 mQ of dimethyl-formamide was allowed to react by heating at 90C for 5 hours. After completion of the reaction insoluble substances were removed by filtration. After concentra-tion under reduced pressure the filtrate was purified through a silica gel column chromatography (silica gel:
Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform-methanol (8:1 by volume)) to obtain 0.3 g of 8-[4-(2-propynyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine as pale yellow rhombic crystals having a melting point of 211 to 213C.
A mixture of 1 g of 8-~1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid, 0.6 mQ of triethylamine, 0.6 mQ oftrifluoromethanesulfonyl chloride and 15 mQ of dimethyl-formamide was stirred at room temperature for 3 hours.
After completion of stirring, the solvent was removed under reduced pressure to concentrate the reaction mixture.
By the addition of 30 mQ of water to the concentrate pale ~' - 6l.
yellow crystals precipitated. Recrystallization of the crystals from a mixture of dimethyl:formamide and water gave 0.7 g of 8-(4-trifluoromethanesulfonyl-1-piperazinyl)-
9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid as pale yellow powder having a melting point of 232 to 235C.
In an analogous manner as in Example 4, the following compounds were prepared:
In an analogous manner as in Example 4, the following compounds were prepared:
10 Example 5 8-(4-Allyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 226 to 227C
Example 6 8-[4-(2-Chloroethyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 284 to 285C
20 Example 7 8-~4-(4-Methoxybenzyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinalizine-2-carboxylic acid Melting point: 270 to 272C
1 15~232 1 Example 8 8-[4-~2-Hydroxyethyl)-l-piperazinyl~-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 228 to 230C
Example 9 8-(4-Pentafluoropropionyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid Melting point: 296 to 297C
Example 10 8-(4-Heptafluorobutyryl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid Melting point: 269.5 to 270.5C
Example 11 ;
: 8-[4-(2-Hydroxyethyl)-l-piperazinyl]-9-fluoro-` 5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-: carboxylic acid Melting point: 288 to 290C
A mixture of 3.1 g of 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic , .
acid, 9.1 g of l-trifluoroacetylpiperazine and 50 mQ of ~: HMPTA was heated at 160C for 4 hours under atmosphere of ~ .
1 15~232 1 argon. After complction of the reaction, the solvent wasremoved by distillation under reduced pressure and the residue was washed with water. Recrystallization of the residue from dimethylformamide gave 2.3 g of 8-(4-trifluoroacetyl-l-piperazinyl~-9-chloro-5-methyl-6,7-dihydro-l-oxo-111,5~1-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 300C or more.
A mixture of 1.6 g of 8,9-dichloro-6,7-dihydro-5-methyl-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid, 3.2 g of l-propargylpiperazine and 25 mQ of HMPTA
was heated with stirring at 160C for 5 hours under atmosphere of argon. After completion of the reaction, the solvent was removed by distillation and the residue was washed with water. The residue was dissolved in 100 mQ
of water and insoluble substances were removed by filtra-tion. The aqueous fraction was extracted with 200 mQ of chloroform and the chloroform fraction was dried over anhydrous sodium sulfate. After concentration, the concentrate was purified through a silica gel column chromatography tsilica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform-methanol (9:1 by volume)~ to obtain 1.2 g of 8-[4-(2-propynyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1 1-oxo-111,51-1-benzo[ij]quinolizine-2-carboxylic acid having a melting point of 211 to 213C.
In an analogous manner as in Example l3, the following compounds were obtained:
Example 14 8-~4-Allyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH~SH-benzo[ij]quinolizine-2-carboxylic acid Melting point: 226 to 227C
Example 15 8-[4-t4-Methoxybenzyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point:. 270 to 272C
Example 16 ~, 8-[4-(2-hydroxyethyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo~ quinolizine-2-carboxylic acid Melting point: 228 to 230C
: Example 17 ;, : 8-[4-(2-chloroethyl)-1-piperazinyl]-9-chloro-:~ ~ 5-methyl-6j7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 284 to 285C
., .
1 15~232 1 Example 18 8-(4-Pentafluoropropionyl-l-piperazinyl~-9-chloro-S-methyl-6,7-dihydro-1-oxo-lH,5~ benzo[ij]-quinolizine-2-carboxylic acid Melting point: 296 to 297C
Example 19 8-~4-lleptafluorobutyryl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-l}l,SH-benzo[ij]quinolizine-2-carboxylic acid 10 ~ Melting point: 269.5 to 270.5C
Example 20 8-(4-Trifluoromethanesulfonyl-l-piperazinyl)-9-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 232 to 235C
Example 21 8-[4-(2-Hydroxyethyl)-l-piperazinyl]-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-: carboxylic acid Melting point: 288 to 290C
P.XAMPLP. 22 A mixture of 2.75 g of 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-5-methyl-2-acetyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine, 3 g of iodine and 20 mQ of , ` :
pyridine was heated at lQ0C for 1 hour. After completion ~ ', -l 156232 - 6~ -1 of the reaction, crystals precipitated were collected byfiltration and washed with 10 mQ of cool pyridine and with 10 mQ of methanol to obtain 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carbonylmethylpyridinium iodide.
This compound was mixed with S0 mQ of methanol and 50 mQ
of a 10% aqueous sodium hydroxide solution and the resulting mixture was refluxed for 1 hour. After comple-tion of the reaction methanol was removed by distillation and the reaction mixture was adjusted to pH 7 with N
hydrochloric acid to give 1.8 g of 8-(4-trifluoroacetyl-l-piperazinyl~-9-chloro-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.
In an analogous manner as in Example 22, the following compounds were prepared:
Example 23 8-[4-(2,2,2-Trifluoroethyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid Melting point: 298 to 299C
Example 24 8-[4-C2-Hydroxyethyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij3quinolizine-2-carboxylic acid Melting point: 228 to 230C
l 156232 1 Example 25 8-[4-(2-Chloroethyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 284 to 285C
Example 26 8-(4-Allyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij~quinolizine-2-carboxylic acld Melting point: 226 to 227C
Example 27 8-[4-~4-Methoxybenzyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 270 to 272C
Example 28 8-[4-(2-Propynyl)-l-piperazinyl]-9-chloro-5-:~ methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 211 to 213C
. ~
Example 29 8-(4-Pentafluoropropionyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzoCij]-quinolizine-2-carboxylic acid Melting point: 296 to 297C
: :~
l 156232 1 Example 30 8-(4-Heptafluorobutyryl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5}1-benzo[ij]quinolizine-2-carboxylic acid Melting point: 269.5 to 270.5C
Example 31 8-(4-Tri1uoromethanesulfonyl-1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo~ij]quinolizine-2-carboxylic acid Melting point: 232 to 235C
Example 32 8-[4-(2-Hydroxyethyl)-l-piperazinyl]-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 288 to 290C
A mixture of 3.4 g of 8-(p-toluenesulfonyloxy)-6,7-d;hydro-1-oxo-lH~5H-benzo[ij]quinolizine-2-carboxylic acid, 9.1 g of l-(trifluoromethyl)piperazine and 200 mQ
of anhdyrous dimethyl sulfoxide was heated with stirring in an autoclave at 150 to 160C for 18 hours under ; nitrogen gas flow at a pressure of 10 atms. After comple-tion of the reaction, the solvent and excessive piperazine compound were removed by distillation under reduced pressure and a mixture of methanol and ethanol was added 1 15~2~2 l to the residue. The precipitates formed were collectedby filtration and washed with ether. The crystals obtained were suspended in a mixture of 200 mQ of water and 40 mQ of a l0% aqueous hydrochloric acid solution and insoluble substances were removed by filtration. The filtrate was rendered neutral with saturated aqueous solution o-f sodium bicarbonate and purified through column chromatography using Amberlite LH-20 (a trade name for a product of Tokyo Organic Chemical Industries Ltd.) (eluent: water, ethanol). Recrystallization of the eluate from dimethylformamide gave 1.7 g of 8-~4-trifluoro-methyl-l-piperazinyl)-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.
A mixture of 4.5 g of 8-~p-toluenesulfonyloxy)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]-quinolizine-2-carboxylic acid, 9.1 g of l-(trifluoroacetyl)-piperazine and 200 mQ of anhydrous dimethyl sulfoxide was heated with stirring in an autoclave at 150 to 160C for 17 hours under nitrogen gas flow at a pressure of 10 atms.
The reaction mixture was treated in the same manner as Example 33 to obtain 2.3 g of 8-C4-trifluoroacetyl-1-piperazinyl~-9-chloro-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.
- 6~ -l 15~232 I~XAMPLE 35 A mixture of 3.37 g of 8-methanesulfonyloxy-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid, 9.1 g of l-(trifluoromethyl)piperazine and 200 mQ
of anhydrous dimethyl sulfoxide was heated with stirring in an autoclave at 170 to 180C for 20 hours under nitrogen gas flow at a pressure of 8 atms. The reaction mixture was treated in the same manner as Example 33 and further treated with concentrated hydrochloric acid to obtain 1.7 g of 8-~4-trifluoromethyl-1-piperazinyl)-6j7-dihydro-l-oxo-lH,5H-benzo[ij3cuinolizine-2-carboxylic acid hydro-chloride as white rhombic crystals having a melting point of 300C or more.
PREPARATION EXAMPLE
8-(4-Trifluoroacetyl-l-piperazinyl)-9- 200 mg chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride Glucose 250 mg Distilled water for injectionq.s. to make 5 mQ
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 121C for 15 minutes to obtain an injectable preparation.
l 156232 8-(4-Trifluoroacetyl-l-piperazinyl)- l00 g 9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Avicel (trade name for a product of 40 g Asahi Kasei Kogyo Kabushiki Kaisha) Corn starch 30 g Magnesium stearate 2 g TC-5 (trade name for hydroxypropyl-l0 g methyl cellulose, produced by Shinetsu Chemical Industry Co., Ltd.) Polyethylene Glycol-6000 3 g ~molecular weight, 6000) Caster oil 40 g Methanol 40 g The active compoundJ Avicel, corn starch and ~` magnesium 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 tablets.
:, .:
' ~
`: ~
- -l 15~232 l PREPAR~TION EXAMPLE 3 8-(4-Trifluoroacetyl~l-piperazinyl)- 2 g 9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5~1-benzo[ij]quinolizine-2-carboxylic acid Purified hydrous lanolin S g Japan wax 5 g White petrolatum 88 g Total: l00 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.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art .:~ that various changes and modifications can be made -~ therein without departing from the spirit and scope thereof.
Example 6 8-[4-(2-Chloroethyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 284 to 285C
20 Example 7 8-~4-(4-Methoxybenzyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinalizine-2-carboxylic acid Melting point: 270 to 272C
1 15~232 1 Example 8 8-[4-~2-Hydroxyethyl)-l-piperazinyl~-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 228 to 230C
Example 9 8-(4-Pentafluoropropionyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid Melting point: 296 to 297C
Example 10 8-(4-Heptafluorobutyryl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid Melting point: 269.5 to 270.5C
Example 11 ;
: 8-[4-(2-Hydroxyethyl)-l-piperazinyl]-9-fluoro-` 5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-: carboxylic acid Melting point: 288 to 290C
A mixture of 3.1 g of 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic , .
acid, 9.1 g of l-trifluoroacetylpiperazine and 50 mQ of ~: HMPTA was heated at 160C for 4 hours under atmosphere of ~ .
1 15~232 1 argon. After complction of the reaction, the solvent wasremoved by distillation under reduced pressure and the residue was washed with water. Recrystallization of the residue from dimethylformamide gave 2.3 g of 8-(4-trifluoroacetyl-l-piperazinyl~-9-chloro-5-methyl-6,7-dihydro-l-oxo-111,5~1-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 300C or more.
A mixture of 1.6 g of 8,9-dichloro-6,7-dihydro-5-methyl-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid, 3.2 g of l-propargylpiperazine and 25 mQ of HMPTA
was heated with stirring at 160C for 5 hours under atmosphere of argon. After completion of the reaction, the solvent was removed by distillation and the residue was washed with water. The residue was dissolved in 100 mQ
of water and insoluble substances were removed by filtra-tion. The aqueous fraction was extracted with 200 mQ of chloroform and the chloroform fraction was dried over anhydrous sodium sulfate. After concentration, the concentrate was purified through a silica gel column chromatography tsilica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform-methanol (9:1 by volume)~ to obtain 1.2 g of 8-[4-(2-propynyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1 1-oxo-111,51-1-benzo[ij]quinolizine-2-carboxylic acid having a melting point of 211 to 213C.
In an analogous manner as in Example l3, the following compounds were obtained:
Example 14 8-~4-Allyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH~SH-benzo[ij]quinolizine-2-carboxylic acid Melting point: 226 to 227C
Example 15 8-[4-t4-Methoxybenzyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point:. 270 to 272C
Example 16 ~, 8-[4-(2-hydroxyethyl)-1-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo~ quinolizine-2-carboxylic acid Melting point: 228 to 230C
: Example 17 ;, : 8-[4-(2-chloroethyl)-1-piperazinyl]-9-chloro-:~ ~ 5-methyl-6j7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 284 to 285C
., .
1 15~232 1 Example 18 8-(4-Pentafluoropropionyl-l-piperazinyl~-9-chloro-S-methyl-6,7-dihydro-1-oxo-lH,5~ benzo[ij]-quinolizine-2-carboxylic acid Melting point: 296 to 297C
Example 19 8-~4-lleptafluorobutyryl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-l}l,SH-benzo[ij]quinolizine-2-carboxylic acid 10 ~ Melting point: 269.5 to 270.5C
Example 20 8-(4-Trifluoromethanesulfonyl-l-piperazinyl)-9-chloro-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 232 to 235C
Example 21 8-[4-(2-Hydroxyethyl)-l-piperazinyl]-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-: carboxylic acid Melting point: 288 to 290C
P.XAMPLP. 22 A mixture of 2.75 g of 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-5-methyl-2-acetyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine, 3 g of iodine and 20 mQ of , ` :
pyridine was heated at lQ0C for 1 hour. After completion ~ ', -l 156232 - 6~ -1 of the reaction, crystals precipitated were collected byfiltration and washed with 10 mQ of cool pyridine and with 10 mQ of methanol to obtain 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carbonylmethylpyridinium iodide.
This compound was mixed with S0 mQ of methanol and 50 mQ
of a 10% aqueous sodium hydroxide solution and the resulting mixture was refluxed for 1 hour. After comple-tion of the reaction methanol was removed by distillation and the reaction mixture was adjusted to pH 7 with N
hydrochloric acid to give 1.8 g of 8-(4-trifluoroacetyl-l-piperazinyl~-9-chloro-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.
In an analogous manner as in Example 22, the following compounds were prepared:
Example 23 8-[4-(2,2,2-Trifluoroethyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]-quinolizine-2-carboxylic acid Melting point: 298 to 299C
Example 24 8-[4-C2-Hydroxyethyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij3quinolizine-2-carboxylic acid Melting point: 228 to 230C
l 156232 1 Example 25 8-[4-(2-Chloroethyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 284 to 285C
Example 26 8-(4-Allyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij~quinolizine-2-carboxylic acld Melting point: 226 to 227C
Example 27 8-[4-~4-Methoxybenzyl)-l-piperazinyl]-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 270 to 272C
Example 28 8-[4-(2-Propynyl)-l-piperazinyl]-9-chloro-5-:~ methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 211 to 213C
. ~
Example 29 8-(4-Pentafluoropropionyl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzoCij]-quinolizine-2-carboxylic acid Melting point: 296 to 297C
: :~
l 156232 1 Example 30 8-(4-Heptafluorobutyryl-l-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,5}1-benzo[ij]quinolizine-2-carboxylic acid Melting point: 269.5 to 270.5C
Example 31 8-(4-Tri1uoromethanesulfonyl-1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo~ij]quinolizine-2-carboxylic acid Melting point: 232 to 235C
Example 32 8-[4-(2-Hydroxyethyl)-l-piperazinyl]-9-fluoro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Melting point: 288 to 290C
A mixture of 3.4 g of 8-(p-toluenesulfonyloxy)-6,7-d;hydro-1-oxo-lH~5H-benzo[ij]quinolizine-2-carboxylic acid, 9.1 g of l-(trifluoromethyl)piperazine and 200 mQ
of anhdyrous dimethyl sulfoxide was heated with stirring in an autoclave at 150 to 160C for 18 hours under ; nitrogen gas flow at a pressure of 10 atms. After comple-tion of the reaction, the solvent and excessive piperazine compound were removed by distillation under reduced pressure and a mixture of methanol and ethanol was added 1 15~2~2 l to the residue. The precipitates formed were collectedby filtration and washed with ether. The crystals obtained were suspended in a mixture of 200 mQ of water and 40 mQ of a l0% aqueous hydrochloric acid solution and insoluble substances were removed by filtration. The filtrate was rendered neutral with saturated aqueous solution o-f sodium bicarbonate and purified through column chromatography using Amberlite LH-20 (a trade name for a product of Tokyo Organic Chemical Industries Ltd.) (eluent: water, ethanol). Recrystallization of the eluate from dimethylformamide gave 1.7 g of 8-~4-trifluoro-methyl-l-piperazinyl)-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.
A mixture of 4.5 g of 8-~p-toluenesulfonyloxy)-9-chloro-5-methyl-6,7-dihydro-1-oxo-lH,SH-benzo[ij]-quinolizine-2-carboxylic acid, 9.1 g of l-(trifluoroacetyl)-piperazine and 200 mQ of anhydrous dimethyl sulfoxide was heated with stirring in an autoclave at 150 to 160C for 17 hours under nitrogen gas flow at a pressure of 10 atms.
The reaction mixture was treated in the same manner as Example 33 to obtain 2.3 g of 8-C4-trifluoroacetyl-1-piperazinyl~-9-chloro-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.
- 6~ -l 15~232 I~XAMPLE 35 A mixture of 3.37 g of 8-methanesulfonyloxy-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid, 9.1 g of l-(trifluoromethyl)piperazine and 200 mQ
of anhydrous dimethyl sulfoxide was heated with stirring in an autoclave at 170 to 180C for 20 hours under nitrogen gas flow at a pressure of 8 atms. The reaction mixture was treated in the same manner as Example 33 and further treated with concentrated hydrochloric acid to obtain 1.7 g of 8-~4-trifluoromethyl-1-piperazinyl)-6j7-dihydro-l-oxo-lH,5H-benzo[ij3cuinolizine-2-carboxylic acid hydro-chloride as white rhombic crystals having a melting point of 300C or more.
PREPARATION EXAMPLE
8-(4-Trifluoroacetyl-l-piperazinyl)-9- 200 mg chloro-5-methyl-6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride Glucose 250 mg Distilled water for injectionq.s. to make 5 mQ
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 121C for 15 minutes to obtain an injectable preparation.
l 156232 8-(4-Trifluoroacetyl-l-piperazinyl)- l00 g 9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid Avicel (trade name for a product of 40 g Asahi Kasei Kogyo Kabushiki Kaisha) Corn starch 30 g Magnesium stearate 2 g TC-5 (trade name for hydroxypropyl-l0 g methyl cellulose, produced by Shinetsu Chemical Industry Co., Ltd.) Polyethylene Glycol-6000 3 g ~molecular weight, 6000) Caster oil 40 g Methanol 40 g The active compoundJ Avicel, corn starch and ~` magnesium 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 tablets.
:, .:
' ~
`: ~
- -l 15~232 l PREPAR~TION EXAMPLE 3 8-(4-Trifluoroacetyl~l-piperazinyl)- 2 g 9-chloro-5-methyl-6,7-dihydro-l-oxo-lH,5~1-benzo[ij]quinolizine-2-carboxylic acid Purified hydrous lanolin S g Japan wax 5 g White petrolatum 88 g Total: l00 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.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art .:~ that various changes and modifications can be made -~ therein without departing from the spirit and scope thereof.
Claims (60)
- Claim 1 continued (c) reacting a compound represented by the formula (XX) (XX) wherein R1 and R2 have the same meaning as defined hereinbefore, with a compound represented by the formula (XXI) R3X (XXI) wherein R3 has the same meaning as defined hereinbefore to give a compound formula (I).
- 2. A process for preparing a benzo[ij]quinolizine-2-carboxylic acid compound of the general formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof wherein R2 represents a halogen atom.
- 3. A process as claimed in claim 2 wherein R2 represents chlorine or fluorine.
- 4. A process as claimed in claim 1(a) wherein the propor-tion of the compound of formula (III) to the compound of formula (II) is at least equimolar.
- 5. A process as claimed in claim 4 wherein the molar proportion of the compound of the formula (III) to the compound of the formula (II) is 1:1 to 5:1.
- 6. A process as claimed in claim l(a) wherein the reaction is carried out in the presence of a deoxidizing agent.
- 7. A process as claimed in claim l(a) whereln the reaction is carried out at a temperature of from about 100°C
to about 250°C for from about 5 hours to about 20 hours. - 8. A process as claimed in claim 7 wherein the reaction is carried out at a temperature of from about 140°C to about 200°C.
- 9. A process as claimed in claim l(a) wherein the reaction is carried out at a pressure of from about 1 atms. to about 10 atms.
- 10. A process as claimed in claim l(c) wherein R3 repre-sents a lower alkanoyl group substituted with one or more halogen atoms and the reaction is carried out in the presence of a deoxidizing agent at a temperature of from about 0°C to about 100°C for from about 0.5 hours to about 6 hours.
- 11. A process as claimed in claim 10 wherein the reaction is carried out at about room temperature.
- 12. A process as claimed in claim 10 wherein the propor-tion of the compound of formula (XXI) to the compound of formula (XX) is at least equimolar.
- 13. A process as claimed in claim 10 wherein R3 represents a lower alkyl group substituted with one or more of a halogen atom and a hydroxy group, a phenylalkyl group substituted with one or more lower alkoxy groups on the phenyl ring, a lower alkane-sulfonyl group substituted with one or more halogen atoms, a Claim 13 continued lower alkenyl group or a lower alkynyl group, and wherein the proportion of the compound of formula (XXI) to the compound of formula (XX) is at least equimolar.
- 14. A process as claimed in claim l(c) wherein the reaction is carried out at a temperature of from about room temperature to about 150°C for from about 1 hour to 10 hours.
- 15. A process as claimed in claim 14 wherein the reaction is carried out at a temperature of from about 50°C to about 100°C.
- 16. A process as claimed in claim 10 wherein the reaction is carried out in the presence of a deoxidizing agent.
- 17. A process as claimed in claim 10 wherein the reaction is carried out in an inert solvent.
- 18. A process as claimed in claim l(b) wherein the propor-tion of said tertiary nitrogen atom-containing aromatic hetero-cyclic compound or trialkylamine and said anion donating compound, respectively, to the compound of the formula (XXVI) are at least equimolar.
- 19. A process as claimed in claim 18 wherein the propor-tion of said tertiary nitrogen atom-containing aromatic hetero-cyclic compound or trialkylamine and said anion donating compound, respectively, to the compound to the formula (XXVI) are each on a molar basis from 1/1 to 2/1.
- 20. A process as claimed in claim l(b) wherein said first reaction step is carried out at a temperature of from about room temperature to about 120°C for about 0.5 hours to about 6 hours.
- 21. A process as claimed in claim 20 wherein said first reaction step is carried out at a temperature of from about 50°C to about 100°C.
- 22. A process as claimed in claim l(b) wherein said hydrolysis is carried out in the presence of an acid or an alkali.
- 23. A process as claimed in claim l(b) wherein said hydrolysis is carried out in an inert solvent.
- 24. A process as claimed in claim l(b) wherein said hydrolysis is carried out in an aqueous medium containing a trialkylamine.
- 25. A process as claimed in claim l(b) wherein said hydrolysis is carried out in the presence of a lower alcohol.
- 26. A process as claimed in claim l(b) wherein said hydrolysis is carried out at a temperature of from about 20°C to about 150°C for from about 0.5 hours to about 6 hours.
- 27. A process as claimed in claim 26 wherein said hydrolysis is carried out at a temperature of from about 80°C
to about 120°C. - 28. A process as claimed in claim l(a).
- 29. A process as claimed in claim 1(b).
- 30. A process as claimed in claim l(c).
- 31. Compounds of the general formula (I) as defined in claim 1 and pharmaceutically acceptable salts thereof whenever prepared by a process as claimed in claim 1 or an obvious chemical equivalent thereof.
- 32. Compounds of the general formula (I) as defined in claim 1 and pharmaceutically acceptable salts thereof whenever prepared by a process as claimed in claim 28 or an obvious chemical equivalent thereof.
- 33. Compounds of the general formula (I) as defined in claim 1 and pharmaceutically acceptable salts thereof whenever prepared by a process as claimed in claim 29 or an obvious chemical equivalent thereof.
- 34. Compounds of the general formula (I) as defined in claim 1 and pharmaceutically acceptable salts thereof whenever prepared by a process as claimed in claim 30 or an obvious chemical equivalent thereof.
- 35. Compounds of the general formula. (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof wherein R2 is defined in claim 2 whenever prepared by a process as claimed in claim 2 or an obvious chemical equivalent thereof.
- 36. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof wherein R2 is defined in claim 3 whenever prepared by a process as claimed in claim 3 or an obvious chemical equivalent thereof.
- 37. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof whenever prepared by a process as claimed in claim 4 or an obvious chemical equivalent thereof.
- 38. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof whenever prepared by a process as claimed in claim 5 or an obvious chemical equivalent thereof.
- 39. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof whenever prepared by a process as claimed in claim 6 or an obvious chemical equivalent thereof.
- 40. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof whenever prepared by a process as claimed in claim 7 or an obvious chemical equivalent thereof.
- 41. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof whenever prepared by a process as claimed in claim 8 or an obvious chemical equivalent thereof.
- 42. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof whenever prepared by a process as claimed in claim 9 or an obvious chemical equivalent thereof.
- 43. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof wherein R3 is defined in claim 10 whenever prepared by a process as claimed in claim 10 or an obvious chemical equivalent thereof.
- 44. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof wherein R3 is defined in claim 10 whenever prepared by a process as claimed in claim 11 or an obvious chemical equivalent thereof.
- 45. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof wherein R3 is defined in claim 10 whenever prepared by a process as claimed in claim 12 or an obvious chemical equivalent thereof.
- 46. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof wherein R3 is defined in claim 13 whenever prepared by a process as claimed in claim 13 or an obvious chemical equivalent thereof.
- 47. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof whenever prepared by a process as claimed in claim 14 or an obvious chemical equivalent thereof.
- 48. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof whenever prepared by a process as claimed in claim 15 or an obvious chemical equivalent thereof.
- 49. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof wherein R3 is defined in claim 10 whenever prepared by the process as claimed in claim 16 or an obvious chemical equivalent thereof.
- 50. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof wherein R3 is defined in claim 10 whenever prepared by the process as claimed in claim 17 or an obvious chemical equivalent thereof.
- 51. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof when-ever prepared by a process as claimed in claim 18 or an obvious chemical equivalent thereof.
- 52. Compounds of the general formula II) as defined in claim 1 and the pharmaceutically acceptable salts thereof when-ever prepared by a process as claimed in claim 19 or an obvious chemical equivalent thereof.
- 53. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof when-ever prepared by a process as claimed in claim 20 or an obvious chemical equivalent thereof.
- 54. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof when-ever prepared by a process as claimed in claim 21 or an obvious chemical equivalent thereof.
- 55. Compounds of the general formula (1) as defined in claim 1 and the pharmaceutically acceptable salts thereof when-ever prepared by a process as claimed in claim 22 or an obvious chemical equivalent thereof.
- 56. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof when-ever prepared by a process as claimed in claim 23 or an obvious chemical equivalent thereof.
- 57. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof when-ever prepared by a process as claimed in claim 24 or an obvious chemical equivalent thereof.
- 58. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof when-ever prepared by a process as claimed in claim 25 or an obvious chemical equivalent thereof.
- 59. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof when-ever prepared by a process as claimed in claim 26 of an obvious chemical equivalent thereof.
- 60. Compounds of the general formula (I) as defined in claim 1 and the pharmaceutically acceptable salts thereof when-ever prepared by a process as claimed in claim 27 or an obvious chemical equivalent thereof.
83 .
1. A process for preparing a benzo[ij]quinolizine-2-carboxylic acid compound represented by the formula (I) (I) wherein R1 represents a hydrogen atom or a lower alkyl group;
R2 represents a hydrogen atom or a halogen atom; R3 represents a lower alkyl group substituted with one or more of a halogen atom and a hydroxy group, a lower alkanoyl group substituted with one or more halogen atoms, a phenylalkyl group substituted with one or more lower alkoxy groups on the phenyl ring, a lower alkanesulfonyl group substituted with one or more halogen atoms, a lower alkenyl group, or a lower alkynyl group; or a pharmaceutically acceptable salt thereof, which comprises select-ing a process from the group of processes consisting of:
(a) reacting a benzo[ij]quinolizine-2-carboxylic acid compound represented by the formula (II) (II) wherein R4 represents a halogen atom, a lower alkanesulfonyl-oxy group or an arylsufonyloxy group, and R1 and R2 have the same meaning as defined hereinbefore, with a piperazine compound represented by the formula (III) Claim 1 continued (III) wherein R3 has the same meaning as defined hereinbefore to give a compound of the formula (I), (b) reacting a compound of the formula (XXVI) (XXVI) wherein R1, R2 and R3 have the same meaning as defined herein-before and R5 and R6 each represents a hydrogen atom or a lower alkyl group, with a tertiary nitrogen containing aromatic heterocyclic compound or a trialkylamine in the presence of an anion donating compound to form a compound of the formula (XXVII) (XXVII) wherein R1, R2, R3, R5 and R6 have the same meaning as defined hereinbefore; 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 compound to give a compound of the formula (I)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP54131630A JPS6019910B2 (en) | 1979-10-11 | 1979-10-11 | Benzo[ij]quinolidine-2-carboxylic acid derivative and method for producing the same |
| JP131630/79 | 1979-10-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1156232A true CA1156232A (en) | 1983-11-01 |
Family
ID=15062532
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000362012A Expired CA1156232A (en) | 1979-10-11 | 1980-10-09 | Benzo(ij)quinolizine-2-carboxylic acid compounds, therapeutic composition containing same and process for producing same |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS6019910B2 (en) |
| AU (1) | AU536230B2 (en) |
| BE (1) | BE885605A (en) |
| CA (1) | CA1156232A (en) |
| CH (1) | CH644859A5 (en) |
| DE (1) | DE3037103A1 (en) |
| ES (1) | ES496312A0 (en) |
| FR (1) | FR2467205A1 (en) |
| GB (1) | GB2062627B (en) |
| IT (1) | IT1143997B (en) |
| NL (1) | NL187020C (en) |
| SE (1) | SE445917B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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. |
| US4400386A (en) * | 1981-11-06 | 1983-08-23 | Riker Laboratories, Inc. | Antimicrobial derivatives of 8-amino and 8-aminomethyl benzo(ij)quinolizine |
| US4472406A (en) * | 1982-11-12 | 1984-09-18 | Riker Laboratories, Inc. | Antimicrobial 6,7-dihydro-8-(imidazol-1-yl)-5-methyl-1-oxo-1H,5H-benzo [ij]quinolizine-2-carboxylic acids and derivatives |
| JPS59137482A (en) * | 1983-01-26 | 1984-08-07 | Otsuka Pharmaceut Co Ltd | Pyrrolo(3,2,1,-ij)quinoline-5-carboxylic acid derivative |
| JPS59155381A (en) * | 1983-02-22 | 1984-09-04 | Kyorin Pharmaceut Co Ltd | Benzoquinolizinecarboxylic acid derivative and its preparation |
| DE3333719A1 (en) * | 1983-09-17 | 1985-04-04 | Bayer Ag | SOLUTIONS MILK ACID SALTS OF PIPERAZINYL CHINOLONIC AND PIPERAZINYL AZACHINOLONE CARBONIC ACIDS |
| JPS60161987A (en) * | 1984-01-31 | 1985-08-23 | Otsuka Pharmaceut Co Ltd | Benzoheterocyclic ring derivative |
| DE3517709A1 (en) * | 1985-01-05 | 1986-07-10 | Bayer Ag | BASIC PREPARATIONS OF CHINOLON CARBON ACIDS |
| CA1253154A (en) * | 1985-05-24 | 1989-04-25 | Atsushi Takagi | Benzo¬ij|quinolizine-2-carboxylic acid derivatives |
| DE3741026A1 (en) * | 1987-12-03 | 1989-06-15 | Muetek Laser Und Opto Elektron | METHOD AND SYSTEM FOR (TRACK) GAS ANALYSIS |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE793524A (en) * | 1971-12-30 | 1973-06-29 | Riker Laboratories Inc | BENZOQUINOLIZINE-CARBOXYLIC ACIDS AND THEIR DERIVATIVES |
| JPS6034957B2 (en) * | 1978-04-12 | 1985-08-12 | 大塚製薬株式会社 | penicillanic acid derivatives |
-
1979
- 1979-10-11 JP JP54131630A patent/JPS6019910B2/en not_active Expired
-
1980
- 1980-10-01 DE DE19803037103 patent/DE3037103A1/en active Granted
- 1980-10-06 CH CH743580A patent/CH644859A5/en not_active IP Right Cessation
- 1980-10-09 AU AU63090/80A patent/AU536230B2/en not_active Ceased
- 1980-10-09 BE BE0/202389A patent/BE885605A/en not_active IP Right Cessation
- 1980-10-09 IT IT49851/80A patent/IT1143997B/en active
- 1980-10-09 CA CA000362012A patent/CA1156232A/en not_active Expired
- 1980-10-10 NL NLAANVRAGE8005613,A patent/NL187020C/en not_active IP Right Cessation
- 1980-10-10 SE SE8007133A patent/SE445917B/en not_active IP Right Cessation
- 1980-10-10 GB GB8032782A patent/GB2062627B/en not_active Expired
- 1980-10-10 FR FR8021722A patent/FR2467205A1/en active Granted
- 1980-10-11 ES ES496312A patent/ES496312A0/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| FR2467205B1 (en) | 1983-10-07 |
| IT1143997B (en) | 1986-10-29 |
| NL187020B (en) | 1990-12-03 |
| GB2062627A (en) | 1981-05-28 |
| NL187020C (en) | 1991-05-01 |
| NL8005613A (en) | 1981-04-14 |
| FR2467205A1 (en) | 1981-04-17 |
| DE3037103A1 (en) | 1981-05-07 |
| CH644859A5 (en) | 1984-08-31 |
| AU536230B2 (en) | 1984-05-03 |
| BE885605A (en) | 1981-02-02 |
| IT8049851A0 (en) | 1980-10-09 |
| ES8106903A1 (en) | 1981-10-01 |
| JPS5655389A (en) | 1981-05-15 |
| DE3037103C2 (en) | 1989-06-15 |
| GB2062627B (en) | 1983-12-07 |
| SE8007133L (en) | 1981-04-12 |
| ES496312A0 (en) | 1981-10-01 |
| SE445917B (en) | 1986-07-28 |
| JPS6019910B2 (en) | 1985-05-18 |
| AU6309080A (en) | 1981-04-16 |
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