FR2467205A1 - BENZO (IJ) QUINOLIZINE CARBOXYLIC-2 ACID DERIVATIVES, PARTICULARLY USEFUL AS ANTIMICROBIAL MEDICAMENTS, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC COMPOSITIONS AND PHARMACEUTICAL FORMS CONTAINING THE SAME - Google Patents

Abstract

The invention relates to derivatives of benzo [ij] quinolizinecarboxylic acid-2 of the formula: (CF DRAWING IN BOPI) where R ** 1 represents a hydrogen atom or a lower alkyl radical, R ** 2 represents an atom of hydrogen or a halo radical, R ** 3 represents a lower alkyl radical substituted by one or more halo or hydroxy radicals, a lower alkanoyl radical substituted by one or more halo radicals, a phenyl-alkyl radical substituted by one or more radicals lower alkoxy on the phenyl ring, a lower alkanesulfonyl radical substituted by one or more halo radicals, a lower alkenyl radical or a lower alkynyl radical, and their pharmaceutically suitable salts; these compounds are useful in particular as antibacterial drugs effective against bacteria resistant to conventional antibiotics and maintaining high blood levels; therapeutic compositions and pharmaceutical forms containing these drugs are also described.

Description

The present invention relates to certain benzo [ij] acid derivatives

  quinolizinecarboxylic-2 useful especially as antimicrobial drugs, a process for their preparation and compositions

  therapeutic and pharmaceutical forms containing them.

  Certain types of polyheterocyte compounds are known to have antimicrobial activities. For example, U.S. Patent No. 3,917,609 discloses substituted derivatives of 1,2-dihydro-6-oxo-6H-pyrrolo [3,2,1-ij] quinoline which are useful antimicrobial agents or intermediaries for preparation

  antimicrobial agents. Also the patents of the United States of America

  No. 3,896,131, No. 3,985,882, No. 3,969,463, No. 4,001,243 and No. 4,014,877 and French Patent Application No. 79-09337 filed on April 12, 1979 in the name of the Applicant disclose dihydro derivatives. -6,7 oxo-1H, 5H-benzo [ij] quinolizine having activities

antimicrobial.

  Following extensive research, the plaintiff

  discovered that certain benzo [ij] quinolizine-carboxylic acid derivatives

  lique-2 have potent antimicrobial activity and low toxicity, they do not show decreased activity in

  serum and are effective against resistant bacteria.

  conventional antibiotics such as penicillin,

  cillin, streptomycin, etc. The invention relates more particularly to derivatives

  of benzo [i] quinolizinecarboxylic acid represented by the formula

mule (I):

R2 O

t - 3COOH / lI

3- N '(N

A \ R1

  R1 represents a hydrogen atom or a lower alkyl radical,

  R represents a hydrogen atom or a halo radical, R represents

  a lower alkyl radical substituted with one or more radicals

  halo or hydroxy, a lower alkanoyl radical substituted with one or more halo radicals, a lower phenylalkyl radical substituted with one or more alkoxy radicals on the phenyl ring, a lower alkanesulfonyl radical substituted with one or more

  several halo radicals, a lower alkenyl radical or a radical

  lower alkynyl cal; and their salts suitable as antimicrobials.

  The invention also relates to therapeutic compositions

  and pharmaceutical forms containing a quantity

  effective treatment of at least one of the compounds of formula (I) and

their pharmaceutically acceptable salts.

  The invention also relates to a process for preparing

  the compounds of formula I and their pharmaceutically acceptable salts.

  In the present description, the term "halo"

  denotes a chloro, bromo, iodo or fluoro radical.

  In the present description, the term "lower alkyl"

  denotes a straight or branched alkyl radical containing 1 to 4 carbon atoms such as a methyl, ethyl, propyl or isopropyl radical,

butyl, tert-butyl and the like.

  In the present description, the term "lower alkanoyl"

  "is a straight or branched alkanoyl radical having 2 to 4 carbon atoms such as acetyl, propionyl, butyryl,

isobutyryl and the like.

  In the present description, the term "alkanesulfonyl

  "lower" means a straight or branched alkanesulfonyl radical

  carrying 1 to 4 carbon atoms such as a methanesulfonyl radical,

  ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfide,

  fonyl, tert-butanesulfonyl and the like.

  In the present description, the term "arylsulfonyl"

  denotes benzylsulfonyl, naphthalenesulfonyl and the like.

  The aryl ring of the arylsulfonyl radical may be substituted by one or more halo, lower alkyl, hydroxy or nitro radicals.

and the like.

  In the present description, the term "lower alkenyl"

  "is an alkenyl radical having 2 to 4 carbon atoms.

  In the present description, the term "lower alkynyl" is

  "is an alkynyl radical having 2 to 4 carbon atoms.

  In the present description, the term "phenylalkyl

  lower "denotes a phenylalkyl radical consisting of a phenyl radical and a straight or branched alkyl alkenyl radical having 1 to 4 carbon atoms such as a benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, phdnyl radical; ethyl, dimethyl-1, 1-phenethyl and the like.

  Examples of lower alkyl radicals are:

  substituted by one or more halo and hydroxy

  used in the invention, trifluoromethyl, trichloro-

  methyl, dichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl,

  2,2,2-trichloroethyl, 2-chloroethyl, 1,2-dichloroethyl, tri-

  3,3,3-chloro-propyl, 3-fluoro-propyl, 4-chlorobutyl, 3-chloro-methyl-ethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 2-hydroxy propyl, etc.

  Examples of alkanoyl radicals include

  Examples which are substituted by one or more halo radicals used in the invention are trifluoroacetyl, trichloroacetyl, tribromoacetyl, dichloro-2,2-propionyl, monochloroacetyl, 2-chlorobutyryl, pentafluoropropionyl, heptafluorobutyryl and the like. Examples of phenylalkyl radicals include

  substituted on the phenyl radical by one or more radicals

  alkoxy, for example C 1 -C 3, 4-methoxybenzyl, 2-isopropoxybenzyl, 3,4-dimethoxybenzyl, 3,4-dimethoxyphenethyl, (3,4-dimethoxyphenyl) ethyl, trimethoxy- 2,3,4 phenethyl, (4-ethoxyphenyl) -3-propyl, (4-methoxyphenyl) -4-butyl, etc. Examples of lower alkanesulfonyl radicals substituted by one or more halo radicals are

  trifluoromethanesulfonyl, trichloromethanesulfonyl, trichloromethanesulfonyl

  bromomethanesulfonyl, dichloromethanesulfonyl, 2,2,2-trifluoro

  ethanesulfonyl, 2,2,2-trichloroethanesulfonyl, 2-chloroethanesulphonyl

  fonyl, 1,2-dichloro-ethanesulfonyl, 3,3,3-trifluoropropanesulfonyl, 3,3,3-trichloropropanea- sulphonyl, 3-fluoro-propanesulphonyl, 4-chlorobutanesulfonyl, 3-chloro-2-methyl-ethanesulfonyl, and the like. Examples of alkenyl radicals include

  lower, for example C2-C4, used in the invention, the radi-

  vinyl, allyl, butene-2-yl, methyl-1-allyl, etc. Examples of alkynyl radicals

  lower, for example C2-C4 ,. used in the invention the radi-

  ethynyl, propyne-2-yl, butyne-2-yl, methyl-1-propyn-2-yl, etc.

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  The compounds of the invention of formula (I) and their salts have excellent general antimicrobial activity against

  gram-positive and gram-negative bacteria at low concentrations.

  These are useful compounds with particularly potent antibacterial activity against Streptococcus, Pseudomonas, Enterobacter, Proteus, etc. against which conventional synthetic antibacterial agents are ineffective or only weakly

  effective. In addition, they have antibacterial activity,

  against coliform bacilli, staphylococci, etc. which are major causes of infectious diseases and also against Serratia, Klebsiella, etc. which also cause infectious diseases that have recently attracted the attention of many specialists in this field and their clinical use is therefore

very important.

  As previously indicated, the compounds of the invention

  are advantageous not only because of their extensive spectrum of

  antimicrobial activity and their potent activity but also

  that they do not show a decrease in antimicrobial activity

  in the presence of serum but rather a tendency to increase

  of this activity. This phenomenon is surprising to those skilled in the art since it has been observed that conventional drugs with antimicrobial activity show a decrease in activity in the presence of serum. This contatatin suggests that the compounds of the invention may have potent antimicrobial activity in

the blood.

  The oral toxicity of the compounds of the invention is very

  low compared to their effective oral dose.

  The compounds of the invention exhibit excellent

  antimicrobial activity against bacteria with resistance

  natural or acquired antibiotics with conventional antibiotics such as penicillin, cephalosporin, ampicillin, streptomycin, erythromycin, kanamycin, nalidixic acid, etc. When administered orally, the compounds of the invention are easily absorbed and their blood content is maintained at high levels which contributes to their activity.

powerful antimicrobial.

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  The list of characteristic examples of compounds of the invention which is given below is given for illustrative purposes only

and in no way limits the inversion.

  (1) 1- (9-Trifluoroacetyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-oxo-1H, 5H-benzo [i] quinolin-2-carboxylic acid. (2) (4-Trifluoroacetyl-4-piperazinyl) -8 fluoro-9 acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (3) (4-Trifluoroacetyl-1-piperazinyl) -8-chloro-10 acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (4) 4-Trichloroacetyl-4-piperazinyl-9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2 (5) (4-Trifluoroacetyl-1-piperazinyl) acid ) -8 chloro-9

  5-ethyl-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (6) 4- (trifluoroacetyl-4-piperazinyl) -8-chloro-9 acid

  butyl-5-dihydro-6,7-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (7) (4-monochloroacetylpiperazinyl) -8 clloro-9 acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (8) 4- (Trifluoromethanesulfonyl-4-piperazinyl) -8-acid

  9-chloro-5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizine

2-carboxylic acid.

  (9) (4-Trifluoromethanesulfonyl-piperazinyl) -8-acid

  9-fluoro-5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizine

2-carboxylic acid.

  (10) [(trifluoro-2,2,2-ethanesulfonyl) -4 piperine

  2S-zinyl-1] -8-chloro-9-methyl-5-dihydro-6,7-oxo-1H, 5H-benzo [i] quinoline

  lizinecarboxylique-2. (11) 4- [Chloro-2-ethyl] -4-piperazinyl] -8-chloro-9 acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (12) 1- (tribromoacetyl-4-piperazinyl) -8-bromo-9 acid

  5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzoftijjquinolizinecarboxylic-2.

  (13) 4- [Chloro-2-butyl] -4-piperazinyl] -8-chloro-9

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (14) 4- (Trifluoroacetyl-4-piperazinyl) -8-methyl-5-acid

  6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (15) 4- (trifluoroacetyl-4-piperazinyl) -8-chloro-9-acid

  6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (16) (4-Allyl-piperazinyl) -8-chloro-9-methyl-5-acid

  6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (17) [(2-Buten-1-yl) -4 piperazinyl-1] -8-chloro-9

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (18) (4-Allyl-piperazinyl-1) -8-methyl-5-dihydro-6-acid,

  7-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (19) 9-Allyl-piperazinyl-8-chloro-9-dihydro-6-acid,

  7-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (20) 1- (4-allyl-piperazinyl) -9-fluoro-9-methyl-5-acid

  6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (21) 1- (4-Trifluoromethyl-piperazinyl) -8-chloroacidic acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (22) (4-Trifluoromethyl-1-piperazinyl) -8-chloro-9 acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (23) (Trichloromethyl-4-piperazinyl-1) -8-chloro-9 acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (24) [(trifluoro-2,2,2-ethyl) -4-piperazinyl] -8-acid

  9-chloro-5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizine

  2-carboxylic acid. (25) 4- [4-chloro-butyl) -1-piperazinyl] chloro-9-acid

  5-methyl-6,7-dihydrooxo-1H, SH-benzo [i] quinolizinecarboxylic-2.

  (26) 1- (4-Trifluoromethyl-1-piperazinyl) -9-fluoroacidic acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (27) (4-Trifluoromethyl-1-piperazinyl) -8-methyl-5-acid

  6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (28) [(trifluoro-2,2,2-ethyl) -4-piperazinyl] -8-acid

  9-chloro-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (29) (4-Trifluoromethyl-1-piperazinyl) -8-chloro-9 acid

  5-ethyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (30) [(4-Hydroxyethyl) -4-piperazinyl] -8-chloro-9-acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (31) [(2-Hydroxyethyl) -4-piperazinyl] -8 fluoro-9 acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (32) [(2-Hydroxyethyl) -4-piperazinyl] -8-chloroacetic acid

  10-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxy-

lic-2.

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  (33) [(2-Hydroxyethyl) -4-piperazinyl] -8-acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] d] quinolizinecarboxylic-2.

  (34) [(2-Hydroxyethyl) -4 piperazinyl] -8-acid

  9-chloro-6,7-dihydrooxo-1H, 5H-benzo [1] quinolizinecarboxylic-2.

  (35) [(2,3-Dihydroxypropyl) -4-piperazinyl] -8-acid

  9-chloro-5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarbonate

  boxylique-2. (36) 4- (4-hydroxy-butyl) -1-piperazinyl] chloro-9-acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (37) [(propyn-2-yl) -4-piptrazinyl-1] -8-chloro-9 acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [1] quinolizinecarboxylic-2.

  (38) [(propyn-2-yl) -4 piperazinyl-1] -8 fluoro-9 acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (39) 4- [4-propyne-4-yl] piperazinyl] methyl-5-acid

  6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (40) [(propyne-2-yl) -4 pipazinyl-1] -8-fluoro-9 acid

  6,7-dihydro-1-oxo-1H, 5H-benzo [1] []] quinolizinecarboxylic-2.

  (41) [1-Methyl-propyn-2-yl] -4-piperazinyl acid

  9-chloro-5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizine

2-carboxylic acid.

  (42) (4-propyne-4-yl) 1-pipdrazinyl] 10-chloro-10-chloroacetate

  5-Mithyl-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (43) 4- (4-Methoxybenzyl) pipErazinyl] -8-acid

  9-chloro-5-methyl-dihydro-6,7-oxo-1H, 5H-benzo [i] quinolizine

2-carboxylic acid.

  (44) 4- (4-Methoxybenzyl) piperazinyl] -8-acid

  9-fluoro-5-methyl-6,7-dihydroxy-1H, 5H-benzo [i] quinolizine

  2-carboxylic acid. (45) 4- (4-Methoxybensyl) piperazinyl] -8-acid

  9-chloro-6,7-dihydrooxo-1H, 5H-beuzo [i] quinolizinecarboxylic-2.

  (46) 4- (4-Methoxy-4-benzyl) -4-piperazinyl] -acetinic acid

  5-Mithyl-6,7-dihydro-1-oxo-1H, 5H-benzo [tri] quinoliznecarboxylic-2.

  (47) 4- [4-Methoxy-benzyl] piperazinyl-1-8-acid

  fluoro-10-methyl-5-dihydro-6,7-oxo-1H, 5H-benco [ij] quinolizinecar-

boxylique-2,

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  (48) 3- [3,4-Dimethoxybenzyl] piperazinyl] -8-acid

  9-chloro-5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizine

  2-carboxylic acid. (49) 1- [1- (3,4-Dimethoxyphenethyl) piperazinyl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2. (50) 3- [4- (4-ethoxyphenyl) propyl] piperazinyl] -8 -acetate

  9-chloro-5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizine

2-carboxylic acid.

  (51) [(2,3,4-Trimethoxyphenethyl) piperazic acid

  9-Nyl-9-chloro-5-methyl-6,7-dihydroxy-1H, 5H-benzo [i] quinoline

  zine-2-carboxylic acid. (52) 4- (trifluoroacetyl-4-piperazinyl) -8-bromoacidic acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (53) (1-trifluoromethyl-1-piperazinyl) -8-bromo-9 acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (54) (4-Allyl-piperazinyl) -8-bromo-9-methyl-5-acid

  6,6-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (55) (Pentafluoropropionyl-4-piperazinyl-1) -8 acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (56) (Heptafluorobutyryl-4-piperazinyl-1) -8 acid

  9-chloro-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (57) (Pentafluoropropionyl-4-piperazinyl-1) -8 acid

  10-chloro-5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizine

2-carboxylic acid.

  (58) (Heptafluorobutyryl-4-piperazinyl-1) -8 acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (59) 4- (Trifluoromethanesulfonyl-4-piperazinyl) -8-acid

  9-chloro-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (60) (Pentafluoropropionyl-4-piperazinyl-1) -8 acid

  9-chloro-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  (61) (Heptafluorobutyl-4-piperazinyl-1) -8 acid

  10-chloro-5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizine

  2-carboxylic acid. (62) 4- (Trifluoromethanesulfonyl-4-piperazinyl) -8-acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

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  (63) (4-Trifluoromethyl-1-piperazinyl) dihydric acid

  6,7-d-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2.

  The compounds of formula (I) of the invention can be prepared

  according to various processes, for example by reaction of a benzo [ij] quinolizinecarboxylic acid-2 of formula (II):

R2 O

xR4 COOH

R4 / N

  R 1 o R 4 represents a halogeno radical, a lower alkanesulphonyloxy radical or an arylsulphonyloxy radical and R and R have the same meanings as above, with a piperazine derivative of formula (III)

HE N-R (III)

  o R3 has the same meaning as above.

  The term "lower alkanesulfonyloxy" applied to R denotes a straight or branched alkanesulfonyloxy radical comprising

  1 to 4 carbon atoms such as a methanesulfonyloxy radical, ethane-

  sulfonyloxy, propanesulfonyloxy, isopropanesulfonyloxy, butane-

  sulfonyloxy or tert-butanesulfonyloxy and the like.

  The term "arylsulfonyloxy" refers herein to

  description, a benzenesulfonyloxy, naphthalenesulphonyloxy radical,

  or the like. The aryl ring of the arylsulphonyloxy radical may be substituted by one or more> preferably 1 to 3, halo radicals,

  lower alkyls, lower alkoxy, hydroxy, nitro and the like.

  As regards the compounds of formula (II) which can be used as a starting material for preparing the compounds of the invention represented by formula (I), some of those where R 4 is a halogeno radical are known compounds described in U.S. Patent Nos. 3,917,609, 3,896,131,

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  Nos. 3,985,882, 3,969,463, 4,001,243 and 4,014,877 and the others can be easily prepared by a suitable choice of starting materials, according to known methods, as described in US Pat.

  Japanese Patent No. 6156/76 and the United States Patent of

No. 4,014,877. They can also be prepared according to reaction scheme 2 below. On the other hand, the compounds of formula (II)

  R represents a lower alkanesulfonyloxy or arylsul radical;

  fonyloxy, that is to say the compounds of formula (IIa) are new and can for example be prepared according to the reaction scheme 1

below.

  In Reaction Scheme 1 below, R is lower alkanesulfonyl or arylsulfonyl, R is lower alkyl, X is halo and R is

  R have the same meaning as before.

  It is therefore possible to prepare the compounds of formula (IIa) to react a compound of formula (IV) with a compound of formula (VI) to form a compound of formula (VIII) and then to react this compound with a compound of formula (IX ) to obtain a compound of formula (X) and to cyclize the compound of formula (X) to form a

  compound of formula (XI) which is then subjected to hydrolysis.

  Among the compounds of formula (VIII), it is also possible to prepare those where R represents a hydrogen atom by reaction of a compound of formula (V) with a compound of formula (VI) for

  forming a compound of formula (VII) and reducing this compound. The com

  poses of formula (IV) and (V) are known and described for example in

  U.S. Patent No. 4,014,877.

  In Reaction Scheme 1 hereinafter, the appropriate amount of the compound of formula (VI) which is reacted with the compound of formula (IV) is an at least approximately equimolar amount. Preferably, 1 to 2 moles of the compound are reacted

  of formula (VI) per mole of the compound of formula (IV).

  The reaction is generally carried out in an inert solvent in the presence of a deoxidizing agent in an at least approximately equimolar amount and preferably with from 1 to 2 moles of the deoxidizing agent per mole of the compound of formula (VII) at a

  temperature of about 0 to about 100 ° C, preferably at room temperature.

  for about 0.5 to about 6 hours to obtain the compound of formula (VIII). Examples of suitable deoxidizing agents include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and the like. , etc., mineral carbonates

  such as sodium carbonate, potassium carbonate, bi-

  potassium carbonate, sodium bicarbonate, etc. and tertiary amines such as pyridine, quinoline, triethylamine, etc.

  Examples of suitable inert solvents are

  of lower alcohols such as methanol, ethanol,

  propanol, etc., ethers such as dioxane, tetrahydrofuran (THF), diglyme, etc., aromatic hydrocarbons such as

  benzene, toluene, etc., dimethylsulfoxide (DMSO), dimethyl-

  formamide (DMF), hexamethylphosphorotriamide (HMPTA), pyridine, etc. More particularly, according to the reaction scheme 1, the reaction between the compound of formula (VIII) and the compound of formula (IX) can be carried out in the absence of a solvent or in the presence of solvents such as the lower alcohols previously described,

  DMF, DMSO, HMPTA, acetonitrile and the like. Preferably

  The reaction is carried out in the absence of a solvent.

  The compound of formula (IX) may be used in molar excess relative to the compound of formula (VIII), preferably in

  equimolecular quantity in the absence of solvent, and

  1.1 to 1.5 moles per mole of the compound of formula (VIII) in

  solvent. The reaction can generally be carried out at a temperature between ordinary temperature (about 15 to 30 ° C) and about 150 ° C, preferably 100 ° to 1300 ° C for a period of about 0.5 to about 6 hours to obtain easily

the compound of formula (X).

  The cyclization reaction of the compound can be carried out

  of formula (X) thus obtained according to conventional cyclic

  for example by heating the compound of formula (X) or by using an acidic substance such as phosphorus oxychloride,

  phosphorus pentachloride, phosphorus trichloride, chlorine

  thionyl chloride, concentrated sulfuric acid, polyphosphoric acid

  and the like. When cyclization is carried out by heating, it is preferred to heat the compound of formula (X) in a solvent such as a high boiling point hydrocarbon or a pointwise ether.

  boiling point, for example diphenyl ether tetra-

  phosphoric acid, dimethyl ether of diethylene glycol, etc. at a temperature of about 100 to about 250 ° C, preferably about 150 to about C for a period of about 0.5 to about 6 hours. When carrying out the cyclization with an acidic substance, it is possible to operate in the presence of an amount of the acid substance of between about the molar equivalence and a large excess, preferably a molar excess of 10 to 20 times, relative to the amount of the compound of formula (X) at a temperature of about 100 to about 150 ° C for a period of about 0.5 to about 6 hours to obtain

  advantageously the desired compound of formula (XI).

  According to the reaction scheme 1 below, the hydrolysis of the compound of formula (XI) in compound of formula (IIa) can be carried out according to a conventional hydrolysis technique in the presence of a typical hydrolysis catalyst, for example a basic compound such as hydroxide

  sodium hydroxide, potassium hydroxide, barium hydroxide and the like.

  or a mineral acid such as sulfuric acid, hydrochloric acid, nitric acid and the like or an organic acid

  such as acetic acid, aromatic sulfonic acid and the like.

  The hydrolysis can be carried out in a solvent such as water, the abovementioned alcohols and ethers, ketones such as acetone, methyl ethyl ketone, dioxane, ethylene glycol and the like. and the acid

  acetic acid and the like at a temperature between

  around 2000C, preferably between 50 and 150C

  lasting from about 0.5 to about 6 hours to easily

the compound of formula (IIa).

  The reaction can be made up of

  mule (V) and the compound of formula (VI) in the same way as the reaction

  of the compound of formula (IV) with the compound of formula (VI) for

  obtain a compound of formula (VII).

  According to reaction scheme 1 below, it is possible to reduce

  the compound of formula (VII) by catalysis or with a hydro-

  conventional generation such as a combination of sodium borohydride or lithium aluminum hydride and a lower fatty acid

2467205 I

  for example, acetic acid, trifluoroacetic acid, propionic acid, etc. Suitable amounts of sodium borohydride or lithium aluminum hydride and lower fatty acid are between approximately the molar equivalence and a large

  preferably 3 to 5 moles excess per mole of the compound of formula (VII).

  It is advantageous to carry out the reduction with a hydrogenation agent in an inert solvent such as the ethers described above, aromatic hydrocarbons, and lower fatty alcohols such as acetic acid, trifluoroacetic acid,

  propionic acid, etc., at a temperature between

  at about 1000C, preferably between 50 and 1000C for about 1 to about 6 hours to obtain the

  formula (VIII) where R represents a hydrogen atom.

  In the formulas of Reaction Scheme 2 below, R, R and X have the same siginifications as before.

  In reaction scheme 2 below, it is possible to carry out

  nitration of the compound of formula (XII) under standard conditions

  In the absence of a solvent or in the presence of a suitable inert solvent with a nitrating agent, the nitrating compounds are nitrated. The compounds of formula (XII) are known compounds described in U.S. Patent No. 4,014,877 and in US Pat.

J.A.C.S. 70, 2381 (1948).

  Examples of suitable inert solvents are acetic acid, acetic anhydride, concentrated sulfuric acid, and the like. Examples of suitable nitrating agents are fuming nitric acid, concentrated nitric acid, mixed acid (mixture of nitric acid and sulfuric acid, fuming sulfuric acid, phosphoric acid or anhydride). acetic acid), alkali metal nitrates such as potassium nitrate and sodium nitrate and sulfuric acid, etc. The reaction is advantageously carried out in the presence of at least an equimolar amount, preferably an excess of

  the nitrating agent with respect to the starting compound at a temperature of

  preferably between 0 and 150 ° C. for 1 to 4 hours.

  The reduction of the nitro radical of the compound of formula (XIII), obtained in the above nitration, can be carried out in an inert solvent in the presence of a reducing agent such as a mixture of iron, zinc, tin or stannous chloride and an acid (eg hydrochloric acid or sulfuric acid) or a mixture of iron, iron sulphite, zinc, tin or stannous chloride and hydroxide sulphate, sulphite, etc. of an alkali metal. Otherwise, the reduction can be carried out by catalysis with a catalyst of

  reduction such as palladium on carbon in an inert solvent.

  Examples of suitable inert solvents are

  water, acetic acid, methanol, ethanol, dioxane, etc. The conditions under which the above reduction of the nitro radical can be suitably chosen. For example, the reduction can advantageously be carried out with a mixture of stannous chloride and hydrochloric acid as reducing agent at a temperature of 70 to 1000 ° C. for 0.5 to 1 hour with at least an equimolar amount, preferably 1 to 2 moles of the reducing agent per mole of the starting compound. When a catalytic reduction is carried out, it is advantageous to operate on the

  ordinary temperature for 0.5 to several hours.

  The amino group of the compound of formula

  mule (XIV) thus obtained by a halo radical according to a Sandmeyer reaction involving diazotation. We can perform

  diazotization of the compound of formula (XIV) in a

  such as water, hydrochloric acid, sulfuric acid, etc. in the presence of a diazotising agent such as a mixture of sodium sulfite or potassium nitrite and hydrochloric acid or

  sulfuric acid at a temperature between -30 ° C and the temperature

  ordinary temperature for 0.5 to 2 hours. Then the diazonium salt of the compound of formula (XV) thus contained can be reacted, without isolating it, with a halogenating agent such as chloride.

  cuprous, cuprous bromide, etc. in an amount at least equi-

  and preferably with 1 to 2 moles of the halogenating agent per mole of the starting compound at a temperature of 0 to 50 C for

  0.5 to 2 hours to form a compound of formula (XV).

  Catalytic reduction of the pyridine ring of the compound of formula (XV) can be carried out in an inert solvent such as dioxane, tetrahydrofuran, acetic acid, water, etc. in acidic conditions with various acids capable of forming a quinolinium salt such as acetic acid, hydrochloric acid, sulfuric acid, etc. in the presence of a catalytic reducing agent such as platinum charcoal, palladium charcoal, rhodium charcoal, ruthenium charcoal, etc. at a temperature between the ordinary temperature and 50 C for 1 & 10 hours to obtain a

compound of formula (XVI).

  Alternatively, it is also possible to prepare the compound of formula (XVI) to reduce the pyridine ring of the compound of formula (XIV) to form a compound of formula (XVII) and then replace the amino radical of the compound of formula (XVII) with a halogeno radical. . The pyridine ring of the compound of formula (XIV) of the same

  whereby the pyridine ring of the compound of formula (XV) is reduced.

  Also, the amino group of the compound of formula (XVII) can be replaced by a halogeno radical in the same way as the

  amino group of the compound of formula (XIV) with a halo radical.

  In addition, to prepare the compound of formula (XVII), the compound of formula (XIII) can be reduced in the same manner as

  reduces the pyridine ring of the compound of formula (XIV).

  The compound of formula (XVI) thus obtained and the compound of formula (IX) can be reacted under the same conditions as

  reacts the compound of formula (VIII) and that of formula (IX).

  Compound (XVIII) formed in the above reaction can be cyclized and hydrolyzed cyclized compound of formula (XIX) in the same manner as the compound of formula (X) is cyclized and the compound of formula (X) hydrolyzed ( XI), to obtain the compound

of formula (IIb).

  Some of the compounds of formula (III) which are other starting compounds used in the invention are known and can be used.

  easily prepare the others according to known methods.

  In the reaction between the compound of formula (II) and the compound of formula (III) according to reaction scheme 1, the second is preferably used in an amount at least equimolar relative to the first and preferably 1 to 5 moles of the second 2467205 compared to the first and in general, the reaction is carried out

  in an inert solvent such as water, the lower alcohols, hydro-

  aromatic carbides and ethers previously described, DMSO, DMF,

  HMPTA, etc. among which DMSO, DMF and HMPTA are preferred.

  In the reaction, the deoxidizing agent described above can be used. Advantageously, the reaction is carried out under a

  pressure of 1 to 20 bar and preferably 1 to 10 bar and b a temperature of

  100 to 250 ° C, preferably 140 to 200 ° C for 5 hours.

  20 hours to obtain the compound of formula (I) of the invention.

  In addition to preparing a compound of formula (I) of the invention, a compound of formula (XX) can be reacted with a compound of formula (XXI) in the presence of a deoxidizing agent.

  as previously described, according to reaction scheme 3 below.

  In the formulas of Reaction Scheme 3 hereinafter

  R1, R2, R3 and X have the same meanings as before.

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

  (II) with a compound of formula (III).

  More particularly, the reaction between a compound of formula (XX) and a compound of formula (XXI) can be carried out according to one of the processes described above, according to the nature of the R3 symbol,

of the compound of formula (XXI).

  1) R3 represents a substituted lower alkanoyl radical

  killed by one or more halo radicals.

  In this case, the reaction is carried out under standard acylation conditions, that is to say in the absence of a solvent or in an inert solvent such as the previously described ethers and aromatic hydrocarbons, DMSO, DMF, HMPTA, pyridine and halogenated hydrocarbons such as chloroform,

  methylene, etc., in the presence of a deoxidizing agent as

  described above, at a temperature of 0 to 100 ° C preferably at

  around the ordinary temperature for about 0.5 to 6 hours.

2467205I

  With regard to the proportions of the starting compounds, the compound of formula (XXI) may be used in an amount at least equimolar and preferably in a proportion of 1 to 2 moles per mole of the compound of formula (XX) in the presence of solvents. and in excess of the molecular equivalence with respect to the compound of

  formula (XX) in the absence of solvent.

  2) R3 represents a radical other than an alkali radical

  halo-substituted lower kernel.

  The reaction is carried out under standard alkylation or aralkylation conditions in the absence of a solvent or in a

  inert solvent with at least an equimolar amount, preferably

  1 to 2 moles, of the compound of formula (XXI) per mole of the compound of foinmule (XX), at a temperature between ordinary temperature and 150 C, preferably between 50 and 100 CO for 1 to 10 hours. One can also carry out the reaction with the agent of

  deoxidation previously described.

  Examples of suitable inert solvents are

  water, alcohols such as methanol, ethanol, isopropanol and

  panol, butanol, pentyl alcohol, isopentyl alcohol, etc., the aromatic hydrocarbons and ethers previously described, DMSO, DMF, IIMPTA etc., of which DMSO is preferred,

DMF and IDIPTA.

  In addition, the compounds of formula (I) of the invention may be prepared according to the process illustrated by the reaction scheme

4 below.

  In the formulas of scheme 4 below R, R> R and R4 have the same meaning as before, R5 and R represent

  each a hydrogen atom or a lower alkyl radical, R represents

  a lower alkyl radical, Y represents a hetero radical,

  aromatic ring having a tertiary nitrogen atom united by the nitrogen atom or a trialkylammonium radical and Z represents an anion. The compounds of formula (XXII) are known and described in US Pat. No. 4,014,877 and the compounds of US Pat.

  formula (XXIII) are known and marketed.

  According to reaction scheme 4, the compounds of formulas (XXIV), (XXV) and (XXVI) can be prepared under the same conditions as those for the preparation reactions of the compounds of formulas (X)

2467205 '

  and (XI) and the reaction between the compound of formula (II) and

layer of formula (III).

  To prepare the compound of formula (XXVII)

  reacting the compound of formula (XXVI) with a heterocyclic compound

  aromatic clique containing a tertiary nitrogen atom or a trialkyl-

  amine in the presence of an anion donor compound.

  Examples of heterocyclic compounds

  aromatic compounds containing an appropriate tertiary nitrogen atom, the py-

  ridine, alkyl-substituted pyridines such as picoline, lutidine, etc., quinoline and alkyl-substituted quinolines such as quinaldine, lepidin, etc. Examples of suitable trialkylamines are those in which each alkyl radical contains 1 to 6 carbon atoms, for example trimethylamine, triethylamine, tripropylamine, triisopropylamine, etc. Examples of suitable donor donor compounds are compounds capable of releasing a halogen ion.

  and compounds capable of releasing a sulfate, phosphate or

  chlorate for example iodine, bromine, chlorine, sulfuric acid, phosphoric acid, perchloric acid, etc. The aromatic heterocyclic compound can be used

  having a tertiary nitrogen atom or the trialkylamine

  described above and the anion donor compound in at least an equimolar amount and preferably at 1 to 2 moles per

mole of the compound of formula (XXVI).

  The reaction can be carried out in an inert solvent such as alcohols, aromatic hydrocarbons and ethers previously

  DMSO, DMF, HMPTA, pyridine, etc., at a temperature of

  It is between room temperature and 120.degree. C., preferably 50.degree. to 100.degree. C., for about 0.5 to 6 hours. We can use

  the compound of formula (XXVII) thus obtained in the subsequent hydrolysis

  after isolation of the reaction mixture and purification or

without isolation.

  The hydrolysis of the compound of formula (XXVII) can be carried out in a suitable solvent in the absence or presence of an acid or alkali, preferably in the presence of an alkali. Examples of alkalis include alkali metal hydroxides such as

2467205;

  sodium hydroxide, potassium hydroxide, etc., hydroxides,

  alkaline earth metals, such as calcium hydroxide, etc.,

  ammonium hydroxide or carbonates of these metals or of am-

  monium. As solvents it is possible to use the lower alcohols, aromatic hydrocarbons and ethers described above, water, pyridine, DMF, DMSO, HMPTA, etc. Hydrolysis can also be carried out in an aqueous medium containing a trialkylamine such as

  as trimethylamine, triethylamine, etc. In the hydrolysis

  above, the addition of a lower alcohol accelerates the reaction.

  The reaction is advantageously carried out at a

  temperature of 20 to 150 ° C, preferably 80 to 120 ° C, for about

  0.5 to 6 hours to obtain the desired compound of formula (I).

  The compounds of formula (I) prepared as previously described can form pharmaceutically acceptable salts with acids when these compounds of formula (I) have a basic group and these pharmaceutically acceptable salts are within the scope of the invention. The pharmaceutically acceptable acids which may be used for salification may be various organic or inorganic acids, for example hydrochloric, sulfuric, nitric, hydrobromic, phosphoric, acetic, oxalic, malonic, succinic, maleic, fumaric or malic acids.

  manddlic, ethanesulfonic, p-toluenesulfonic and the like.

  The compounds of formula (I) can be converted into a corresponding carboxylate by reaction of the carboxylic acid with a basic compound which is suitable for use in pharmacy. Examples of such basic compounds include basic inorganic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, sodium bicarbonate and the like and basic compounds organic compounds such as morpholine, piperazine,

  pyridine, piperidine, ethylamine, dimethylamine, tri-amine

  ethylamine, aniline and the like.

  Compounds of formula (I) and their salts can be isolated

  obtained as above as previously described, reaction mixtures

  corresponding reactions after completion of the reaction and purify them according to conventional techniques, for example solvent extraction,

  dilution, precipitation, recrystallization, chromatography,

column and the like.

  As is obvious to those skilled in the art, the compounds of formula (I) may exist in optically active forms and

  these optical isomers are within the scope of the invention.

  To use benzo [ij] quinolizine acid derivatives,

  The carboxylic acid-2 of the invention of formula (I) and their salts, as antimicrobial agents, can be combined with ordinary pharmaceutical carriers to form therapeutic compositions and pharmaceutical forms. Suitable carriers are, for example, diluents or excipients such as fillers,

  binders, wetting agents, disintegrants, surfactants,

  active ingredients and lubricants commonly used for this purpose according to the

nature of pharmaceutical forms.

  It is possible to choose according to various therapeutic objective

  forms of administration of therapeutic agents. Forms of admi-

  The typical drugs that can be used are tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, injectables (solutions, suspensions, etc.), ointments, etc. In order to form a compound from a pharmaceutical composition containing one or more compounds of formula (I) or their pharmaceutically acceptable salts as an active ingredient, it is preferred to formulate a pharmaceutical composition containing one or more compounds of formula (I) or their pharmaceutically acceptable salts as an active ingredient. can use a wide variety of media known in the art. of the

  Examples of suitable media are excipients such as

  tose, sucrose, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, cellulose

  crystalline and silicic acid, binders such as water,

  nol, propanol, simple syrup, glucose, a starch solution, a gelatin solution, carboxymethylcellulose, shellac,

  methylcellulose, potassium phosphate and polyvinylpyridine

  rolidone, disintegrams such as dried starch, sodium alginate, powdered agar, laminar powder, sodium bicarbonate, calcium carbonate, Tween, sodium lauryl sulfate, acid monoglyceride stearic acid, starch and lactose, dekintegration inhibitors such as sucrose, a glycerol ester of stearic acid, cocoa butter and oils 2467205i

  hydrogen, absorption enhancers such as amine bases,

  quaternary monium and sodium lauryl sulphate, 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 of a poly-

  ethylene glycol from Shinetsu Chemical Industry Co., Ltd.) and poly-

solid ethylene glycol.

  If desired, the tablets can be coated and converted into coated tablets, gelatin-coated tablets, intestinal disintegrating tablets, film-coated tablets

  or tablets consisting of two or more layers.

  For shaping the therapeutic pill composition a wide variety of conventional carriers known in the art can be used. Examples of suitable carriers are excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oils, kaolin and talc, binders such as

  gum arabic powder, gum tragacanth powder, gelatine

  tine and ethanol and disintegrants such as laminaria and

agar.

  For shaping a pharmaceutical composition into

  sitoires, a large variety of known media can be used

  in art. Examples of suitable supports are polyethylene

  glycol, cocoa butter, higher alcohols, esters of alcohols,

  higher cools, gelatin and semi-synthetic glycerides.

  Injectable pharmaceutical compositions are

  preferably isotonic sterile solutions and suspensions to the blood.

  To prepare pharmaceutical solutions or suspensions, all diluents commonly employed in the art can be used. We can

  Examples of suitable diluents are water, ethyl alcohol and

  propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylenesorbitol and sorbitan esters. Sodium chloride, glucose or glycerol may be incorporated into a therapeutic agent, for example an agent for the treatment of nephritis, in an amount sufficient for the solution to be isotonic. The therapeutic agent may further contain customary components such as dissolution aids, buffers, pain relievers, and preservatives and optionally dyes, fragrances, flavors, sweeteners and other drugs. To form a pharmaceutical composition into a paste, a cream or a gel, it is possible to use as a diluent

  white petrolatum, paraffin, glycerol, derivatives of this

  lulose, polyethylene glycol, silicone, etc.

  The amount of compound of formula (I) and salts

  corresponding pharmacy of the invention, which is incorporated

  as an active ingredient to a therapeutic antimicrobial composition

  biennial has no particular limitation and may vary in a wide range. The effective therapeutic amounts of the compounds of general formula (I) and their pharmaceutically acceptable salts of the invention are generally from about 1 to about 70% by weight and preferably from 5 to 50% by weight relative to

to the total weight of the compositions.

  There is no particular limitation on the use of the therapeutic agent and the therapeutic agent can be administered in appropriate routes to the corresponding dosage form. For example, tablets, pills, liquid preparations, suspensions,

  emulsions, granules and capsules. The pre-

  intravenous injectable solutions either alone or in combination

  association with ordinary auxiliaries such as glutamine

  and amino acids. In addition, if necessary, injectable preparations can be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally. The suppositories are administered rectally and the ointments are applied to the skin. The dosage of administration of the antimicrobial agent depends on the intended use, symptoms, etc. Generally the preferred dosage of the compounds of the invention is from about 10 mg to 5 g / kg body weight per day in three to four times. The antimicrobial activity of the compounds of the invention

  has been studied as follows.

2467205.I

  Test Technique The antimicrobial activity of the following compounds was investigated on various microorganisms according to the serial dilution technique on gelose plates (Difco Co. heart infusion agar) (see Chemotherapy 22). , pp. 1126-1128 (1974)) and

  the minimum inhibitory concentrations (pg / ml) were determined.

  For the study, a sample of each of the microorganisms is prepared to obtain about 1 x 108 cells / ml

(D at 660mp = 0.13-0.14).

  Compounds of the invention studied 1. (9-Trifluoroacdtyl-piperazinyl-1) -8-chloro-9-acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  2. [(Trifluoro-2,2,2-ethyl) -4-piperazinyl] -8-acid

  9-chloro-5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizine

2-carboxylic acid.

  3. (Pentafluoropropionyl-4-piperazinyl-1) -8 acid

  9-chloro-5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizine

* carboxylic-2. 4. (8-pentafluorobutyryl-4-piperazinyl) -8-chloro-9 acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  5. [(4-Hydroxyethyl) -4-piperazinyl] -8 fluoro-9 acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  6. [(4-Methoxy-benzyl) -4-piperazinyl] -8-chloro-9

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

  7. (4-Allyl-piperazinyl) -8-chloro-9-methyl-5-acid

  6,7-dihydrooxo-1H, SH-benzo [i] quinolizinecarboxylic-2.

  8. [(2-propyl-1-yl) -4 pipErazinyl-1] -8-chloro-9 acid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2.

Comparative compounds

  A. Ethyl-1-dihydro-1,4-methyl-7-oxo-4-naphthyridine

  1,8 carboxylic acid-3 (nalidixic acid).

  B. 9-Fluoro-5-methyl-6,7-dihydrooxo-1H, 5SH-

  benzo [ij] quinolizinecarboxylic-2 (flumtquin).

  Micro-orRanisms studied: Her Staphylococcus aureus VDA 209 P Sp Streptococcus pyogenes IID S-23 Ec Escherichia coli NIHJ JC-2 (IFO 12734) Kp Klebsiella pneumoniae Pr Proteus rettgeri NIH 96 St SsalmDnella typhi 0-901 (NCTC 8393) Ss Shigella sonnei EW 33 Sm Serratia 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 the table below.

  The results in the table below show that the compounds of the invention have a potent antibacterial activity

  compared to nalidixic acid and flumequine.

  Acute Toxicity The acute toxicity of the compounds (I) of the invention is

  determined by intravenous administration to fasting mice

  12 hours before the test. LD50 values (50% lethal dose) are

  for all compounds are at least 500 mg / kg.

  The invention is illustrated by the reference examples,

  examples and examples of preparation that are not

  limiting. Unless otherwise indicated, parts, percentages

  and ratios are by weight.

  Unless otherwise indicated, elementary analyzes have been

  were determined on samples at 70-80 C maintained under pres-

  reduced pressure (11 mmHg) for 6 hours with P 2 O 5 as a dehydrogenation

  dratant. Reference Example 1 10 g of 5-hydroxy-3,4-dihydro-carbostyril are added to 100 ml of methanol in which 3.8 g of potassium hydroxide have been dissolved and the mixture is stirred at room temperature for ethanol is removed under reduced pressure. Benzene is added to the residue to form crystals and then the benzene is distilled off. The residue thus obtained is suspended in 50 ml of dimethylformamide and 10.6 g of methanesulfonyl chloride are added dropwise to the suspension under ice-cooling and with stirring. 3.5 g of chloride of

  methanesulfonyl and the resulting mixture is stirred at room temperature.

  for 4 hours. When the reaction is complete, we hunt

  the solvent under reduced pressure and the residue is purified by chromatography.

  silica gel column chromatography (silica gel: Wako C-200, trade name of a product of Wako Junyaku Co., Ltd., eluent: chloroform). The eluate is recrystallized from aqueous ethanol to give 5.7 g of 5-methanesulfonyl-5-dihydro-3,4-carbostyryl in the form of colorless prismatic crystals having a melting point of

227 to 231 C.

  Reference Example 2 As in Reference Example 1, p-toluenesilfonyloxy-5-dihydro-3,4-carbostyril having a

fusion of 215-216 C.

  Reference Example 3 4.5 g of 5-methanesulfonyloxy-3,4-dihydro-carbostyril are suspended in 90 ml of dioxane and 35 g of sodium borohydride are added to the suspension. 5.3 ml of acetic acid is then added dropwise to the mixture. After refluxing for 1 hour, the solvent is removed under reduced pressure. To the residue is added a saturated aqueous solution of sodium bicarbonate to

  form a precipitate which is filtered and washed with chloroform. The filtrate is extracted with chloroform and the chloride layer is dried.

  roformic over sodium sulfate and then the solvent is removed. The residue is purified by chromatography on a column of silica gel (silica gel: Wako C-200, trade name of a product of Wako Junyaku Co., Ltd., eluent: chloroform) and the eluate thus obtained is crystallized. in petroleum ether. The crystals are recrystallized

  thus obtained in methanol to obtain 1.9 g of methanesulphonyl-

  5-oxy-1,2,3,4-tetrahydroquinoline in the form of colorless prisms

  having a melting point of 74 to 76 C.

  Reference Example 4 As in Reference Example 3, p-toluenesulfonyloxy-5-tetrahydro-1,2,3,4 quinoline having one point is prepared.

melting point of 112 to 113 ° C.

  Reference Example 5 21.6 g of ethyl ethoxymethylenemalonate are added to 22.4 g of 5-methanesulfonyloxy-1,2,3,4-tetrahydroquinoline and

  The mixture is heated to 110 ° C. in an oil bath while stirring for 30 minutes.

  during which the distillation of ethanol is observed. After heating, 240 g of polyphosphoric acid prepared from 120 g of phosphoric acid and 120 g of pentoxide are added to the mixture.

  phosphorus and the mixture is allowed to react with the oil bath at 140.degree.

  45 minutes. After completion of the reaction, the mixture is allowed to cool to room temperature and poured into 400 ml of water.

2467205 -

  then the mixture is neutralized with 40% aqueous sodium hydroxide solution to precipitate crystals. We mix

  crystals thus obtained to 150 ml of a 10% aqueous solution of hy-

  sodium hydroxide and reflux the mixture for 40 minutes during which the crystals dissolve to form a uniform solution. The solution is heat treated with activated charcoal and filtered. The filtrate is allowed to cool and the pH is adjusted to 2 to

  precipitate crystals that are filtered. We recrystallize the crystals

  crude levels thus obtained in dimethylformamide to obtain 21.3 g

  8-methanesulfonyloxy-6,7-dihydroxy-1H, 5H-benzo [i] quinoline

  lizinecarboxylic-2 in the form of white needles having a point

melting point 270 to 275 C.

  Reference Example 6 As in Reference Example 5, the acid is prepared

  p-toluenesulphonyloxy-8-dihydro-6,7-oxo-1H, 5H-benzo [i] quinolizine

  carboxylic acid-2 having a melting point of 300 C or higher.

  Reference Example 7 It is heated in an oil bath between 170 and 180 C during

  6 hours stirring 19.2 g of 8-chloro-6,7-dihydro-1-oxo-1H, 5H-

  benzo [ij] quinolizinecarboxylic-2 and 35.5 g of anhydrous piperazine.

  When the reaction is complete, the solvent is removed under reduced pressure. 500 ml of water are added to the residue and the pH of the mixture is adjusted to 2 and the insoluble matter in water is filtered. The filtrate is concentrated to 100 ml under reduced pressure and basified (pH = 9) with a 10% aqueous solution of sodium hydroxide. After extracting the chloroform solubles from the aqueous alkaline solution, the aqueous alkaline solution layer is allowed to stand for precipitation of crystals which is filtered. The crude crystals thus obtained are dissolved in 10 ml of a 10% aqueous solution of sodium hydroxide and the solution is treated with activated charcoal and the pH is adjusted to 8 with a 10% aqueous solution 7. hydrochloric acid to precipitate

  crystals filtered and washed with enough water. We are

  crystallizes the crystals in dimethylformamide to obtain 6.5 g

  (1,2-piperazinyl) -6,7-dihydro-oxo-1H, 5H-benzo [i] quinolizine

  carboxylic acid-2 in the form of white needles having a

fusion of 267 to 268 C.

  6.4 g of acid are suspended in 50 ml of water.

  (1,2-piperazinyl) -6,7-dihydrooxo-1H, 5H-benzo [i] quinolizine

  carboxylic acid-2 and 15 ml of a solution are added to the solution obtained.

  aqueous 10% hydrochloric acid. Inso-

  After filtration, the water is distilled off to obtain 5.7 g of (piperazinyl-1) -8-dihydro-6,7-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid hydrochloride. 2 in the form of crystals

  amorphous whites having a melting point of 300 C or more.

  Reference Examples 8 to 11 As in Reference Example 7, the following are prepared:

following compounds.

  Reference Example 8 (Piperazinyl-1) -8-methyl-5-dihydro-6,7-oxo-1H, H-benzo [i] quinolizinecarboxylic acid-2 in the form of colorless needles

  having a melting point of 264-265 C.

  Reference Example 9 (9-pipdrazinyl) -9-chloro-5-methyl-6-dihydro-6,7-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2 as crystals

  white rhombic having a melting point of 246 & 247 C.

  Reference Example 10 (Piperazinyl-1) -8-chloro-6-dihydro-6,7-oxo-1H, 5H-benzo [i] quinolizinecaboxylic acid hydrochloride-2 in form

  white amorphous crystals having a melting point of 300 C or higher.

  Reference Example 11 (Piperazinyl-1) -8-chloro9-dihydro-6,7-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid hydrochloride in form

  white amorphous crystals having a melting point of 300 C or higher.

  Reference Example 12 11 g of 6-chloro-guinaldine are dissolved in 15 ml of concentrated sulfuric acid and the solution is cooled with ice. A solution of 7.1 g is then added dropwise to the solution.

  of potassium nitrate dissolved in 20 ml of concentrated sulfuric acid

  In addition, the reaction temperature is maintained at or below OC. After completion of the addition, the mixture is stirred at the same temperature as above for one hour and then poured onto 200 g of ice. The mixture is then basified with 10% sodium hydroxide, ensuring that

  does not rise above 20 C to form a

  pale yellow peit. The precipitate was collected by filtration, washed with water and recrystallized from ethanol to give 12 g of 6-nitro-6-chloro-quinaldine as pale yellow rhombic crystals having a melting point of 123-124 ° C. Reference Example 13 To 50 ml of concentrated hydrochloric acid in which 25 ml of stannous chloride was dissolved, 6.7 g of 5-nitro-6-chloro-quinaline was added and the mixture was allowed to react in a water bath.

  between 80 and 90 C for 30 minutes. The reaction mixture is cooled

  On ice, the mixture is basified (pH 10) with 30% sodium hydroxide, filtered and extracted with 500 ml of chloroform and celite (diatomaceous earth). After drying on sulphate of sodiun

  anhydrous, the chloroform fraction is concentrated and recrystallized

  in a mixture of benzene and hexane to obtain 4.6 g of 5-amino-6-chloro-quinaldine in the form of colorless tables having a

melting point 196 to 197 C.

  REFERENCE EXAMPLE 14 4 g of 5-amino-6-chloro-quinalidine was dissolved in 40 ml of concentrated hydrochloric acid and the solution obtained was cooled with ice. A solution of 2.1 g of sodium nitrite dissolved in 5 ml of water is then added dropwise under cooling with ice. The reaction is allowed to proceed at the same temperature as above, then a solution of 7 g of cuprous chloride dissolved in 15 ml of concentrated hydrochloric acid is added to the reaction mixture and the mixture is allowed to react with the water bath for one hour, during which there is a significant release of nitrogen. The reaction mixture is then cooled, basified with 30% sodium hydroxide, filtered and extracted with 300 ml of chloroform and celite (diatomaceous earth). After drying over anhydrous sodium sulphate, the chloroform fraction is concentrated

  and recrystallized from a mixture of isopropanol and water to obtain

  add 3.5 g of dichloro-5,6 quinaldine in the form of white needles

  having a melting point of 84 to 85 C.

  Reference Example 5,5 g of 5,4-dichloro-quinaldine are dissolved in 50 ml of acetic acid and 0.1 g of 5% platinum charcoal are added to the solution, and then the catalytic reduction is carried out using the Pearl process. compounds under a hydrogen gas pressure of 4 bar. When the theoretical amount of hydrogen has been absorbed, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. After alkalinization with 50 ml of 20% aqueous sodium hydroxide, the residue is extracted with 100 ml of chloroform. The residue is dried by adding anhydrous potassium carbonate and concentrated to give 4.4 g of 5,6-dichloro-1,2,3,4-tetrahydroquinaldine under

form of an oily product.

  NMR analysis in CDCl13 6: 1.23 (d, 3H, J = 6Hz), 1.7 (m, 2H), 2.72 (m, 2H), 3.28 (m, 1H), 3, 75 (m, 1H), 6.62 (q, 2H, J = 9Hz) Reference Example 16 A mixture of 3.2 g of 5,6-dichloro-1-tetrahydro-1 is reacted by heating at 160 ° C. for 30 minutes. , 2,3,4 quinaldine and 3,2 g of diethyl ethoxymethylenemalonate. 13 g of polyphosphoric acid prepared from 6.5 g of phosphorus pentoxide and 6.5 g of phosphoric acid are then added to the mixture.

  the resulting mixture reacts hot at 140-150 ° C for one hour.

  When the reaction is complete, the mixture is poured onto 100 g of ice and the pH is adjusted to between 4 and 5 with an aqueous solution of sodium hydroxide to precipitate crystals. The crystals are collected by filtration, dried and mixed with 50 ml of a 10% aqueous solution of sodium hydroxide. The mixture is allowed to react for one hour between 100 and 110 C. After cooling, the reaction mixture is acidified with concentrated hydrochloric acid to precipitate crystals. The crystals thus obtained are recrystallized from ethanol to give 2.3 g of 8,9-dichloro-5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2.

  having a melting point of 269 to 271 C.

  Reference Example 17 20 ml of hexamethylphosphorotriamide is added to a

  mixture of 3 g of 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-

  benzo [ij] quinolizinecarboxylic-2 and 5 g of anhydrous piperazine and

  the mixture is heated with stirring between 150 and 160 ° C. for 3 hours.

  When the reaction is complete, the solvent is removed under reduced pressure and the residue is washed with 10 ml of ethyl acetate. Dissolve

  the crystals obtained in 100 ml of water and adjust the pH of the solution.

  at 4 with acetic acid. Filtration is separated

  insoluble substances and the filtrate is treated with activated charcoal.

  The aqueous solution thus obtained is concentrated under reduced pressure and the residue is recrystallized from a mixture of isopropanol and water to obtain 1.8 g of (piperazinyl-1) -8-hydrochloride.

  9-chloro-5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarbonate

  box-2 having a melting point of 300 C or more.

  The hydrochloride is dissolved in water with addition of a 2% aqueous solution of sodium hydroxide and the pH is adjusted to 9 with 1N hydrochloric acid to obtain crystals.

  white having a melting point of 246 to 247 C.

  EXAMPLE 1 A mixture of 2.5 g of (9-piperazinyl) -9-chloro-9-methyl-6,7-dihydroxy-1-oxo-l is refluxed for 3 hours.

  1H, 5H-benzo [ij] quinrolizinecarboxylic-2 and 50 ml of trisodium

  -fluoro. When the heating is complete,

  the excess trifluoroacetic anhydride is reduced under reduced pressure, 50 ml of water are added to the residue and the mixture is then stirred to precipitate

  white crystals. The crystals are recrystallized from dimethyl

  formamide to give 2.3 g of (4-trifluoroacetylpiperazine)

  9-N-chloro-5-methyl-6-dihydro-6,7-oxo-1H, 5H-benzo [i] quinoline

  lizinecarboxylic-2 in the form of white rhombic crystals having

  a melting point of 300 C or more.

  Elemental analysis for C20H19GClF3N304: (Molecular weight: 4575

C H N

  Found (%) 52.46 4.15 9.18 Calculated (%) 52.31 4.11 9.22

Example 2

  A mixture of 1 g is heated at 80 ° C. for 5 hours.

  of 9-piperazinyl-8-chloro-9-methyl-6-dihydro-6,7-oxo-1H, 5H-

  benzo [ij] quinolizinecarboxylic-2, 15 ml of dimethylformamide, 1.2 ml of 2,2,2-trifluoroethyl iodide and 2 ml of triethylamine. After cooling, the insoluble substances are removed by filtration and the filtrate is concentrated under reduced pressure. The residue is mixed

  with 30 ml of water, and the insoluble substances are separated by filtration.

2467205,

  After concentration under reduced pressure, the filtrate is purified by chromatography on a column of silica gel [silica gel: Wako C200, trade name of a product of Wako Junyaku Co., Ltd .; eluent: chloroform / methanol (9/1 by volume)) to obtain 0.5 g of [(trifluoro-2,2,2 ethyl) -4 piperazi] iodide monohydrate;

  9-N-chloro-9-methyl-6-dihydro-6,7-oxo-1H, 5H-benzo [i] quinoline

  lizinecarboxylic-2 in the form of white rhombic crystals having

a melting point of 298 to 299 C.

Example 3

  A mixture of 0.8 g of (piperazinyl-1) -8-chloro-9-methyl-5-dihydro-6,7-oxo-1H, 5H-benzo [i] monohydrate is allowed to react with heating at 90 ° C. for 5 hours. ] quinolizine, 0.4 ml of propyne-2-yl bromide, 0.8 ml of triethylamine and 10 ml of dimethylformamide. When the reaction is complete, the insoluble substances are filtered off. After concentration under reduced pressure, the filtrate is purified by chromatography on a column of silica gel [silica gel: Wako C-200, trade name of a product of Wako Junyaku Co., Ltd .; glutinous: chloroform / methanol

  (8/1 by volume)] to obtain 0.3 g of [(propyne-2-yl) -4 piper-

  9-zinyl-9-chloro-5-methyl-6,7-dihydro-oxo-1H, 5H-benzo [i] quinoline

  lizine as pale yellow rhombic crystals having a point

melting point 211 to 213 C.

Example 4

  A mixture of 1 g of (9-piperazinyl) -9-chloro-5-methyl-6-dihydro-6,7-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid (2 g) is stirred at room temperature for 3 hours. 0.6 ml of triethylamine, 0.6 ml of trifluoromethanesulfonyl chloride and 15 ml of dimethylformamide. When stirring is complete, the solvent is removed under reduced pressure to concentrate the reaction mixture. Pale yellow crystals precipitate when ml of water is added to the concentrate. The crystals are recrystallized from a mixture of dimethylformamide and water to give 0.7 g of (4-trifluoromethanesulfonyl-1-piperazinyl) -8-chloro-9-methyl-6,7-dihydroxy-1-oxo-1H, SH- benzo [ij] quinolizinecarboxylic-2 in form

  a pale yellow powder having a melting point of 232 to 235 C.

Examples 5 to 13

  The following compounds are prepared as in Example 4.

Example 5

  1- (9-allylpiperazin-1-yl) -9-chloro-5-methyl-6,7-dihydro-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2; point

melting point 226 to 227 C.

Example 6

  1- [9-chloro-ethyl] -4-piperazin-1-yl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2;

melting point 284 to 285 C.

Example 7

  4 - [(4-methoxy-benzyl) -4-piperazinyl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2;

mp 270 to 272 C.

Example 8

  1- [6-hydroxy-ethyl] -4-piperazinyl] -5-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [e] quinolizinecarboxylic acid-2;

melting point 228 to 230 C.

Example 9

  (9-Pentafluoropropan-9-chloro-4-piperazinyl) -8-methyl-5-dihydro-6,7-oxo-1H, 5H-benzyl] quinolizinecarboxylic acid;

melting point 295 to 296 C0.

Example 10

  (9-Heptafluorobutyryl-4-piperazin-1-yl) -9-chloro-5-methyl-6,7-dihydro-1H, 5H-benzo] quinolizinecarboxylic acid;

melting point 269.5 to 270.5 C.

Example 11

  2- [9-Hydroxyethyl) -1-piperazinyl] -9-fluoro-5-methyl-6,6-dahydroxo-1H-benzo [i] quinolinecarboxylic acid-2;

melting point.288 at 290 ° C.

Example 12

  A mixture of 3.1 g of 8,9-dichloro-5-methyl-6,7-dihydrohydroxide is heated at 160 ° C. for 4 hours under an argon atmosphere.

  1-oxo-1H, 5H-benzo [ij] quinolizinecarboxylic-2, 9,1 g of trifluoro-

  acetyl-1 piperazine and 50 ml of HMPTA. After completion of the reaction, the solvent is distilled off under reduced pressure and

  Wash the residue with water. The residue is recrystallized from dimethyl

  formamide to give 2.3 g of (4-trifluoroacetylpiperazine)

  9-methyl-9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinoline

  lizinecarboxylic-2 in the form of white rhombic crystals having a melting point of 300 C or higher.

Example 13

  It is heated with stirring at 160 ° C. for 5 hours under

  argon atmosphere, a mixture of 1.6 g of 8.9 dichlorodoro

  6,7-methyl-5-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2, 3.2 g of (propyne-2-yl) -1 piperazine and 25 ml of HMPTA. After completion of the reaction, the solvent is distilled off and the residue is washed with water. The residue is dissolved in 100 ml of water and the insoluble substances are separated by filtration. Fractions are extracted

  with 200 ml of chloroform and the chloroform fraction is dried

  formic anhydrous sodium sulfate. After concentration, the concentrate is purified by chromatography on a column of silica gel [silica gel: Wako C-200, trade name of a product of Wako Junyaku Co., Ltd .; eluent: chloroform / methanol (9/1 by volume)] to obtain 1,2 g of [(2-propyl-2-yl) -4-piperazinyl] -8-chloro-9-methyl-5-dihydro-6,7-oxoate 1H, 5H-benzo [ij] quinolizinecarboxylic-2

  having a melting point of 211 to 213 C.

Examples 14 to 21

  The following compounds are prepared as in Example 13.

Example 14

  1- (9-allylpiperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid; point

melting point 226 to 227 C.

Example 15

  1- (9-Methoxy-benzyl) -4-piperazinyl] -9-chloro-9-methyl-5-dihydro-6,7-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2

Mp 270-272 ° C.

Example 16

  2- (9-hydroxy-ethyl) -4-piperazin-1-yl] -9-chloro-5-methyl-6,7-dihydro-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2;

melting point 228 to 230 C.

2467205.

Example 17

  1- [9-chloro-ethyl] -4-piperazinyl] -9-chloro-5-methyl-6,7-dihydroxy-1H, 5H-benzo [i] quinolizinecarboxylic acid-2; mp 284 to 285 ° C

Example 18

  1- (9-pentafluoropropionyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolin-2-carboxylic acid;

mp 295-296: C.

Example 19

  1- (9-heptafluorobutyryl-1-piperazinyl) -9-chloro-9-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [im] quinolin-2-carboxylic acid;

melting point 269.5 to 270.5 C.

Example 20

  1- (9-Trifluoromethanesulfonyl-1-piperazinyl) -9-chloro-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2;

m.p. 232-235C.

Example 21

  1- (4-hydroxy-ethyl) -4-piperazinyl] -9-fluoro-5-methyl-6,7-dihydro-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2;

m.p. 288-290C.

Example 22

  A mixture of 2.75 g of (4-trifluoroacetyl-1-piperazinyl) -9-chloro-9-methyl-5-acetyl-2-dihydro-6,7-oxo-1H, 5H-benzo [i] is heated at 100 ° C. for one hour. ] quinolizine, 3 g of iodine and 20 ml of pyridine. When the reaction is complete, the precipitated crystals are collected by filtration and washed with 10 ml of cold pyridine and 10 ml of methanol to give (4-trifluoroacetyl-1-piperazinyl) -8-chloro-9-methyl-5-iodide 6,7-dihydrooxo-1H, SH-benzo [i] quinolizinecarbonylmethylpyridinium-2. The compound is mixed with 50 ml of methanol and 50 ml of a 10% aqueous solution of sodium hydroxide and the mixture is refluxed for one hour. After completion of the reaction, the methanol is distilled off and the pH of the mixture is adjusted to 7 with

  hydrochloric acid to give 1.8 g of trifluoro-

  4-acetyl-1-piperazinyl-8-chloro-9-methyl-5-dihydro-6,7-oxo-1H, 5H-

  benzo [ijl] quinolizinecarboxylic-2 in the form of rhombic crystals

  whites having a melting point of 300 C or more.

2467205 '

Examples 23 to 32

  The following compounds are prepared as in Example 22.

Example 23

  1- (9-Trifluoro-2,2,2-ethyl) -4-piperazinyl] -8-chloro-9-methyl-5-dihydro-6,7-oxo-1H, 5H-benzo [i] quinolizine-car-

  boxylique-2; melting point 298 to 299 C.

Example 24

  2- [9-Hydroxyethyl) -1-piperazinyl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2;

melting point 228 at 230 ° C.

Example 25

  1- [9-chloroethyl] -4-piperazinyl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2;

fusion policy 284 to 285 C.

Example 26

  1- (9-allylpiperazin-1-yl) -9-chloro-5-methyl-6,7-dihydro-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2; point of

fusion 226 to 227 C.

Example 27

  4 - [(4-Methoxy-benzyl) -4-piperazinyl] -9-chloro-5-methyl-6,6-dihydro-7-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2;

mp 270 to 272 C.

Example 28

  1- [9-propyne-4-piperazinyl] -9-chloro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2;

mp 211-213 ° C.

Example 29

  1- (9-Pentafluoropropionyl-pipdrazin-1-yl) -9-chloro-5-methyl-6,6-dihydro-oxo-1H, 5H-benzofl] quinolizinecarboxylic acid;

* melting point 295 to 296 C.

Example 30

  1- (9-Heptafluorobutyryl-piperazinyl) -9-chloro-9-methyl-6-dihydro-6,7-oxo-1H, 5H-benzo [i] quinolin-2-carboxylic acid;

melting point 269.5 to 270.5 C.

Example 31

  1- (5-Trifluoromethanesulfonyl-1-piperazinyl) -5-methyl-6,7-dihydro-1-oxo-5H-benzo [i] quinolinecarboxylic acid;

melting point 232 to 235 C.

Example 32

  2- [1- (4-hydroxy-ethyl) -4-piperazinyl] -9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid-2;

m.p. 288-290C.

Example 33

  It is heated by stirring in an autoclave between 150 and C for 18 hours, under a stream of nitrogen at the pressure of

  bars, a mixture of 3.4 g of p-toluenesulphonyloxy-8-dihydroxy-

  6,7-oxo-1H, 5H-benzo [i] quinolizinecarboxylic acid, 2.9 g of

  1-trifluoromethyl piperazine and 200 ml of anhydrous dimethylsulfoxide.

  When the reaction is complete, the solvent and the excess of piperazine derivative are distilled off under reduced pressure and a mixture of methanol and ethanol is added to the residue. The precipitate formed is collected by filtration and washed with ether. The crystals obtained are suspended in a mixture of 200 ml of water and 40 ml of a 10% aqueous solution of hydrochloric acid and

  separates the insoluble materials by filtration. We neutralize the

  treated with a saturated aqueous solution of sodium bicarbonate and purified by column chromatography with Amberlite LH-20 (trade name of a product of Tokyo Organic Chemical Industries Ltd .;

  eluent: water, ethanol). The eluate is recrystallized from dimethyl

  formamide to give 1.7 g of 4-trifluoromethylpiperazine

  1-nyl-dihydro-6,7-oxo-11H, 5H-benzo [i] quinolizinecarboxylic-2 in the form of white rhombic crystals having a melting point

300 C or more.

Example 34

  With stirring in an autoclave at 150 ° C. for 17 hours under a stream of nitrogen at a pressure of bar, a mixture of 4.5 g of p-toluenesulphonyloxy-8-chloro-9-methyl-5-dihydro-6-one is heated with stirring in an autoclave. , 7,1-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-9.1 g of trifluoroacetyl-1 piperazine and 200 ml of anhydrous dimethylsulfoxide. The reaction mixture is treated as in Example 33 to obtain 2.3 g of (4-trifluoroacetylpiperazinyl) -8-acid.

  9-chloro-5-methyl-6,7-dihydrooxo-1H, 5H-benzo [ij] quinolizinecar-

  boxylic-2 in the form of white rhombic crystals having a point

melting point of 300 C or more.

2467205.

Example 35

  A mixture of 3.35 g of methanesulphonyloxy-8-dihydro-6,7 oxo-1H acid is heated with stirring in an autoclave at 170 ° C. for 20 hours under a stream of nitrogen at a pressure of 8 bar. 5H-benzo [1] quinolizinecarboxylic-2,9.1 g of 1-trifluoromethyl piperazine and 200 ml of anhydrous dimethylsulfoxide. The reaction mixture is treated as in Example 33 and then treated with concentrated hydrochloric acid to give 1.7 g of (4-trifluoromethyl-1-piperazinyl) -6,7-dihydroxychloroacid hydrochloride. l

  1H, 5H-benzo [ij] quinolizinecarboxylic-2 in the form of rhombic crystals

  white beakers having a melting point of 300 C or higher.

  Preparation Example 1 (4-Trifluoroacetylpiperazinyl) -8-hydrochloride

  9-chloro-5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinoline

  lizinecarboxylic-2 200 mg glucose 250 mg distilled water for injection q.s.p. 5 ml The active compound and glucose are dissolved in injectable distilled water and the solution is introduced into a 5 ml ampoule. The air is replaced by nitrogen, the ampule is sealed and sterilized at 121 ° C. for 15 minutes to obtain a preparation.

injectable.

  Preparation Example 2 (4-Trifluoroacetyl-piperazinyl-1) -8 chloro9

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinoline

  lizinecarboxylic-2,100 g Avicel (trade name for Asahi Kasei Kogyo Kabushiki Kaisha product) 40 g starch 30 g magnesium stearate 2 g TC-5 (trade name for hydroxypropyl methylcellulose produced by Shinetsu Chemical Industry Co Polyethylene glycol-6000 (molecular weight: 6000) 3 g Castor oil 40 g Methanol 40 g 2467205.i The active compound, Avicel, maize starch and magnesium stearate and then

  tablets with a conventional press (R: 10 mm) for

  cation (produced by Kikusui Seiyakusho Co., Ltd.). The resulting tablets are coated with a coating agent consisting of TC-5, polyethylene glycol-6000, castor oil and methanol for

  obtain film-coated tablets.

  Preparation Example 3 (4-Trifluoroacetyl-4-piperazinyl) -8-chloroacid

  5-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinoline

  zinecarboxylic-2 2 g Purified hydrated lanolin 5 g Wax from Japan 5 g White Vaseline 88 g Total 100 g Hot wax is melted in Japan and the active compound, purified lanolin hydrate and white petrolatum are added and melted again hot. Stir the mixture until it starts

  to solidify to prepare an ointment.

  Of course, various modifications can be made.

  by those skilled in the art to the devices or processes which have just been described solely by way of non-limiting examples without

depart from the scope of the invention.

2467205 1

REACTION SCHEME 1

  ## STR1 ## where R7X (VI) Reduction (t) O1R7 OR7 R7X (VI) R2 '

(VIII) 8

/ COOR

C H OCH = C 8

1 2 5 11COOR -

  (Ix) (VII) R2 (x) Hydrolysis - t R1 (IIa)

REACTION SCHEME 2 NO2 Nitration> (xm) Nitro radical reduction Cycle reduction %%%.

  pyridine Replacement of the amino radical

by a radical.

halog4no X

X I

4 'Reduction

(XVII)

  R1 (xv) Reduction of the pyridine ring x X X N 'M1 Replacement of the amino group by a radical halogno (xvi)

(XI I)

  NH (XIV) 2467205i REACTION SCHEME 2 (continued)

/ COOR 8

C2H5OCH = C co 8 COOR (lx) R1

(XVI I I)

  X COOR8 Cyclization Hydrolysis -> X (XIX) COOH (Ilb) (XVI) X x

2467205;

REACTION SCHEME 3

R2 N .. /

HN N

? 2 o t, oi.1R2 .1

8 0OH -. I

N 1lili 1 "" '-

  N - 3zCU S N. 1RX tR3 / - - 1 (XXI) COOH (XX) (i)

(AMXX)

  HOD \ e1OOD "40tIIX tkcScIX / 9x \, HDOD D s D

8X003 /

= HDOSHZD +

  i7 T13NROUDwau IVKHDS l Oz9'Z (i ixx) He ZI

2467205.

  REACTION SCORE 4 (continued) R RCOCH XR6 (XXV)

(XXV) + HN-NR3 R-N

\! v -

(III) (G

R2 O

cc

3 / - \

-> R -N N

\ vI- / R i R5 COCH \ R6 (XVI) Rs

0 / - Y @ Z

\ R6

(XXVII)

Hydrolysis

2 0

R \

I I COOH

R3-N N

R1 (I) Cyclis tion

TABLFAU I

  Minimum inhibitory concentrations (/ μg / ml) Microorganism of study S. a S.p E.c K.p. P.r S.t S.

3.13 6.25. 0.39 0.39 1.56 0.2 0> 39

0.1 1.56 0.39 0.39 0.39 0.39 052

1.56 12.5 0.39 0.39 0.2 0.2 0.1

3.13 6.25 0.39 0.39 0.2 0.2 0.2

0.78 3; 13 0.39 0.78 0.39 0.2 0.39

0.78 3.13 0.78 0.78 0.39 0.1 0578

0.78 3.13 0.78 0.78 0.78 0.2 0.78

0.39 1.56 1.56 0.78 0.78 052 0.78

> 100 3.1 3.1 1.6 3.1 3.1 3.1

3.1> 100 0M8 0.8 0.2 0> 2 0.8

S.m P.al

1.56 3.13

1.56 6.25

0578 6) 25

0.78 6525

0.78 12.5

1.56 12.5

1.56 12: 5

1.56 25

3.1> 100

08 50

  Test compound AB P.a2 1) 56 0:78 3,13 3,13 12,5 12 5 12,5 12,5> 100 P.a3 3> 13 3,13 1,56 1,56 6.25 12 12.5> 100 ua r0 M - Pa o C u,

Claims (10)

R E V E N D I C A T IONS   1 - New derivatives of benzo [ij] quinolizine   carboxylic acid-2, characterized in that they correspond to the formula: 2, CO0'-   R 31 or R 1 represents a hydrogen atom or a lower alkyl radical,   R represents a hydrogen atom or a halo radical, R3 represents   a lower alkyl radical substituted with one or more radicals   halo and hydroxy, a substituted lower alkanoyl radical   by one or more halo radicals, a substituted phenylalkyl radical   killed by one or more alkoxy radicals on the phenyl ring, a radical   lower alkanesulfonyl cal substituted by one or more radicals   halogeno, a lower alkenyl radical or a lower alkynyl radical   and their pharmaceutically acceptable salts.   2 - Derivative of benzo [ij] quinolizinecarboxylic acid-2   or its pharmaceutically acceptable salts according to claim 1,   characterized in that R represents a halogen atom.   3 - Derivative of benzo [ij] quinolizinecarboxylic acid-2   or its pharmaceutically acceptable salts according to claim 2, being 2to   characterized in that R represents chlorine or fluorine.   4 - Derivative of benzo [ij] quinolizinecarboxylic acid-2 according to claim 1, characterized in that it is selected from (4-trifluoroacetyl-4-piperazinyl) -9-chloro-9-methyl-6-dihydro-6, 7-oxo-1H, 5H-benzo [i] quinolizinecarboxylic-2 and its acceptable salts in pharmacy.   Benzo [ij] quinolizinecarboxylic acid-2 derivative according to claim 1, characterized in that it is chosen from [(trifluoro-2,2,2-ethyl) -4-piperazinyl] -8-chloroacetic acid. 9-methyl-6,7-dihydrooxo-1H, 5H-benzo [i] quinolizinecarboxylic-2 and its acceptable salts in pharmacy.   6 - Derivative of benzo [ij] quinolizinecarboxylic acid-2 according to claim 11, characterized in that it is chosen from [2- (4-hydroxy-ethyl) -1-piperazinyl] -9-fluoro-9-methyl-5-methyl   6,7-dihydro-1-oxo-1H, 5R-benzo [i] quinolizinecarboxylic-2.   7 - Process for the preparation of the compounds according to claim 1, characterized in that one reacts a benzo [ij] quinolizinecarboxylic acid-2 of general formula R2 o COOR R <COOH (II) R   wherein R4 represents a halogen atom or an alkane group   sulfonyloxy or arylsulfonyloxy and R1 and R2 are as defined above, with a piperazine of the general formula HN "N-R3 (III) \ -   wherein R3 is as defined above.   8 - Process for the preparation of the compounds according to claim 1, characterized in that a compound of general formula is reacted 2 0 202 O X9 COON   in which R1 and R2 are as defined above, with a compound of genomic formula R3X (XXI)   wherein R3 is as defined above.   9 - Process for the preparation of the compounds according to claim 1, characterized in that a compound of the general formula R <XXVI) R3-OtR is reacted in which R, R2 and R3 are as defined above and R5 and   R5 each represents a hydrogen atom or a lower alkyl group.   with an aromatic heterocyclic compound containing a tertiary azo atom or a trialkylamine in the presence of an anion donor compound, to form a compound of the general formula R2 0 5 I, E> 1S. - CR2y3 ( R3- (3> / <RXXVII)   in which R 1, R, R 3, R 5 and R 6 are as defined above, Y represents an aromatic heterocyclic radical containing a   tertiary nitrogen atom connected by the nitrogen atom or a tertiary radical   alkylamonium and Z represents an anion and then this compound is hydrolysed - New drugs, useful especially as antimicrobial agents, characterized in that they consist of compounds according to claim 1.   11 - Therapeutic compositions, characterized in that   that they contain as an active ingredient at least one of the medi- cameras according to claim 10.   12 - Pharmaceutical forms of oral, parenteral or rectal administration of the therapeutic compositions according to claim 11, characterized in that the daily dose of administration of the active ingredient is between about   mg and 5 g per kg of body weight in three or four doses.