BE875470A - PIPERAZINYL-BENZOHETEROCYCLIC COMPOUNDS, THEIR PREPARATION AND THEIR THERAPEUTIC USES - Google Patents

Description

       

  1

  
The present invention relates to novel piperazinyl-benzoheterocyclic compounds and their acceptable salts for use.

  
 <EMI ID = 1.1>

  
as antimicrobial agents or as intermediates in the preparation of antimicrobial agents.

  
United States of America Patents Nos. 3,896,131,

  
 <EMI ID = 2.1>

  
the invention have a structure different from that of the quinoline and quinolizine compounds which have just been discussed.

  
The invention therefore comprises in the first place, as

  
 <EMI ID = 3.1>

  

 <EMI ID = 4.1>


  
 <EMI ID = 5.1>

  
formula :

  

 <EMI ID = 6.1>
 

  
R 4 represents a hydrogen or halogen atom, n is a number equal to 0 or 1, R <1> and R 2 can also form together and with the atoms

  
 <EMI ID = 7.1>

  
the present application designates a chlorine, bromine, iodine or fluorine atom.

  
the expression “lower alkyl” as used in the present application denotes a straight or branched alkyl group in

  
 <EMI ID = 8.1>

  
butyl or the like.

  
The term "lower alkanoyl", as it is

  
 <EMI ID = 9.1>

  
aulfonyl or the like.

  
The term "phenylalkyl" as used in the present application denotes a group which consists of a group

  
 <EMI ID = 10.1>

  

 <EMI ID = 11.1>


  
 <EMI ID = 12.1> <EMI ID = 13.1>

  
ketone.

  
The compounds of the invention are particularly effective against bacteria belonging to the genera Streptococcus, Pseudomonas, Enterobacter, etc. and they exhibit potent antibacterial activity

  
 <EMI ID = 14.1>

  
with tetracycline.

  
A list of compounds representative of the invention is given below for purely illustrative purposes, without this enumeration limiting the scope of the invention:

  
 <EMI ID = 15.1> <EMI ID = 16.1> <EMI ID = 17.1> <EMI ID = 18.1>

  
heterocyclic corresponding to the formula:

  

 <EMI ID = 19.1>
 

  
in which R, R, R and n have the meanings given with reference to formula 1 and represents a halogen atom, a lower alkanesulfonyloxy group or an arylsulfonyloxy group, with a pipeconcept

  
 <EMI ID = 20.1>

  

 <EMI ID = 21.1>


  
in which R has the meanings indicated with reference to formula I.

  
 <EMI ID = 22.1>

  
propanesulfonyloxy, isopropanesulfonyloxy, butanesulfonyloxy, tert-butanoeulfonyloxy or the like.

  
The term "arylaulfonyloxy" as used in the present application denotes a benzenesulfonyloxy, naphthaleneaulfonyloxy group or the like. The aryl ring of the arylsulfonyloxy group may carry one or more substituents selected from halogen atoms, lower alkyl, hydroxy, nitro and the like.

  
More specifically, the reaction between the compound of formula II and the compound of formula III can be carried out in an inert solvent under pressure, i.e. at a pressure of about 1 to 20 atmospheres, of

  
 <EMI ID = 23.1>

  
preferably from 140 to 200 [deg.] C and over a period of about 5 to 20 h.

  
The relative proportions between the compound of formula III and the compound of formula II are not particularly limited and can vary over a wide range. Usually the reaction can be carried out with the at least equimolecular amount and, preferably,

  
from 1 to 5 moles of the compound of formula III per mole of the compound of formula II.

  
Suitable inert solvents include water, lower alcohols such as methanol, ethanol, isopropanol, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane, ether

  
 <EMI ID = 24.1> amount of 1 to 2 moles of deoxidizing agent per mole of the compound of formula II.

  
Parai deoxidizing agents which are suitable, one will quote

  
alkali metal hydroxides such as sodium hydroxide, potassium hydroxide etc., inorganic carbonates such as sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, etc., tertiary amines such as pyridine, quinoline, triethylamine, etc.

  
 <EMI ID = 25.1>

  
of formula II, which can be used as the starting product for the preparation of compounds of formula 1 according to the invention, some of which are known and described in United States Patents No. [deg.] 3 917 609, 3,896,131, 3,985,882, 3,969,463, 4,001,243 and 4,014,877; others are new and

  
 <EMI ID = 26.1>

  
On the other hand, the compounds of formula III, that &#65533;. constitute

  
 <EMI ID = 27.1>

  
are known and available commercially.

  
Reaction scheme 1
 <EMI ID = 28.1>
 v

  
 <EMI ID = 29.1>

  
with reference to formula 1 and R, R, which may have the same or different meanings, each represents a lower alkyl group.

  
With reference to reaction scheme 1 above, among the compounds of formula IV which are used as starting materials, those for

  
 <EMI ID = 30.1>

  
in Annalen. 278, page 105 (1894); Schmidt and Sitward in Berichte, 45, page
1979 (1912); etc., or they can easily be prepared by known methods described in these publications; those for which represents a lower alkanesulfonyloxy or arylsulfonyloxy group are novel and can be easily prepared as illustrated by reaction scheme 2 below.

  
Furthermore, the compounds of formula V, other products

  
starting point, are known and commercially available.

  
 <EMI ID = 31.1>

  
represents a halogen atom can also be easily prepared by the method illustrated by Reaction Scheme 2 below.

  
Reaction_ scheme 2
 <EMI ID = 32.1>
  <EMI ID = 33.1>

  
the meanings already specified and R represents a lower alkanesulfonyl or arylsulfonyl group, X represents a halogen atom.

  
The term "lower alkanesulfonyl" as it is

  
 <EMI ID = 34.1>

  
nyl or the like.

  
The term "arylsulfonyl" as used in the present application denotes a benzenesulfonyl, naphthalenesulfonyl or the like.

  
The aryl ring of the arylsulfonyl group may carry a

  
or more substituents selected from halogen atoms, lower alkyl, hydroxy, nitro and the like.

  
More specifically, in Reaction Scheme 1, the reaction between the compound of formula IV and the compound of formula V can be carried out in the absence of a solvent or in the presence of solvents such as methanol, ethanol, isopropanol , acetonitrile, dimethylformamide,

  
dimethylsulfoxide, hexamethylphosphorotriamide and the like solvents; one operates preferably. in the absence of solvent.

  
The compound of formula V can be used in excess of the compound of formula IV; however, it is preferable to operate with a

  
 <EMI ID = 35.1>

  
1.1 to 1.5 moles per mole of the compound of formula III in the presence of solvent. The reaction can generally be carried out at a temperature between room temperature (about 15 to 30 [deg.] C) and about 150 [deg.] C, preferably between 100 and 130 [deg.] C, over a period of time. about 1/2 h to 6 h; the compound of formula VI is thus easily obtained.

  
The subsequent cyclization reaction of the compound of formula VI can be carried out according to conventional cyclization techniques and, for example, by heating the compound of formula VI or by cyclization on an acidic substance such as phosphorus oxychloride, phosphorus pentachloride , phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, polyphosphoric acid or the like. If the cyclization is carried out by heating, it is preferable to heat the compound of formula VI in a solvent such as

  
 <EMI ID = 36.1> diphenyl, diethylene glycol dimethyl ether, etc. to one

  
 <EMI ID = 37.1>

  
of an acidic substance, it is possible to use the latter in an amount between the approximately equimolecular amount and a strong excess

  
preferably an excess of 10 to 20 moles of acid per mole of the compound of formula VI, at a temperature of about 100 to 150 [deg.] C and over a period of

  
from 1/2 to 6 hours approximately; this reaction advantageously gives the compound

  
of formula VII.

  
In Reaction Scheme 1 above, the hydrolysis of the compound of Formula VII to the compound of Formula II can be carried out by a conventional technique in the presence of usual catalysts and, for example, basic compounds such as hydroxide. sodium, potassium hydroxide, barium hydroxide and the like, or a mineral or organic acid such as sulfuric acid, hydrochloric acid, nitric acid, acetic acid, a aromatic sulfonic acid or the like. The hydrolysis can be carried out in a solvent such as water, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, dioxane, ethylene glycol, acetic acid and the like solvents, at a temperature between room temperature and
200 [deg.] C approximately, preferably between 50 and 150 ° C and over a period of 1/2 h

  
 <EMI ID = 38.1>

  
With reference to reaction scheme 2 above, the compound of formula X is reacted with the compound of formula VIII or IX in an amount of preferably at least substantially equimolecular and preferably 1 to 2 moles of compound X is reacted with mole of the compound of formula VIII or IX.

  
The reaction is usually carried out in an inert solvent in the presence of a deoxidizing agent in an amount of at least approximately equimolecular and, preferably in an amount of 1 to 2 moles per mole of the compound of formula VIII or IX, at a temperature between 0 and 100 ° C approximately, preferably at room temperature and over a period of 1/2 h at

  
6 hrs; the reaction therefore gives, depending on the case, the compound of formula IV or

  
the compound of formula XII.

  
Parai deoxidizing agents which are suitable, one will quote

  
alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., mineral carbonates such as sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, etc., tertiary amines such as pyridine, quinoline, triethylamine, etc.

  
Suitable inert solvents include lower alcohols such as methanol, ethanol, isopropanol, etc., ethers such as dioxane, tetrahydrofuran, diglycol methyl ether, etc., aromatic hydrocarbons such as benzene, toluene, etc., dimethylsulfoxide, dimethylformamide, hexamethylphosphorotriamide, pyridine, etc.

  
Still referring to reaction scheme 2 above,

  
 <EMI ID = 39.1>

  
catalytic or reduction using a conventional reducing agent, for example a combination of sodium borohydride or lithium aluminum hydride and a lower fatty acid such as acetic acid, trifluoroacetic acid , propionic acid, etc.

  
The sodium borohydride or lithium aluminum hydride and the lower fatty acid are advantageously used in an amount between the approximately equimolecular amount and a large excess; we

  
 <EMI ID = 40.1>

  
of formula XI or XII, respectively.

  
The reduction using a reducing agent can be carried out advantageously in an inert solvent such as an ether such as dioxane, tetrahydrofuran, methyl ether, diglycol, etc., an aromatic hydrocarbon such as benzene, toluene, etc., lower fatty acid such as trifluoroacetic acid, propionic acid, etc.,

  
 <EMI ID = 41.1>

  
preferably between 50 and 100 ° C., and over a period of approximately 1 to 6 hours.

  
The compounds according to the invention corresponding to formula 1 can also be prepared as illustrated by reaction scheme 2a below.

  
Reaction scheme 2a
 <EMI ID = 42.1>
 Diagram: hold back! 2a (continued)

  

 <EMI ID = 43.1>


  
&#65533;

  
 <EMI ID = 44.1>

  
With reference to reaction scheme 2a above, the reaction between the compound of formula IV and the compound of formula V 'can be carried out as the reaction between the compound of formula IV and the compound

  
 <EMI ID = 45.1>

  
of formula 1 ', the latter can be reacted with a heterocyclic aromatic compound containing a tertiary nitrogen atom or with a trialkylamine and an anion donor compound in a suitable inert solvent.

  
 <EMI ID = 46.1>

  
isolation or without isolating it.

  
In this reaction, it is possible to use, among the heterocyclic aromatic compounds containing a tertiary nitrogen atom, unsubstituted pyridine and alkylated pyridines such as picolines, lutidines, etc., quinoline and alkylated quinolines such as quinaldine, lepidin, etc.

  
Among the trialkylamines which are suitable, mention will be made of those

  
 <EMI ID = 47.1>

  
etc.

  
Among the suitable anion-donor compounds, there will be mentioned those which can yield a halide ion such as an iodide, bromide, chloride, etc. ion. and, for example, iodine, bromine and elemental chlorine,

  
and compounds capable of giving a sulfate anion, a phosphate anion, a perchlorate anion and, for example, sulfuric acid, phosphoric acid, perchloric acid; etc.

  
Among the inert solvents which are suitable for this reaction, there will be mentioned lower alcohols such as methanol, ethanol, isopropanol, etc., aromatic hydrocarbons such as benzene, toluene, etc., ethers such as tetrahydrofuran, dioxane, methyl ether

  
 <EMI ID = 48.1>

  
phosphorctriamide, pyridine, etc.

  
The heterocyclic aromatic compound containing tertiary nitrogen or the trialkylamine and the anion donor compound can be used in excess with respect to the theoretical amount corresponding to the

  
 <EMI ID = 49.1>

  
from 1 to 2 moles per mole of the compound of formula I '.

  
The reaction can, in general, be carried out at a temperature between room temperature and approximately 120 [deg.] C, preferably between 50 and 100 [deg.] C, over a period of 30 min to 6 h.

  
The hydrolysis of the compound of formula I "obtained under these conditions can be carried out in a suitable solvent in the absence or

  
in the presence of an acidic or alkaline hydrolyzing agent but, preferably,

  
in the presence of such an agent.

  
Among the alkaline hydrolysing agents which are suitable, mention will be made of alkali metal hydroxides such as sodium hydroxide,

  
 <EMI ID = 50.1>

  
such as calcium hydroxide etc., ammonium hydroxide and carbonates of these metals and ammonium carbonate.

  
 <EMI ID = 51.1>

  
etc.

  
Among the suitable solvents are lower alcohols such as methanol, ethanol, isopropanol, etc., aromatic hydrocarbons such as benzene, toluene, etc., ethers such as tetrahydrofuran, dioxane,. diglycol methyl ether,

  
 <EMI ID = 52.1>

  
hexamethylphosphorptriamide, etc.

  
 <EMI ID = 53.1>

  
from 30 min to 6 h. It can be accelerated by adding a lower alcohol.

  
Among the compounds according to the invention corresponding to formula I, those in which R <3> represents a lower alkyl, lower alkanoyl, benzoyl, lower alkanesulfonyl, p-toluenesulfonyl, phenylalkyl group or the group of formula:

  

 <EMI ID = 54.1>
 

  
(and which will hereinafter be called compounds of formula Ib) can also

  
 <EMI ID = 55.1>

  
hydrogen atom (hereinafter compounds of formula la) with a compound of formula XIII below in the presence of a deoxidizing agent.

  

 <EMI ID = 56.1>


  
 <EMI ID = 57.1>

  
sulfonyl, phenylalkyl or the group of formula:

  

 <EMI ID = 58.1>


  
 <EMI ID = 59.1>

  
can form pharmaceutically acceptable salts with acids when carrying a basic group and the invention also includes such pharmaceutically acceptable salts. For the formation of the salts, acids acceptable for pharmaceutical use can be used, including various organic and mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, 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 analogous acids.

  
 <EMI ID = 60.1>

  
can be converted to the corresponding carboxylates by reacting the free carboxylic acid with a basic compound acceptable for pharmaceutical use. Among the basic compounds, there are minerals like <EMI ID = 61.1>

  
aniline and analogous compounds.

  
The compounds of formula 1 and their salts obtained as

  
 <EMI ID = 62.1>

  
on column and analogous techniques.

  
The compounds of formula 1 and their salts possess excellent broad spectrum antimicrobial activities on bacteria.

  
 <EMI ID = 63.1>

  
on which the known synthetic antibacterial agents are ineffective or have only low effectiveness. They also have a strong antibacterial activity against coliform bacteria, staphylococci, etc. which are the main causes of infectious diseases; they are also effective on Serratia, Klebsiella, etc. which also cause infectious diseases that have recently attracted the attention of many researchers; the compounds according to the invention therefore have very great clinical use.

  
Alongside as said previously, the compounds according to the invention have advantages, not only because they are distinguished

  
 <EMI ID = 64.1>

  
ment because their antimicrobial activity does not decrease and would

  
 <EMI ID = 65.1>

  
is surprising because experts in the field know that drugs known until now and which exhibit antimicrobial activity have their activity which decreases in the presence of serum. This property obviously suggests that the compounds according to the invention are capable of manifesting a potent antimicrobial activity in the blood.

  
The oral toxicity of the compounds according to the invention is very low compared to the effective doses administered orally.

  
 <EMI ID = 66.1>

  
antimicrobial on bacteria that are resistant or have acquired resistance to known antibiotics such as penicillin, cephalosporin, ampicillin, streptomycin, erythromycin, kanamycin, nalidixic acid, etc.

  
 <EMI ID = 67.1>

  
can be converted into penicillanic acid derivatives corresponding to

  
formula XIV below, which themselves exhibit excellent antimicrobial activity on gram-positive and negative bacteria, and especially on Pseudomonac and Streptococcus. These conversions are illustrated by reaction scheme 3 below and described in the preparation examples.

  
 <EMI ID = 68.1>

  
Reaction scheme 3
 <EMI ID = 69.1>
 v

  
 <EMI ID = 70.1>

  
lower alkyl, X represents a halogen atom, R11 represents a hydrogen atom or a hydroxy group, M represents a hydrogen atom or a

  
 <EMI ID = 71.1>

  
The reaction scheme 3 above is described in detail in French patent application No. [deg.] 79 filed today in the name

  
by the Applicant and entitled 'New compounds of the 9-lactam type useful

  
 <EMI ID = 72.1>

  
that these can exist in enantiomorphic forms; these optical isomes come within the scope of the invention.

  
 <EMI ID = 73.1>

  
salts in therapy, they can be formulated into therapeutic compositions with conventional carriers acceptable for pharmaceutical use. Among the vehicles that can be used, we can cite for example

  
 <EMI ID = 74.1>

  
agents, binders, wetting agents, disintegrating agents, surfactants and lubricants of the type commonly used to prepare these medicaments, depending on the desired dosage form.

  
The therapeutic compositions can be put into various dosage forms depending on the intended therapy. Thus, for example, the therapeutic compositions can be put in the form of tablets,
-the pills, powders, liquid products, suspensions, emulsions, granules, capsules, suppositories, or injectable compositions
(solutions, suspensions, etc.).

  
To convert a therapeutic composition containing a compound of formula 1 or a salt of such a compound acceptable for pharmaceutical use as an active substance in tablet form, it is necessary to

  
 <EMI ID = 75.1>

  
suitable vehicles include excipients such as lactose, sucrose, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose and acid silicic; binders such as water, ethanol, propanol,

  
simple syrup, glucose, starch solution, gelatin solution,

  
 <EMI ID = 76.1> of laminaria, sodium bicarbonate, calcium carbonate, the commercial product Tween, sodium lauryl sulphate, stearic monoglyceride, starch and lactose; disintegration inhibitors such as sucrose, stearic acid glyceryl ester, cocoa butter and hydrogenated oils; additives facilitating absorption such as quaternary ammonium bases and sodium lauryl sulphate; humectants such as glycerol and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silica:

  
lubricants such as purified talc, stearates, powdered boric acid, the commercial product Macrogol (polyethylene glycol from Shinetsu Chemical Industry Co. Ltd.) and solid polyethylene glycol.

  
If desired, the tablets can be coated with

  
eg by sugar, by gelatin, by enteric coating, by film and tablets consisting of two or more layers can also be prepared.

  
To put the therapeutic compositions by molding

  
in the form of pills, one can use known and varied vehicles. Among those which are suitable, mention will be made of excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils,

  
kaolin and talc, binders such as gum arabic powder, gum tragacanth powder, gelatin and ethanol, and disintegrants such as kelp and agar.

  
 <EMI ID = 77.1> various. Among those which are suitable, mention will be made of polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols,

  
gelatin and semi-synthetic glycerides.

  
When the therapeutic composition is put in the form of an injectable product, the solution or suspension obtained is preferably sterilized, which must be isotonic with respect to the blood. In order to put the therapeutic composition in the form of a solution or a suspension, all the diluents commonly used for this purpose can be used. Among the suitable diluents, mention will be made of water, ethyl alcohol, propylene-

  
 <EMI ID = 78.1>

  
sorbitan esters. Sodium chloride, glucose or glycerol in sufficient quantity to obtain an isotonic solution can be incorporated into a therapeutic composition intended for example for the treatment of nephritis. The therapeutic compositions may additionally contain dissolution aids. tampons, pain relievers and preservatives and, where appropriate, dyes, perfumes, flavors, sweeteners, and other drugs.

  
The amount of the compound of formula 1 or of pharmaceutically acceptable salts which is incorporated as an active substance in a therapeutic composition for use as an antimicrobial drug is not particularly limited and may vary within limits.

  
 <EMI ID = 79.1>

  
of salt acceptable for pharmaceutical use is about 1 to

  
70% and preferably 5 to 50% of the weight of the total composition.

  
There is no particular restriction on how to use the therapeutic composition and they can be administered by the routes suitable for the particular forms.

  
of the composition. Thus, for example, tablets, pills, liquid products, suspensions, emulsions, granules and capsules are administered orally. Injectables are administered intravenously alone or with common auxiliary agents such as glucose and amino acids. In addition, if desired, the therapeutic agent can be administered alone intramuscularly, intracutaneously, subcutaneously or intraperitoneally. Suppositories are administered intrarectally, and ointments are applied to the skin.

  
The dosage of the antimicrobial composition is correctly chosen depending on the intended use, symptoms, etc. Usually, the preferred dosage for a compound according to the invention is about 10 mg to 5 g per kilogram of body weight and per day, divided into three or four doses.

  
I. Antimicrobial activity.

  
1. Test method:

  
The antimicrobial activity of the compounds according to the invention on various microorganisms listed below has been demonstrated by

  
the serial dilution procedure on agar plates (heart infusion agar from the firm Difco Co.) (cf. Chemothorapy 22, pages 1126

  
 <EMI ID = 80.1>

  
are reported in Table 1 below.

  
2. A sample of each of the micro-

  
 <EMI ID = 81.1> previous).

  
 <EMI ID = 82.1>

  
3. Klebsiella pneumoniae

  
4. Klebsiella pneumoniae ST-101

  
5. Proteus rettgeri NIH 96

  
 <EMI ID = 83.1>

  
10. Yersinia enterocolitica 0-3

  
11. Yersinia enterocolitica 0-5

  
12. Hafnia alvei IFO 3731

  
 <EMI ID = 84.1>

  
14. Pseudomonas aeruginosa NCTC 10490

  
15. Pseudomonas aeruginosa ATCC 10145

  
16. Pseudomonas maltophilia IFO 12692

  
17. Pseudomonas putida IFO 13696

  
18. Salmonella typhi 0-901 (NCTC 8393)

  
19. Shigella sonnei EW 33

  
 <EMI ID = 85.1>

  
24. Streptococcus pyogenes IID Cook

  
 <EMI ID = 86.1>

  
26. Streptococcus pneumoniae type II

  
 <EMI ID = 87.1> <EMI ID = 88.1>

  
sodium quinoline-5-carboxylate,

  
 <EMI ID = 89.1>

  
3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2carboxylic,

  
 <EMI ID = 90.1>

  
By operating by an identical procedure, the antimicrobial activity of the compounds listed in Table II below on various microorganisms causing infectious diseases in fish was determined. The results obtained are reported in Table II below. II. Influence of the addition of horse serum on the minimum inhibitory concentration of quinoienin derivatives.

  
The minimum inhibitory concentration of compounds A, C and F was determined on various microorganisms listed in Table III below. For this determination, the minimum inhibitory concentration of each of the compounds was measured by the dilution method. series

  
on plates with culture medium based on heart infusion agar

  
 <EMI ID = 91.1> <EMI ID = 92.1>

  
The results obtained are reported in Table III below. III. Human serum protein deactivation rate.

  
To Moni-Trol 1 powder (dehydrated human serum from the firm Midori Juji Co. Ltd), phosphate buffer & 0.067 mol / 1 is added so as to prepare a composition having the same concentration of serum proteins as the serum. natural human; the product obtained is considered to be "serum

  
 <EMI ID = 93.1>

  
Each of the compounds A and E is dissolved in an appropriate amount of the above sera, so as to achieve final concentrations of

  
 <EMI ID = 94.1>

  
The rate of deactivation of active compounds A and E in human serum is calculated from the following equation:

  

 <EMI ID = 95.1>


  
where Co is the concentration of the active compound in the absence of serum and C the concentration of the active compound in the serum.

  
The results obtained are reported in Table IV below. Acute toxicity.

  
The acute toxicity of compounds of formula I was determined by

  
 <EMI ID = 96.1>

  
below.

  
acute toxicity

  

 <EMI ID = 97.1>


  
 <EMI ID = 98.1>

  
other active compounds; 500 mg / kg or more were found in all cases.

  
The following examples illustrate the invention without however limiting it; in these examples, the indications of parts and% are understood by weight, unless otherwise specified.

  
In the following, crystals without a completely defined shape

  
 <EMI ID = 99.1>

PREPARATION EXAMPLE 1

  
 <EMI ID = 100.1>

  
100 ml of methanol containing 3.8 g of potassium hydroxide in solution and stirred at room temperature for 30 min, then the methanol is removed in vacuo. To the residue is added benzene; crystals form; the benzene is removed by evaporation. The residue is taken up in suspension in
50 ml of dimethylformamide and added dropwise, while cooling

  
 <EMI ID = 101.1>

  
A further 3.5 g of methanesulfonyl chloride is added and the mixture is stirred at room temperature for 4 h. When the reaction is complete, the solvent is removed in vacuo and the residue is purified by chromatography on a column of silica gel (Wako C-200 from the firm Wako Junyaku Co. Ltd; eluent: chloroform). Recrystallization of the eluate from water containing ethanol

  
 <EMI ID = 102.1>

PREPARATION EXAMPLE 2

  
By operating as described in Preparation Example 1, 5- (p-tolueneaulfonyloxy) -3,4-dihydrocarbostyril, melting at

  
 <EMI ID = 103.1>

PREPARATION EXAMPLE 3

  
45 g of 5-amino-3,4-dihydrocarbostyril are suspended in 250 ml of 15% hydrochloric acid and added dropwise.

  
 <EMI ID = 104.1>

  
tion 20 g of sodium nitrite. The solution obtained is added dropwise to a solution of 41.2 g of cuprous chloride in 120 ml of concentrated hydrochloric acid, with stirring at room temperature. When the addition is complete, the mixture is heated in a water bath at 50-60 ° C for 1 hour with stirring. Leave to cool; it precipitates crystals that are filtered and

  
 <EMI ID = 105.1>

  
and the insolubles are filtered. The filtrate is dried over anhydrous sodium sulfate. After removal of the solvent, the residue is dissolved in hot ethanol and the hot solution is treated with activated carbon. The ethanol solution is concentrated in vacuo. Recrystallization of the concentrate from

  
 <EMI ID = 106.1>

  
194 "C.

PREPARATION EXAMPLE 4

  
 <EMI ID = 107.1> <EMI ID = 108.1>

  
(d = 1.05). After heating under reflux for 2 h, the solvent is removed in vacuo. Water is added to the residue, the insolubles are filtered off and washed with ether. The filtrate is extracted with ethyl ether, dried over anhydrous sodium sulfate and distilled in vacuo; we obtain 36.0 g of

  
 <EMI ID = 109.1>

  
dihydrocarbostyril in 90 ml of dioxane and 35 g of NaBH4 are added then, dropwise, 5.3 ml of acetic acid. After heating under reflux for 1 hour, the solvent is removed in vacuo. A saturated aqueous solution of sodium bicarbonate is added to the residue. The precipitate is filtered off and washed with chloroform. The filtrate was extracted with chloroform and the chloroform layer was dried over Na2SO4 then the solvent was removed. We purify

  
the residue by chromatography on a silica gel column (Waco C-200 from the firm Waco Junyaku Co. Ltd., eluent: chloroform) - the eluate is recrystallized from petroleum ether. A new recrystallization in the.

  
 <EMI ID = 110.1>

  
in the form of colorless prisms melting at 74-76 [deg.] C.

PREPARATION EXAMPLE 6

  
By operating as described in Preparation Example 5,

  
 <EMI ID = 111.1>

  
112-113 [deg.] C.

PREPARATION EXAMPLE 7

  
5.5 g of 4-chlorooxindole are dissolved in

  
80 ml of dioxane, 6.2 g of sodium borohydride are suspended in this mixture and 12.7 ml of trifluoroacetic acid (d - 1) are added dropwise at room temperature under eg:! , 48). After heating under reflux for 4 h 30 min, the solvent is removed in vacuo. Water is added to the residue and the insolubles are filtered off and then washed with ethyl ether. The filtrate is extracted with ether and the ethereal layer is dried over dry sodium sulfate and then the solvent is removed. The residue is distilled under vacuum; 3.9 g of 4-chloroindoline are obtained in the oil state

  
 <EMI ID = 112.1>

PREPARATION EXAMPLE 8

  
 <EMI ID = 113.1>

  
Gradually adds 10.6 g of fine powdered aluminum chloride while cooling with ice with stirring. When the addition is complete, it is left to react with stirring at room temperature for 27 h. The solvent is then removed in vacuo. Water is added to the residue and extracted

  
the mixture with 100 ml of benzene. The benzene layer is washed with saturated brine and then concentrated. 10% hydrochloric acid is added to the residue, which causes foaming. When these foaming ceases, it is neutralized with an aqueous solution of sodium carbonate and the mixture is extracted with 100 ml of benzene. The benzene layer is dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the extract is purified by chromatography on a column of silica gel (eluent: chloform); yield: 3.4 g of 2-methyl-4-chloroindoline of which

  
the structure is confirmed by the nuclear magnetic resonance spectrum. PREPARATION EXAMPLE 9

  
 <EMI ID = 114.1>

  
110 [deg.] C in an oil bath with stirring for 30 min; during this operation, ethanol distillation is observed. After this heating, we add
240 g of polyphosphoric acid prepared from 120 g of phosphoric acid and 120 g of phosphoric anhydride and allowed to react in an oil bath at

  
 <EMI ID = 115.1>

  
room temperature and poured into 400 ml of water; neutralized with 40% sodium hydroxide solution; it precipitates crystals which are mixed with

  
 <EMI ID = 116.1>

  
which crystals dissolve with formation of a homogeneous solution. The hot solution is treated with activated carbon and filtered. We let

  
 <EMI ID = 117.1>

  
quinolizine-2-carboxylic in the form of white needles melting at 270-275 [deg.] C. PREPARATION EXAMPLE 10

  
21.6 g of ethyl ethoxymethylenemalonate are added to
30.0 g of 5- (p-toluenesulfonyloxy) -1, 2,3,4-tetrahydroquinoline and heated to 110 [deg.] C in an oil bath for 30 min with stirring; during this time, ethanol distillation is observed. After this heating, 240 g of polyphosphoric acid prepared from 120 g of phosphoric acid are added and
120 g of phosphorus pentoxide and allowed to react in an oil bath at 140 [deg.] C for 40 min. When the reaction is complete, the mixture is left to cool to room temperature and then the mixture is poured into 400 ml of water. Neutralized with 40% sodium hydroxide solution; it precipitates crystals which are mixed with

  
 <EMI ID = 118.1>

  
during which the crystals dissolve and a homogeneous solution is formed. The solution is filtered and the filtrate is allowed to cool. It is adjusted to pH 2. There is precipitation of crystals which are filtered. Recrystallization of the crude crystals from dimethylformamide gives 27.4 g of acid.

  
 <EMI ID = 119.1>

  
PREPARATION EXAMPLE 11

  
4.4 g of diethyl ethoxymethylenemalonate are added

  
 <EMI ID = 120.1>

  
this time, there is a release of ethanol. 20 g of polyphosphoric acid formed from 10 g of phosphoric acid and 10 g are added.

  
 <EMI ID = 121.1>

  
40 min. When the reaction is complete, it is allowed to return to 60 [deg.] C, on. flows into water and neutralized with 10% sodium hydroxide solution. The crystals are filtered and washed with water. We mix these crystals with

  
 <EMI ID = 122.1>

  
for 1 hour. During this time, the mixture turns into a homogeneous solution. The hot solution is treated with activated carbon and filtered. The filtrate is acidified with concentrated HCl; the crystals which have precipitated are separated and recrystallized from dimethylformamide. We obtain

  
 <EMI ID = 123.1>

  
carboxylic in the form of white needles melting at 307.5 [deg.] C (decomposition). PREPARATION EXAMPLE 12

  
4.4 g of diethyl ethoxymethylenemalonate are added

  
to 3.4 g of 2-methyl-4-chloroindoline and heated in an oil bath at 100-

  
 <EMI ID = 124.1>

  
it is refluxed in an oil bath for 1 h. The mixture turns

  
 <EMI ID = 125.1>

  
The filtrate is acidified with concentrated HCl. There is precipitation of crystals which are recrystallized from dimethylformamide. Yield: 3.8 g of acid

  
 <EMI ID = 126.1>

  
boxylic in the state of white needles melting at 288-290 [deg.] C. PREPARATION EXAMPLE 13

  
25 g of ethyl ethoxymethylenemalonate are added to 21 g

  
 <EMI ID = 127.1>

  
of oil at 110-120 [deg.] C. Ethanol distillation is observed. After heating at the same temperature for 30 min, 160 g of polyphosphoric acid formed from 80 g of phosphoric acid and 80 g of phosphoric anhydride are added, followed by heating in an oil bath at 130-140. [deg.] C for 1 h. When the reaction is complete, poured into 600 ml of water and neutralized with 10% sodium hydroxide solution. The crystals which have precipitated are filtered off and

  
 <EMI ID = 128.1>

  
for 1 h during laq uel the crystals dissolve and a homogeneous solution is formed which is treated with hot activated carbon and filtered. The filtrate is allowed to cool and the pH is adjusted to 2 with concentrated HCl. There is

  
 <EMI ID = 129.1>

  
at 290-291 [deg.] C.

  
PREPARATION EXAMPLE 14

  
By operating as described in Preparation Example 13,

  
 <EMI ID = 130.1>

  
carboxylic in the form of colorless needles not melting below
300 [deg.] C.

  
PREPARATION EXAMPLE 15

  
 <EMI ID = 131.1>

  
 <EMI ID = 132.1>

  
110 [deg.] C in an oil bath for 30 min with stirring; during this time, ethanol distillation is observed. After heating, 100 g of polyphosphoric acid formed from 50 g of phosphoric acid and 50 g of phosphoric anhydride are added and the mixture is left to react in an oil bath at 140 [deg.] C for 40 min.

  
 <EMI ID = 133.1>

  
500 ml of ice water. There is precipitation of yellow colored crystals pays off

  
 <EMI ID = 134.1>

  
forms a homogeneous solution which is treated with hot activated carbon; the pH of the solution is adjusted to 2 with concentrated hydrochloric acid; we

  
 <EMI ID = 135.1>

  
pays fondant at 273-275 [deg.] C.

  
PREPARATION EXAMPLE 16

  
0.78 g of 8- (1-piperazinyl) acid is suspended.

  
 <EMI ID = 136.1>

  
anhydrous dimethylformamide and 0.42 ml of triethylamine is added while cooling in ice, with stirring, over 15 min. 0.4 ml of isobutyl chloroformate is then added dropwise and the mixture is stirred for 45 min at

  
the same temperature as above. On the other hand, 1.3 g of ampicillin are suspended in 15 ml of anhydrous dimethylformamide and to the suspension are added, while cooling with ice, 0.7 ml of triethylamine and 0.5 g of sodium sulfate. anhydrous magnesium; it is stirred at the same temperature as above for 30 min and the insolubles are filtered off. The triethylamine salt of ampicillin obtained under these conditions was added to the reaction mixture obtained first and stirred for 2 h while cooling in ice. When the reaction is complete, the insolubles are filtered off, then 2.5 ml of 20% potassium 2-ethylhexanoate n-butanol solution is added to the filtrate, and then 300 ml of ethyl ether is added to precipitate.

  
 <EMI ID = 137.1>

  
of pale yellow amorphous substance melting at 218-225 [deg.] C (reddening) and decomposing at 245-250 [deg.] C.

  
PREPARATION EXAMPLE 17

  
 <EMI ID = 138.1>

  
perature. On the other hand, 1 g of ampicillin is suspended in 10 ml of anhydrous dimethylformamide and 0.56 ml of triethylamine and 0.4 g of anhydrous magnesium sulfate are added while cooling in ice; the mixture is stirred at the same temperature as above for 30 min and the insoluble

  
 <EMI ID = 139.1>

  
 <EMI ID = 140.1>

  
ice. When the reaction is complete, the insolubles are separated by

  
 <EMI ID = 141.1> <EMI ID = 142.1>

  
washed with water and dried at room temperature under reduced pressure. The product is treated in the same way as in preparation example 1

  
 <EMI ID = 143.1>

  
of white amorphous substance, melting at 214-219 [deg.] C (decomposition).

  
PREPARATION EXAMPLE 18

  
0.81 g of 8- (4-methanesulfonyl-1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H-benzo [ij] quinolizine-2-carboxylic acid is suspended in 25 ml of dimethylformamide and 0.42 ml of triethylamine is added while cooling in ice; stirred for 15 min. 0.4 ml of isobutyl chloroformate is added dropwise and the mixture is stirred for

  
45 min at the same temperature as above. On the other hand, 1.3 g of ampicillin is suspended in 15 ml of anhydrous dimethylformamide and 0.7 ml of triethylamine and 0.5 g of anhydrous magnesium sulfate are added while cooling with ice; the mixture is stirred at the same temperature as above for 30 min and the insolubles are filtered off. The triethylamine salt of ampicillin obtained under these conditions is added to the first reaction mixture. Stir for 2 h while cooling in ice and the reaction mixture is worked up as described in Preparation Example 17;

  
 <EMI ID = 144.1>

  
of white amorphous substance, melting at 182-187 [deg.] C (decomposition). PREPARATION EXAMPLE 19

  
21.6 g of ethyl ethoxymethyleneacetylacetate are added to 18 g of 5-chloro-2-methyl-1,2,3,4-tetrahydroquinoline and the mixture is heated.

  
 <EMI ID = 145.1>

  
ethanol distillation. 100 g of polyphosphoric acid prepared from 50 g of phosphoric acid and 50 g of phosphoric anhydride are added, then

  
 <EMI ID = 146.1>

  
fondant PREPARATION EXAMPLE 20

  
8 g of anhydrous piperazine are added to 5 g of 8-chloro5-methyl-2-acetyl-6,7-dihydro-1-oxo-1H, 5H-benzo [ij] quinolizine. To this mixture,

  
 <EMI ID = 147.1>

  
in an oil bath for 6 h. When the reaction is complete, the excess solvent and piperazine are distilled off in vacuo and 100 ml are added to the residue.

  
 <EMI ID = 148.1>

  
filter; 300 ml of water are added to the crystals and the solution is adjusted to pH 2 with HClN. The mixture is heated and filtered. The filtrate is concentrated to volume

  
 <EMI ID = 149.1>

  
benzo [ij] quinolizine.

  
EXAMPLE 1

  
19.2 g of 8-chloro-6,7-dihydro-1-oxo- acid are introduced.

  
 <EMI ID = 150.1>

  
350 ml of anhydrous dimethylsulfoxide and heated in an oil bath to 170-
180 [deg.] C for 6 h with stirring. When the reaction is complete, the solvent is removed in vacuo. 1/2 1 water is added to the residue, the

  
pH at 2 and the insolubles are filtered off. The filtrate is concentrated to a final volume of 100 ml under vacuum and basified to pH 9 with sodium hydroxide solution.

  
10%. The alkaline aqueous solution is extracted with chloroform and then the alkaline aqueous layer is left to stand; there is precipitation of crude crystals which are filtered and redissolved in 10 ml of 10% sodium hydroxide solution; the solution is treated with activated carbon and in order to pH 8 with HCl at

  
10%; it precipitates crystals which are filtered and washed with water. Recrystallization of the crystals from dimethylformamide gives 6.5 g of acid

  
 <EMI ID = 151.1>

  
lic in the state of white needles melting at 267-268 [deg.] C.

  

 <EMI ID = 152.1>


  
The above elemental analysis is carried out at room temperature under reduced pressure (1 to 2 mm Hg) for 6 h on

  
 <EMI ID = 153.1> filters out insolubles and); '1 distils the water; 5.7 g of the hydrochloride of the acid are obtained, used in the form of white crystals, melting at

  
 <EMI ID = 154.1>

  

 <EMI ID = 155.1>


  
EXAMPLE 2

  
19.5 g of 8-chloro-5-methyl-6,7- acid are introduced.

  
 <EMI ID = 156.1>

  
melting at 300 [deg.] C or more.

  

 <EMI ID = 157.1>


  
3.8 g of 8- (1-pipé) acid hydrochloride are introduced.

  
 <EMI ID = 158.1>

  
lique in 100 ml of water, add N sodium hydroxide solution and heat

  
 <EMI ID = 159.1>

  

 <EMI ID = 160.1>


  
EXAMPLE 3

  
By a procedure similar to that of Example 2,

  
 <EMI ID = 161.1> <EMI ID = 162.1>

  
for 8 h with stirring. When the reaction is complete, we eliminate

  
the solvent and the excess of N-methylpiperazine in vacuo and a mixture of methanol and ethyl ether is added; a precipitate forms which is filtered

  
and washed with ethyl ether. The crystals obtained are suspended in 20 ml of an aqueous solution of 10% hydrochloric acid and

  
 <EMI ID = 163.1>

  
commercial resin Amberlite LH-20 from Tokyo Organic Chemical Industries Ltd. (eluent: water, ethanol). Recrystallization of the eluate in

  
 <EMI ID = 164.1>

  

 <EMI ID = 165.1>


  
EXAMPLE 5

  
 <EMI ID = 166.1>

  
 <EMI ID = 167.1>

  
7 h with stirring. By processing the reaction mixture as described in

  
 <EMI ID = 168.1>

  
the state of an amorphous substance melting at 300 [deg.] C or above.

  

 <EMI ID = 169.1>


  
EXAMPLES 6 to 14

  
By operating as described in Examples 1 to 5, the "compounds below bearing various substituents, the nature of which is indicated in Table V below, in which the melting point and the physical form of the products will also be found. obtained.

  
The results are shown in Table VI below.

  
 <EMI ID = 170.1> razine to 200 ml of anhydrous dimethylsulfoxide and heated in an autoclave with nitrogen flushing at a pressure of 10 atmospheres and at a temperature.

  
 <EMI ID = 171.1>

  
Once completed, the solvent and excess piperazine are removed in vacuo and a mixture of methanol and ethanol is added to the residue. The precipitate is filtered off and washed with ethyl ether. The crystals are resuspended in a mixture of 200 ml of water and 40 ml of a 10% aqueous hydrochloric acid solution and the insolubles are filtered off. The filtrate is neutralized with a saturated aqueous solution of sodium bicarbonate and purified by column chromatography of the commercial resin Amberlite LH-20 from Tokyo Organic Chemical Industries Ltd. (eluent: water, ethanol). Recrystallization of the eluate from dimethylformamide gives 2.7 g of 8- (1-piperazinyl) -6,7-dihydro-1-oxo-1H, 5H- acid.

  
 <EMI ID = 172.1>

  
at 267-268 [deg.] C.

  
EXAMPLE 16

  
20.0 g of 8- (p-nitrobenzenesulfonyloxy) 6,7-dihydro-1-oxo-1H, 5H-benzo [ij] quinolizine-2-carboxylic acid and 12.9 g of piperazine are added to 200 ml of anhydrous dimethylsulfoxide and heated in an autoclave under nitrogen purging at a pressure of 10 atmospheres at a temperature of 150 to 160 [deg.] C for 17 h with stirring. By treating corme

  
in Example 15, 2.1 g of 8- (1-piperazinyl) -6,7-dihydrol-oxo-1H, 5H-benzo [ij] quinolizine-2-carboxylic acid, melting at 264-268 [ deg.] C. EXAMPLE 17

  
 <EMI ID = 173.1>

  
6,7-dihydro-1-oxo-1H, 5H-benzo [ij] quinolizine-2-carboxylic acid and 12.9 g of piperazine to 200 ml of anhydrous dimethylsulphoxide and heated in an autoclave under nitrogen flushing at the pressure of 8 atmospheres at a temperature

  
 <EMI ID = 174.1>

  
lic as a white amorphous substance not melting below
300 [deg.] C.

  
EXAMPLE 18

  
 <EMI ID = 175.1>

  
200 ml of anhydrous dimethylsulfoxide and heated in an autoclave with nitrogen sweeping at 10 atmospheres, at a temperature of 160-170 [deg.] C, for 20 h, with stirring. By ending as described in Example 15, we obtain

  
 <EMI ID = 176.1>

  
lizin-2-carboxylique in the form of white needles melting at 267-268 [deg.] C. EXAMPLE 19

  
20.7 g of 8- (o-methoxybenzenesulfonyloxy) acid are added -

  
 <EMI ID = 177.1>

  
 <EMI ID = 178.1>

  
 <EMI ID = 179.1>

  
Examples 15 to 19 lea compounds identified below by the nature of their substituents in Table VII below in which the melting point and the physical form of the products obtained will also be found.

  
EXAMPLE 27

  
 <EMI ID = 180.1>

  
sodium in 30 ml of water and stirred 8 at room temperature for 30 min. Was added dropwise, while cooling in ice, 5 ml of acetone

  
 <EMI ID = 181.1>

  
temperature for 30 min then at room temperature for 1 h 30 min. It precipitates crystals which are filtered and washed with water. The recrystallisa-

  
 <EMI ID = 182.1>

  
white needles not melting below 300 [deg.] C. EXAMPLE 28

  
2.0 g of 8- (1-piperazinyl) -6,7-dihydro- acid are dissolved.

  
 <EMI ID = 183.1>

  
 <EMI ID = 184.1>

  
wash with water. They are redissolved in an N aqueous solution of sodium hydroxide, treated with activated carbon and neutralized with a solution.

  
 <EMI ID = 185.1> which is filtered and.washed with water. Recrystallization from dimethyl

  
 <EMI ID = 186.1>

  
white not melting below 300 [deg.] C.

  
EXAMPLE 29

  
2.0 g of 8- (1-piperazinyl) -6,7-dihydro-1- acid are added.

  
 <EMI ID = 187.1>

  
solution 2.0 g of potassium carbonate and stirred at room temperature for 30 min. Complete dissolution is brought about by adding 3 ml of N aqueous sodium hydroxide solution and then 10 ml of methanol containing 0.9 g of benzyl chloride are added dropwise, while cooling in ice. When the reaction is complete, the mixture is heated under reflux for 3 h; a homogeneous solution is obtained which is treated with hot activated carbon

  
 <EMI ID = 188.1>

  
melting at 274-278 [deg.] C.

  
EXAMPLE 30

  
 <EMI ID = 189.1>

  
for 6 h. When the reaction is complete, the solvent is removed in vacuo and the residue is dissolved by adding 50 ml of water. The solution is stirred with 100 ml of. chloroform, the aqueous layer is separated and treated with activated carbon. The aqueous solution is acidified with an aqueous solution

  
 <EMI ID = 190.1>

  
by activated carbon and concentrated. The addition of ethanol to the concentrated product causes the formation of crystals which are recrystallized from an ethanol / water mixture; 1.5 g of 9- (1-

  
 <EMI ID = 191.1>

  

 <EMI ID = 192.1>
 

V

  
EXAMPLE 31

  
20 ml of dimethyl sulfoxide are added to a mixture of 1.6 g

  
 <EMI ID = 193.1>

  
carboxylic acid and 3 g of anhydrous piperazine and heated in an oil bath

  
at 140-150 [deg.] C for 6 h. When the reaction is complete, the solvent is removed in vacuo and the residue is dissolved by adding 50 ml of water. The aqueous solution is stirred with 100 ml of chloroform, the layer is separated.

  
 <EMI ID = 194.1>

  
10% hydrochloric acid and filtered. The filtrate is again treated with activated charcoal and offset. The addition of ethanol causes the formation of crystals which are recrystallized from an ethanol-water mixture. Yield: 0.9 g

  
 <EMI ID = 195.1>

  
melting at 269-273 [deg.] C (decomposition).

  

 <EMI ID = 196.1>


  
EXAMPLE 32

  
 <EMI ID = 197.1>

  
of oil for 4 h with stirring. When the reaction is complete, the solvent is removed in vacuo. 200 ml of water and 200 ml are added to the residue.

  
of chloroform, shake and separate the aqueous layer. We adjust the pH

  
of the aqueous layer to 3 and filtered. The filtrate is treated with activated carbon and concentrated; a pale yellow precipitate is obtained which is washed with a small quantity of water and dried. Yield: 1.3 g of hydrochloride

  
 <EMI ID = 198.1>

  

 <EMI ID = 199.1>


  
EXAMPLE 33 a) 3 g of iodine and 20 ml of pyridine are added to 2.75 g of <EMI ID = 200.1> lizine and the mixture is heated at 100 [deg.] C for 1 h. After the reaction, the crystals are filtered and washed with 10 ml of cold pyridine and 10 ml.

  
 <EMI ID = 201.1>

  
melting at 264-265 [deg.] C.

  
This compound was converted to its hydrochloride by reaction with hydrochloric acid; the hydrochloride is an amorphous substance melting at 300 [deg.] C.

  
EXAMPLE 34

  
By operating as described in Example 33, we obtain

  
 <EMI ID = 202.1>

  
EXAMPLE 35

  
By operating as described in Example 33, we obtain

  
 <EMI ID = 203.1>

  
 <EMI ID = 204.1>

  
EXAMPLE 36

  
By operating as described in Example 33, the

  
 <EMI ID = 205.1>

  
benzo [ij] quinolizine-2-carboxylic in the form of white amorphous substance not melting below 300 [deg.] C.

  
EXAMPLE 37

  
By operating as described in Example 33, we obtain

  
 <EMI ID = 206.1>

  
lizin-2-carboxylic white needle not melting below 300 ° C.

  
EXAMPLE 38

  
By operating as described in Example 33, we obtain

  
 <EMI ID = 207.1>

  
EXAMPLE 39

  
By operating as described in Example 33, the

  
 <EMI ID = 208.1>

  
pyrrolo [3,2, l-ij] quinoline-5-carboxylic in the state of yellow needles pays melting at 269-273 [deg.] C decomposition).

  
EXAMPLE 40

  
By operating as described in Example 33, the

  
 <EMI ID = 209.1>

  
ij] quinoline-5-carboxylic in the form of pale yellow needles not melting below 300 [deg.] C.

  
EXAMPLE 41

  
By operating as described in Example 33, the

  
 <EMI ID = 210.1>

  
position).

  
EXAMPLE 42

  

 <EMI ID = 211.1>


  
 <EMI ID = 212.1>

  
The active compound and glucose are dissolved in distilled water for injection and the solution is added to a 5 ml ampoule.

  
 <EMI ID = 213.1>

  
for 15 min.

  
EXAMPLE 43

  
Therapeutic composition in coated tablets

  

 <EMI ID = 214.1>


  
 <EMI ID = 215.1>

  
corn and magnesium stearate, then put into tablets $ using a <EMI ID = 216.1>

  
film-forming product consisting of TC-5, polyethylene glycol 6000, castor oil and methanol.

  
EXAMPLE 44

  

 <EMI ID = 217.1>


  
 <EMI ID = 218.1>

  
hot the active compound, the purified hydrated lanolin and white petrolatum. Stirred until the start of solidification.

  
EXAMPLE 45

  

 <EMI ID = 219.1>


  
filter for injection and the solution is placed in a 5 ml ampoule. The air is removed with nitrogen, the ampoule is sealed and sterilized at 121 [deg.] C for 15 min.

  
 <EMI ID = 220.1>

  

 <EMI ID = 221.1>


  
We mix and grind the active compound, Avicel, starch

  
 <EMI ID = 222.1> <EMI ID = 223.1>

  
Kikusui Seisakusho Co., Ltd.). The tablets are coated with a film forming product consisting of TC-5, polyethylene glycol 6000, castor oil and methanol.

  
EXAMPLE 47

  

 <EMI ID = 224.1>


  
The active compound, the Avicel, the mata starch and the magnesium stearate are mixed and crushed, then they are put into tablets using a

  
 <EMI ID = 225.1>

  
film forming consisting of TC-5, polyethylene glycol 6000, castor oil and methanol.

  

 <EMI ID = 226.1>


  

 <EMI ID = 227.1>
 

TABLE II

  
Antimicrobial activity on bacteria causing disease
- infectious of fish

  

 <EMI ID = 228.1>
 

TABLE III

  
 <EMI ID = 229.1>

  
quinoline

  

 <EMI ID = 230.1>
 

TABLE IV

  
Human serum protein deactivation

  

 <EMI ID = 231.1>
 

TABLE V

  

 <EMI ID = 232.1>
 

TABLE VI

  

 <EMI ID = 233.1>
 

TABLE VII

  

 <EMI ID = 234.1>
 

CLAIMS

  
 <EMI ID = 235.1>

  

 <EMI ID = 236.1>


  
in which R represents a hydrogen atom or a lower alkyl group, R <2> represents a hydrogen atom, R <3> represents a hydrogen atom, a lower alkyl, lower alkanoyl, alkane-

  
 <EMI ID = 237.1>

  
formula group

  

 <EMI ID = 238.1>


  
 <EMI ID = 239.1>


    

Claims (1)

<EMI ID = 240.1> 3. Compounds according to claim 2, characterized in that R represents a hydrogen atom. 4. Composts according to claim 3, characterized in that R represents a C 1-C 4 alkyl group. 5. Compounds according to claim 3, characterized in that <EMI ID = 241.1> <EMI ID = 242.1> represents a C 1-C 4 alkyl group. 8. Compounds according to claim 1, characterized in that <EMI ID = 243.1> formula group <EMI ID = 244.1> 9. A compound according to claim 1, taken from the group formed by the following: <EMI ID = 245.1> <EMI ID = 246.1> claim 1 and their pharmaceutically acceptable salts, <EMI ID = 247.1> <EMI ID = 248.1> <EMI ID = 249.1> <EMI ID = 250.1> Jt <EMI ID = 251.1> wherein R <3> has the meanings given in claim 1. 11. Process for preparing the compounds of formula (I) according to <EMI ID = 252.1> general formula <EMI ID = 253.1> <EMI ID = 254.1> compound of general formula <EMI ID = 255.1> <EMI ID = 256.1> hydrogen atoms or lower alkyl groups, to obtain a compote of general formula <EMI ID = 257.1> <EMI ID = 258.1> the compound (VI ') is reduced to obtain a compound of general formula <EMI ID = 259.1> <EMI ID = 260.1> <EMI ID = 261.1> in which R3 is as defined above to obtain a compost of general formula <EMI ID = 262.1> <EMI ID = 263.1> in an inert solvent to obtain a compound of the formula generated <EMI ID = 264.1> <EMI ID = 265.1> obtain the compound of general formula (I). 12. As new drugs, useful in particular because of their antimicrobial properties, the compounds according to claim 1. 13. Therapeutic compositions containing as substance <EMI ID = 266.1> 14. Forms of administration of the therapeutic compositions according to claim 13.