BE875469A - NEW BETA-LACTAM-TYPE COMPOUNDS USEFUL AS ANTIMICROBIAL AGENTS AND THEIR PREPARATION PROCESS - Google Patents

Description

       

  The present invention relates to 0-lactam derivatives represented by the formula (I) defined below and their "pharmaceutically suitable salts, which are useful as antimicrobial agents, a process for their preparation and therapeutic and pharmaceutical compositions.

  
containing them.

  
It is known that certain types of polyheterocyclic compounds have antimicrobial activity. For example, United States Patent No. [deg.] 3,917,609 describes substituted derivatives of 1,2-dihydro-6-

  
 <EMI ID = 1.1>

  
goods or as intermediates for the preparation of antimicrobial agents.

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

  
 <EMI ID = 2.1>

  
However, the β-lactam compounds of the invention have a different structure from that of these quinoline and quinolizine compounds. In addition, the P-lactams of the invention have antimicrobial activity.

  
 <EMI ID = 3.1>

  
 <EMI ID = 4.1>

  
The present invention relates to antimicrobial agents
(as well as anticancer and antiviral agents) represented by the

  
 <EMI ID = 5.1>

  

 <EMI ID = 6.1>


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

  
R2 represents a hydrogen atom, R <3> represents a halogeno, nitro, amino, hydroxy, lower alkyl, lower alkoxy, lower alkanoylamino, lower alkanesulfonyloxy radical or a radical of formula:

  

 <EMI ID = 7.1>


  
 <EMI ID = 8.1>

  
a lower alkanesulfonyl radical, <EMI ID = 9.1>

  
 <EMI ID = 10.1> or a radical of formula:

  

 <EMI ID = 11.1>


  
 <EMI ID = 12.1>

  
equal to 0, R <1> and R <2> can combine to form a cyclohexane ring with the carbon atoms to which they are attached, their salts suitable in pharmacy and a process for their preparation.

  
In the present description, the term 'halo radical' denotes a chloro, bromo, iodo or fluoro radical.

  
 <EMI ID = 13.1>

  
laughing "denotes a straight or branched alkyl radical containing 1 to 4 'atoms

  
of carbon such as a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.

  
In the present description, the term “lower alkoxy radical” denotes a straight or branched alkoxy radical comprising 1 to

  
4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like.

  
In the present description, the term "lower alkanoylamino radical" denotes a straight or branched alkanoylamino radical having 1 to 4 carbon atoms, such as a formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino and the like.

  
 <EMI ID = 14.1>

  
ethanesulfonyloxy, propaneaulfonyloxy, isopropanesulfonyloxy, butaneaulfonyloxy, tert-butanesulfonyloxy and the like.

  
In the present description, the term “lower alkanoyl radical” denotes a straight or branched alkanoyl radical comprising 1 to

  
4 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl and the like.

  
In the present description, the term "lower alkanesulfonyl radical denotes a straight or branched alkanesulfonyl radical.

  
 <EMI ID = 15.1>

  
ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, tert-butanesulfonyl and the like.

  
In the present description, the term "lower alkanoyloxy radical" denotes a straight or branched alkanoyloxy radical having 1 to 4 carbon atoms, such as a formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy and the like.

  
The [hundred] -lactam type compounds represented by formula (I) are novel compounds which, together with their pharmaceutically suitable salts, exhibit excellent antimicrobial activity against gram positive and gram negative bacteria and which are therefore useful as antibacterial agents.

  
The compounds of the invention are particularly effective

  
 <EMI ID = 16.1>

  
robacter, etc., and they possess potent antibacterial activity against those bacteria which are resistant to streptomycin, ampicillin and / or tetracycline.

  
The following compounds may be mentioned as characteristic examples which are illustrative, but not limiting, of the compounds of the invention:

  
 <EMI ID = 17.1>

  
azabicyclo [3.2.0] heptane-2-carboxylic,

V

  
 <EMI ID = 18.1>

  
1-Azabicyclo [3.2.0] heptane-2-carboxylic acid, <EMI ID = 19.1>

  
carbazole-5-carboxamido) -2- (4-hydroxyphenyl) acetamido] -3,3-dimethyl-7-oxo4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic,

  
 <EMI ID = 20.1> <EMI ID = 21.1> <EMI ID = 22.1>

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

  
 <EMI ID = 23.1> <EMI ID = 24.1>

  
[3.2.0] heptane-2-carboxylique,

  
6- [2- (10-hydroxy-6,7-dihydro-1-oxo-1H, 5H-benzo [ij] quinolizine-2- acid

  
 <EMI ID = 25.1>

  
[3.2.0] heptan-2-carboxylic acid, <EMI ID = 26.1> <EMI ID = 27.1>

  
(4-hydroxy) phenylacetamido] -3- (acetoxymethyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 -carboxylic, <EMI ID = 28.1>

  
[3.2.0] heptan-2-carboxylic acid, <EMI ID = 29.1>

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

  
 <EMI ID = 30.1>

  
[3.2.0] heptane-2-carboxylique,

  
6- [2- (8-hydroxy-1,2-dihydro-6-oxo-6H-pyrrolo [3,2,1-ij] quinoline-5- acid

  
 <EMI ID = 31.1> <EMI ID = 32.1>

  
quinoline-5-carboxamido) -2-phenylacetamido] -3,3-dimethyl-7-oxo-4-thia-lazabicyclo [3.2.0] heptane-2-carboxylic,

  
 <EMI ID = 33.1> <EMI ID = 34.1> <EMI ID = 35.1>

  
boxylic.

  
The compounds of the invention are derivatives of penicillanic acid and cephalosporic acid and they can be prepared according to various processes from compounds comprising a carboxylic acid function, represented by the formula:

  

 <EMI ID = 36.1>


  
123

  
where R, R, R, 1 and n have the same meaning as above.

  
Some of the compounds represented by formula (II) are new and others are known as described in US Patents Nos. 3,917,609, 3,896,131, 3,985,882, 3,969,463. , 4,001,243 and

  
4 014 377. They can be prepared, for example, according to the following reaction scheme 1:

  
Reaction scheme 1
 <EMI ID = 37.1>
 
 <EMI ID = 38.1>
 <EMI ID = 39.1>

  
 <EMI ID = 40.1>

  
The compounds of formula (III) which are used as starting materials in the above process are known compounds, as described in the US Patents in the name of Gerater et al. this-

  
 <EMI ID = 41.1>

  
 <EMI ID = 42.1>

  
Known Assignments, as described in the US Patents and Bibliographic References mentioned above. Compounds of formula

  
 <EMI ID = 43.1>

  
The reaction can be carried out between the compound of formula
(III) and the compound of formula (IV) in the absence of a solvent or in the presence of solvents such as methanol, ethanol, isopropanol, aceto-

  
 <EMI ID = 44.1>

  
triamide and the like, but is preferably carried out in the absence of solvent.

  
The compound of formula (IV) can be used in excess relative to the equimolecular amount of the compound of formula (III). Preferably, the reaction is carried out in equimolecular proportions in the absence of solvent or with 1.1 to 1.5 moles of compound of formula (IV) per mole of compound of formula (III) in the presence of solvents. In general, the reaction can be carried out at a temperature between the temperature

  
 <EMI ID = 45.1>

  
for a period of between about 0.5 and about 6 hours, to easily obtain the compound represented by the formula (V).

  
The cyclization reaction of the compound can be carried out

  
of formula (IV) according to a conventional technique, for example by heating the compost of formula (IV) or by cyclization with an acidic substance such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride , concentrated sulfuric acid, polyphosphoric acid and the like. When performing the hot cyclization, it is preferred to heat the compound of formula (V) in

  
a solvent such as a high boiling point hydrocarbon or an ether

  
high boiling point, for example tetralin, diphenyl ether, diethylene glycol dimethyl ether, etc. at a temperature of about

  
 <EMI ID = 46.1>

  
acidic substance, the amount of acidic substance present may be between about the equimolecular amount and a large excess, preferably a 10 to 20 times molar excess relative to the amount of the compound of formula (V), at a temperature of about 100 & about 150 [deg.] C, over a period of about 0.5 hrs about 6 hrs, to advantageously obtain the desired compound of formula (VI).

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

  
potassium, barium hydroxide and the like or an inorganic or organic acid, such as aulfuric acid, hydrochloric acid, nitric acid, acetic acid, aromatic sulfonic acid and 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, at a temperature between room temperature and about 200 [deg.] C, preferably between 50 and

  
 <EMI ID = 47.1>

  
The compounds of formula (IIb) below, which form part of the compounds of formula (II), are preferably prepared by reaction of the compounds of formula (IIa) with a piperazine derivative of formula (VII), as illustrated by reaction scheme 2 below:

  
Reaction scheme 2

  

 <EMI ID = 48.1>


  
1235

  
where R, R, R, R and n have the meanings indicated above and

  
 <EMI ID = 49.1>

  
In the reaction of the compound of formula (IIa) and the compound of formula (VII), the relative proportions of the two compounds are not critical and can vary widely. Generally, the reaction is carried out with an at least equimolecular amount of pre-

  
 <EMI ID = 50.1>

  
formula (IIa) in an inert solvent.

  
Examples of suitable inert solvents are water, lower alcohols, such as methanol, ethanol, isopropanol, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane, diglyme (diethylene glycol dimethyl ether), etc., dimethylsulfoxide, dimethylformamide, hexamethylphosphorotriamide and the like, among which preferred are dimethylsulfoxide, dimethylformamide and hexa-

  
 <EMI ID = 51.1>

  
The above reaction can be carried out under pressure, i.e. at a pressure of about 1 to about 20 bar, and preferably 1 to 10 bar, at a temperature of about 100 to about 250 bar. [deg.] C, preferably 140 to 200 [deg.] C for a period of about 5 to about 20 h.

  
Among the starting compounds of formula (III), the compounds of formula (IIIa) and (IIIc) can be easily prepared according to

  
 <EMI ID = 52.1>

  
Reaction scheme 3

  

 <EMI ID = 53.1>


  
where R and 1 have the same meaning as above, and B represents a methylene or ethylene radical.

  
Reaction scheme 4

  

 <EMI ID = 54.1>


  
 <EMI ID = 55.1>

  
 <EMI ID = 56.1>

  
lower alkanesulfonyloxy, R <1> <3> represents an alkanesulfonyl radical

  
 <EMI ID = 57.1>

  
represent a hydroxy radical, and X represents a halo radical.

  
The reduction of the compounds of formula (VIII) can be carried out according to reaction scheme 3 above catalytically, or with a conventional hydrogenating agent, such as a combination of sodium borohydride or lithium hydride. and aluminum and a lower fatty acid such as, for example, acetic acid, txifluoroacetic acid, propionic acid, etc.

  
The appropriate amounts of sodium borohydride or

  
 <EMI ID = 58.1>

  
between approximately equimolecular amounts and a large excess, preferably 3 to 5 moles per mole of the compound of formula (VIII),

  
The reduction reaction can be advantageously carried out with a hydrogenating agent in an inert solvent such as an ether, such as dioxane, tetrahydrofuran, diglyme, etc., an aromatic hydrocarbon such as benzene. , toluene, etc., or a lower fatty acid such as trifluoroacetic acid, propionic acid, etc., at a temperature between room temperature and about 100 [deg.] C,

  
preferably between 50 and 100 [deg.] C, for about 1 to about 6 h.

  
According to Reaction Scheme 4 above, the appropriate amount of compound of formula (IX) which is reacted with the compound of formula (IIIb) (described in US Patents in the name of Gerster and the bibliographical references above) above) is equal to at least about an equimolecular amount and is preferably 1 to 2 moles per mole of the compound of formula (IIIb).

  
The reaction is generally carried out in an inert solvent in the presence of a deoxidizing agent, in an amount at least about equimolecular and, preferably, equal to 1 to 2 moles per mole of the compound.

  
 <EMI ID = 59.1>

  
 <EMI ID = 60.1>

  
As examples of suitable deoxidizing agents, mention may be made of alkali metal hydroxides such as sodium hydroxide,

  
 <EMI ID = 61.1>

  
sodium nate, potassium carbonate, potassium bicarbonate,

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

  
As examples of suitable inert solvents, there may be mentioned lower alcohols such as methanol, ethanol, isopropanol, etc., ethers such as dioxane, tetrahydrofuran, diglyme, etc., aromatic hydrocarbons such as benzene, toluene, etc., dimethylsulfoxide, dimethylforcnamide, hexamethylphosphorotriamide, pyridine, etc.

  
The compounds of formula (II) thus obtained can be converted into penicillanic acid derivatives of the invention, according to various processes which can, in general, be divided into the following two groups:

  
(<1>) the deformulc compound (II), one of its derivatives containing an activated carboxy radical, is reacted with a conventional derivative of ampicillin or of cephaloglycine, and

  
(<2>) the compound of formula (II), or one of its derivatives, is reacted with

  
activated carboxy radical, with a derivative of phenylglycine or a derivative 'corresponding activated amino radical and the product is then reacted

  
 <EMI ID = 62.1>

  
sporic, It is possible to carry out the methods (1) and (2) above, according to the conventional reactions for the formation of an amide function.

  
As characteristic examples of the processes of group (1), mention may be made of: a) The mixed acid anhydride process.

  
The compound of formula (II) is reacted with a halo-

  
 <EMI ID = 63.1>

  
it is then reacted with an ampicillin derivative or a cephaloglycine derivative.

  
b) The activated ester process.

  
The compound of formula (II) is converted into a reactive ester such as p-nitrophenyl ester, N-hydroxysuccinimidic ester, 1-hydroxybenzotriazolic ester, etc., then reacted with an ampicillin derivative or a derivative. cephaloglycine.

  
c) The carbodiimide process.

  
The compound of formula (II) and an ampicillin derivative or a cephaloglycine derivative are condensed with release of water in the presence of a

  
 <EMI ID = 64.1>

  
dazole, etc.

  
d) Other processes.

  
The compound of formula (II) is converted into an acid anhydride with a dehydrating agent such as acetic anhydride, etc. or an acid halide with a halogenating agent, followed by reacting the product with an ampicillin derivative or a cephaloglycine derivative; it is also possible to operate according to a process according to which a lower alcohol ester of the compound of formula (II) is reacted with an ampicillin derivative or a cephaloglycine derivative, at high temperature and under pressure.

  
Of the above processes, particularly preferred is the mixed acid anhydride process which can be practiced, for example according to the following reaction scheme:

  
Reaction scheme 5

  

 <EMI ID = 65.1>


  
 <EMI ID = 66.1>

  
 <EMI ID = 67.1>

  
represents a lower alkyl radical and X represents a halo radical.

  
According to Reaction Scheme 5 above, the reaction between the compound of formula (II) and the alkyl haloformate of formula (X), which is a known compound, can be carried out according to the classical Schotten-Baumann reaction and subjecting the compound obtained of formula (XI) (derivative with activated carboxy radical of the compound of formula (II)) to a subsequent reaction

  
 <EMI ID = 68.1>

  
without intermediate isolation.

  
Ampicillin and cephaloglycine derivatives of formula
(XII) are described by F.P. Doyle et al. in J. Chem. Soc. page 1440

  
 <EMI ID = 69.1>

  
The compounds of formula (II) and the compounds of formula (X) can be reacted according to the Schotten-Baumann reaction without solvent in the presence of a basic compound. The reaction is advantageously carried out in a solvent in the presence of a basic compound.

  
Examples of suitable solvents which may be mentioned are chloroform, dichloromethane, dichloroethane, acetonitrile,

  
 <EMI ID = 70.1>

  
etc.

  
As examples of suitable basic compounds, mention may be made of amines such as triethylamine, trimethylamine,

  
 <EMI ID = 71.1>

  
 <EMI ID = 72.1>

  
sodium, potassium bicarbonate, sodium bicarbonate, etc. and metal salts of organic acids such as sodium acetate,

  
sodium propionate, etc.

  
Examples of suitable alkyl haloformates that may be mentioned are methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, etc.

  
The proportion of the compound of formula (X) to the compound of formula (II) is preferably, when the operation is carried out in a solvent, from 1.1 to 1.5 moles of compound of formula (X) per mole of compound of formula (II).

  
The reaction can be carried out at a temperature of about <EMI ID = 73.1> <EMI ID = 74.1>

  
The reaction of the compound of

  
 <EMI ID = 75.1>

  
described, or in a mixture of water and solvent, with an amount at

  
 <EMI ID = 76.1>

  
of formula (XII) per mole of compound (XI), at a temperature between room temperature and approximately 100 [deg.] C, preferably at room temperature, for approximately 2 h to approximately 10 h.

  
Reaction scheme 6 below constitutes a typical example of processes of group (2).

  
 <EMI ID = 77.1>

  

 <EMI ID = 78.1>


  
 <EMI ID = 79.1>

  
According to reaction scheme 6, the compound of the invention, represented by formula (I), can be obtained by reacting the compound of formula (II) or one of its derivatives containing an activated carboxy radical, with a

  
 <EMI ID = 80.1>

  
compound of formula (XIV) which is reacted with a derivative of 6-aminopenicillanic acid or 7-aminocephalosporic acid or their corresponding salts of formula (XV).

  
The derivatives of penicillanic acid and cephalosporanic acid and their salts are described by F.P. Doyle et al. in J. Chem. Soc.

  
 <EMI ID = 81.1>

  
page 746 (1966).

  
The reaction stages are easily carried out, for example according to the conventional reaction of forming an amido bond.

  
The compounds of the invention, represented by formula CI) and prepared as previously described, can form suitable salts

  
in pharmacy when they contain a basic group and these salts which are suitable in pharmacy also come within the scope of the invention. Pharmaceutical suitable acids which can be used to form the salts can be various organic or inorganic acids, for example hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, acid phosphoric acid, acetic acid, oxalic acid, malonic acid, succinic acid, malic acid, fumaric acid, acid

  
 <EMI ID = 82.1>

  
sulfonic and the like.

  
 <EMI ID = 83.1>

  
 <EMI ID = 84.1>

  
basic compound suitable in pharmacy. We can cite as examples of

  
 <EMI ID = 85.1>

  
sodium, potassium hydroxide, calcium hydroxide, aluminum hydroxide, sodium bicarbonate and the like, and, as examples of basic organic compounds, morpholine, piperazine, pyridine, piperidine, ethylamine, dimethylamine, triethylamine, aniline and the like.

  
The compounds of formula (I) and their salts can be isolated

  
 <EMI ID = 86.1>

  
after completion of the reaction and purify them according to conventional techniques, for example solvent extraction, dilution, precipitation, crystallization, column chromatography, preparative thin layer chromatography and the like.

  
As is evident to those skilled in the art, the compounds of formula (I) exist in optically active forms and these optical isomers come within the scope of the invention.

  
In order to use the compounds of the invention of formula (I) and their salts as therapeutic agents, they can be incorporated into pharmaceutical compositions with ordinary pharmaceutical carriers. As examples of suitable carriers, mention may be made of diluents or excipients such as fillers, binders, wetting agents, disintegrating agents, surfactants and lubricants commonly used to prepare medicaments according to the particular pharmaceutical form.

  
Various pharmaceutical forms containing the active ingredients of the invention can be used as antimicrobial agents, depending on the treatment envisaged. As characteristic examples of useful pharmaceutical forms, mention may be made of pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories and injectable preparations (solutions, suspensions, etc.).

  
For preparing pharmaceutical forms consisting of tablets containing the compounds of formula (I) or their suitable salts

  
in pharmacy as an active ingredient, it is desired to use a wide variety of carriers known in the art. Examples of suitable carriers are excipients such as lactose, sucrose, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, binders such as water, ethanol: propanol; simple syrup, glucose;

  
 <EMI ID = 87.1>

  
sodium alginate, agar powder, kelp powder, sodium bicarbonate, calcium carbonate, a Tween, lauryl sulfate

  
 <EMI ID = 88.1>

  
disintegration inhibitors such as sucrose, a glyceryl ester of stearic acid, cocoa butter and hydrogenated oils,

  
absorption activators such as quaternary ammonium bases 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,

  
salts of stearic acid, powdered boric acid, Macrogol (trade name of a polyethylene glycol produced by Shinetsu Chemical Ir.dustry Co.,

  
 <EMI ID = 89.1>

  
If desired, the tablets can be coated to form sugar coated tablets, gelatin coated tablets, enteric coated tablets, film coated tablets or tablets having two or more layers.

  
To prepare pharmaceutical forms consisting of pills, a wide variety of conventional carriers known in the art can be used. As examples of suitable carriers, mention may be made of excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oils, kaolin and talc, binders such as powdered gum arabic, gum tragacanth. powder, gelatin and ethanol, and disintegrants such as kelp powder and agar.

  
To prepare pharmaceutical forms consisting of suppositories, gold can use a wide variety of known carriers.

  
in art. As examples of suitable carriers, mention may be made of polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides.

  
When the pharmaceutical forms are injectable preparations, the solution or suspension is preferably sterilized and

  
they are made isotonic with blood. To prepare a pharmaceutical form consisting of a solution or a suspension, any diluents usually employed in the art can be used. We can cite as examples

  
suitable diluents water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylenesorbitol and sorbitan esters. Sodium chloride, glucose or

  
from glycerol to the therapeutic agent used, for example, as an antinephritic agent, in an amount sufficient to obtain an isotonic solution. The therapeutic agent may further contain customary components such as dissolving aids, buffers, analgesics, preservatives and, optionally, colors, fragrances, flavors, sweeteners and other drugs.

  
The amount of the compound of formula (I) and corresponding pharmaceutically suitable salts of the invention which is used as an active ingredient in an antimicrobial therapeutic composition is not critical and can vary over a wide range. The appropriate therapeutic amount of compound of general formula (I) and corresponding pharmacologically suitable salts is generally from about 1 to about

  
707 by weight and preferably from 5 to 50% by weight relative to the totality of the composition.

  
There is no particular limitation on the mode of use of the therapeutic agent as an antinephritic agent and it can be administered by routes suitable for the particular dosage form. For example, tablets, pills, liquid preparations, suspensions, granules and

  
the capsules. The injectables are administered intravenously, alone or in combination with common auxiliary agents such as glucose and amino acids. In addition, the therapeutic agent can be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally. The suppositories are administered rectally and the ointments are applied to the skin.

  
The dosage of the antimicrobial agent is chosen according to the purpose to be achieved, the symptoms, etc. Generally, the daily dosage of the compounds of the invention is about 10 mg to 5 g in three to four divided doses.

  
Antimicrobial activity.

  
1. Method of determination.

  
The antimicrobial activity of the following test compounds is determined on various test microorganisms listed below

  
 <EMI ID = 90.1>

  
series on agar bundles and minimum inhibitory concentrations

  
 <EMI ID = 91.1>

  
Samples of each microorganism are prepared

  
 <EMI ID = 92.1>

  
 <EMI ID = 93.1>

  
2. Test microorganisms.

  
A: Staphylococcus aureus FDA 209 P

  
B: Streptococcus pyogenea IID S-23

  
 <EMI ID = 94.1>

  
D: Klebsiella pneumoniae

  
3. Test compounds.

  
E: Proteus rettgeri NIH 96

  
F: Salmonella typhi 0-901 (NCTC 8390)

  
G: Shigella sonnei EW 33

  
H: Serratia marcescens IFO 12648

  
 <EMI ID = 95.1>

  
J: Pseudomonas aeruginosa NCTC 10490

  
 <EMI ID = 96.1>

  
L Pseudomonas aeruginosa NC-5

  
 <EMI ID = 97.1>

  
 <EMI ID = 98.1>

  
[3.2.0] heptane-2-carboxylic, <EMI ID = 99.1> n [deg.] 16 acid 6- [2- (9-fluoro-6,7-dihydro-1-oxo-1H, 5H-benzo [ ij] quinolizine-2-

  
 <EMI ID = 100.1>

  
dicyclohexylamine,

  
n [deg.] 25 carbenicillin (control)

  
n [deg.] 26 ampicillin,

  
n [deg.] 27 cephaloglycine,

  
 <EMI ID = 101.1>

  
sodium carboxylate.

  
acute toxicity

  
Acute toxicity is determined compounds of the invention

  
 <EMI ID = 102.1>

  
in Table II below.

  
 <EMI ID = 103.1>

  
other test compounds which are equal to 500 mg / kg or more.

  
The invention is illustrated by the reference examples (preparation of starting materials) and the following examples which are in no way limiting. The antimicrobial activity of characteristic compounds of the invention is also illustrated in the examples. Unless otherwise indicated, parts, percentages and ratios are expressed by weight.

  
When crystals without a completely defined shape are obtained, they are hereinafter referred to as "amorphous crystals".

  
REFERENCE EXAMPLE 1

  
12.6 g of p-fluoroaniline are dissolved in 100 ml of ethanol and a catalytic amount of p-toluenesulfonic acid is added.

  
Then 9.8 g of cyclohexanone are added dropwise to the mixture at room temperature. After completion of the addition, the

  
mixture at room temperature for 1 hour and concentrated under reduced pressure. Prepared dilute sulfuric acid is added to the residue

  
from 190 ml of water and 20 ml of concentrated sulfuric acid, and the mixture is heated to 110 [deg.] (; for 15 min in an oil bath to precipitate

  
 <EMI ID = 104.1>

  
washed three times with water and dried to obtain 17.4 g of 6-fluoro1,2,3,4-tetrahydrocarbazole which is identified by its NMR spectrum. REFERENCE EXAMPLE 2

  
 <EMI ID = 105.1>

  
in 75 ml of glacial acetic acid and 15 g of metallic tin are added to the solution. The mixture is heated in an oil bath at reflux, then 50 ml of concentrated hydrochloric acid are added dropwise. The color of the reaction system changes from orange to colorless with vigorous production of hydrogen. After 3.5 h of reaction, the excess metallic tin is filtered off and the filtrate is concentrated. 50 ml of water are added to the residue and the mixture is basified with 4N sodium hydroxide, followed by extraction with ethyl ether. The ether layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 10 g.

  
 <EMI ID = 106.1>

  
 <EMI ID = 107.1>

  
REFERENCE EXAMPLE 3

  
9 g of ethyl ethoxymethylenemalonate are added to 8 g of

  
 <EMI ID = 108.1>

  
of ethanol during the heating of the mixture in an oil bath at 110 [deg.] C, After heating at this temperature for 30 min, 100 g of polyphosphoric acid are added, followed by heating at 140 [deg.] C for 30 min. When the reaction is complete, the reaction mixture is poured into 500 ml of water to obtain light brown crystals which are recrystallized from a mixture.

  
 <EMI ID = 109.1>

  
in the form of white tables having a melting point of 97-98 [deg.] C. REFERENCE EXAMPLE 4

  
21.6 g of ethyl ethoxymethylenemalonate are added to

  
 <EMI ID = 110.1>

  
tion of ethanol while the mixture is heated to 110 [deg.] C in an oil bath for 30 min. After heating, 240 g of polyphosphoric acid prepared from 120 g of phosphoric acid and 120 g of phosphorus pentoxide are added to the mixture and the mixture is left to react in an oil bath at 140 [deg.] C for 45 min. When the reaction is complete,

  
the mixture was allowed to cool to room temperature and poured into 400 ml of water, then neutralized with 40% aqueous sodium hydroxide to precipitate light purple crystals. The crystals thus obtained are recrystallized from a 1/1 mixture of benzene and hexane - for

  
 <EMI ID = 111.1>

  
Ethyl carbazole-5-carboxylate having a melting point of 71-73 [deg.] C. REFERENCE EXAMPLE 5

  
 <EMI ID = 112.1>

  
carbazole and ethanol distillation is observed while the mixture is heated in an oil bath at 110 [deg.] C. After heating the mixture

  
at this temperature, 100 g of polyphosphoric acid are added, then

  
heated to 140 [deg.] C for 40 min. When the reaction is complete, the reaction mixture is poured into 200 ml of water and the mixture is neutralized with 20% aqueous sodium hydroxide with cooling to precipitate the light brown crystals which are recrystallized from a mixture.

  
 <EMI ID = 113.1>

  
REFERENCE EXAMPLE 6

  
 <EMI ID = 114.1> for 40 min. Crystals in the starting material dissolve

  
to form a uniform solution. The hot solution is treated with

  
activated carbon and filtered. The filtrate was cooled and the pH adjusted to 2 with concentrated hydrochloric acid to obtain 8 g of white crystals. The crystals are recrystallized from ethanol to obtain

  
 <EMI ID = 115.1>

  
carbazole-5-carboxylic in the form of white needles melting
281-282 [deg.] C.

  
REFERENCE EXAMPLE 7

  
250 ml of a 107% aqueous solution of hydroxide are added.

  
 <EMI ID = 116.1>

  
Ethyl carbazole-5-carboxylate, then heated under reflux for 2 h. As the reaction proceeds, the reaction system changes from

  
 <EMI ID = 117.1>

  
reaction, then filtered and the filtrate acidified with concentrated hydrochloric acid to precipitate light yellow crystals. The crystals are separated by filtration, washed successively with water and a small amount of methanol, dried and recrystallized from a 1/1 by volume mixture of chloroform and hexane, to obtain

  
 <EMI ID = 118.1>

  
 <EMI ID = 119.1>

  
REFERENCE EXAMPLE 8

  
 <EMI ID = 120.1>

  
 <EMI ID = 121.1>

  
reflux for 1.5 h, allowed to cool to room temperature '

  
and we filter. The filtrate was cooled and the pH adjusted to 2 with concentrated hydrochloric acid to obtain 3.2 g of light yellow crystals. Recrystallized from ethanol to obtain 2-methyl-7a, 8.9,

  
 <EMI ID = 122.1>

  
REFERENCE EXAMPLES 9 TO 13

  
As described in Reference Example 8, the following compounds are prepared comprising the substituents indicated in Table III below. The melting point and crystal form of <EMI ID = 123.1>

  
REFERENCE EXAMPLE 14

  
 <EMI ID = 124.1>

  
of a 2% aqueous solution of potassium hydroxide and the solution is subjected to catalytic reduction for 3 hours according to the Parr method (3 bars) in the presence of 5 g of Raney nickel. When the reduction is complete, the mixture is filtered and the cake washed on the filter paper with water, the filtrate and the washings are combined and neutralized with glacial acetic acid to precipitate crystals. browns. The crystals obtained are filtered, washed

  
with water, they are dried and recrystallized in a mixture of dimethyl-

  
 <EMI ID = 125.1>

  
253-256 [deg.] C (decomposition).

  
REFERENCE EXAMPLE 15

  
 <EMI ID = 126.1>

  
 <EMI ID = 127.1>

  
acetic anhydride while cooling with ice to precipitate orange crystals. The crystals are separated by filtration, washed with water

  
 <EMI ID = 128.1>

  
concentrated sulfuric acid and stirred while cooling with ice, then a mixture of 4.3 ml of concentrated nitric acid of density 1.42 and 15 ml of concentrated sulfuric acid is added dropwise. When the addition is complete, the mixture is stirred for 1 hour at room temperature.

  
 <EMI ID = 129.1>

  
 <EMI ID = 130.1>

  
REFERENCE EXAMPLE 17

  
9 g of diethyl ethoxymethylenemalonate are added

  
 <EMI ID = 131.1>

  
lation of ethanol when the mixture without solvent is heated to 110 [deg.] C in an oil bath for 30 min, with stirring. After heating, 100 g of polyphosphoric acid prepared from 50 g of phosphoric acid and 50 g of phosphorus pentoxide are added to the mixture and the mixture is left to react in an oil bath at 140 [deg.] C for 40 min. When the reaction is

  
 <EMI ID = 132.1>

  
of ice water to precipitate light yellow crystals. The crystals thus formed are filtered off and washed with sufficient water, then

  
they are brought to reflux with 100 ml of a 10% aqueous sodium hydroxide solution for 1 h. The crystals dissolve as a uniform solution which is treated hot with activated charcoal and the pH is adjusted to 2 with concentrated hydrochloric acid to

  
 <EMI ID = 133.1>

  
clear, melting at 273-275 [deg.] C.

  
REFERENCE EXAMPLE 18

  
 <EMI ID = 134.1>

  
 <EMI ID = 135.1>

  
of anhydrous piperazine and 50 ml of dimethyl sulfoxide and the mixture is heated to 140-150 [deg.] C in an oil bath for 4 h with stirring. When the reaction is complete, the solvent is removed under reduced pressure. 200 ml of water and 200 ml of chloroform are added to the residue and, after stirring, the aqueous layer is separated. The pH of the aqueous layer is adjusted to 3, then filtered. The filtrate is treated with activated charcoal and concentrated to obtain a light yellow precipitate. The precipitate is washed with a small amount of water and dried to obtain

  
 <EMI ID = 136.1>

  
289-294 [deg.] C (decomposition).

  
REFERENCE EXAMPLE 19

  
10 g of 5-hydroxy-3,4-dihydrocarbostyril are added

  
 <EMI ID = 137.1>

  
 <EMI ID = 138.1> 30 min, then the methanol is driven off under reduced pressure. Benzene is added to the residue to form crystals, then the benzene is evaporated off. The residue thus obtained is suspended in 50 ml of dimethylformamide and added dropwise to the suspension.

  
10.6 g of methanesulfonyl chloride, cooling with ice

  
 <EMI ID = 139.1>

  
nyl, the mixture obtained is stirred at room temperature for

  
4 h. When the reaction is complete, the solvent is removed under reduced pressure and the residue is purified by chromatography on a

  
silica gel column (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 obtain 5.7 g of 5-methane-

  
 <EMI ID = 140.1>

  
colorless, melting at 227-231 [deg.] C.

  
REFERENCE EXAMPLE 20

  
4.5 g of 5-methanesulfonyloxy-3,4-dihydrocarbostyril are suspended in 90 ml of dioxane, 35 g of

  
 <EMI ID = 141.1>

  
to the mixture 5.3 ml of acetic acid. The mixture is heated under reflux for 1 h, then the solvent is removed under reduced pressure. A saturated aqueous solution of sodium bicarbonate is added to the residue to form a precipitate which is filtered off and washed with chloroform. The filtrate is extracted with chloroform and the chloroform layer is dried over sodium sulfate, then the solvent is removed. The residue is purified by chromatography on a column of

  
 <EMI ID = 142.1>

  
by Wako Junyaku Co., Ltd. ; eluent: chloroform) and the eluate obtained is crystallized from petroleum ether. The crystals thus obtained are recrystallized from methanol to obtain 1.9 g of 5-methanesulfonyl-

  
 <EMI ID = 143.1>

  
 <EMI ID = 144.1>

  
REFERENCE EXAMPLE 21

  
9.5 g of ethyl ethoxymethylenemalonate are added

  
 <EMI ID = 145.1>

  
 <EMI ID = 146.1>

  
The mixture is heated to the temperature indicated for 30 min,

  
60 g of polyphosphoric acid are added &#65533; then heated to 140 [deg.] C for 30 min. When the reaction is complete, the reaction mixture is poured into 200 ml of water and the mixture is neutralized with 40% aqueous sodium hydroxide solution to precipitate light yellow crystals. The crystals are mixed without having purified them with 100 ml of a 10% sodium hydroxide solution and the mixture is heated at reflux for 40 min during which the

  
 <EMI ID = 147.1>

  
hot tion with activated carbon and filtered. The filtrate is allowed to cool and the pH is adjusted to 2 to obtain 6 g of white crystals. These crystals are recrystallized from a mixture of dimethylformamide and

  
 <EMI ID = 148.1>

  
quinolizine-2-carboxylic in the form of white needles melting IL
256-258 [deg.] C.

  
REFERENCE EXAMPLE 22

  
 <EMI ID = 149.1>

  
&#65533; 4 g of 6-chloro-1,2,3,4-tetrahydroquinoline and ethanol distillation is observed while the mixture is heated in a bath.

  
 <EMI ID = 150.1>

  
quée for 30 min, 30 g of polyphosphoric acid are added, then

  
 <EMI ID = 151.1>

  
The reaction mixture is poured into 200 ml of water and the mixture is neutralized with 40% aqueous sodium hydroxide solution to precipitate light brown crystals. We mix the crystals, without

  
 <EMI ID = 152.1>

  
sodium and heated to reflux for 40 min during which time they dissolve into a uniform solution. The solution is treated hot with activated carbon and filtered. Leave the filtrate

  
 <EMI ID = 153.1>

  
 <EMI ID = 154.1>

  
of light yellow crystals melting at 282-286 [deg.] C.

  
REFERENCE EXAMPLE 23

  
 <EMI ID = 155.1>

  
ethanol preparation while heating the mixture in an oil bath at

  
 <EMI ID = 156.1>

  
then 30 g of polyphosphoric acid are added and the mixture is heated to 140 [deg.] C for

  
 <EMI ID = 157.1>

  
 <EMI ID = 158.1>

  
 <EMI ID = 159.1>

  
 <EMI ID = 160.1>

  
10% sodium hydroxide and the mixture is heated at reflux for 40 min during which time the crystals dissolve into a uniform solution. The solution is treated hot with activated carbon and filtered. The filtrate is allowed to cool and the pH is adjusted to 2 to obtain 2.7 g of acid.

  
 <EMI ID = 161.1>

  
in the form of light yellow crystals melting at 300-304 [deg.] C. REFERENCE EXAMPLE 24

  
 <EMI ID = 162.1>

  
of oil for 30 min with stirring. After heating, the mixture is added
240 g of polyphosphoric acid prepared from 120 g of phosphoric acid and 120 g of phosphorus pentoxide and the mixture is left to react in an oil bath at 140 [deg.] C for 45 min. When the reaction is complete,

  
the mixture is allowed to cool to room temperature and is poured into 400 ml of water and then neutralized with aqueous sodium hydroxide

  
at 40% to precipitate crystals. The crystals thus obtained are mixed

  
 <EMI ID = 163.1>

  
mixing at reflux for 40 min during which time the crystals dissolve to form a uniform solution. The hot solution is treated with activated carbon and filtered. The filtrate is allowed to cool and

  
the pH is adjusted to 2 to precipitate crystals which are separated by filtration. The crude crystals thus obtained are recrystallized from dimethylformamide to obtain 21.3 g of 8-methanesulfonyloxy-6,7-dihydro-1- acid.

  
 <EMI ID = 164.1>

  
REFERENCE EXAMPLE 25

  
19.2 g of 8-chloro-6,7-dihydro-1-oxolH, 5H-benzo [ij] quinolizine-2-carboxylic acid and 35.5 g of piperazine are added to 350 ml of anhydrous dimethylsulfoxide and the mixture is heated. mixing in an oil bath

  
 <EMI ID = 165.1>

  
 <EMI ID = 166.1>

  
 <EMI ID = 167.1>

  
to remove matter soluble in chloroform, and the aqueous alkaline solution layer is allowed to stand to precipitate crystals which are filtered off. 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 then the pH is adjusted to 8 with

  
 <EMI ID = 168.1>

  
 <EMI ID = 169.1>

  
carboxylic acid in the form of white needles having a melting point of
267 to 268 [deg.] C. 6.4 g of 8- (1-piperazinyl) -6.7- acid are suspended.

  
 <EMI ID = 170.1>

  
 <EMI ID = 171.1>

  
hydrochloric acid. The insoluble matter is separated by filtration and

  
 <EMI ID = 172.1>

  
 <EMI ID = 173.1>

  
lic in the form of white amorphous crystals with a melting point of
300 [deg.] C or more.

  
REFERENCE EXAMPLES 26 to 28

  
As described in Reference Example 25, the following compounds having various substituents were prepared as shown in Table IV below. Table IV also indicates the melting point

  
 <EMI ID = 174.1>

  
REFERENCE EXAMPLE 29

  
 <EMI ID = 175.1> <EMI ID = 176.1>

  
white amorphous crystals having a melting point of 300 [deg.] C or more. REFERENCE EXAMPLE 30

  
5.5 g of 4-chlorooxindole dissolved in 80 ml of dioxane are dissolved and 6.2 g of sodium borohydride are suspended in the solution obtained. 12.7 ml of trifluoroacetic acid (d = 1.48) are added dropwise at room temperature with stirring. We

  
 <EMI ID = 177.1>

  
insoluble in water by filtration and then washed with ethyl ether. The filtrate is extracted with ethyl ether and the ether layer is dried over anhydrous sodium sulfate and then the solvent is removed. The residue is distilled under reduced pressure to obtain 3.9 g of chloro-4-indoline in the form of

  
 <EMI ID = 178.1>

  
gradually to the mixture 10.6 g of fine powdered aluminum chloride

  
cooling with ice and stirring. When the addition is complete, the mixture is stirred and allowed to react at room temperature for 27 h, then the solvent is removed under reduced pressure. Water is added to the residue and the mixture is extracted with 100 ml of benzene. We wash

  
the benzene layer with a saturated aqueous solution of sodium chloride and then concentrated. Aqueous hydrochloric acid is added to the residue at

  
 <EMI ID = 179.1>

  
Foaming has ceased, the mixture is neutralized with an aqueous solution of sodium carbonate and then extracted with 100 ml of benzene. The benzene layer is dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the extract is purified by chromatography on a column.

  
 <EMI ID = 180.1>

  
chloroindoline, the nature of which is confirmed by the NMR spectrum.

  
REFERENCE EXAMPLE 32

  
4.4 g of diethyl ethoxymethylenemalonate are added to 3 g of 4-ehloroindoline and a release of ethanol is observed for

  
 <EMI ID = 181.1>

  
polyphosphoric prepared from 10 g of phosphoric acid and 10 g

  
 <EMI ID = 182.1> <EMI ID = 183.1>

  
The mixture was cooled to 60 [deg.] C, poured into water and neutralized with 10% aqueous sodium hydroxide solution. The precipitated crystals are collected by filtration and washed with water. The crystals thus treated are mixed with 50 ml of 10% aqueous sodium hydroxide solution and the mixture is refluxed in an oil bath for 1 h. During the reaction, the mixture turns into a uniform solution.

  
The hot solution is treated with activated carbon and then filtered. The filtrate is acidified with concentrated hydrochloric acid to obtain

  
 <EMI ID = 184.1>

  
carboxylic. The product is recrystallized from dimethylformamide to obtain 3.5 g of colorless needles having a melting point of 307.5 [deg.] C
(decomposition).

  
REFERENCE EXAMPLE 33

  
 <EMI ID = 185.1>

  
from 10 g of phosphoric acid and 10 g of phosphorus pentoxide

  
 <EMI ID = 186.1>

  
the reaction is completed, the mixture is allowed to cool to 60 [deg.] C, it is poured

  
 <EMI ID = 187.1>

  
of sodium hydroxide. The precipitated crystals are collected by filtration and washed with water. The crystals thus treated were mixed with 50 ml of a 10% aqueous solution of sodium hydroxide and the mixture was refluxed in an oil bath for 1 h. During the reaction, the mixture turns into a uniform solution. The hot solution is treated with activated carbon and then filtered. The filtrate is acidified with chlor- 'acid.

  
 <EMI ID = 188.1>

  
dihydro-6H-pyrrolo [3,2,1-ij] quinoline-5-carboxylic acid. This product is recrystallized from dimethylformamide to obtain 3.8 g of colorless needles.

  
 <EMI ID = 189.1>

  
the solvent under reduced pressure and 50 ml of water is added to the residue to dissolve it. The solution is stirred with 100 ml of chloroform and the aqueous layer is separated and treated with activated charcoal. The aqueous solution is acidified with 10% aqueous hydrochloric acid and filtered. The filtrate is again treated with activated charcoal and then concentrated. Ethanol is added to the concentrate to form crystals which are recrystallized from a mixture of ethanol and water to obtain 1.5 g of hydrochloride.

  
 <EMI ID = 190.1>

  
leine-5-carboxylique in the form of pale yellow needles having a melting point of 300 [deg.] C or more.

  
REFERENCE EXAMPLE 35

  
 <EMI ID = 191.1>

  
nolein-5-carboxylique and 3 g of anhydrous piperazine and the mixture is heated

  
 <EMI ID = 192.1>

  
the solvent is removed under reduced pressure and 50 ml of water is added to the residue to dissolve it. The solution is stirred with 100 ml of chloroform and the aqueous layer is separated and treated with activated charcoal. The aqueous solution is acidified with 10% aqueous hydrochloric acid. and we filter. The filtrate is again treated with activated charcoal and then concentrated. Ethanol is added to the activated charcoal to obtain crystals which are recrystallized from a mixture of ethanol and water. To obtain 0.9 g of 9- (1-piperazinyl) -2 acid hydrochloride. -methyl-6-oxo-

  
 <EMI ID = 193.1>

  
of pale yellow needles having a melting point of 269-273 [deg.] C (decomposition). EXAMPLE 1

  
 <EMI ID = 194.1>

  
The reaction is completed, the mixture is allowed to react for 30 min with ice-cooling and 100 ml of sodium bicarbonate are added dropwise.

  
 <EMI ID = 195.1>

  
penicillanic trihydrate. When the addition is complete, the mixture is allowed to react for 1 hour with ice cooling and then at room temperature for 6 hours. During the reaction, the reaction mixture turns into a white suspension. The aqueous layer is separated

  
 <EMI ID = 196.1> to form a light yellow precipitate which is extracted with 100 ml of methylene chloride. The methylene chloride layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain 0.8 g.

  
 <EMI ID = 197.1>

  
amorphous having a melting point of 212-215 [deg.] C (decomposition). EXAMPLE 2

  
 <EMI ID = 198.1>

  
the mixture is left to react for 30 min while cooling it with ice and 100 ml of a sodium bicarbonate solution are added dropwise

  
3% in which 2.1 g of D - (-) - α-aminobenzylpenicillanic acid trihydrate have been dissolved. When the addition is complete, the mixture is allowed to react for 1 h while cooling it with ice and then at room temperature for 6 h. During the reaction, the reaction mixture turns into a white suspension. The aqueous layer is separated by centrifugation and the pH is adjusted to 2 with 6N hydrochloric acid to form

  
a white precipitate which is dissolved in 50 ml of an aqueous solution. 3%

  
of sodium bicarbonate and the pH is adjusted to 2 with 6N hydrochloric acid to precipitate crystals which are washed with water and dried for

  
 <EMI ID = 199.1>

  
amorphous whites having a melting point of 238-240 [deg.] C (decomposition). EXAMPLES 3 to 12

  
As described in Example 2, the following compounds were prepared having the various substituents indicated in Table V below. The melting point and the crystalline form of the products obtained are also shown in Table V.

  
EXAMPLE 13

  
1.1 g of 1-piperatinyl acid hydrochloride is added.

  
 <EMI ID = 200.1>

  
 <EMI ID = 201.1>

  
while cooling with ice and stirred for 20 min. 0.4 ml of isobutyl chloroformate is then added dropwise and the mixture is stirred for

  
1 h while cooling with ice. On the other hand, 15 ml of dimethylformamide are added to a mixture of 1.3 g of ampicillin and 0.5 g of anhydrous magnesium sulfate and 0.7 ml is added dropwise to the mixture obtained.

  
of triethylamine while cooling with ice and then the mixture is left to react for 30 min. The reaction mixture is filtered and the filtrate is added all at once to the previous reaction mixture and the mixture is left to react for 2 h while cooling with ice. When the reaction is.

  
 <EMI ID = 202.1>

  
a 20% solution of potassium 2-ethylhexanoate in butanol and the mixture is stirred for 30 min while cooling with ice. We

  
 <EMI ID = 203.1>

  
having a melting point of 261 to 265 [deg.] C (decomposition). EXAMPLE 14

  
1.1 g of 1-piperazinyl acid hydrochloride are added.

  
 <EMI ID = 204.1>

  
to 25 ml of dimethylformamide and 0.84 ml of triethylamine is added to the mixture while cooling with ice, and the mixture is stirred for 20 min. 0.4 ml of isobutyl chloroformate is then added dropwise and the mixture is stirred for 1 h while cooling with ice. On the other hand, we add 15 ml

  
of dimethylformamide to a mixture of 1.3 g of amoxicillin and 0.5 g of anhydrous magnesium sulphate and 0.7 ml of triethylamine is added dropwise to the mixture while cooling with ice, it is left to react for
30 min. The reaction mixture is filtered and the filtrate is added all at once to the previous reaction mixture and the mixture is left to react for 2 h while cooling with ice. When the reaction is complete, filter the reaction mixture and the filtrate is mixed with 2.5 ml of a solution of

  
 <EMI ID = 205.1>

  
potassium carboxylate in the form of white amorphous crystals having a

  
 <EMI ID = 206.1>

  
EXAMPLE 15
(a) 1.44 g of 2-fluoro-7a, 8, <EMI ID = 207.1> are suspended

  
in 20 ml of methylene chloride and 0.85 ml is added to the suspension

  
triethylamine while cooling with ice and then the mixture is left to react for 10 min. 0.85 ml of isobutyl chloroformate is then added dropwise and the mixture is left to react for 30 min at the same temperature as above. To the reaction mixture is added 10 ml of a 10% aqueous solution of sodium hydroxide in which 0.9 g of D - (-) - phenylglycine has been dissolved at the same temperature as above, then added to the mixture. mixture 80 ml of dimethylformamide and allowed to react for 3 h. When the reaction is complete, the reaction mixture is neutralized with 6N hydrochloric acid and the solvent is removed under reduced pressure. To say

  
 <EMI ID = 208.1>

  
at 10% sodium hydroxide, the solution is treated with activated charcoal and filtered. The pH of the filtrate is adjusted to 2 with concentrated hydrochloric acid to obtain light yellow crystals, washed with water, dried, mixed with 50 ml of chloroform with stirring and filtered. We leave it

  
 <EMI ID = 209.1>

  
(b) 2.1 g of D - (-) - 2- (2-fluoro-7a, 8.9,
10, ll, lla-hexahydro-4-oxo-4H-pyrido [3,2, l-jk] carbazole-5-carboxamido) phenylacetic to 50 ml of purified acetone and 0.85 ml of triethylamine is added while cooling with ice. The mixture is stirred for 30 min <EMI ID = 210.1>

  
same temperature as above. We let the mixture react to the same

  
 <EMI ID = 211.1>

  
precipitation of triethylamine hydrochloride. The reaction mixture is cooled to -30 [deg.] C and stirred vigorously then 45 ml are added.

  
 <EMI ID = 212.1>

  
dissolved 1.3 g of 6-aminopenicillanic acid. We let the mixture react

  
 <EMI ID = 213.1>

  
then at room temperature for 10 min. When the reaction is complete, the reaction mixture is extracted with 100 ml of sodium chloride.

  
 <EMI ID = 214.1>

  
aqueous solution with 6N hydrochloric acid to obtain a white precipitate which was filtered off and dissolved in 100 ml of methylene chloride and the insoluble matters removed. The solution is dried over anhydrous sodium sulfate then the solvent is removed under reduced pressure to obtain a white powder. The powder is recrystallized from a mixture of dioxane and petroleum ether to obtain 1.2 g of 6- acid.

  
 <EMI ID = 215.1>

  
(decomposition).

  
EXAMPLE 16 <EMI ID = 216.1> methylene chloride and 0.85 ml of triethylamine is added to the suspension while cooling with ice, then the mixture is allowed to react for 10 min. 0.85 ml of isobutyl chloroformate is then added dropwise and the mixture is left to react for 30 min at the same temperature as above. 110 ml of an aqueous solution are added to the reaction mixture.

  
 <EMI ID = 217.1>

  
the reaction is complete, the reaction mixture is neutralized with 6N hydrochloric acid and the solvent is removed under reduced pressure. To dissolve the residue, 20 ml of water and 100 ml of a

  
 <EMI ID = 218.1>

  
with activated carbon and then filtered. The pH of the filtrate is adjusted to 2 with concentrated hydrochloric acid to give light yellow crystals which are washed with water, dried and mixed with 50 ml of chloroform with stirring and filtered. The filtrate is mixed with 30 ml of ether

  
 <EMI ID = 219.1> to 50 ml of purified acetone and 0.85 ml of triethylamine is added while cooling with ice. The mixture is stirred for 30 min and then allowed to react at the same temperature as above for 30 min during which the precipitation of triethylaine hydrochloride is observed. <EMI ID = 220.1>

  
 <EMI ID = 221.1>

  
in which 1.3 g of 6-amiuopenicillanic acid was dissolved. We let

  
 <EMI ID = 222.1>

  
0 [deg.] C for 30 min then at room temperature for 10 min. When the reaction is complete, 100 ml of methylene chloride is added to the reaction mixture to extract it (when the reaction mixture is in the form of a suspension, the suspension is centrifuged) and the aqueous layer is separated. The pH of the aqueous layer is adjusted to 2 with 6N hydrochloric acid to obtain a light yellow precipitate which is separated by

  
 <EMI ID = 223.1>

  
removes insoluble matter. The solution is dried over anhydrous sodium sulfate and then the brightener is removed under reduced pressure to obtain a light yellow powder. The powder is recrystallized from a mixture of dioxane

  
 <EMI ID = 224.1>

  
lic in the form of white amorphous crystals with a melting point of

  
 <EMI ID = 225.1>

  
EXAMPLES 17 to 26

  
As described in Example 16, the following compounds "comprising various substituents are prepared as indicated in Table VI below. The melting point and the crystalline form of the products obtained are also shown in Table VI below.

  
EXAMPLE 27

  
2.28 g of 6,7-dihydro-1-oxo-1H, 5H-benzo [ij] quinolizine-2-carboxylic acid are dissolved in 80 ml of methylene chloride and 1.65 ml of methylene chloride are added dropwise. triethylamine then 1.65 g of isobutyl chloroformate while cooling with ice. When the addition is complete, the mixture is allowed to react for 30 min while cooling it with ice and a mixture of 20 ml of methylene chloride and 3 ml of triethylamine in which the mixture has been placed in cooling is added all at once.

  
 <EMI ID = 226.1>

  
the mixture reacted for 2.5 h while cooling with ice to form

  
 <EMI ID = 227.1>

  
glacial, then stirred with 70 ml of water to wash off the chlorine

  
 <EMI ID = 228.1> of sodium bicarbonate to the methylene chloride layer and the mixture is stirred to form a white suspension. The aqueous layer is separated by centrifugation and then the pH is adjusted to 2 with 6N hydrochloric acid to form a white precipitate which is washed with water and dried under

  
 <EMI ID = 229.1>

  
Amorphous white levels having a melting point of 195-197 [deg.] C (decomposition). EXAMPLE 28

  
 <EMI ID = 230.1>

  
then 0.75 g of isobutyl chloroformate. When the addition is complete, the mixture is allowed to react for 30 min while cooling it with ice, and a mixture of 10 ml of methylene chloride and 1.5 ml of triethylamine in which there is added at once while cooling is added. set

  
 <EMI ID = 231.1>

  
the mixture to react for 2 h while cooling it with ice, then the mixture is concentrated under reduced pressure in a water bath between 35 and 40 [deg.] C. 100 ml of a 7% aqueous solution of sodium carbonate are added to the concentrate.

  
 <EMI ID = 232.1>

  
6N hydrochloric acid to close a white precipitate which is washed with water and dried under reduced pressure to obtain 1.1 g of 6- [D - (-) - 2- (9-chloro-

  
 <EMI ID = 233.1>

  
in the form of white amorphous crystals having a melting point of 220-223 [deg.] C
(decomposition) .

  
EXAMPLES 29 to 41

  
As described in Example 28, the following compounds are prepared comprising the various substituents indicated in Table VII below. The melting points and the crystalline forms of the products obtained are also shown in Table VII below.

  
EXAMPLE 42

  
2.4 g of 5-methyl-6,7-dihydro- acid are suspended.

  
 <EMI ID = 234.1>

  
anhydrous mamide and 1.66 ml of triethylamine are added to the mixture, while cooling with ice, and the mixture is stirred for 15 min. 1.6 ml of isobutyl chloroformate are then added dropwise and the mixture is stirred for

  
45 min at the same temperature as above. On the other hand, we put 5 g of ampi-

  
 <EMI ID = 235.1>

  
to the suspension while cooling with ice 2.8 ml of triethylamine and 1 g of anhydrous magnesium sulfate, then the mixture is stirred at the same temperature as above for 30 min and the insoluble matters are separated by filtration. Add the triethylamir.e salt of ampicillin

  
 <EMI ID = 236.1>

  
cooling by ice. When the reaction is complete, or. The insoluble matters are separated by filtration and 10 ml of a 20% solution of sodium 2-ethylhexanoate in normal butanol followed by 500 ml of ethyl ether are added to the filtrate to precipitate the crystals. The crystals are collected by filtration, dissolved in 300 ml of water and the solution is acidified.

  
(pH 3) to form a precipitate which is washed with water and dried at room temperature under reduced pressure to obtain 5.2 g of crystals

  
 <EMI ID = 237.1>

  
having a melting point of 203-205 [deg.] C (decomposition). EXAMPLE 43

  
 <EMI ID = 238.1>

  
Anhydrous formamide, 0.83 ml of triethylamine is added to the mixture while cooling with ice, and the mixture is stirred for 15 min. Then add drop to

  
 <EMI ID = 239.1>

  
the same temperature as above. On the other hand, 2.5 g of amoxicillin are suspended in 30 ml of anhydrous dimethylformamide and added to the suspension, while cooling with ice, 1.4 ml of triethylamine and 1 g.

  
 <EMI ID = 240.1>

  
Strips as above for 30 min and separates insolubles therefrom by filtration. The triethylamine salt of amoxicillin thus obtained is added to the above reaction mixture and the mixture is stirred for 2 h while cooling with ice. The mixture obtained is treated as in Example 42

  
 <EMI ID = 241.1>

  
EXAMPLE 44

  
0.85 g of 8- (4-formyl-1-

  
 <EMI ID = 242.1>

  
stirred for 45 min at the same temperature as above. On the other hand,

  
 <EMI ID = 243.1>

  
 <EMI ID = 244.1>

  
anhydrous magnesium sulphate while cooling with ice and the

  
 <EMI ID = 245.1>

  
of ampicillin thus obtained to the previous reaction mixture and stirred for 2 h while cooling with ice. When the reaction is complete, insoluble matter is removed by filtration and added to the filtrate.

  
 <EMI ID = 246.1>

  
normal, then 200 ml of ethyl ether to precipitate crystals. The crystals are collected by filtration, the crystals are dissolved in 100 ml

  
 <EMI ID = 247.1>

  
washed with water and dried at room temperature under reduced pressure

  
 <EMI ID = 248.1>

  
of white amorphous crystals having a melting point of 217 to 224 [deg.] C (decomposition).

  
EXAMPLE 45

  
0.85 g of 8- (4-formyl-1-

  
 <EMI ID = 249.1>

  
0.42 ml of triethylamine is added to the mixture in 25 ml of anhydrous dimethylformamide while cooling with ice and the mixture is stirred for 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,

  
 <EMI ID = 250.1>

  
anhydrous, 0.7 ml of triethylamine and 0.5 g of anhydrous magnesium sulfate are added to the suspension while cooling with ice and the mixture is stirred at the same temperature as above for 30 min and then the insolubles are removed by filtration. The amoxicillin triethylamine salt thus obtained is added to the above reaction mixture and the mixture is stirred for 2 h while cooling with ice. The resulting mixture is treated as in Example 44 to obtain 1.0 g of 6 - 2- [8- (4-for-

  
 <EMI ID = 251.1>

  
[3.2.0] 2-heptanecarboxylic in the form of white amorphous crystals having a melting point of 249-254 [deg.] C (decomposition).

  
EXAMPLE 46

  
 <EMI ID = 252.1>

  
of anhydrous dimethylformamide, 0.42 ml of triethylamine is added to the mixture while cooling with ice and the mixture is stirred for 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 0.7 ml of triethylamine and the suspension is added 0.5 g of magnesium sulfate.

  
 <EMI ID = 253.1>

  
temperature than above for 30 min and the insoluble material removed by filtration. The triethylamine salt of ampicillin thus obtained is added to the above reaction mixture and the mixture is stirred for 2 h while cooling with ice. When the reaction is complete, insoluble matters are removed by filtration and 2.5 ml of solution are added to the filtrate.

  
 <EMI ID = 254.1>

  
of ethyl ether to precipitate crystals to obtain 0.97 g of

  
 <EMI ID = 255.1>

  
potassium bicyclo [3.2.0] heptane-2-carboxylate in the form of crystals

  
 <EMI ID = 256.1>

  
245 to 250 [deg.] C (decomposition).

  
EXAMPLE 47

  
0.78 g of 8- (1-piperazinyl) -6.7- acid is suspended.

  
 <EMI ID = 257.1>

  
Anhydrous dimethylformamide, 0.42 ml of triethylamine is added to the mixture while cooling with ice and the mixture is stirred for 15 min. 0.4 ml of iaobutyl chloroformate is then added dropwise and the mixture is stirred for
45 min at the same temperature as above. On the other hand, we add- <EMI ID = 258.1>

  
0.7 ml of triethylamine, 0.5 g of anhydrous magnesium sulfate is added to the suspension with ice-cooling and the mixture is stirred at the same temperature as above for 30 min, then the insoluble matter is removed by filtration. The triethylamine salt of amoxicillin thus obtained is added to the above reaction mixture and the mixture is stirred for 2 h while cooling with ice. When the reaction is complete, the insoluble matters are removed by filtration and 2.5 ml of a 20% solution of sodium 2-ethylhexanoate in normal butanol are added to the filtrate, followed by addition of 2.5 ml.
300 ml of ethyl ether to precipitate crystals. The crystals were collected by filtration and dissolved in 100 ml of water to remove a small amount of insoluble material by filtration. We freeze it

  
 <EMI ID = 259.1>

  
sodium late in the form of white amorphous crystals.

  

 <EMI ID = 260.1>


  
EXAMPLE 48

  
0.7 g of 8- (4-acetyl-1-

  
 <EMI ID = 261.1>

  
in 20 ml of anhydrous dimethylformamide, 0.34 ml of triethylamine is added to the mixture while cooling with ice and the mixture is stirred for 15 min. 0.32 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 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 is added to the suspension while cooling with ice and the mixture is stirred. the mixture at the same temperature as above for 30 min, then separated

  
 <EMI ID = 262.1>

  
of ampicillin thus obtained to the preceding reaction mixture and stirred for 2 h while cooling with ice. The resulting mixture is treated

  
 <EMI ID = 263.1>

  
heptan-2-carboxylic in the form of white amorphous crystals having a melting point of 214-219 [deg.] C (decomposition).

  
EXAMPLE 49

  
0.81 g of 8- (4-methane-

  
 <EMI ID = 264.1>

  
carboxylic acid in 25 ml of anhydrous dimethylforroamide, 0.42 ml of triethylamine is added to the mixture while cooling with ice and the mixture is stirred for
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 dimethylfo &#65533; mide and 0.7 ml of triethylamine and 0.5 g of anhydrous magnesium sulfate is added to the suspension while cooling. With ice, the mixture was stirred at the same temperature as above for 30 min and the insoluble matters were filtered off.

   The triethylamine salt of ampicillin thus obtained is added to the previous reaction mixture and the mixture is stirred for 2 h while cooling with ice, then the mixture obtained is treated as in Example 44 to obtain 1.25 g of 6- acid. &#65533; 2-

  
 <EMI ID = 265.1>

  
azabicyclo [3.2.0] heptane-2-carboxylique in the form of white amorphous crystals having a melting point of 182-187 [deg.] C (decomposition). EXAMPLE 50
(a) 2.3 g of 6,7-dihydro-1- acid is suspended <EMI ID = 266.1>

  
1.65 ml of triethylamine are added to the suspension while cooling with

  
ice, then the mixture is allowed to react for 10 min. Then added dropwise 5 ml of dimethylformamide in which 1.65 g of isobutyl chloroformate was dissolved and allowed to react for 30 min at the same temperature as above to form a uniform solution. 10 ml of a 10 X aqueous solution of sodium hydroxide in which 2 g of D - (-) - phenylglycine has been dissolved at the same temperature as above are added all at once to the reaction mixture and then left the mixture reacted at room temperature for 3 h. When the reaction is complete, the reaction mixture is concentrated under reduced pressure and 70 ml of water is added to form a precipitate which is filtered off. We adjust the

  
pH of the filtrate to 2 with concentrated hydrochloric acid while cooling

  
 <EMI ID = 267.1>

  
 <EMI ID = 268.1> <EMI ID = 269.1>

  
 <EMI ID = 270.1>

  
 <EMI ID = 271.1>

  
methylformamide and 0.7 ml of triethylamine is added to the suspension while cooling with ice. Then added dropwise. drip to the same

  
 <EMI ID = 272.1>

  
30 min at the same temperature as above to form a uniform solution.

  
 <EMI ID = 273.1>

  
 <EMI ID = 274.1>

  
 <EMI ID = 275.1>

  
mixture react at room temperature for 3 h. When the reaction is complete, the reaction mixture is concentrated under reduced pressure and 30 ml of water is added to form a precipitate which is separated by filtration.

  
 <EMI ID = 276.1>

  
cooling with ice to obtain white crystals which are filtered,

  
 <EMI ID = 277.1> <EMI ID = 278.1>

  
acetic having a melting point of 190-192 "C.

  
(b) 2.0 g of D - (-) - 2- (9-chloro-6,7- <EMI ID = 279.1> acid is added)

  
80 ml of purified acetone and 0.85 ml of triethylamine is added while cooling with ice. The mixture is stirred for 30 min then 0.85 g of isobutyl chloroformate is added dropwise at the same temperature and the mixture is left to react at the same temperature as above for 30 min during which the precipitation of triethyl hydrochloride

  
 <EMI ID = 280.1>

  
then 45 ml of a 3% aqueous solution of sodium bicarbonate in which 1.3 g of 6-aminopenicillanic acid have been dissolved. The mixture is allowed to react at a temperature below 0 [deg.] C for 40 min, at 0 [deg.] C for 30 min and then at room temperature for 20 min. When the reaction is complete, the pH of the reaction mixture is adjusted to 7 with glacial acetic acid and concentrated under reduced pressure. 50 ml of a 7% aqueous sodium bicarbonate solution is added to the concentrate and then filtered. The pH of the filtrate is adjusted to 2 with 6N hydrochloric acid while cooling with ice to obtain 1.2 g of 6- [D - (-) - 2- (9-

  
 <EMI ID = 281.1>

  
in the form of white amorphous crystals having a melting point of 220-223 [deg.] C
(decomposition).

  
EXAMPLES 52 to 69

  
As described in Example 51, various compounds are prepared having various substituents as indicated in Tables VIII and IX below. The melting points and the crystalline forms of the products obtained are also shown in Tables VIII and IX below.

  
EXAMPLE 70

  
2.2 g of 1,2-dihydro-6-oxo-6H-pyrrolo- acid are dissolved.

  
 <EMI ID = 282.1>

  
1.65 ml of triethylamine then 1.65 g of isobutyl chloroformate are added dropwise while cooling with ice. When the addition is complete, the mixture is allowed to react for 30 min while cooling by

  
ice and added at once while cooling a mixture of 20 ml of methylene chloride and 3 ml of triethylamine containing in suspension

  
 <EMI ID = 283.1>

  
react for 2.5 h while cooling it with ice to form a

  
 <EMI ID = 284.1> then stirred with 70 ml of water to wash off the hydrochloride

  
 <EMI ID = 285.1>

  
sodium bonate to the methylene chloride layer and the mixture is stirred to form a white suspension. The aqueous layer is separated

  
 <EMI ID = 286.1>

  
 <EMI ID = 287.1>

  
reduction to obtain 2.8 g of 6- [D - (-) - 2- (1,2-dihydro-6-oxo-6H- acid

  
 <EMI ID = 288.1> Amorphous white levels having a melting point of 215-218 [deg.] C (decomposition). EXAMPLE 71

  
According to the procedure of Example 70, one obtains

  
 <EMI ID = 289.1>

  

 <EMI ID = 290.1>


  
EXAMPLE 72

  
According to the procedure described in Example 70,

  
 <EMI ID = 291.1>

  
1-Azabicyclo [3.2.0] heptane-2-carboxylic acid as yellow amorphous crystals.

  

 <EMI ID = 292.1>


  
EXAMPLE 73

  
According to the procedure of Example 70, one obtains

  
 <EMI ID = 293.1>

  
thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid in the form of white amorphous crystals.

  

 <EMI ID = 294.1>
 

  
EXAMPLE 74

  
2.3 g of 6,7-dihydro-1-oxo acid are suspended.

  
 <EMI ID = 295.1>

  
anhydrous, 1.66 ml of triethylamine are added and the mixture is stirred for
15 min, cooling with ice. 1.6 g of isobutyl chloroformate are then added dropwise while cooling with ice. When the addition is complete, the mixture is stirred for 45 min under ice-cooling. On the other hand, 4.5 g of cephaloglycine are suspended in

  
60 ml of anhydrous dimethylfozinamide and 2.8 ml of

  
 <EMI ID = 296.1>

  
 <EMI ID = 297.1>

  
insoluble by filtration. The solution of cephaloglycine triethylamine salt thus obtained is added to the above reaction mixture and the mixture is stirred for 2 h while cooling with ice.

  
When the reaction is complete, insoluble matters are removed by filtration and 10 ml of a 20% solution of sodium 2-ethylhexanoate in normal butanol followed by 500 ml of ethyl ether are added to precipitate crystals.

  
The crystals are collected by filtration, dissolved in 300 ml of water and the solution is acidified to pH 3 to form a precipitate which is washed with water and dried at room temperature under

  
 <EMI ID = 298.1>

  
5-thia-1-azabicylo [4.2.0] oct-2-ene-carboxylic acid in the form of white amorphous crystals having a melting point of 226-230 [deg.] C (decomposition).

  
EXAMPLE 7 5

  
2.4 g of 5-methyl-6,7-di- acid are suspended.

  
 <EMI ID = 299.1>

  
Anhydrous formamide, 1.66 ml of triethylamine are added and the mixture is stirred for 15 min while cooling it with ice. We then add drop

  
1.6 ml of isobutyl chloroformate by drop, cooling in ice. When the addition is complete, the mixture is stirred for 45 min under ice-cooling. On the other hand, 4.5 g of cephaloglycine are suspended in 60 ml of anhydrous dimethylformamide and 2.8 ml of triethylamine and 1 g of magnesium sulfate is added to the suspension. The mixture was stirred at the same temperature as above for 30 min and the insolubles were filtered off. The solution of cephaloglycine triethylamine salt thus obtained was added to the above reaction mixture and stirred for 2 h while cooling with ice.

  
After completion of the reaction, insoluble matters are filtered off, and 10 ml of a 20% solution of sodium 2-ethylhexanoate in normal butanol is added to the filtrate, followed by addition of 10 ml.
500 ml of ethyl ether to precipitate crystals. The crystals are collected by filtration and dissolved in 300 ml of water and then acidified.

  
 <EMI ID = 300.1>

  
dries at room temperature under reduced pressure to obtain 4.3 g

  
 <EMI ID = 301.1>

  
oct-2-en-2-carboxylic in the form of white amorphous crystals having a melting point of 233-237 [deg.] C (decomposition).

  
EXAMPLE 76

  
1.7 g of 8- (4-formyl-1-

  
 <EMI ID = 302.1>

  
in 25 ml of anhydrous dimethylformamide and 0.83 ml of triethylamine is added and the mixture is then stirred for 15 min while cooling it with ice. 0.8 ml of isobutyl chloroformate is then added dropwise while cooling with ice. When the addition is complete, the mixture is stirred for 45 min under ice-cooling. On the other hand, 2.3 g of ceph & loglycine are suspended in 30 ml of anhydrous dimethylformamide and 1.4 ml of triethylamine and 0.5 g of magnesium sulfate are added to the suspension. The mixture was stirred at the same temperature as above for 30 min and the insolubles were filtered off. The solution of cephaloglycine triethylamine salt thus obtained is added to the above reaction mixture and the mixture is stirred for 2 h while cooling with ice.

   When the reaction is complete, insoluble matters are filtered off and 5 ml of a 20% solution of sodium 2-ethylhexanoate in normal butanol followed by 250 ml of ethyl ether are added to the filtrate to precipitate crystals. We collect the crystals

  
 <EMI ID = 303.1>

  
tion (pH 3) to form a precipitate which is washed with water and dried at room temperature under reduced pressure to obtain 2.1 g of acid

  
 <EMI ID = 304.1>

  
bicyclo [4.2.C] oct-2-en-2-carboxylic acid in the form of light yellow amorphous crystals having a melting point of 261-265 [deg.] C (decomposition).

  
EXAMPLE 77

  
 <EMI ID = 305.1>

  
 <EMI ID = 306.1> prepared according to the procedure of Example 75 and then heated to reflux for 5 h with stirring. When the reaction is complete, the solvent is removed by evaporation under reduced pressure. The concentrate is washed with acetonitrile then acetone and dried under vacuum to obtain

  
 <EMI ID = 307.1>

  
methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic. EXAMPLE 78

  
 <EMI ID = 308.1>

  
a mixture of 15 ml of acetonitrile and 1.7 g of the cephalosporin derivative prepared according to the procedure of Example 75, then refluxed for 6 h with stirring. When the reaction is complete, the solvent is removed by evaporation under reduced pressure and the residue is dissolved in

  
10 ml of ethanol. A mixture of 5 ml of ethanol and 0.5 ml of dicyclohexylamine is added dropwise to the solution to obtain the dicyclo salt.

  
 <EMI ID = 309.1>

  
EXAMPLE 79

  
2.1 g of 6-oxo-1,2-dihydro-6H-pyrro- acid are added.

  
 <EMI ID = 310.1>

  
1.66 ml of triethylamine are added to the mixture while cooling with ice

  
 <EMI ID = 311.1>

  
Isobutyl chloroformate and stirred for 45 min while cooling with ice. On the other hand, 4.5 g of cephaloglycine are suspended in
60 ml of anhydrous dimethylformamide and 2.8 ml of triethylamine and 1 g of anhydrous magnesium sulphate is added to the mixture while cooling in ice and then the mixture is stirred for 30 min. Insoluble matters are separated by filtration and the filtrate is added all at once to the previous reaction mixture and allowed to react for 2 h while cooling with ice. When the reaction is complete, the insoluble matters are removed by filtration and the filtrate is mixed with 10 ml of a solution of 2-

  
 <EMI ID = 312.1>

  
 <EMI ID = 313.1>

  
by filtration and dissolved in 300 ml of water. The resulting solution (pH 3) was acidified with dilute hydrochloric acid to precipitate a solid which was washed with water and dried under reduced pressure to obtain 4.0 g of 7- [acid. 2- (1,2-dihydro-6-oxo-6H-pyrrolo- <EMI ID = 314.1>

  
White amorphous crystals having a melting point of 245-248 [deg.] C (decomposition).

  
EXAMPLE 80

  
2.3 g of 2-methyl-1,2-dihydro-6-oxo-

  
 <EMI ID = 315.1>

  
Anhydrous, 1.66 ml of triethylamine are added to the mixture while cooling with ice and the mixture is stirred for 15 min. 1.6 ml of isobutyl chloroformate are then added dropwise and the mixture is stirred for 45 min while cooling with ice. On the other hand, 4.5 g of cephaloglycine are suspended in 60 ml of anhydrous dimethylformamide and 2.8 ml of triethylamine and 1 g of anhydrous magnesium sulfate is added to the mixture while cooling.

  
 <EMI ID = 316.1>

  
insoluble matter by filtration and the solution of the triethylamine salt of cephaloglycine thus obtained is added all at once to the previous reaction mixture and the mixture is left to react for 2 h while cooling by

  
ice. When the reaction is complete, the insoluble matters are removed by filtration, mixed with 10 ml of a solution of 2-ethylhexanoate.

  
 <EMI ID = 317.1>

  
precipitate crystals. The crystals were collected by filtration and dissolved in 300 ml of water and then the solution was acidified (pH 3) with dilute hydrochloric acid to precipitate a solid material which was washed with water and then acidified. dried under reduced pressure to obtain 3.7 g of 7- [2-

  
 <EMI ID = 318.1>

  
2-carboxylic.

  
EXAMPLE 81

  
 <EMI ID = 319.1>

  
hexahydro-4-oxo-4H-pyrido [3,2, l-jk] carbazole-5-carboxylique in 50 ml of anhydrous dimethylformamide, 0.83 ml of triethylamine is added to the mixture and the mixture is stirred for 15 min while cooling with the ice. We then add

  
1.6 ml of isobutyl chloroformate and stirred for 45 min while cooling with ice. On the other hand, 2.3 g of cephaloglycine are suspended in 30 ml of anhydrous dimethylformamide and 2.8 ml of triethylamine, one adds

  
 <EMI ID = 320.1>

  
ice and then the mixture is stirred for 30 min. The insoluble matters are separated by filtration and the solution of cephaloglycine triethylamine salt thus obtained is added all at once to the previous reaction mixture and the mixture is left to react for 2 hours under ice-cooled conditions. When the reaction is complete, insoluble matter is removed by filtration, the filtrate is mixed with 5 ml of a 2C% solution of sodium 2-ethylhexanoate in butanol, then 250 ml of ethyl ether is added to precipitate particles. crystals. The crystals are collected by filtration and dissolved in 150 ml of water. The resulting solution (pH 3) is acidified with dilute hydrochloric acid to precipitate a solid which is washed with water and dried under reduced pressure to obtain 2.2 g of 7- acid.

  
 <EMI ID = 321.1>

  
oct-2-en-2-carboxylic acid in the form of white amorphous crystals having a dot

  
 <EMI ID = 322.1>

PREPARATION EXAMPLE 1

  

 <EMI ID = 323.1>


  
The active compound and glucose are dissolved in distilled water for injection and the solution is added to a 5 ml ampoule. The air is removed with nitrogen and the ampoule is sealed, which is sterilized at 121 [deg.] C for 15 min to obtain an injectable preparation.

PREPARATION EXAMPLE 2

  

 <EMI ID = 324.1>


  
The active compound and glucose are dissolved in distilled water for injection and the solution is added to a 5 ml ampoule. The air is expelled with nitrogen and the ampoule is sealed and sterilized with
121 [deg.] C for 15 min to obtain an injectable preparation.

  
 <EMI ID = 325.1>

  

 <EMI ID = 326.1>


  
The active compound and glucose are dissolved in distilled water for injection and the solution is added to a 5 ml ampoule. The air is expelled with nitrogen and the ampoule is occluded and sterilized with

  
 <EMI ID = 327.1>

PREPARATION EXAMPLE 4

  

 <EMI ID = 328.1>


  
The active compound, Avicel, corn starch and magnesium stearate are mixed and ground and then shaped into tablets with a conventional tableting machine (R = 10 mm) for shaping dragees (product of Kikusui Seisakusho Co., Ltd.). The tablets are coated with a film-forming coating agent consisting of TC-5, polyethylene glycol-
6000, castor oil and methanol to obtain film coated tablets.

PREPARATION EXAMPLE 5

  

 <EMI ID = 329.1>


  
The Japanese wax and the active compound are hot melted, the purified hydrated lanolin and the white petrolatum are added and then melted.

  
when hot, the mixture is stirred until it begins to solidify in the form of a pointa.

  
Of course, various modifications can be made by those skilled in the art to the devices or methods which have just been described solely by way of nonlimiting examples without departing from the scope.

  
of intention.

  

 <EMI ID = 330.1>


  

 <EMI ID = 331.1>
 

  

 <EMI ID = 332.1>


  

 <EMI ID = 333.1>
 

  

 <EMI ID = 334.1>


  

 <EMI ID = 335.1>
 

  

 <EMI ID = 336.1>


  

 <EMI ID = 337.1>


  

 <EMI ID = 338.1>
 

  

 <EMI ID = 339.1>


  

 <EMI ID = 340.1>


  

 <EMI ID = 341.1>
 

TABLE V

  

 <EMI ID = 342.1>
 

TABLE VI

  

 <EMI ID = 343.1>
 

TABLE VII

  

 <EMI ID = 344.1>
 

'. CABLE VIII

  

 <EMI ID = 345.1>
 

TABLE IX

  

 <EMI ID = 346.1>
 

  
 <EMI ID = 347.1>

  
 <EMI ID = 348.1>

  

 <EMI ID = 349.1>


  
 <EMI ID = 350.1>

  
R2 represents a hydrogen atom; R3 represents a halogeno, nitro, amino, hydroxy, lower alkyl, lower alkoxy, lower alkanoylamino, lower alkanesulfonyloxy radical or a radical of formula:

  

 <EMI ID = 351.1>


  
 <EMI ID = 352.1>

  
a lower alkanesulfonyl radical; R4 represents a hydrogen atom or

  
 <EMI ID = 353.1> <EMI ID = 354.1> lower alkanoyloxy, a radical of the formula:

  

 <EMI ID = 355.1>


  
 <EMI ID = 356.1>

  
 <EMI ID = 357.1>

  
hexane with the carbon atoms to which they are attached, and their pharmaceutically suitable salts.


    

Claims (1)

2. Compounds according to claim 1, characterized in that that R <1> and: R <2> do not combine to form a cyclohexane ring, <EMI ID = 358.1> <EMI ID = 359.1> where R represents a hydrogen atom, a lower alkanoyl radical or a lower alkanesulfonyl radical, and 1 is equal to 1 or 2. 4. Compounds according to claim 2, caractériel? <EMI ID = 360.1> in that R3 represents a nitro radical and 1 is equal to 1 or 2. 6. Compounds according to claim 2, characterized <EMI ID = 361.1> 7. Compounds according to claim 2, characterized in that R represents a lower alkyl radical and 1 edt equal to 1 or 2. 8. Compounds according to claim 2, characterized <EMI ID = 362.1> 9. Compounds according to claim 2, characterized in that R3 represents an amino radical and 1 is equal to 1 or 2. 10. Compounds according to claim 2, characterized <EMI ID = 363.1> or 2. <EMI ID = 364.1> <EMI ID = 365.1> 12. Compounds according to claim 2, characterized in that 1 is equal to zero. <EMI ID = 366.1> in that n is zero and R <1> and R <2> combine with the carbon atoms to which they are attached to form a cyclohexane ring. 14. A compound according to claim 13, characterized in that 1 is equal to zero. 15. Compounds according to claim 13, characterized in that is a halogen atom and 1 is equal to 1 or 2. 16. Compounds according to claim 13, characterized in that represents a nitro, amino, hydroxy, alkyl group. lower, lower alkoxy, lower alkanoylamino, lower alkanesulfonyloxy or a group of the formula <EMI ID = 367.1> wherein R5 represents a hydrogen atom or a lower alkyl or lower alkanesulfonyl group and 1 is equal to 1 or 2. 17. Compounds according to claim 1, characterized in that they <EMI ID = 368.1> <EMI ID = 369.1> 4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid. 18. Process for the preparation of the compounds according to claim 1, characterized in that a compound of general formula is reacted. <EMI ID = 370.1> <EMI ID = 371.1> alkyl haloformate of formula <EMI ID = 372.1> wherein R15 represents a lower alkyl group and X represents a halogen atom, in a solvent or without a solvent to prepare an activated carboxyl compound of the general formula <EMI ID = 373.1> 15 <EMI ID = 374.1> the compound of formula (XI) is then reacted with an ampicillin or cephaloglycin derivative of formula <EMI ID = 375.1> in which R4 and A are as defined above. 19. The method of claim 18, characterized in that the reaction is carried out between the compound of formula (II) and the compound. of formula (X) in the presence of a basic compound. 20. The method of claim 18, characterized in that the proportion of the compound of formula (X) is at least equimolar relative to the compound of formula (II). 21. The method of claim 18, characterized in that the reaction is carried out between the compound of formula (II) and the compound. of formula (X) in a solvent. 22. The method of claim 21, characterized in that the proportion of the compound of formula (X) is from 1.1 to 1.5 moles per mole of the compound of formula (II). 23. The method of claim 18, characterized in that the reaction is carried out between the compound of formula (II) and the compound of <EMI ID = 376.1> 24. The method of claim 23, characterized in that the reaction is carried out between the compound of formula (II) and the compound of. <EMI ID = 377.1> 25. Method according to claim 18, characterized in that that the reaction between the compound of formula (XI) and the compound of formula (XII) is carried out in said solvent or a mixture of said solvent and water or solvent-free. 26. The method of claim 18, characterized in that that the proportion of the compound of formula (XII) is at least equimolar relative to the compound of formula (XI). 27. The method of claim 26, characterized in that that the proportion of the compound of formula (XII) is from 1 to 1.5 moles per mole of the compound of formula (XI). 28. The method of claim 18, characterized in that that the reaction between the compound of formula (XI) and the compound of formula (XII) is carried out between room temperature and about 100 [deg.] C for about 2 to 10 h. 29. The method of claim 28, characterized in that that the reaction between the compound of formula (XI) and the compound of formula (XII) is carried out at room temperature. <EMI ID = 378.1> claim 1, characterized in that a compound of <EMI ID = 379.1> activated with a phenylglycine derivative of the formula <EMI ID = 380.1> <EMI ID = 381.1> formula <EMI ID = 382.1> 1234 <EMI ID = 383.1> reacts the compound of formula (XIV) with a 6-amino acid derivative <EMI ID = 384.1> general <EMI ID = 385.1> in which A is as defined above. '' <EMI ID = 386.1> characterized in that they consist of a compound according to claim 1. 32. Therapeutic compositions, characterized in that they contain as active ingredient at least one of the medicaments according to claim 31. 33. Pharmaceutical forms of oral administration or parenteral therapeutic compositions according to claim 32, characterized in that the daily administration dose of the active ingredient is between approximately 10 mg and 5 g in three to four doses, in adult humans.