DERIVATIVES OF 7-(1-AZETIDINYL)-1,4-DIHYDRO-4-OXO-3- GUINOLINECARBOXYLIC ACIDS, THEIR PREPARATION AND APPLICATION AS MEDICINES

J.. AU6TKAUA„,±- PATENTS ACT 1952-1973 COMPLETE SPECIFICATION (ORIGINAL) FOR OFFICE USE Form Class:

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TO BE COMPLETED BY APPLICANT Name of Applicant: LABORATORIOS DEL DR. ESTEVE S.A.

Spanish Body Corporate, of Av. Mare 221 08026 BARCELONA, SPAIN.

de Deu Montserrat Address of Applicant:

Address for Service:

Actual Inventor: Juan Pares Corominas, Jordi and Augusto Colombo Pinol COME, raEI a KtMBY PATE IT..". c:V-r<".TTONEYS 7"' '' ' '' . '* — 'AD meleol:. Ti/sco, AUo trali a Complete Specification for the invention entitled r DERIVATIVES OF acids, Frigola Constansa 7-(1azetidinyl)- their preparation 1,4-dihydro-4-oxo-3-quinolinecarboxylic and application as medicines.

The following statement is a full description of this invention, including the best method of performing it known to me:—* - 1 - 'Note: The; ascription is to be typed in double spacing, pied type face, in an area not exceeding 250 mm in depth and 160 mm in width, on tough white papar of good quality and it is to be inserted inside this form.

C. J. tno-M»*ON. CcmffibftweultfrGovernnleM Primer. Cinbeffa - 1A The present invention relates to new derivatives of l,4-dihydro-4-oxo~3-quinolinecarboxyXic acids substituted in the 7 position by a 1-azetidinyl radical which is itself substituted in position 2 and/or position 3.

Azetidines linked to the 7 position of 1,4-dihyciro- 4-oxo-3-quinolinecarboxylic acids have been very little studied. As far as is known, there are only a small number of publications in the scientific literature which relate to this type of compound, itiree Patents (Japan Kokai Tokkyo Koho JP 58/72589 (83/72589), and Eur. Pat.

Appl. EP 106489, EP 153163) describe 1-ethyl-7-(3-(ethylamino)- quinolinecarboxylic acid, 9-fluoro-2,3-dihydro-10-(3- hydroxy-l-azet idinyl)-3-methyl-7-oxo-7H-pyrido [ 1,2,3-de ]- l,4-benzoxazine-6-carboxylic acid, and 9-fluoro-2,3- dihydro-10- (3-hydroxymethyl-1-azetidinyl) -3-methyl-7-oxo- 7-H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid.

The invention relates to heterocyclic compounds represented by formula (I) hereinafter, as well as therapeutically acceptable salts of these compounds:

C00R- (I) where . R1 represents a lower alkenyl or alkyl radical, a lower haloalkyl radical, a cycloalkyl radical, an amino- alkyl radical, an aryl radical or a substituted aryl radical, particularly one having one or more fluorine atom substituents; . R2 represents a hydrogen atom, a halogen atom, or R1 and R2 may together form an X group; . R3 represents a hydrogen atom or a lower alkyl radical; , R* and R5 and R6 independently represent a hydrogen atom, a lower alkyl radical, a hydroxyl radical, an amino radical, an aminoaikyl radical, an alkylamino radical, a dialkylamino radical, an alkylaminoalkyl radical, an alkoxy radical, a mesyloxy radical, a hydroxyalkyl radical, a cyano radical, an acylaminoalkyl radical, a carboxyi radical, a carboxamido radical, a carboxyalkyl radical, a halogen atom, an alkylcarboxy radical e.g. acetoxy, an acetamido radical or an acetamido- alkyl radical; in these last two radicals, the terminal free alkyl group may be fluorinated and the nitrogen atom in the acetamidoalkyl radical may carry an alkyl substituent; . X represents -CH2-CH2-CHR7-, -0-CH2-CHR7- or -C-fV' r where . R7 represents a hydrogen atom or a lower alkyl radical, . R8 represents a hydrogen atom or a halogen atom, and Y represents CH or N, with the exception however of compounds of formula (I), in which:

R1 and R2 together form a link represented by a group -0-CH2-CH(CH3)- and R3, R* and R6 represent a hydrogen atom, and R5 represents a hydroxyl radical (OH) or a hydroxymethyl radical (CHz0H), and of the compound of formula (I) in which:

R1 represents an ethyl radical R2 represents a fluorine atom R3, R* and R6 represent hydrogen atoms, and R3 represents an ethylaminomethyl radical (CH3CH2NHCH2).

Certain compounds according to the invention are more precisely represented by the general formula (la) COOH (la) in which Rj/ R and R_ have the same meaning as hereinbefore.

The invention also relates to a pharmaceutical composition containing a compound of formula (I) or one of its pharmaceutically acceptable salts in sufficient quantity to confer efficient antimicrobial activity.

Moreover, the invention relates to processes for preparing compounds of formula (I) and their pharma¬ ceutically acceptable salts.

Throughout this description the term lower alkyl will designate linear or branched hydrocarbon radicals preferably containing 1 to 4 carbon atoms.

The compounds of the invention represented by formula (I) may be prepared by various processes< For instance, one process comprises reacting a heterocyclic compound of formula (II) (II) »1 o2 where R , R and R have the same meaning as hereinbefore.

and Z represents a halogen atom; with a compound repre¬ sented by formula (III) R6 r5 H , (III) where R* and R5 and R8 have the same meaning as hereinbefore.

The reaction may be carried out in a large number of solvents. Examples of such solvents are lower alcohols such as ethanol, isopropanol etc., ethers such as tetra- hydrofuran, dioxane, diglyme, etc., nitriles such as acetonitrile, pyridine, dimethyl sulphoxide, dimethyl- formamide and hexamethylphosphorotriamide.

The above reaction may be carried out in the pres¬ ence of an acid-acceptor, in a quantity at least approxi¬ mately between 1 and 2 moles per mole of compound of formula (II). Examples of appropriate acid-acceptors which may be mentioned are alkali metal hydroxides, inorganic carbonates, and tertiary amines such as triethylamine.

The above reaction may be carried out under pres¬ sure, i.e. at a pressure of about 1 to 15 kg/cm2, and at a temperature of about 50 to 250oC for a duration of about 2 to 24 hours.

The heterocyclic compounds of formula (II) that may be used as starting materials for preparing the compounds of the invention represented by formula (I) are known compounds, as described for example by H. Koga, A. Itoh, S. Murayama, S. Suzue and T, Irikura in J. Med. Chem., 1980, 22, 1358.

On the other hand, compounds of formula (III) which are other starting materials for preparing the compounds of the invention represented by formula (I) are known, or I are eynthesised as described for example in various articles (A.G. Anderson and R. Lok, J. Org. Chem.. 1972 21, 3953, R.H. Higgins and N.H. Cromwell, J. Heterocycl.

Chem., 1971, 8, 1059).

The compounds of the invention represented by formula (I) may also be prepared by a process which comprises reacting a heterocyclic compound of formula (II), where R1, Rz and R3 have the same meaning as herein¬ before, and Z represents an amino radical, with a com- pound represented by formula (IV) c V-- (IV) where R* and R3 and R6 have the same meaning as herein¬ before, and A represents a halogen atom, a hydroxy1 radical, a lower alkylsulphonyloxy radical or an aryl- sulphonyloxy radical. > The reaction may be carried out in solvents such as lower alcohols or dipolar non-protonic solvents, such as dimethylsulphoxide, dimethylformamide and hexamethyl- phosphorotriamide.

The above reaction may be carried out in the pres¬ ence of ah appropriate acid-acceptor, such as alkali metal hydroxides, inorganic carbonates, and tertiary amines such as pyridine or triethylamine.

The above reaction may be carried out at atmospheric 3& pressure or at a pressure of about 1 to 15 kg/cmz, and at a temperature of about 10 to 50oC. ioi a duration of about 1 to 5 days and afterwards at a temperature of about 50 to 150oC for a duration of about 8 to 72 hours.

The heterocyclic compounds of formula (II) in which Z represents an amino radical, which may be used as starting materials for preparing the compounds of the invention represented by formula (I) are known compounds, as described for example in Patent EF 0 134 165 and in two publications (T. Uno, M. Takamatsu, Y. Inone, Y.

Kawahata, K. luchi, G. Tsukamoto, J. Med. Chem.. 1987, JJl, 2163; and by H, Koga, A. Itoh, S. Murayama, S. Suzue and T. Iri3aira in J. Med Chem., 1980, 21, 1358). On the other hand, the compounds of formula (IV), which are other starting materials, are commercial products.

Among the compounds represented by formula (I), those where R3 represents a hydrogen atom and/or R* or R5 or R6 represent an amino radical, an aminoalkyl radical, an alkylamino radical, an alkylaminoalkyl radical, may be prepared by hydrolysis of those compounds represented by formula (I) where R3 represents a lower alkyl radical and/or R* or R5 or R6 represent an acylamino radical, an acylaminoalkyl radical, an alkylacylamino radical or an alkylacylaminoalkyl radical.

The hydrolysis reaction may be carried out by conventional processes for example in the presence of a conventional catalyst, such as a basic compound, for example sodium hydroxide, potassium hydroxide and similar compounds, a mineral acid such as sulphuric acid, hydro- chloric acid, or an organic acid such as an aromatic sulphonic acid and similar compounds.

In a general way, the reaction may be carried out in a conventional solvent such as water, alcohols, dioxane, acetone or a mixture of these. Reaction temperature is generally between the prevailing laboratory temperature and 150oC, for a duration of about 2 to 24 hours.

The preparation of new derivatives according to the invention will be shown in the following examples. Some typical uses in the various fields of application will also be described.

The examples hereinafter, given solely by way of illustration, must nevertheless in no way limit the scope of the invention.

Example 1 ♦.

Method A Preparation of ethyl i-cy€lopropyl-6,8-difluoro-7-(3- hydroxy-l-azetidinyl)-l,4-dihydro-4-oxo-3-quinoline- carboxylate.

A solution of 1.22 g (3.92 mmoles) of ethyl 1- cyclopropyl-6,7,8-trifluoro-1,4~dihydro-4-oxo-3-quino- linecarboxylate, 0.86 g (7.85 raraoles) of 3-hydroxy- azetidine hydrochloride, 2 g (19.8 mmoles) of triethyl- amine and 20 ml of dimethyl sulphoxide (DMSO) is heated for 4 hours at 80oC. The solution is allowed to cool and is added to a mixture of ice and water, giving a precipitate which is filtered and washed with water. The solid is dried under vacuum yielding 1.40 g (97%) of ethyl 1- cyclopropyl-6f8-difluoro-7-(3-hydroxy-1-azetidinyl)-1,4- dihydro-4-oxo-3-quinolinecarboxylate melting at 260o-270oC.

Spectroscopic data:

1H NMR, 6, [DMSO-dg] : 1.08 (d, 4H, J = 5 Hz); 1.26 (t, 3H, J = 7 Hz); 3.60-4 80 (m, 6H); 5.66 (d, 1H, J = 4 Hz); 7.52 (d, 1H, J = 13.5 Hz); 8.32 (s, 1H).

IR (KBr) : 3300; 1725; 1615 crtTl .

Method B Preparation of ethyl 1 -cyclopropyl-6,8-difluoro-7-(3- hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinoline- carboxylate A solution of 0.8 g (2.60 mmoles) of ethyl 7-amino- 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-e-quinoline- carboxylate, 0.33 g (2.60 mmoles) of 1,3-dichloro-2- propanol and 25 ml of pyridine is agitated for 3 days, protected from light at ambient temperature; then left °25 refluXing for 3 days and more. The solution is concentrated almost to dryness, poured onto water giving a precipitate which is filtered and washed with water. The solid is dried under vacuum, yielding 0.52 g (55%) of ethyl 1-cyclopropyl- 6 ,.8-dif luoro-7-( 3-hydroxy-1 -azetidinyl) -1 , 4-dihydro-4-oxo- 3Q 3-quinolinecarboxylate. Its melting point and spectroscopic data are identical to those of the derivative obtained according to method A.

EXAMPLE 2; Method C Preparation of 1-cyclopropyl-6,8-difluoro-7-(3-hydroxy- 1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acidi A solution of 0.4 g (1.10 mmoles) of ethyl 1-"cyclo- propyl-6,8-difluoro-7-(3-hydroxy-1-azetidinyl)-1,4- dihydro-4-oxo-3-quinolinecarboxylate, 2 ml of ethanol and ml of 0.5N sodium hydroxide is left to reflux for 1,5 hours. It is then allowed to cool, diluted with water, adjusted to pH 5 and a precipitate is obtained which is filtered and washed with water. The solid is dried under vacuum yielding 0.37 g (100%) of 1-cyclopropyl-6,8- difluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid melting at 286-2880C.

Spectroscopic data:

1H NMR, 6, [DMSO-dg, TFA] : 1.13 (m, 4H); 4.10 (m, 3H); 4.55 (m, 3H); 7.75 (d, 1H, J = 13 Hz); 8.55 (s, 1H).

IR (KBr) : 3400; 1700; 1625 cm" .

Method D Preparation of 1-cycl©propyl-6,8-difluoro-7-(3-hydroxy- 1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A solution of 0.9 g (3,2 mmoles) of 1-cyolopropyl- 6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.7 g (6.4 mmoles) of 3-hydroxyazetidine, 1,6 g (16.0 mmoles) of triethylamine and 15 ml of DMSO is heated to 80oC for 4 hours. It is allowed to cool, added to a mixture of ice and water, and adjusted to pH giving a precipitate which is filtered and washed with water. The solid is dried under vacuum to yield 0.86 q (80%) of 1-cyclopropyl-6,8-difluoro-7-(3-hydroxy-1- azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid melting at 286-2880C, Spectroscopic data are identical to those of method C.

EXAMPLE 3:

Preparation of ethyl 1-cyclopropyl-6,8-difluoro-7-(3- mesyloxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinoline- cafboxylate 6.3 g (55.0 mmoles) of mesyl chloride are slowly added to a solution of 1.0 g (2.75 mmoles) of ethyl 1- cyclopropyl-6,8-difluoro-7-(3-hydroxy-1-azetidinyl)-1,4- dihydro-4-oxo-3-quinolinecarboxylate in 50 ml of pyridine cooled to 0oC, and the reaction is maintained at 0oC for 3 hours. The solution is added to a mixture of ice and water giving a precipitate which is filtered and washed with water. The solid is dried under vacuum yielding 0.90 g (73%) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3- mesyloxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinoline- carboxylate melting at 191-1930C.

Spectroscopic data:

1H NMR, 6, : 1.11 (b, 4H); 1.38 (t, 3H, J = TRz); 3.08 (s, 3H); 3.80 (m, 1H); 4.36 (q, 2H, J = 7 Hz); 4.53 (m, 2H); 4.70 (m, 2H); 5.36 (if 1H); 7.83 (dd, 1H, J = 13 Hz, J' = 1 Hz); 8.45 (s, 1H).

ir 'RBr) : 1720; 1615; 1475; 1340; 1165 cm-1.

EXAMPLE 4:

Preparation of ethyl 7-(3-acetamidomethyl-1-azetidinyl )- 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylate.

a solution of 1.0 g (3.2 mmoles) of ethyl 1-cyclo¬ propyl-6 ,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylate, 1.05 g (6.4 mmoles) of 3-acetamido-methyl- azetidine hydrochloride, 1.6 g (16 mmoles) of triethyl- amine and 20 ml of DMSO is heated to 80oC for 4 hours.

it is allowed to cool, poured onto a mixture of ice and water giving a precipitate which is filtered and washed with water. The solid is dried under vacuum yielding 0.93 g (69%) of ethyl 7-(3-acetamidomethyl-1-azetidinyl)- 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline- '25 carboxylate melting at 170-190oC.

Spectroscopic data:

1H NMR, 6, : 1.11 (m, 4H); 1.37 (t, 3H, J = 7 Hz); 2.04 (s, 3H); 2.97 (m, 1H); 3.4-4.7 (m, 9H); 6.64 (m, 1H); 7.67 (d, 1H, J = 13 Hz); 8.44 (s, 1H).

IR(KBr) : 3300; 1720; 1650; 1615; 1545 cm-1.

EXAMPLE 5:

Preparation of 1-cyclopropyl-6,8-difluoro-7-(3-carboxy- 1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

,35 a mixture of 0.3 g (1 mmole) of 1-cyclopropyl-6,7,8- trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.2 g (2 mmoles) of azetidine-3-carboxylic acid, 0,5 g (5 mmoles) of triethylamine and 5 ml of DMSO is heated to 100oC for 24 hours!.

The mixture is allowed to cool, added to a mixture of ice and water, filtered and the product recrystallised from DMF/H20 (15:2) to yield 0.11 g (28%) of 1-cyclo- propyl-6,8-difluoro-7-(3-carboxy-1-azetidinyl)-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid, melting at 251- 50C.

Spectroscopic data:

1H NMR, 6, [DMSO-dg] : 1.2 (m, 4H); 3.55 (m, 1H); 3.95 (m, 1H); 4.52 (m, 5H); 7.65 (d, 1H, J = 12 Hz); 8.55 (s, 1H).

IR(KBr) : 2920, 1725, 1630, 1460 cm-1.

EXAMPLE 6:

Preparation of 1~cyclopropyl-6,8-difluoro-7-(3-carbamoyl- 1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

A mixture of 0.57 g (2 mmoles) of 1-cyclopropyl- 6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.35 g (2.6 mmoles) of azetidine-3-carboxamide hydrochloride and 0.6 g ( 6 mmoles) of triethylamine in mi of DMSO is heated to 100oC for 2 hours.

The mixture is allowed to cool, and added to a water/acetic acid mixture. Filtering and washing with water yield 0.62 g (66%) of 1-cyclopropyl-6,8-difluoro- 7-(3-carbamoyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quino- "25 linecarboxylic acid melting at 295-80C.

Spectroscopic data:

1H NMR, S, [DMSTO-ea, TFA.] ; 1.15 (m, 4H); 3.55 (m, 1H) ; 4.05 (m,1H); 4.45 (m, 4H); 7.1 (s, 1H); 7.55 (m, 2H); 8.6 (s, 1H).

IR(KBr) : 3390, 3190, 1740, 1665, 1640, 1450 cm-1.

EXAMPLE 7:

Preparation of 1-cyclopropyl-6,8-difluoro-7-(3-cyano-1- azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A solution of 0.57 g (1.5 mmoles) of 1-cyclopropyl- 6,8-difluoro-7-(3-carbamoyl-1-azetidinyl)-1 ,4-dihydro-4- oxo-3-quinolinecarboxylic acid (example 6) in 12 ml of acetic anhydride is heated under reflux for 24 hours.

Cooling, filtering and washing with water and ethancl yield 0.15 g (27%) of 1-cyclopropyl-6,8-difluoro-7-(3- - 11 cyano-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid melting at > 3250C.

Spectroscopic data:

1H NMR, 6, [DMS0-6d, TFA] : 1.20 (m, 4H); 3.95 (m, 1H); 4.6 (m, 5H); 7.75 (d, J = 12 Hz, 1 H); 8.6 (s, 1H).

IR(KBr) : 2250, 17 35, 1635, 1650 cm"1.

EXAMPLE 8:

Preparation of 1-cyclopropyl-6,8-difluoro-7-(3-methyl-3- hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid A mixture of 0.9 g (2.9 mmoles) of ethyl 1-cyclo¬ propyl-6, 7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylate, 0.54 g (4.3 mmoles) of 3-hydroxy-3-methyl- azetidine hydrochloride, 1 g (10.8 mmoles) of triethyl- amine and 10 ml of pyridine is heated under reflux for hours. The product is cooled, and diluted with water.

Filtering and washing yields 0.95 g (89%) of ethyl 1- cyclopropyl-6,8-difluoro-7-(3-methyl-3-hydroxy-1-azeti¬ dinyl )-1,4-dihydro-4-oxo-3-guinolinecarboxylate which is then hydrolysed by heating a mixture of 0.38 g (1 mmole) of this ester with 1.5 ml of ethanol, and 8 ml of 0.5 N sodium hydroxide under reflux for 3 hours. The mixture is cooled, filtered and acidified with acetic acid.

Filtering and washing with water yield 0.34 g (97%) of 1-cyclopropyl-6,8-difluoro-7-(3-methyl-3-hydroxy-1- azetxdinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid melting at 290-4oC.

Spectroscopic data:

1H NMR, 6, [DMSO-6d, TFA] : 1.16 (d, J = 7Hz, 4H); 1.48 (s, 3H); 4.05 (m, 1H); 4.26 (m, 4H); 7.66 (dd J = 13 Hz, J = 2 Hz, 1H); 8.56 (s, 1H).

IR(KBr) : 3450,1725, 1630, 1530, 1460 cm-1.

EXAMPLE 9:

Preparation of 7-(3-trifluoroacetamidomethyl-1-azeti- dinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo«3- quinolinecarboxylic acid A solution of 0.8 g (2.8 mmoles) of 1-cyclopropyl- 6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.92 g (4.2 mmoles) of 3-trifluoroacetamidomethyl- azetidine hydrochloride, 8 ml of pyridine and 1.7 g of triethylamine is heated under retlux for 3 hours. It is then evaporated under vacuum, diluted with water and filtered. 1,12 g (88.9%) of 7-(3-triflucroacetamido- methyl-1-azetidinyl)-1-cyclopropyl-6,8-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 145-150oC.

Spectroscopic data:

1H NMR, 6, [DMS0-6d, TFA] : 1.10 (m, 4H); 3.0 (m, 1H); 3.50 (m, 2H); 4.20 (m, 3H); 4.50 (m, 2H); 7.65 (d J = 13HzlH); 8.45 (s, 1H).

IR(KBr) : 3300,1725, 1630, 1450 cm-1.

EXAMPLE 10:

Preparation of 7-(3-aminomethyl-1-azetidinyl)-1-cyclo- propyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid.

A solution of 0.8 g (1.6 mmoles) of 7-(3-trifluoro- acetamidomethyl-1-azetidinyl)-1-cyclopropyl-6,8-difluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (example9) in 30 ml of IN sodium hydroxide is maintained at 80oC for [ 3 hours, cooled and acidified with acetic acid. Tiltering and washing yield 0.41 g (65%) of 7-(3-aminomethyl-1- azetidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid jnelting at 190-195oC.

'25 Spectroscopic data:

H NMR, 5, [DMSO-6d, TFA] : 1.16 (m, 4H); 3.0 (m, 2H); 4.25 (m, 5K); 7.71 (m, 3H)j 8.55 (s, 1H).

IR(KBr) : 3500, 1730, 1680, 1630 cm-1.

EXAMPLE 11:

Preparation of 1-cyclopropyl-6,8-difluoro-7-(3-mesyloxy- » 1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid '* A solution of 0.2 g (0.4 ffimole) of ethyl 1-cyclo- propyl-6,8-difluoro-7-(3-mesyloxy-1 -azetidinyl)-1 ,4- d7,hydro-4-oxo-3-quinolinecarboxylate (example 3) in 6 ral of 0.5 N sodium hydroxide and 1 ml of ethanol is refluxed for 1 hour. It is evaporated under vacuum, and acetic acid is added. Filtering and washing yield 0.18 g (-96%) of 1-cyclopr©pyl-6,8-difluoro-7-(3-mesyloxy-1 -azeti- - 13 dinyl)-t,4-dihydra-4-oxQ-3-quinolinecarboxylic acid melting at 240-4oC.

Spectroscopic data:

1H NMR, 5, {DMSG-6d, TFA] : 1.19 (m, 4H); 3.3 (s, 3H); 4.06 (m, 2H)? 4.54 (m, 2H); 4.77 (m, 2H); 5.44 (m, 1H); 7.68 (d, J = 14Hz 1H); 8.57 (s, 1H).

EXAMPLE 12:

Preparation of 7-[3-(N'-ethyl-N1-trifluoroacetamido- methyl)-1-azetidinyl]-6,8-difluoro-1,4-dihydro-1-cyclo- propyl-4-oxo-3-quinolinecarboxylic acid A solution of 1.0 g (3.5 mmoles) of 1 -cyclopropyl- 6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.4 g (5.7 mmoles) of 3-(N'-ethyl-N'-trifluoro- acetamidomethyl)-azetidine hydrochloride, 9 ml of pyridine and 2.9 g (28.5 mmoles) of triethylamine is heated under reflux for 2 hours. It is evaporated under vacuum and diluted with a 1:1 solution of ethanol in water. After filtering and washing, 1.3 g (78%) of 7- [3-(N'-ethyl-N'-trifluoroacetamidomethyl)-1-azetidinyl]- 6,8-difluoro-1,4-dihydro-1-eyclopropyl-4-oxo-3-quinoline- carboxylic acid are obtained, melting at 208-120C.

Spectroscopic data:

1H NMR, 5, [DMSO-6d, TFA] : 1.15 (m, 7H); 3.0 (m, 1H>; 3.35 (m, 2H); 3.72 (m, 2H); 4.1 (m, 3H); 4.45 (m, 2H); 7.6 (d, J = 13Hz 1H); 8.55 (s, 1H).

IR(KBr) : 1729, 1688, 1466, 1326. cm-1.

EXAMPLE 13:

Preparation of 7-(3-ethylaminomethyl-1-azetidinyl)- 6,8-difluoro-T,4-dihydro-1-cyclopropyl-4-oxo—3-quinoline- '30 carboxylic acid A solution of 0.7 g (1,5 mmoles) of 7-[3-(N*-ethyl- N1 -trif luoroacetamidomethyl >-1 -azetidinyl ] -6., 8-dif luoro- 1,4-dihydro-1-cyclopropyl-4-oxo-3-quinolinecarboxylic acid (example 12) in 9 ml of IN sodium hydroxide and 3 mi of ethanol is refluxed for 3 hours. It is cooled, and acetic acid is added. After filtering and washing with cold ethanol, 0.37 g (66%) of 7- (3-ethyla-minoinethyl- 1-azetidinyl)-6,8-difluoro-1,4-dihydro-1-cyelopropyl-4- oxo-3-quinolinecarboxylic acid are obtained., melting at 23?-420C.

Spectroscopic data:

1H NMR, 5, [DMS0-6d, TFA] : 1.2 (m, 7H); 2.6 (m, 1H); 3.0 (ra, 2H); 3.25 (m, 2H); 4.05 (m, 1H); 4.25 (m, 2H>; 4.5 (m, 2H); 7.6 (d, J = 13Hz, 1H); 8.5 (s, 1H).

IR(KBr) ; 3300, 1624, 1474, 1323 cm-1.

EXAMPLE 14; Preparation of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7- (1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid A mixture of 0.6 g (2.1 mmoles) of 1-cyclopropyl- 1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarDoxylic acid with 0.25 g (4.4 mmoles) of azetidine, 8 ml of pyridine and 1 ml of triethylamine is maintained at 110- 120oC for 2 hours in a closed vessel. After cooling, evaporating under vacuum, filtering and washing, 0.6 g (88%) of 1-cyclopropyl-6,8-difluoro-1 ,4-dihydro-7-(1 - azetidinyl)-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 289-930C.

Spectroscopic data:

1H NMR, tS, [DMSO-6d] : 1.15 (m, 4H); 2.J.0 (m, 2H) ; 4.07 (m, 1H); 4.45 (m, 4H); 7.70 (d, J = 13Hz, 1H); 8,58 (s, 1H).

IR(KBr) : 1724, 1629, 1460 cm-1.

EXAMPLE Preparation of 1 -cycLopropyl-6,8-difluoro-7-(3-methyl-3- trifluoroacetamido-1-azetidinyl)-4-oxo-3-quinoline- carboxylic acid.

A solution of 1 g (3.5 mmoles) of 1-cyclopropyl- 6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid, 1.15 g •30 (5.3 mmoles) of 3-methyl~3-trifluoroacetamidoazetidine hydrochloride, .2 ml of triethylamine in 1 0 ml of pyridine is refluxed for 3 hours.

The solution is evaporated under vacuum, water is added, the product is acidified with acetic acid and filtered. After washing with water and cold ethanol, 1.15 g (73%) of 1-cyclopropyl-6,8-difluoro-1r4-dihydro- 7-(3-methyl-3-trifluoroacetamido-1-azetidinyl)-4-oxo-3- quinolineearboxylic acid are obtained, melting at 208- 213°C.

Spectroscopic data:

1H NMR, 6, IDMSO-dg-TFA] : 1.1 (broadened, 4H); 1.5 (s, 3H); 4.0 (m, 1H); 4.2 (m, 2H)j 4.5 (m, 2H); 7.5 (m, 1H); 8.5 (s, 1H); 9.8 (s, 1H).

IR(KBr) : 3320, 1725, 1628, 1465 cm-1.

EXAMPLE 16:

Method E: Preparation of 1-cyclopropyl-6r8-difluoro-1,4- dihydro-7-(3-methyl-3-amino-1-azetidinyl)-4-oxo-3-quino- I i linecarboxylic acid A solution of 0,8 g (1.8 mmoles) of 1-cyclopropyl- 6,8-ciif luoro-1,4-ciihydro-7- (3-methyl-3-trif luoroacet- amido-1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid (example 11) in a mixture of 10 ml of IN sodium hydroxide and 2 ml of ethanol is refluxed for 3 hours. It is evaporated under vacuum and acetic acid is added. The product is filtered and washed with water and ethanol.

0.35 g (55%) of l-cyclopropyl-6,8-difluoro-l,4-dihydro- 7-(3-methyl-3-amino-l-azetidinyl)-4-oxo-3-quinoline- carboxylic acid are obtained having a melting point of 298-300oC.

Spectroscopic data:

1KNHR,<S , [pMSO-d TTaI: 1.18 (d, 4H, J - 6.2Hz); 1.64 (s, 3H) > -,05 ** 6 (m, 1H); 4.42 (m, 4H) ; 7.74 (dd 1H, J - 12.5Hz, J' = 1.7Hz); 8.61 (S, 1H).

XR(KBr): 3100, 1627, 1466, 1319 ca" .

Method F; Preparation of l-cyclopropyl-6,8-difluoro-l,4- dihydro-7-(3-methyl-3-amino-l-azetidinyl)-4-oxo-3-quino- linecarboxylic acid A mixture of 0.23 g (0.82 mmoles) of 1-cyclopropyl- 6, 7,8-trif luoro-4-oxo-l,4-dihydro-3-quinolinecarboxyliG acid, 0.26 g (1.64 mmoles) of 3-methyl-3-aminoazetidine dihydrochloride and 0.5 ml of triethylamine is refluxed in ml of pyridine for 2 hours. Filtering and washing with water and ethanol yield 0.250 g (87%) of 1- cyclopropyl-6,8-difluoro-l,4-dihydro-7-( 3-methyl-3-amino- l-azetidinyl)-4-oxo-3-quinolinecarboxylic acid having a melting point and spectroscopic data identical to those of the derivative obtained by Method E.

EXAMPLE 17? Preparation of l-cyclopi:opyl-6,8<-difluoro-7-( 3-acetoxy- 1-azetidinyl) -1,4-dihyda:0-4-dxo- 3-quinolinecarboxylic acid 0.7 g (2 mmoles) of l-cyclopropyl-6,8-difluoro-7-(3- hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinoline¬ carboxylic acid (example 2) are dissolved in 20 ml of - 17 pyridine. 0,64 g (6.2 mmoles) of acetic anhydride are added slowly and the solution is left at room temperature for 24 hours. It is diluted with water, filtered, and the precipitate is washed. This yields 0.54 g- (68%) of 1 -cyclopropyl-6,8-difluoro-7-(3-acetoxy-1-azetidinyl)- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid melting at 259-2620C.

Spectroscopic data:

1H NMR, 6, [DMSQ-6d-TFA] : 1.2 (d, J=6Hz, 4H); 2.1 (s, 3H); 4.05 (q, J-6Hz, 1H); 4.4 (m, 2H); 4.8 (m, 2H); 5.3 (rn, 1H), 7.7 (dd, J=13Hz/ J,=2Hz, 1H); 8.60 (s, 1H).

IR(KBr) : 1742, 1727, 1626, 1481 cm-1.

EXAMPLE 18:

Preparation of 1-cyclopropyl-6-fluoro-7-(3-hydroxy-1- azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A mixture of 1 g (3.5 mmoles) of 1-cyclopropyl-7- chloro-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 0.77 g (7.9 mmoles) of 3-hydroxyazetidine hydro¬ chloride, 2.15 g (21.3 mmoles) of triethylamine is heated to 160oC in 10 ml of dimethyl sulphoxide for 6 hours.

The mixture is cooled, diluted with- water and acidified with acetic acid. After filtering and recrystallising from dimethylformamide 0.3 g (27%) of 1-cyclopropyl-6- quinolinecarboxylic acid are obtained, melting at 296-80C.

Spectroscopic data:

1H NMR, 6, [DMSO-ed, TFA]: 1.14 (m, 4H); 3.95 (m, 3H); 4.40 (m, 3H); 6.90 (d, 1H, J = 8 Hz); 7.7 (d, 1H, J = 12 Hz); 8.53 (s, 1H).

IR(KBr): 3406, 1703, 1632, 1524, 1340 cm-1.

EXAMPLE 19:

Preparation of 1-(4-fluorophenyl)-6,8-difluoro-7-(3- methyl-3-trifluoroacetamido-l-azetidinyl)-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid A mixture of 1 g (3 mmolea) of l-(4-fluorophenyl)- 6,7, 8-trif luoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.98 g (4.5 mmoles) of 3-methyl-3-trifluoroacet- amidoazetidine hydrochloride and 0.6 g (6 mmoles) of triethylamine is heated under reflux for 3 hours in 10 ml of pyridine.

The mixture is evaporated under vacuum, water is added, and the mixture is acidified with acetic acid and filtered. After washing with water, 1.25 g (84.5%) of 1- (4-f luorophenyl) -6,8-dif luoro-7- (3-amino-3-trif luoroacet- amido-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinoline- carbcxylic acid are obtained, melting at 198-203oC.

Spectroscopic data:

1H NOR, £, [DMSOr-6d, TFa] : 1.45 (s, 3H) ) 4.35 (m, 4H) i 7.0-8 0 (m, SB) I 8.45 (s, 1H); 9.8 (s, 1H).

IR(KBr)'} 3400, 1734, 1701, 1627, 1489 cm" .

EXAMPLE 20i Preparation of l-(4-fluorophenyl)-6,8-difluoro-7-(3- amino-3-methyl-l-azetidinyl) -1,4-dihydro-4-oxo-3-quino- linecarboxylie acid A solution of 1.25 g (2.5 mmoles) of l-(4-fluoro- phenyl)-6,8-dif luoro-7-(3-amino-3-trif luoroacetamido-1- azetidinyl)-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid (example 19), in 8 ml of IN sodium hydroxide and 10 mi of water is heated under reflux for 3 hours. It is cooled, filtered, and acetic acid is added. After filtering and washing with water and cold ethanol, 0.8 g (72%) of l-(4- f luorophenyl) -6,8-dif luoro-7- (3-amino-3-methyl-l-azeti- dinyl)-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 272-70C.

Spectroscopic data:

lll NMR, 6, [DMS0-6d]: 1.40 (s, 3H); 4.1 (broadened, 4H); 7.4 (m, 2H); 7.7 (m, 3H) j 8.3 (s, 1H).

IR(KBr): 34010, 1728, 1626, 1466, 1325 cm"1.

EXAMPLE 21; Preparation of l-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3- inethyl-3-trifluoroacetamido-l-azetidinyl)-3-quinolinecarboxyl- ic acid.

A solution of l.lg (4 mmoles) of l-ethyl-6,7,8-trifluoro- 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.32g (6 mmoles) of 3-methyl-3-trifluoroacetamidoazetidine hydrochloride and 0.8g (8 mmoles) of triethylamine in 10 ml of pyridine is heat¬ ed under reflux for 3 hours. Cooling, filtering and washing with water acidified with a little acetic acid yields 0.65g (37%) of l-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-methyl-3- trifluoroacetamido-1-azetidinyl)-3-quinolinecarboxylic acid, melting at 196-210oe.

Spectroscopic data:

1H NMR, 6, [DMS0-6d, TFa]: 1.45 (m, 3H); 1.60 (s, 3H); 4.51 (m, 6H); 7.68 (d, 1H, J = 13Hz); 8.76 (s, 1H); 9.80 (m, 1H).

IR(KBr) : 3400, 1724, 1707, 1629, 1497 cm"1.

EXAMPLE 22:

ft S V • e * * ,. Preparation of l-ethyl-6,8-difluoro-7-(3-amino-3-methyl-l- l , ",20 azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A mixture of 0.65 g (1.5 mmoles) of l-ethyl-6,8-difluoro- ">s * 1, 4-dihydro-4-oxo-7-(3-methyl-3-trifluoroacetamido-l-azetid- ' * inyl)-quinoline -3-carboxylic acid (example 21), 2 ml of 10% sodium hydroxide and 3 ml of ethanol is refluxed in 10 ml of water for 3 hours. It is filtered while hot, cooled, acid¬ ified with acetic acid, and filtered. After washing with water, 0.48 g (95%) of l-ethyl-6,8-difluoro-7-(3-as)ino-3-methyl-l- azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 293-6 C.

Spectroscopic data:

1H NMR, 8, [DMSO-6d, TFiQ : 1.41 (m, 3H) ; 1.60 (s, 3H) ; 4.4 (m, 6H); 7.76 (d, 1H, J= 13Hz); 8.43 (m, 2H); 8.77 (s, 1H).

IR(KBr): 3400, 1723, 1628, 1467 cm"1.

EXAMPLE 23:

Preparation of l-cyclopropyl-e, 8-dif luoro-7-(3-amino-l-azetid- inyl) '-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

A mixture of 1 g (3.2 mmoles) of ethyl 1-cyclo propyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3- carboxylate, 0.98 g (4.8 mmoles) of 3-trifluoroacetamido- azetidine hydrochloride and 2 ml of triethylamine is heated in 15 ml of dimethyl sulphoxide for 4 hours at 80- 50C. It is diluted with water and extracted with chloro¬ form. The organic phase is washed with water and evap¬ orated yielding 0.31 g (22%) of ethyl 1-cyclopropyl-6,8- difluoro-1,4-dihydro-7-(3-trifluoroacetamido-1-azeti- dinyl)-4-oxo-3-quinolinecarboxylate which is then hydro- lysed by heating a mixture of 0.1 g (0.22 mmoles) of this ester with 5 ml of IN sodium hydroxide and 5 ml of ethanol. The mixture is cooled, evaporated and acidified with acetic acid. Filtering and washing with water yields 70 mg (96%) of 1-cyclopropyl-6,8-difluoro-7-(3- amino-1-azetidinyl)-1,4-dihydro-4-oxo-3-guinolinecarbox- ylic acid, melting at 214-60C.

Spectroscopic data:

1H NMR, 6, [DMSO-6d, TFA]: 1,0 (m, 4H); 3.40 (m, 1H); 3.9 * ' ->n (m, 1H); 4.45 (m, 4H); 7.5 (d, 1H, J = 7Hz); 8.3 (broadened, 2H); 8.5 (s, 1H).

:.'. , IR(KBr): 3420, 2950, 1620, 1470, 1320 cm-1.

**• EXAMPLE 24:

Preparation of 1-cyclopropyl-6,8-difluoro-7-(3-trifluoro- acetamidomethyl-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid A mixture of 1 g (3.5 mmoles) of 1-cyclopropyl- «' * 6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline -3-carboxylic acid, 1.32 g (5.7 mmoles) of 3-methyl-3-trifluoroacet- amidomethylazetidine hydrochloride and 2.3 g of triethyl- • 0 amine is heated under reflux in 12 ml of pyridine for 3 hours. The mixture is evaporated, water is added, and the product filtered. 1.6 g (100%) of 1-cyclopropyl-6,8- *, ; difluoro-7-(3-trifluoroacetamidomethyl-3-methyl-1-azeti¬ dinyl )-1,4-dihydro-4-oxo-3-quinolinecarboxylie acid are obtained, melting at 232-70C.

Spectroscopic data:

1H NMR, 6, [DMSO-6d]: 1.25 (m, 7H); 3.5 (s, 2H); 4.20 (m„ 5H)J 7.62 (d, 1H, J = 13Hz); 8.56 (s, 1H); 9.27 (broad¬ ened , 1H) 4 » I IR(KBr): 3300,1728, 1719, 1628, 1487, 1483 cm"1.

EXAMPLE 25:

Preparation of 1-cyclopropyl-6,8-difluoro-7-(3-N-ethyl- trifluoroacetamidomethy1-3-methyl-1-azetidinyl)-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid A mixture of 1.5 g (5.3 mmoles) of 1-cyclopropyl- 6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 2.1 g (8 mmoles) of 3-methyl-3-(N'-ethyl-trifluoro- acetamidomethyl) azetidine hydrochloride and 3.3 g of triethylamine is heated under reflux for 3 hours in 15 ml of pyridine, it is evaporated, water is added, the product filtered and washed with water and ethanol. 1.8 g (70%) of 1-cyc]opropyl-6,8-difluoro-7-(S-N'-ethyl-tri- fluoroacetamidomethyl-3-methyl-1-azetidinyl)-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid are obtained, melting at 210-2oC.

Spectroscopic data:

1H NMR, 6, [DMS0-6d,]: 1.25 (m, 10H); 3.48 (q, 2H, J = 7Hz); 3.72 (s, 2H); 4.18 (m, 5H); 7.67 (d, 1H, J = 13Hz); 8.58 (s, 1H).

IR(KBr): 1725, 1701, 1627, 1530, 1470 cm"1.

EXAMPLE 26:

Preparation of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4- oxo-7-(3-aminomethyl-3-methyl-1-azetidinyl)-3-quinoline- carboxylic acid A solution of 1.5 g (3.3 mmoles) of 1-cyclopropyl- 6,8-difluoro-7-(3-trifluoroacetamidomethy1-3-methyl-1 - azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (example 24), 15 ml of IN sodium hydroxide and 6 ml of ethanol are heated under reflux for 3 hours, and evap¬ orated under vacuum. Acetic acid is added, and the product filtered and washed with water. 0.88 g (74%) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-amino- methyl-3-methyl-1-azetidinyl)-3-quinolinecarboxyliC acid are obtained, melting at 268-70oC.

Spectroscopic data:

1H NMR, 6, [DMSO-6d,]: 1.16 (d, 4H, J = 6 2Hz); 1.28 (s, 3H); 2.74 (s, 2H); 4.1 (m, 5H); 7.65 (d, 1H, J = 13Hz); 8.55 (s, 1H).

IR(KBr); 3400, 1725, 1627, 1465, 1455, 1322 cm"1.

EXAMPLE 27:

Preparation of 1-cyclopropyl-6,8-difluoro-7-(3-ethyl- aminomethyl-3-methyl-1 -azetidinyl)-1 ,4-dihyclro-4-oxo-3- quinolinecarboxylic acid, A solution of 1.7 g (3.5 mmoles) of 1-cyclopropyl- 6,8-difluoro-7-(3-N'-ethyl-trifluoroacetamidomethyl-3- methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid (example 25), 15 ml of IN sodium hydrox- ide and 6 ml of ethanol are heated under reflux for 3 hours, and evaporated under vacuum. The mixture is cooled, acetic acid is added, the product is filtered and washed with water. 1.08 g (80%) of 1-cyclopropyl-6,8-di- fluoro-7-(3-ethylaminomethyl-3-methyl-1-azetidinyl)-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 250-5oC.

Spectroscopic data:

1H NMR, 6, [DMSO-d6,]: 1.1 (m, 7H); 1.31 (s, 3H); 2.7 (m, 4H); 4.1 (rft, 5H); 7.63 (d, 1H, J = 13Hz); 8.55 (s, TH).

IR(KBr): 3440, 1615, 1475, 1400, 1320 cm-1.

EXAMPLE 28:

Preparation of [S ] - ( - ) -9-f luoro-3-methyl-7-oxo--2 ,3-dihydro- 7H-pyrido [1,2,3-de] [1,4] benzoxazine-10-(3-amino-3-methyl- 1-azetidinyl)-6-carboxylic acid.

A mixture of 0.7 g (2.5 mmoles) of-(-)-9,10- difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzpxazine-6-carboxylic acid, 1.1 g (5 mmoles) of 3-methyl-3-trifluoroacetamidoazetidine hydrochloride and 1 g (9.9 mmoles) of triethylamine is heated under reflux in 10 ml of pyridine for 6 hours. The mixture is evap¬ orated under vacuum, diluted with water, acidified with acetic acid, filtered and the product washed with water and with a 50% aqueous solution of ethanol. 0.67 g (60%) of-(-)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyriao [1,2,3-de] [1,4] benzoxazine-10-(3-methyl-3-trifluoro- acetamido-1-azetidinyl)-6-carboxylic acid are obtained, which is subsequently added to a solution of 2 ml of ethanol in 9 ml of IN sodium hydroxide. This mixture is » V 3 heated to reflux for 3 hours, filtered, evaporated, and water and acetic acid are added. The product is filtered, washed with water and 0.37 g (70%) of-(-)-9-fluoro-3- methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][1,4] benzoxazine-10-(3-ainino-3-methyl-1-azetidinyl-6-carboxylic acid are obtained melting at > 300oC.

Optical rotation: [(*]„ 3 [con. (%) solvent ] =-83.1 (c = 0.41 ; 0.5N; NaOH) Spectroscopic data:

1H NMR, 6, [DMSO-d6, TFA]: 1.45 (d, 3H, J = 6Hz); 1.4 (s, 3H); 4.28 (m, 6H); 4.72 (m, 1H); 7.47 (d, 1H, J = 13 4Hz); 8.66 (s, 1H) IR(KBr): 3493, 1706, 1623, 1473 cm"1.

EXAMPLE 29:

Preparation of R-(+)-9-fluoro-3-methyl-7-oxo-2,3-dihydro- 7H-pyrido [1,2,3-de][1,4]benzoxazine-10-(3-amino-3-methyl- 1-azetidinyl)-6-carboxylic acid The same method is followed as was described for the preparation of the S enantiomer (Example 28), but starting from-(+)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H- pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid. 0.28 g (53%) of R-(+)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][1,4]benzoxazine-l0-(3-amino-3-methyl-1- azetidinyl)-6-carboxylic acid are obtained, melting at > 300QC.

Optical rotation:- [con. (%) solvent]= +82.2 (c = 0.43; 0.5N; NaOH) Spectroscopic data:

1H NMR, 5, [DMSO-d6, TFA]: 1.48 (d, 3H, J = 6Hz); 1.43 (s, 3H); 4.3 (m, 6H); 4.69 (m, 1H); 7.50 (d, 1H, J = 13,5Hz); 8.62 (s, 1H) IR(KBr): 3500, 1708, 1620, 1472 cm-1.

EXAMPLE 30:

Preparation of 1-cyclbpropyl-6-fluoro-7-(3-trifluoroacet- amidomethyl-3-methyl-1-azetidinyl)-1 ,4-dihydro-4-oxo-3- quinolinecarboxylic adid A mixture of 0.7 g (2.6 mmoles) of 1-cyclopropyl- 6,7-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 0.92 g (3»96 mmoles) of 3-methyl-3-trifluoroacet- .-, , .- 2- araidomethylazetidine hydrochloride and 1.6 g of triethyl- amine are heated under reflux for 2 hours in 12 ml of pyridine. The mixture is evaporated, water is added, the product is filtered, and 1.05 g (90%) of 1-cyclopropyl- 6-fluoro-7-(3-trifluoroacetamidomethyl-3-methyl-1-azeti- dinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 265-720C.

Spectroscopic data:

1H NMR, 6, [DMS0-6d,]: 1.28 (m, 7H); 3.53 (s, 2H); 4.0 (m, 5H); 6.85 (d, 1H, J = 6.9Hz]; 7.76 (d, 1H, J = 12.9Hz); 8.56 (s, 1H) IR(KBr): 3300, 1725, 1720, 1630, 1487, 1517, 1474 cm-1.

EXAMPLE 31 :

Preparation of 1-cyclopropyl-6-fluoro-7-(3-N'-ethyl-tri- fluoroacetamidomethyl-3-methyl-1-azetidinyl)-1,4-di- hydro-4-oxo-3-quinolinecarboxylic acid A mixture of 0.7 g (2.6 mmoles) of 1-cyclopropyl- 6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.04 g (3.9 mmoles) of 3-methyl-3-(N'-ethyl-tri- fluoroacetamidomethyl)-azetidine hydrochloride and 1.6 g of triethylamine are heated under reflux in 12 ml of pyridine, evaporated, water is added, the product is filtered and washed with water. 0.78 g (63%) of 1- cyGlopropyl-6-fluoro-7-(3-N'-ethyl-trifluoroacetamido- methyl-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quino- linecarboxylic acid are obtained, melting at 230-6oC.

Spectroscopic data; 1H NMR, 6, [DMS0-6d,]: 1.25 (m, 10H); 3.48 (q, 2H, J = 6.5Hz); 3.72 (s, 2H); 4.04 (m, 5H); 7.90 (d, 1H, J= 8Hz); 7.76 (d, 1H, J = 12 8Hz); 8.56 (s, 1H}.

IR(KBr): 1721, 1701, 1631, 1519, 1474, 1450 cm"1.

EXAMPLE 32:

Preparation of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo- 7-( 3-aniinomethyl-3-methyl-1 -azetidinyl )-quincline-3- carboxylic acid A solution of 1.05 g (2.38 mmoles) of 1-cyclopropyl- 6-fluoro-7-(3-trifluoroacetamidomethy1-3-methyl-1 -azeti¬ dinyl)-! ,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Example 30), in 15 ml of IN sodium hydroxide and 6 ml of ethanol is heated to reflux for 3 hours, and evaporated under vacuum. Acetic acid is added, the product is filtered and washed with water, and 0.7 g (85%) of 1- cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-aminoniethyl- 3-methyl-1-azetidinyl)-3-quinolinecarboxylic acid, melting at 274-90C, are obtained.

Spectroscopic data:

1H NMR, 6, [DMSO-ed,]: 1.24 (m, 7H); 2.76 (s, 2H); 3.90 (m, 5H); 6.84 (d, 1H, J = 7.6Hz); 7.75 (d, 1H, J = 12.9Hz); 8.55 (s, 1H).

IR(KBr): 3400, 1721, 1631, 1520, 1470, 1395 cm-1.

EXAMPLE 33:

Preparation of 1-cyclopropyl-6-fluoro-7-(3-ethylamino- methyl-3-methyl-1-azetidinyl)-1 ,4-dihydro-4-oxo-3-quino- linecarboxylic acid A solution of 0.78 g (3.5 mmoles) of 1-cyclopropyl- 6-f luoro-7- ( 3-trif luproacetamidoethylaiiiinomethyl-3-methyl- 1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (example 31) is heated under reflux for 3 hours in 15 ml of sodium hydroxyde IN and 6 ml of ethanol then evaporated under vacuum. The mixture is cooled, acetic acid is added, filtrated and washed with water to obtain 0.4 g (65%) of 1 -cyclopropyl-6-fluoro-7-(-3-ethylaminomethyl-3-methyl- 1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid melting at 221-6°C.

Spectroscopic data:

1H NMR, 6, [DMSO-dg,]: 1.15 (m, 10H); 2.68 (m, 4H); 3.9 (m, 5H); 6.84 (d, 1H, J = 7.6Hz); 7.75 (d, 1H, J = 12 8H2) ; 8.55 (s, IE) .

IRfKBr): 3420, 1629, 1619, 1578, 1517, 1484, 1402 cm-1.

EXAMPLE 34:

Preparation of 1 - (2 , 4-dif luorophenyl)-6,.8-dif luoro-7-( 3- methyl-3-trifluoroacetamido-1-azetidinyl)-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid A mixture of 0.8 g (2.3 mmoles) of 1 -(2,4-difluoro¬ phenyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid, 0.8 g (3.7 mmoles) of 3-methyl-3-tri- fluoroacetamidoazetidine hydrochloride and 0.6 g (6 mmoles) of triethylamine is heated under reflux in 15 ml of pyridine.

The fixture is evaporated under vacuum, water is added, the mixture acidified with acetic acid, and the product is filtered and washed with water. 1.10 g (57%) of 1 -(2,4-difluorophenyl)-6,8-difluoro-7-(3-amino-3- trifluoroacetamido-1-azetidinyl)-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid are obtained, melting at 190- 60C.

Spectroscopic data:

1H NMR, 5, [DMSO-6d, TFA]: 1.54 (s, 3H); 4.4 (m, 4H); 7.0-8.0 (m, 4H); 8.60 (s, 1H); 9.7 (s, 1H).

IR(KBr): 3400, 1720, 1711, 1626, 1459 cm-1.

gYAMPT.E 35 t Preparation of l-(2,4-difluorophenyl)-6,8-difluoro-7-(3- amino-3-methyl-l-azetidinyl)-l,4-dihydro-4-oxo-3-quino- linecarboxylic acid A solution of 1.1 q (2.1 mmolaa) of l-(2,4-difluoro- phenyl) -6,8-dif luoro-7- (3-» metnyij-fcrif luoroacetamido-l- azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (example 34), 4ml of 10% sodium hydroxide, 5 ml of ethanol and 25 ml of water is heated under reflux for 3 hours. It is cooled, filtered, acetic acid is added and the product filtered and washed with water and cold ethanol. 0.2 g (22%) of l-(2,4-difluorophenyl)-6,8-di- f luoro-7-(3-amino-3-methyl-l-azetidinyl)-l,4-dihyciro-4- oxo-3-quinolinecarboxylic acid are obtained, melting at 185-60C.

Spectroscopic data:

*& NMR, 5, [DMS0-6d, TPA]: 1.54 (s, 3H); 4.31 (broadened, 4H); 7.3 - 8.1 (ra, 4H); 8,48 (breadened, 2H); 8,62 (s, 1H), IR(KBr): 3410, 1729, 1625, 1510, 1461 cm"1.

EYAMPO! 36 1 Preparation of l-ethyl-6-fluo*o-7-(3-£«aino-3-methyl-l- azetidinyl)-l,4-diMyciro-4-oxo-3-quinolinecarboxylic acid.

A mixture of 0.8 g (3.16 mmoles) of l-ethyl-6,7 difluoro-4-oxo-l,4'dihyciro-guinoline-3-carboxylic acid, 1,5 g (6.8 mmoles) of 3-methyl-3-trifluoroacetamido- azetidine hydrochloride and 1 g (10 mmoles) of triethyl- amine is heated under reflux in 15 ml of pyridine.

The mixture is diluted with water and extracted with chloroform. The organic phase is washed with water and evaporated to obtain 1.0 g (76%) of 1-ethyl-6-fluoro-4- oxo-1,4-dihydro-7-(3-methyl-3-trifluoroacetamido-1- azetidinyl)-4-oxo-3-quinolinecarboxylic acid which is subsequently hydrolysed by heating a mixture of 1.0 g (2.4 mmoles) of this acid with 3 ml of 10% sodium hydrox¬ ide and 20 ml of water under reflux for 3 hours. The mixture is cooled and acidified with acetic acid. The product is filtered and washed With water to obtain 370 mg (48%) of T-ethyl-6-fluoro-7-(3-methyl-3-amino-1- azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting at 280-3oC.

Spectroscopic data:

1H NMR, 6, [DMSO-6d]: 1.46 (m, 6H); 4.00 (m, 4H); 4.50 (m, 2H); 6.6 (d, 1H, J = 7 8Hz); 7.82 (d, 1H, J = 12.9Hz); 8.87 (s, 1H).

IR(KBr): 3420, 1709, 1631, 1430, 1360 cm-1.

EXAMPLE 37:

Preparation of 1 - ( 2—f luoroethyl) -6-f luoro-?- ( 3-methyl-3- amino-1-azetidinyl)-1,4-dihydro~4-oxo-3-quinoline- carboxylic acid.

A mixture of 0.8 g (2.5 mmoles) of 1-(2-fluoro- ethyl)-6,7-difluoro-1,4-dihydfo-4-oxo-3-quinoline- carboxylic acid, 1.37 g (6.3 mmoles) of 3-methyl-3- trifluoroacetamidoazetidine hydrochloride and 1.1 g (10 mmoles) of triethylamine is heated under reflux in 10 ml of pyridine.

The mixture is evaporated under vacuum, and extracted with methylene chloride. After washing with water 1.2 g (99%) of 1-(2-fluoroethyl)-6-flucro-7-(3-methyl-3- trifluoroacetamido-1-azetidinyl)-T,4-dihydro-4-oxo-3- quinsiinecarboxylic acid are obtained, melting at My% 2? a v 225-80C.

This product is hydrolysed by heating a solution of 1.1 g (2,3 mmoles) of this trifluoroacetamide in 25 ml of water to which have been added 3 ml of 10% sodium hydroxide under reflux for 2 hours. The solution is filtered while hot, acidified with acetic acid, the product filtered, washed with water and ethanol, and 0.3 g (34%) of 1-(2-fluoroethyl)-6-fluoro-7-(3-methyl-3- amino-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 265-70°C.

Spectroscopic data:

1H NMR, 6, [DMSO-ed]: 1.47 (s,, 3H) ; 4.04 (m, 4H); 4.65 (m, 2H); 6.02 (s, 2H); 6.60 (d, 1H, J = 7.3Hz); 7.31 (d, 1H, J = 12.9Hz) 8.78 (s, 1H) IR(KBr): 3480, 1719, 1632, 1463 cm-1.

EXAMPLE 38:

Preparation of 1 -(2,4-difluorophenyl)-6-fluoro-7-(3- methy1-3-amino-1-azetidinyl)-1,4-dihydro-4-oxo-3-quino- linecarboxylic acid A mixture of 1.3 g (6 mmoles) of 3-methyl-3-tri- fluoroacetamidoazetidine hydrochloride, 0.8 g (2.4 mmoles) of 1-(2,4-difluorophenyl)-6,7-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid and 0.8 g (8 mmoles) of triethylamine is heated under reflux in 20 ml of pyridine for 2 hours. The mixture is evaporated, extracted with methylene chloride to obtain 1.1 g (92%) of 1 -(2,4-difluorophenyl)-6-fluoro-7-(3-methyl-3-trifluoro- acetamido-1-azetidinyl)-T,4-dihydro-4-oxo-3-quinoline- carboxylic acid which is subsequently hydrolysed by adding it to a solution of 3 ml of 10% sodium hydroxide in 20 ml of water and refluxing for 2 hours. The solution is filtered while hot, acidified with acetic acid, filtered and the product washed with water and ethanol.

* 0.27 g (30%) of 1-(2,4-difluorophenyl)-6-fluoro-7-(3- methyl-3-amino-1-azetidinyl)-1,4-dihydro-4-oxo-3-quino- linecarboxylic acid are obtained, melting at 2'%%DESCRIPTION%%-6°C.

<MV5 to Spectroscopic data:

1H NMR, 6, [DMSO-ed, TFA]: 1.56 (s, 3H); 4.00 (m, 4H); 6.72 (d, 1H, J = 7.1H2); 7.3 - 8.1 (m, 4H); 8.44 (broad¬ ened, 2H) 8.70 (s, 1H).

IR(KBr): 3400, 1725, 1630, 1509, 1474 cm-1.

EXAMPLE39:

Preparation of 1-cYclopropyl-6,8-difluoro-1,4-dihydro-4- oxo-7-(3-methyl-3-N,N-dimethylamino-1-azetidinyl)-3- quinolinecarboxylic acid.

a solution of 1.5 g (5.3 mmoles) of 1-cyclopropyl- 6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.5 g (8 mmoles) of 3-methyl-3-N,N-dimethylamino- azetidine hydrochloride and 3.3 g (33 mmoles) of tri- ethylamine in 15 ml of pyridine is heated under reflux for 3 hours. It is cooled, evaporated under vacuum, water is added, the mixture is made alkaline with 10% sodium hydroxide solution, filtered then acidified with acetic acid. A precipitate is obtained which is made slightly alkaline with ammonia. The product is heated to evaporate excess ammonia, yielding 1.85 g (92%) of 1 -cyclopropyl-6 , 8-dif luoro-1 , 4-dihydro-4-oxo-7-1( 3-methyl- 3-N,N-dimethylamino-1-azetidinyl)-3-quinolinecarboxylic acid melting at 280-4oC.

Spectroscopic data:

1H NMR, 6, [DMSO-6d, TFA]: 1.19 (d, 4H, J = 6.5Hz) ; 1.71 (s, 3H); 2.82 (s, 6H); 4.03 (m, 1H); 4.52 (m, 4H); 7.76 (dd, 1H, J = 12.8Hz, J' = 1.8Hz); 8.62 (s, 1H) IR(KBr): 1723, 1626, 1552, 1492, 1451 cm"1.

EXAMPLE 40:

Preparation of 1-cyclopropyl-6-fluoro-7-(3-amino-3- methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid.

A mixture of 0.8 g (3.0 mmoles) of 1-cyclopropyl- 6,7-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 1.7 g (7.8 mmoles) of 3-methyl-3-trifluoroacet- amidomethylazetidine hydrochloride and 1.4 g of triethyl- /MJ amine is heated under reflux in 15 ml of pyridine. The mixture is evaporated, water is added and the product filtered yielding 0.55 g (42%) of 1-cyclopropyl-6-fluoro- 7-(3-trifluoroacetamido-3-methyl-1-azetidinyl)-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid, which is subsequently hydrolysed by heating it under reflux with a solution of 3 ml of 10% sodium hydroxide in 10 ml of water for 2 hours. The volume is reduced by half, a few drops of acetic acid are added, and the product is filtered and washed with water. This yields 0.36 g (84%) of 1-cyclopropyl-6-fluoro-V-(3-amino-3-methyl-1-azeti- dinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting at 293-5°C.

Spectroscopic data:

1H NMR, 6, [DMS0-6d]; 1.2.2 (m, 4H) ; 1.45 (s, 3H) \ 3.69 (m, 1H); 4.0 (m, 4H); 6.85 (d, 1H, J = 7.8 Hz) 7.75 (d, 1H, J = 12 9 Hz); 8.55 (s, 1H).

IR(KBr): 3340, 1722, 1630, 1528, 1471 cm-1.

EXAMPLE 41 :

Preparation of 1 -(2-fluoroethyl)-6,8-difluoro-7-(3-amino- 3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid A mixture of 0.8 g (2.8 mraoles) of 1-(2-fluoro¬ ethyl )-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3- carboxylic acid, 1.3 g (6 mmoles) of 3-methyl.-3-tri- fluoroacetaraidoazetidine hydrochloride and 1 g (10 mmoles) of triethylamine is heated under reflux in 15 ml of pyridine for 2 hours.

The mixture is evaporated under vacuum and extracted with methylene chloride. Filtration and evaporation yield 1.2 g (95%) of 1-(2-fluoroethyl)-6,8-difluoro-1,4-dihydro- 7-(3-methyl-3-trif luoroacetamido-1 -azetidinyl) -4-oxo--3- quinolinecarboxylic acid melting at 205-150C. This product is subsequently hydrolysed by heating a mixture of 1.0 g (2.0 mmoles) of this acid with 3 ml of 10% sodium hydroxide and 20 ml of water under reflux for M 3 hours. The mixture is cooled and acidified with acetic acid and filtered. The product is washed with water " yielding 380 mg (48%) of 1-(2-fluoroethyl)-6,8-difluoro- 7-(3-methyl-3-amino-1-azetidinyl)-1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid, melting at 281-40C.

Spectroscopic data:

1H NMR, 6, [DMSO-6d]: 1.41 (s, 3H); 4.17 (m, 4H); 4.62 (m, 2H); 5.04 (m, 2H); 7.66 (d, 1H, J = 12.3Hz); 8.73 (s, 1H).

IR(KBr): 3410, 1725, 1629, 1614, 1474 cm-1.

EXAMPLE 42:

Preparation of 1-(4-fluorophenyl)-6-fluoro-7-(3-amino-3- methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid -5 A mixture of 0.8 g (2.5 mmoles) of 1-(4-fluoro¬ phenyl >-6 ,7-difluoro-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid, 1.3 g (6 mmoles) of 3-methyl-3-tri- fluoroacetamidoazetidine hydrochloride and 1 g of tri- ethylamine is heated under reflux in 20 ml of pyridine 2Q for 3 hours. The mixture is evaporated, and extracted with methylene chloride. Filtration and evaporation yield 1.1 g of 1-(4-fluorophenyl)-6-fluoro-7-(3-tri- fluoroacetamido-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo- 3-quinolinecarboxylic acid, melting at 146-1510C, which is subsequently hydrolysed in a manner similar to that in example 41, to obtain 0.5 g (56%) of 1-(4-fluorophenyl) 6-fluoro-7-(3-amino-3-methyl-1-azetidinyl)-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid, melting at 270-6oC.

Spectroscopic data:

1H NMR, 6, [DMSO-ed]; 1.35 (s, 3H); 2.9 (m, 2H); 3.76 (m, 4H); 5.70 (d, 1H, J = 7.9Hz); 7.2 - 7.9 (m, 5H); 8.48 (s, 1H).

IR(KBr): 3420, 1720, 1630, 1505 cm"1.

Mtf '- S" S3 EXAMPLE 43:

Preparation of 1-cyclopropyl-6,8-difluoro-7-(3-dimethyl- amino-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid A mixture of 1.5 g (5.3 mmoles) of 1-cyclopropyl- 6,7,8 - trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.4 g (8 mmoles) of 3-dimethylaminoazetidine dihydrochloride and 6.6 g of triethylamine is heated under reflux in 15 ml of pyridine for 3 hours. It is \q evaporated, water is added and the resulting mixture is made alkaline with IN sodium hydroxide, heated, filtered while hot, acidified with acetic acid, and filtered.

After washing with water, 1.7 g (88%) of 1-cyclopropyl- 6,8-difluoro-7-(3-dimethylamino-1-azetidinyl)-1,4-di- j_5 hydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 256-60oC.

Spectroscopic data:

1H NMR, 6, [DMS0-6d]; 1.18 (d, 4H, J = 5.7Hz); 2.16 (s, 6H); 3.28 (m, 1H); 4.24 (m, 5H); 7.68 (d, 1H, J = 12.9Hz); 8.57 (s, 1H).

IR(KBr): 1718, 1629, 1528, 1459, 1439 cm-1.

EXAMPLE 44:

Preparation of 1-cyclopropyl-6-fluoro-7-(3-dimethylamino- 1-azetidinyl)-1,4-dihydro-4-oxo-3-quinoiinecarboxylic acid.

A mixture of 0.25 g (1.32 mmoles) of 1-cyclopropyl- 6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.34 g (2 mmoles) of 3-dimethylaminoazetidine dihydrochloride and 3.3 g (33 mmoles) of triethylamine is heated under reflux in 10 ml of pyridine for 2 hours.

The mixture is evaporated under vacuum, water is added and the resulting mixture made alkaline with IN sodium hydroxide, heated, filtered while hot, acidified with ; acetic acid and filtered again. After washing with "#.35 water, 0.4 g (88%) of 1-cyclopi'opyl-6-fluoro-7-(3-di- methylamino-1 -azetidinyl )-1,4--dihydro-4-oxo-3~quinoline- carboxylie acid are obtaiaed, melting at 255-61"C.

i;/ <f$> J 'I c Jf- Spectroscopic data:

1H NMR, 6, [DMS0-6a]; 1.21 (m, 4H); 2.18 (s, 6H); 3.34 (m, 1H); 3.70 (m, 1H); 4.14 (m, 4H); 6.88 (d, 1H, J = 7.5Hz); 7.76 (d, 1H, J = 12,9Hz); 8.56 (s, 1H).

EXAMPLE 45:

Preparation of 1 -cyclopropyl-6 ,8-dif luoro-7-(3-ainino-3- methyl-l-azetidinyl)-1,4-dihydro-4-oxo-3-quinoline- carboxylic acid hydrochloride 0.5 g (1.4 mraoles) of 1-cyclopropyl-6,8-difluoro-7- (3-ainino-3-methyl-1-azetidinyl )-1 ,4-dihydro-4-oxo-3- quinolinecarboxylic acid are suspended in 10 ml of methanol, and to this is added an excess of a methanolic solution of gaseous hydrogen chloride. The mixture is agitated for 30 minutes, and ethyl ether and petroleum ether are added. After filtering, washing with ethyl ether and drying by heating, 0.45 g (82%) of 1-cyclo¬ propyl-6 ,8-difluoro-7-(3-amino-3-methyl-1-azetidinyl)- 1.4-dihydro-4-oxo-3-quinolinecarboxylic acid hydro¬ chloride are obtained, melting at 249-250oC.

Spectroscopic data:

1H NMR, 6, [DMSO-Sd]; 1.20 (m, 4H); 1.65 (m, 3H); 3.29 (broadened, H20) 4.05 (m, 1H); 4.46 (m, 4H); 7.76 (d, 1H, J = 12.8 Hz); 8.61 (s, 1H) 8.72 (broadened, 2H).

IR(KBr): 3431, 1719, 1629, 1531, 1462, 1333 cm"1.

EXAMPLE 46:

Preparation of the sodium salt of 1-cyclopropyl-6,8- dif luoro-7- ( 3-amino-3-methyl-1-azetidinyl)-1,4-dihydro- 4-oxo-3-quinolinecarboxylic acid.

95 mg (0.27 mmoles) of 1-cyclopropyl-6,8-difluoro- 7-(3-amino-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid are added to a solution of 2 2.8 mg (0.27 mmoles) of sodium bicarbonate in 5 ml of water, and vigorously agitated; a few drops of ethanol are added and the mixture is heated to 800C for 18 hours then M& .3?.

evaporated. Ethanol is added and the mixture filtered.

After washing with ethanol, 62 mg (63%) of the sodium salt of 1-cyclopropyl-6,8-difluoro-7-(3-amino-3-methyl- 1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at >300 C.

Spectroscopic data:

1H NMR, 6,; 0.89 (m, 2H); 0.98 (m, 2H); 1.29 <s, 3H); 3.72 (m, 1H); 3.94 (m, 2H); 4.04 (m, 2H); 7.44 (dd, 1H, J = 12.93 Hz, J' = 1.45 Hz); 8.23 (s, 1H).

IR(KBr): 3400, 1620, 1462, 1400 cm-1.

EXAMPLE 47; Preparation of 1-cyclopropyl-6,8-difluoro-7-3-methylamino- 1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A mixture of 0.85 g (3.0 mmoles) of 1-cyclopropyl 6,7,8-trifluoro-4-oxo-1,4-dihydrO"3-quinolinecarboxylic acid 1.3 g (6 mmoles) of 3-methyl-3-trifluoroacetamido- azetidine hydrochloride and 0.8 g (8 mmoles) of triethyl- amine in 15 ml of pyridine is refluxed for 2 hours.

The mixture is evaporated under vacuum and acidified with aqueous acetic acid to obtain (1.1 g of 1-cylco- propyl-6,8-difluoro-4-oxo-1,4-dihydro-7-(3-methyl-3-tri- fluoroacetamido-1-azetidinyl)-4-oxo~3-quinolinecarboxylic and which is subsequently hydrolysed by heating a mixture * of 1.0 g (2.0 mmoles) of this acid vith 3 ml of sodium hydroxyle and 20 ml of water under reflux for 3 hours.

The solution is cooled and acidified with acetic acid, filtrated, washed with water to obtain 0.6 g (48%) of 1-cyclopropyl-6,8-difluoro-7-(3-methylamino-1-azetidinyl)- 1 ,4-dihydro-4-oxo-3-quin,olinecarboxylic and melting at 270-2oC.

Spectroscopic data:

1H RMN, 6, [DMSO-6d3: 1,17 (d, 4H, J - 6,5Hz); 2,31 (s, 3H); 3,66 (m, 1H); 4,12 (m, 3H); 4,52 (m, 2H); 7,66 (dd, 1H, J = 12,3Hz, J" = 1,7Hz); 8,58 (s, 1H).

IR(KBr): 3468, 3387, 2912, 1718, 1629, 1617, 1472 EXAMPLE 48:

-1 cm Preparation of 1-cyclopropyl-6-fluoro-7-(3-methylamino- 1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A mixture of 0.5 g (2.0 mmoles) of 1-cyclopropyl- 6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylie acid, 1.2 g (6 mmoles) of 3-methyl-3-trifluoroacetamidoazetidine hydrochloride and 0.8 g of triethylamine is heated under refluxed in 20 ml of pyridine for 3 hours. The mixture is evaporated and water is added to obtain 0.7 g of 1- cyclopropyl-6-fluoro-7-(3-methyl-3-trifludromethylacetamido- 1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid which is subsequently hydrolysed with the same method as was described in the example 47 to obtain 250 mg of 1-cyclo- propyl-6-fluoro-7-(3-methylamino-1-azetidinyl)-1 ,4-dihydro- 4-oxo-3-quinolinecarboxylic acid of melting point 245-90C.

Spectroscopic data; 1H RMN, 6, [DMSO-6d]; 1,25 (m, 4H); 2,32 (s, 3H); 3,72 (m, 1H); 3,90 (iti, 3H); 4,36 (m, 2H); 6,86 (d, 1H, J = 7,9Hz); 7,77 (d, 1H, J = 12,9Hz); 8,56 (s, 1H) IR{KBr): 3468, 3387, 2912, 1718, 1629, 1515, 1480 -1 cm fWS *z EXAMPLE 49; Preparation of 1-cyclopropyl-6-fluoro-7-(3-amino-1- azetidin-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

A mixture of 1.2 g (4,53 mmoles) of 1-cyclopropyl 6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.3 g (9.05 mmoles) of 3-aminoazetidine hydrochloride and 0.5 ml of triethylamine heated in 15 ml of pyridine for 2 hours. The mixture is filtrated and washed with water and ethanol to obtain 0.83 g (58%) of 1-cyclopropyl-6- fluoro-7-(3-amino-1-azetidinyl)-1,4-dihydro-4-oxo-3-quino- linecarboxylic acid melting at 246-70C.

1H RMN, 6, [DMSO-6d]; 1,28 (m, 4H); 3,87 (m, 4H); 4,40 (m, 2H); 6,60 (elargie, 2H); 6,86 (d, 1H, J = 8Hz); 7,77 (d, 1H, J = 12Hz); 8,56 (s, 1H).

The pharmacological antimicrobial activity of these compounds has been studied according to the information given hereinafter.

Pharmacological antimicrobial activity (G.L. Daquet and Y.A. Chabbect, Techniques en Bacteriologie, Vol. 3, Flammarion Medecine-Sciences, Paris 1972 and W. B. Hugo and A. D. Rusell, Pharmaceutical Microbiology, Blaekwell Scientific Publications, London (1977).

- Culture medium and solvent:

Antibiotic Agar N0 1 (Oxoid CM 327) Tryptone-soya Broth (Oxoid CM 129) Dextrose Agar (BBL-11165) NaOH 0.1 N - Microorganisms:

"Bacillus subtilis" ATCC 6633 "Citrobactgr fgeundii" ATCC 11606 "Enterobacter aerogenes" ATCC 15038 "Enterobacter cloacae" ATCC 23355 C >- ,T O 1$ "Bacillus cereus" ATCC 1178 "Escherichia coli" ATCC 1079? "Escherichia coli" ATCC 23559 "Klebsiella pneumoniae" ATCC 10031 "Proteus Vulgaris " ATCC 8 427 "Morq. morqanii" ATC 8019 "Pseudomonas aeruginosa" ATCC 9721 "Pseudomonas aeruginosa" ATCC 10145 "Salmonella tiphymurium" ATCC 14 028 "Salmonella tiphymurium" ATCC 6539 "Serratia marcescens" ATCC 13880 "Shigella flexnerii" ATCC 12022 "Staphylococcus epidermis ATCC 155-1 "Staphylococcus aureus" ATCC 25178 "Streptococcus faecalis"ATCC 10541 - Preparation of the inocula Each of the microorganisms is seeded in striae in tubes containing Antibiotic Aga? No 1, and left to incubate at 370C for 20 hours. TJien a culturing loop is taken aad the microorganisms ate seeded into a Tryptone- soya broth and incubated at 370C tot 2.0 hours. The resulting culture is diluted with linger physiological dairdised 107-109 cfu/ml suspension of each organism.

- Preparation of the medium containing the dsrivativeS-Ql general formula T A solution of 1000 /ig/ml of each product in 0.1 N NaOH is diluted in Dextrose Agar (previously melted and maintained at 50oC) in successive stages so as to obtain the following concentrations: 64 - 32 - 16 - 8 -- 4 - 2 - 1 - 0.5 - 0.25 - 0.125 /ig of product per ml of medium.

Ait #5- Subsequently, each concentration of each product is dispensed into 10 cm diameter Petri dishes, in quantities of 10 ml of medium per dish, there being as many dishes as there are microorganisms for testing.

Once the medium has cooled, the dishes are seeded with the inocula in quantities of 0.4 ml of inoculum per dish. They are spread with a Driglasky loop and the supernatant is collected. The seeded dishes are in¬ cubated at 370C for 20 hours.

Resulta The results obtained are described in the following tables. The activities of the compounds "in vitro" are compared with that of pipemidic acid.

*M£ " 'A n °, 1 4tf - MICROORGANISMSBacillus subtilisATCC 6633 Pipemidic 2acid8 <0.015 EXAMPLES5 68 0.06 70.06 80.03 Bacillus cereusATCC 11778 16 0.3 64 0.25 0.50 0.25 Strep, faecalisATCC 10541 >64 0.5 64 0.50 4 1 Staph. aureusATCC 25178 64 0.06 64 0.25 1 0.25 Staph, epidermidisATCC 155-1 64 0.12 64 0.50 0.50 0.25 Ps. aeruginosaATCC 9721 32 1.0 64 2 4 1 Ps. aeruginosaATCC 10145 32 2.0 64 4 8 4 Citr. freundiiATCC 11606 4 0.06 64 0.5 1 0.5 Morg. morganiiATCC 8019 8 0.6 64 0.25 1 0.5 Proteus vulgarisATCC 8427 16 0.6 64 0.25 1 0.5 ,25 Kleb. pneumoniaeATCC 10031 2 0.015 64 0.06 0.50 0.5 Sal. typhimurium ATCC 14028 8 0.12 64 0.5 1 0.5 Sal. typhiATCC 6539 4 Escherichia coliATCC 10799 16 it Escherichia coliATCC 2 3559 2 ** 9' * 35 Ent. aerogenesATCC 15038 32 Ent. cloaca>eATCC 23355 8 Serr. marcescensATCC 13880 16 Shigella flexnerii ATCC 12022 4 0.06 64 0.25 1 0.5 0.12 64 0.50 1 0.5 0.06 64 0.25 1 0.5 0.12 64 0.50 1 0.5 0.06 64 0.25 1 0.5 0.25 64 1 1 0.5 0.06 64 0.25 0.50 0 z M& '40 -1.

MICROORGANISMS 90.06 100.06 EXAMPLES11 120.03 0.12 130.5 Bacillus subtilisATCC 6633 14<0.03 Bacillus cereusATCC 11778 1 0.12 0.12 0.5 0.5 0.25 Strep. FaecalisATCC 10541 1 0.12 0.5 2 2 1 Staph, aureusATCC 25178 0 .25 0.12 0.06 0.5 1 0.25 Staph, epidermidisATCC 155-1 1 0.12 0.06 0.5 0.5 0.12 PS. aeruginosaATCC 9721 1 1 4 2 2 1 Ps. aeruginosaATCC 10145 4 2 8 4 8 2 Citr. freundiiATCC 11606 1 0.25 0.5 0.5 1 0.25 Morg. morganiiATCC 8019 1 0.25 0.5 0.5 1 0.25 Proteus vulgarisATCC 8427 1 1 0.25 1 1 0.25 Kleb. pneumoniaeATCC 100 31 1 0.25 <0.03 0.5 1 0.25 Sal. typhimuriumATCC 1402 8 1 0.25 4 1 1 0.5 Sal. typhiATCC 65 39 1 0.25 0.5 0.5 1 0.25 Escherichia coliATCC 10 799 1 0.5 0.25 0.5 1 0.5 Escherichia coliATCC 235.59 0.5 0.25 0.25 0.5 1 0.25 Ent. aerogenesATCC 150 38 1 0.25 0.5 0.5 1 0.25 Ent. cloacaeATCC 23355 1 0.25 0.5 0.5 1 0.25 Serr. marcescensATCC 13880 1 0.5 2 1 2 0.5 Shigella flexaeriiATCC 12022 1 0.25 0.25 0.12 1 0.25 < nA& '>*. r s L f2 ., MICROORGANISMS EXAMPLES Bacillus subtilisATCC 6633 0.06 0.03 <0.03 0.12 0.12 40.03 Bacillus cereusATCC 11778 0.25 0.12 0.12 0.12 0.50 0.12 Strep, faecalisATCC 10541 1 0.12 1.0 2.0 2.0 0.25 Staph, aureusATCC 25178 0.25 0.12 0.12 0.12 0.5 0.12 Staph, epidermidisATCC 155-1 0.25 0.12 0.12 0.12 0.5 0.12 Ps. aeruginosaATCC 9721 2 0.5 1.0 2.0 2.0 0.50 Ps. aeruginosaATCC 10145 2 0.5 2.0 2.0 2.0 0.50 Citr. freundiiATCC 11606 0.12 0.06 0.12 0.12 0.125 <0.03 Morg. morganiiATCC 8019 0.12 0.06 0.25 0.25 0.125 <0.03 Proteus vulgarisATCC 8427 0.25 0.25 0.12 1.0 1.0 0.06 Kleb. pneumoniaeATCC 10031 0.25 0.06 0.12 0.03 <0.03 <0.0 3 Sal. typhimuriumATCC 14028 0.25 0.06 0.12 0.5 1.0 0.06 Sal. typhiATCC 65 39 0.25 <:0.0 3 0.12 0.5 0.5 «0.03 Escherichia coliATCC 10799 0.25 0.06 0.25 0.5 0.5 0.06 Escherichia coliATCC 2 3559 0.12 0.03 0 ,12 0.25 0.12 <0.0 3 Ent. aerogenesATCC 15038 0.25 0.06 0.12 0.25 0.25 <0.03 Ent. cloacaeATCC 23355 0.25 <0.03 0.12 0.25 0.12 <O.03 Serr. marcescensATCC 13880 0.50 0.12 0.25 0.50 0.25 0.12 Shigella flexneriiATCC 12022 0.12 <0.0 3 0.06 0.12 0.12 <0.03 MS - 4$ MICROORGANISMS EXAMPLES Bacillus subtilisATCC 6633 0.25 0.12 «0.03 2 0.06 0.12 Bscillus cereusATCC 11778 0.50 0.25 0.06 4 0.12 0.12 Strep, faecalisATCC 10541 2.0 1.0 2 4 0.5 1.0 Staph, aureusATCC 25178 1.6 0.25 0.03 4 0.25 0.25 Staph, epidermidisATCC 155-1 0.5 0.25 0.03 4 0.25 0.5 Ps. aeruginosaATCC 9721 4.0 1.0 2 >16 0.5 4.0 Ps. aeruginosaATCC 10145 4.0 2.0 2 >16 1.0 4.0 Citr. freundiiATCC 116 06 1.0 0,25 1 16 0.12 0.25 Moeg. morgan!iATCC 8019 1.0 0.25 0.5 8 0.12 0.5 Proteus vulgarisATCC 8427 1.0 0.25 0.12 8 .0.12 0.25 Kleb. pneumoniaeATCC 100 31 0.25 0.25 <0.03 8 0.25 0.5 Sal. typhimuriumATCC 14028 1.0 0.5 1 16 0.25 0.5 Sal. typhiATCC 6539 1.0 0.5 1 16 0.25 0.5 Escherichia coliATCC 10799 1.0 0.5 1 16 0.25 0.5 Escherichia coliATCC 23559 0,5 0.25 0.5 8 0.12 0.12 Ent. aerogenesATCC 15038 1.0 0.25 1 16 0.25 0.5 Ent. cloacaeATCC 2 3355 0.5 0.25 1 4 0.25 0.25 Serr. marcescensATCC 13880 2.0 0.5 1 16 0.5 1.0 Shigella flexnerii ATCC 12022 0.5 0.25 0.5 4 0.06 0,25 MICROORGANISMS Bacillus subtilis ATCC 66 33 Bacillus cereus ATCC 11778 Strep, faecalis ATCC 10541 Staph, aureus ATCC 25178 Staph, epidermidis ATCC 155-1 Ps. aeruginosa ATCC 9721 Ps aeruginosa ATCC 10145 Citr. freundii ATCC 11606 Morg morganii ATCC 8019 Proteus vulgaris ATCC 8427 Kleb. pneumoniae ATCC 10031 7 5 Sal. typhimurium ATCC 1402 8 Sal. thyphi ATCC 65 39 Escherichia coli ATCC 10799 Escherichia coli ATCC 2 3559 Ent. ae rohene s ATCC 15038 Eftt. cloacae ATCC 2 3355 Serr. marcescens ATCC 13880 Shigella flexherii ATCC 12022 - 4+*& - EXAMPLES 0.25 0.25 0.25 0.12 0.06 0.06 0.5 1 1 0.25 0.25 0.12 0.25 0.25 2 0.12 1 0,5 0.25 0.5 1 0.25 0.25 0.12 0.5 0.5 1 0.25 0.25 0.12 4.0 2 4 2 2 1.0 2.0 2 4 2 2 0.5 0.25 0.25 0.5 0.12 0.12 0.05 0.5 0.25 0.5 0.25 0,25 0.06 0.5 1 1 0.25 0.5 0.06 0.5 0.5 0.5 0.12 0.25 0.12 0.5 1 0.5 0.25 0.25 0,12 0.25 0.5 0.5 0.25 0,12 0.12 0.5 1 1 0.2 5 0.25 0.12 0.25 0.5 0.5 0.12 0.12 0.06 0.5 0.5 1 0.25 0.25 0.12 0.25 0,5 1 0.2S 0.12 0.12 1 1 1 1 1 0.25 0.25 0.25 0.5 0.12 0.06 0.06 HC vt O* MICROORGANISMS Bacillus subtilis ATCC 66 33 EXAMPLES 0.25 0.06 «0.03 <0.03 <0.03 <0.03 Bacillus cereus ATCC 11778 Strep, faecalis ATCC 10541 0.2 0.25 0.12 0.12 0.12 0.12 0.12 Staph, aureus ATCC 25178 Staph, epidermidis ATCC 155-1 0.12 0.25 0.12 0.12 0.12 0.12 0.25 0.12 0.12 0.12 Ps. aeruginosa ATCC 9 721 Ps. aeruginosa ATCC 10145 0.5 0.5 0.5 0.5 Citr. freundii ATCC 11606 Morg. inorganii ATCC 8019 0.12 0.06 0.12 0.06 0.25 0.12 0.12 0.06 0.06 Proteus vulgaris ATCC 8427 Kleb. pneumoniae ATCC 10031 0.25 0.25 0.12 0.25 0.25 0.12 0.06 <0.03 0.06 0,06 Sal. typhimurium ATCC 14028 Sal. typhi ATCC 65 39 0.12 0.12 0.12 0.D6 0.06 0.12 0,06 0.06 <0.Q3 <0.03 Escherichia coli ATCC 10799 Escherichia coli ATCC 2 3559 0.25 0.12 0.12 0.06 0.06 0.12 0..06 0.06 40.03 <0.03 Ent. aerogenes ATCC 15038 Ent. cloacae ATCC 2 3355 0.12 0.2 0.12 0.06 0.06 0.12 0.06 0.06 0.03 0.03 Serr. marcescens ATCC 13880 0.5 0.25 0.25 0.12 0.12 Shigella flexnerii ATCC 12022 0.06 0.06 0.06 <0.03 0.03 -4" - M® MICROORGANISM EXAMPLES 47 4B 49 Bacillus aubtilisATCC 6633 0.06 « 0.05 < O.Oj Bacillus cereusATCC 11778 0.25 0.12 0.12 Strep, faecalisATCC 10541 1 .0 1 .0 0.5 Staph, aureusATCC 25178 0.25 0.25 0.25 Staph, epidermzdiaATCC 155-1 0.12 0. 12 0.12 Pa. aeruginosaATCC 9721 1.0 0.5 O.j Ps. aeruginosaATCC 10145 0.5 0.5 0.25 Citr. freundiiATCC 11606 .0.03 « 0.03 N< 0.03 Morg. raorganiiATCC 8019 0.06 ,< 0.03 0.03 Proteus vulgarisATCC 8427 0.5 0.25 0,12 Kleb. pneumoniaeATCC 10031 0.03 .s< 0.0 3 0.03 Sal. typhinmriuraATCC 14028 0.05 0.06 « 0.03 Sal. typhiATCC 6539 4: 0.03 0.03 $ 0.03 Escherichia coliATCC 10799 0.06 0.06 0.06 Escherichia coliATCC 23559 $ 0.03 0.03 0.03 Ent. aerogenesATCC 15038 0.06 0.03 0.03 Ent. cloacaeATCC 23355 <: 0.03 0.03 '4: 0.0,J Serr. marcescensATCC 13880 0.12 0.12 0*12 Shigella flexneriiATCC 12022 < 0.03 0.03- $. 0,03 - *g - Taking account of their good pharmacological prop¬ erties, derivatives of general formula I are therefore likely to be used in human medicine and/or veterinary medicine to treat systemic or localised acute, chronic and recurring infections, caused by Gram-positive and Gram-negative microorganisms that are sensitive to the products which are the subject of the present invention, in the gastrointestinal or genito-urinary tracts, the respiratory system, the skin and soft tissues, and also neurological and odonto-stomatological infections.

In human therapy, the proposed dose of the deriv¬ atives of the present invention is approximately between 400 and 1200 mg/day for an adult, administered for example as tablets or capsules. This dosage may however be varied in relation to the gravity of the illness.

Two particular pharmaceutical forms of the deriv¬ atives which are the subject of the present invention will be shown hereinafter, by way of example.

Example of a formula ngr tablet Compound of example 2 0.400 g Carboxymethylstarch 0.018 g Polyvinylpyrrolidone K29-32 0.030 g Microcrystalline cellulose 0.146 g Colloidal silica 0.003 g Magnesium stearate 0.003 g 0.600 g Example of a formula oar (yalatin capsule Compound of example 16 0.400 g Microcrystalline cellulose 0.0356 g Colloidal silica 0.0022 g Magnesium stearate 0.0022 g 0.440 g 1 " O y rA/T The claims defining the invention are as follows:

1. Heterocyclic compounds characterised in that they correspond to formula I ,6 N-ivxX--- COOR (I) where R1 represents a lower alkenyl or alkyl radical, a haloalkyl radical, a cycloalkyl radical, an aminoalkyl radical, an aryl radical or a substituted aryl radical, R2 represents a hydrogen atom or a halogen atom, or R1 and R2 may together form an X group; R3 represents a hydrogen atom or a lower alkyl radical; R4 and R5 and R6 independently represent a hydrogen atom, a lower alkyl radical, a hydroxyl radical, an amino radical, an aminoalkyl radical, an alkylamino radical, a dialkylamino radical, an alkylaminoalkyi radical, an alkoxy radical, a mesyioxy radical, a hydroxyalkyl radical, a cyano radical, an acylaminoalkyl radical, a carboxylic radical, a carboxamido radical, a carboxyalkyl radical, a halogen atom, an alkylcarboxy radical, an acetamido radical or an acetamidoalkyl radical, in these last two radicals the terminal free alkyl group may be fluorinated and the nitrogen atom in the acetamidoalkyl radical may carry an alkyl substituent; X represents -CH2CH2-CHR7- , -0-CH2-CHR7- or where R7 represents a hydrogen atom or a lower alkyl radical, R8 represents a hydrogen atom or a halogen atom, and Y represents CH or N, with the exception however of compounds of formula (I) in which: R1 and R2 together form a link represented by the group -O-CJ-CJCHj)- and R3, R4 and R6 represent a hydrogen atom, and R5 represents a hydroxyl radical (OH) or a hydroxymethyi radical (CHjOH), and of the compound of formula (I) in which:

R1 represents an ethyl radical R2 represents a fluorine atom R3, R4 and R6 represent hydrogen atoms, and R5 represents an ethylaminOmethyl radical (CCBjNHCEy, with the proviso that *-Kn O