CA2094082A1

CA2094082A1 - Substituted azetidinyle pyridone derivatives, antimicrobial agents

Info

Publication number: CA2094082A1
Application number: CA002094082A
Authority: CA
Inventors: Jordi Corbera-Arjona; Jordi Frigola-Constansa; Juan Pares-Corominas
Original assignee: Laboratorios del Dr Esteve SA
Current assignee: Esteve Pharmaceuticals SA
Priority date: 1992-04-16
Filing date: 1993-04-15
Publication date: 1993-10-17
Also published as: ES2103218A1; KR930021633A; FR2690161A1; JPH0625224A; FR2690161B1; ES2103218B1; ZA932678B; RU2088581C1; PT101252A

Abstract

BREVET D'INVENTION "Dérivés de pyridone azétidinyl substitués avec activité antimicrobienne" Déposant: LABORATORIOS DEL DR ESTEVE S.A. La présente invention concerne de nouveaux dérivés azétidiniques de formule générale 1 : I leur procédé de préparation, leur emploi à titre de médicament et les compositions pharmaceutiques les comprenant.PATENT OF INVENTION "Substituted pyridone azetidinyl derivatives with antimicrobial activity" Applicant: LABORATORIOS DEL DR ESTEVE SA The present invention relates to new azetidine derivatives of general formula 1: I their preparation process, their use as medicaments and pharmaceutical compositions understanding them.

Description

La pr~ente inven~ion decrit de nouveaux d~rivé~
az~tidiniques de~ acide.~ pyridonecarboxyliqueQ telq q~e 1,4-dihydro-4-oxoquinoléine-3-carboxylique, 1,8-naphtyridine-4-oxo-3-carboxylique et 2,3-dihydro-7-oxo-7H-pyrido~1,2,3-del-1,4-benzoxazine-6-carboxylique, leo sels th~rapeutiquement acceptable~ de ces composés, leur procéd~ de pr~paration, ainsi que leur application comme médicaments.
Le~ composés objets de la présente invention peuvent ~tre utili~és dans l'industrie pharmaceutique comme interm~diaire~ et pour la préparation de médicaments.
I0 La pr~sente invention est une suite du brevet européen EP 32429fl, où l'on décrit des dérivés az~tidinique~ de quinolone~
et de pyritobenzoxazines. C'est également une suite du brevet europ6en EP 388298 où l'on décrit différents dérivés az~tidiniques de naphtyridines, de quinolones et de pyridobenzoxazine~, tou~ étant des compos~ po~sédant une trè~
bonne activite antimicrobienne.
Nous avons maintenant découvert que les nouveaux derivés azétidinique~ de~ acides 1,4-dihydro-4-oxoquinoléine-3-carboxylique, 1,8-naphtyridine-4-oYo-3-carboxylique et 2,3-dihydro-7-oxo-7H-pyridoll,2,3-del-1,4-benzoxazine-6-carboxylique, qui font l'objet de la présente invention, presentent une tr~s bonne activité anti-microbienne.
~ es composé- ob~ets de la présente invention répondent à la formule gén~rale I
R, O O The present inven ~ ion describes new rivals az ~ tidiniques of ~ acid. ~ pyridonecarboxylicQ such as q ~ e 1,4-dihydro-4-oxoquinoline-3-carboxylic, 1,8-naphthyridin-4-oxo-3-carboxylic and 2,3-dihydro-7-oxo-7H-pyrido ~ 1,2,3-del-1,4-benzoxazine-6-carboxylic, leo salts th ~ rapeutically acceptable ~ of these compounds, their process of preparation, as well that their application as drugs.
The ~ compounds objects of the present invention can ~ be used in the pharmaceutical industry as an intermediary and for the preparation of medicines.
I0 The present invention is a continuation of the European patent EP 32429fl, which describes az ~ tidinic derivatives of quinolone ~
and pyritobenzoxazines. It is also a continuation of the patent European EP 388298 in which various derivatives are described az ~ tidiniques of naphthyridines, quinolones and pyridobenzoxazine ~, tou ~ being compos ~ po ~ sedating a very ~
good antimicrobial activity.
We have now discovered that the new derivatives azetidinic ~ of ~ 1,4-dihydro-4-oxoquinoline-3- acids carboxylic, 1,8-naphthyridine-4-oYo-3-carboxylic and 2,3-dihydro-7-oxo-7H-pyridoll, 2,3-del-1,4-benzoxazine-6-carboxylic, which are the subject of the present invention, present a tr ~ s good anti-microbial activity.
~ es compound- ob ~ ets of the present invention meet the general formula I
R, OO

2 5 ~R~

dans laquelle A repr~4ente un atome un atome d'azote ou bien un atome de carbone avec un atome d'hydrogène attache ~C-H), ou bien un atome de carbone avec un halogène attaché (C-X), tans ce cas X

2 ~ 8 2 repr~sente un atome de chlore, de fluor ou de brome ou bien un atome de carbone avec un radical hydroxy ~C-OH).
R1 repré~ente un radical alkyle ou cycloalkyle inférieur, un radical halogénoalkyle inf~rieur, un radical aryle ou un radical aryle substitué notamment par un ou plusieurs atome~s) de fluor.
R2 et R3 repr~entent un atome d'hydrogène, un radical alkyle inférieur, un radical hydroxyle, un radical amino, un radical aminoalkyle, un radical alkylamino, un radical dialkylamino, un radical hétérocyclique azoté de préférence aromatigue pouvant être un cycle de troi~ à ~ix maillons, un radical alkylaminoalkyle, un radical alkylcarboxamido, et dans ce dernier cas, le radical alkyle pouvant 8tre sub~titué par un ou plusieur~ halog~nes, un radical arylsulfonyloxy, un radical alkylsulfonyloxy, un radical carboxamido, pouvant être Qubstitué
ou non 3ur l'azote, ou un radical cyano.
R, et R,, égaux ou différent~, repréQentent un atome d'hydrogène ou un radical alkyle inférieur.
R~ représente un atome d'hydrog~ne, un radical nitro, un radical amino ou amino substitué.
R7 représente un radical hydroxy ou un radical alkyloxy inférieur de C ~ C~.
A et R~ peuvent former ensemble une liaison repré~entée par un groupe C-CH2-CH2-CHR~- ou C-O-CH2-CHR~- dans lesquel Q Ra repré~ente un ato~e d'hydrogène ou un radical alkyle inférieur, et dans cè dernier cas, on a un centre chiral avec une configuration ~R~ ou ~S~.
Le~ substituants azétidinigues peuvent avoir, selon le nombre, la nature et la position relative des substituant~, ju8qu 'a deux centres chiraux, chacun d'eux avec une configuration "R~ ou ~S~, ainsi que leurs sels d'acides minéraux tel~ le~
chlorhydrates, ou d'acides organigues tels les toluènesulfonates o~ m~thylsulfonate~ physiologiquement acceptables.
La stéréochimie des produits objet de la presente invention est déterminée par celle des produits de départ. Par s~lection de la stéréoisomérie de chacun des produits de départ on peut obtenir tous les ~téréoisomères possibles et dan~ le ca~ o~ le produit de reaction est un mélange stéréoiso~érigue, le~
composant~ peuvent être sépar~s et leur configuration ~tablie par des procédé~ bien connus.

2 ~ 2 Les nouveaux dériv~ de formule g~n~rale I peuvent ~tre préparé~, conformément ~ l'invention, ~elon la méthode ~uivante:
Par réaction d'un composé de formule générale II
5~ o o Z~
1 0 R~
dan~ laquelle A, R1, R~ et R, ont les significations mentionnée~
préc6demment et Z représente un atome d'halogène, de préf~rence un chlore ou un fluor, avec une azétidine, de formule 5 g~nérale III.
R~
R2~ 111 dans laquelle R,, R3, R~ et R,, ont les significations mentionnées préc~demment.
25Les composés hétérocycliques de formule gén6rale II, que l'on peut utili~er comme matières de départ pour preparer les compo~6~ de l'invention, sont deJ composé- decrits, comme dans H.
Koga, A. Itoh, ~. Murayama, S. Suzue et T. Irikura, J Med.
Chem., 19~0, 23, 1358; ou bien dans H. Egawa, T. Miyamoto, A.
Minamida, Y. Ni~himura, H. Okada, H. Uno et J. Matsumoto, J Med.
30Chem., 1984, 27, 1543; ou bien dans D.T.W. Chu, P.~. Fernandes, A.K. Claiborne, L. Shen et A.G. Pernet, Druqn ExPtl. Chim. Res., 19~, 14, 379.
D'autre part, le~ composes de formule générale III, qui constituent les autres matierea de départ pour la preparation des composés de l'invention sclon la formule générale I, sont connus ou bien gont synthétisés comme par exemplo danJ A.G. Ander~on et R. Lok, J Orq. Chem. 1972, 37, 3953 ou bien dan~ R.H. Higgins et N.H. Cromwell, J HeterocYcl. Chem., 1971, 8, 1059 ou bien dans 2 ~ 2 N.H. Cromwell et R- Phillips, Chem. Rew~., 1979, 79, 331, et au~i dans J. Frigola-Con~tansa, A. Colombo-PiAol, J.
Paré -Coromina~, Eur Pat. Appl. EP 406,112.
Les az~tidine~ de formule générale III peuvent avoir, selon le nombre, la nature et la position relative de~ subxtituant3, jusqu'~ deux centre~ chiraux, et on peut obtenir les différent~
stéréoi30mèses soit par synthè~e a~ymétrique soit par différentes ~orte~ de séparation~, selon les procédés connus dans la chimie organique.
La réaction ~'effectue en pr~sence d'un solvant adéquat, par exemple le diméthylsulfoxyde, le diméthylformamide, la pyridine, leq trialkylamine~ comme la triéthylamine, le chlorure de méthylène, le chloroforme, ou bien de~ éther~ comme le tétrahydrofurane ou le dioxane, ou des m~langes de ceQ ~olvant~.
Les température~ le~ plu~ adéquate~ o~cillent entre la temperature ambiante et la température de reflux du solvant et le temps réactionnel est compri~ entre 1 heure et 24 heure~.
Dans les exemple~ suivants on indique la préparation de nouveaux dérivés selon l'invention. On dêcrira également quelques forme~ d'emploi.
Le~ exemple~ ci-aprè~, donnes à simple titre d~illustration~
ne doivent cependant, en aucune façon, limiter l'étendue de l'invention.
ExemPle 1.- Préparation de l'acide 7-t(2S,3R)-3-amino-2-méthyl-l-azétidinyll-1-(2,4-difluorophényl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
On chauffe à llO'C dans un récipient clos et pendant 2 heures un m~lange de 8.0 9 (23.7 mmoles) de 1'acide 1-(2,4-difluoroph~nyll-6,7-difluoro-1,4-tihydro-4-oxo-3-guinol~incarboxylique, 5.7 9 ~35.8 mmoleq) de dichlorhydrate de ~2S,3R~-3-amino-2-methylazétidine et 25 ml (245 mmoles) de triéthylamine dans 80 ml de pyridine. On lai~qe refroidir, on filtr~ et on lave à l'eau, l'éthanol et l'éther. On obtient ainsi 7.7 9 ~19.1 mmole~) de l'acide 7-~2,3R~-3-amino-2-méthyl-1-asétidinyll-1-~2,4-difluorophényl) 6-fluoro-1,4-dihydro-4-oxo-3-35 quinoleincar~oxylique de point de fu~ion 227-230-C.
~o 1~l = - 40.8 ~c = 1.08, NaOH 0.5 N) 2 ~
RMN lH (300 MHz) ~DMSQ-d~/T~A): 1.25 et 1.31 ~2xd,J=6.50Hz,3H); 2 5 ~ R ~

in which A ~ 4 atom represents a nitrogen atom or an atom of carbon with a hydrogen atom attaches ~ CH), or else an atom carbon with attached halogen (CX), in this case X

2 ~ 8 2 represents a chlorine, fluorine or bromine atom or a carbon atom with a hydroxy radical (C-OH).
R1 represents a lower alkyl or cycloalkyl radical, a lower haloalkyl radical, an aryl radical or a radical aryl substituted in particular by one or more atom (s) of fluorine.
R2 and R3 represent a hydrogen atom, a radical lower alkyl, a hydroxyl radical, an amino radical, a aminoalkyl radical, an alkylamino radical, a radical dialkylamino, preferably a heterocyclic nitrogen radical aromatigue can be a cycle of three ~ to ~ ix links, a alkylaminoalkyl radical, an alkylcarboxamido radical, and in this last case, the alkyl radical being able to be sub ~ substituted by one or several ~ halog ~ nes, an arylsulfonyloxy radical, a radical alkylsulfonyloxy, a carboxamido radical, which can be substituted or not on nitrogen, or a cyano radical.
R, and R ,, equal or different ~, represent an atom hydrogen or a lower alkyl radical.
R ~ represents a hydrogen atom ~ ne, a nitro radical, a amino or substituted amino radical.
R7 represents a hydroxy radical or an alkyloxy radical lower than C ~ C ~.
A and R ~ can together form a connection represented by a group C-CH2-CH2-CHR ~ - or CO-CH2-CHR ~ - in which Q Ra represented ~ ente an ato ~ e of hydrogen or a lower alkyl radical, and in this last case, we have a chiral center with a configuration ~ R ~ or ~ S ~.
The azetidinig substituents may have, depending on the number, nature and relative position of the substituents ~, up to two chiral centers, each with a configuration "R ~ or ~ S ~, as well as their mineral acid salts such as ~ le ~
hydrochlorides, or organic acids such as toluenesulfonates o ~ m ~ thylsulfonate ~ physiologically acceptable.
The stereochemistry of the products which are the subject of the present invention is determined by that of the starting materials. By selection of the stereoisomerism of each of the starting materials we can get all ~ possible tereoisomers and dan ~ the ca ~ o ~ the reaction product is a stereoiso mixture ~ erects, the ~
component ~ can be separated ~ s and their configuration ~ established by well known processes ~.

2 ~ 2 The new derivatives of general formula I may be prepared ~, in accordance with ~ the invention, ~ according to the following method:
By reaction of a compound of general formula II
5 ~ oo Z ~
1 0 R ~
dan ~ which A, R1, R ~ and R, have the meanings mentioned ~
previously and Z represents a halogen atom, preferably a chlorine or a fluorine, with an azetidine, of formula 5 general III.
R ~
R2 ~ 111 in which R ,, R3, R ~ and R ,, have the meanings mentioned previously.
25The heterocyclic compounds of general formula II, which can be used as starting materials for preparing ~ 6 ~ compo of the invention, are deJ compose- described, as in H.
Koga, A. Itoh, ~. Murayama, S. Suzue and T. Irikura, J Med.
Chem., 19 ~ 0.23, 1358; or in H. Egawa, T. Miyamoto, A.
Minamida, Y. Ni ~ himura, H. Okada, H. Uno and J. Matsumoto, J Med.
30 Chem., 1984, 27, 1543; or in DTW Chu, P. ~. Fernandes, AK Claiborne, L. Shen and AG Pernet, Druqn ExPtl. Chim. Res., 19 ~, 14, 379.
On the other hand, the ~ compounds of general formula III, which constitute the other starting materials for the preparation of compounds of the invention, according to general formula I, are known or gont synthesized as for example danJ AG Ander ~ on and R. Lok, J Orq. Chem. 1972, 37, 3953 or dan ~ RH Higgins and NH Cromwell, J HeterocYcl. Chem., 1971, 8, 1059 or else in 2 ~ 2 NH Cromwell and R- Phillips, Chem. Rew ~., 1979, 79, 331, and au ~ i in J. Frigola-Con ~ tansa, A. Colombo-PiAol, J.
Paré -Coromina ~, Eur Pat. Appl. EP 406,112.
The az ~ tidine ~ of general formula III may have, depending on the number, nature and relative position of ~ subxtituant3, up to ~ two chiral centers, and we can get the different ones ~
stereoi30meses either by synth ~ ea ~ ymetric or by different ~ separation ~ ~ ~, according to methods known in organic chemistry.
The reaction is carried out in the presence of an adequate solvent, by example dimethylsulfoxide, dimethylformamide, pyridine, leq trialkylamine ~ like triethylamine, chloride methylene, chloroform, or ~ ether ~ like tetrahydrofuran or dioxane, or mixtures of ceQ ~ olvant ~.
The temperatures ~ the ~ most ~ adequate ~ o ~ blink between the room temperature and the reflux temperature of the solvent and the reaction time is between ~ 1 hour and 24 hours ~.
In the following examples, the preparation of new derivatives according to the invention. We will also describe some form of employment.
The ~ example ~ below ~, just for illustration purposes ~
should not, however, in any way limit the scope of the invention.
EXAMPLE 1. Preparation of 7-t (2S, 3R) -3-amino-2- acid methyl-1-azetidinyll-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic.
It is heated to 10'C in a closed container and for 2 hours a mixture of 8.0 9 (23.7 mmol) of acid 1- (2,4-difluoroph ~ nyll-6,7-difluoro-1,4-tihydro-4-oxo-3-guinol ~ incarboxylic, 5.7 9 ~ 35.8 mmoleq) of dihydrochloride ~ 2S, 3R ~ -3-amino-2-methylazetidine and 25 ml (245 mmol) of triethylamine in 80 ml of pyridine. We let it cool down, we filtered ~ and washed with water, ethanol and ether. We thus obtain 7.7 9 ~ 19.1 mmol ~) of acid 7- ~ 2,3R ~ -3-amino-2-methyl-1-asétidinyll-1- ~ 2,4-difluorophenyl) 6-fluoro-1,4-dihydro-4-oxo-3-35 quinoleincar ~ oxylic fu point ~ ion 227-230-C.
~ o 1 ~ l = - 40.8 ~ c = 1.08, NaOH 0.5 N) 2 ~
1 H NMR (300 MHz) ~ DMSQ-d ~ / T ~ A): 1.25 and 1.31 ~ 2xd, J = 6.50Hz, 3H);

3.62-3.92 ~m,2H); 4.20-4.42 (m,2H); 5.76 ~d,J=6.84Hz,lH); 7,41 (m,lH); 7.67 5m,1H); 7.84-7.98 (m,2H,(~=7.94,J-12.7Hz)); 8.23 (~,3H~; 877 et 8.80 (2x~,1H).
IR ~KBr): 1630, 1611, 1509.
Les compoC~s identifié4 paF les exemple~ 2, 3, 4, 5, 6, 10, 11, 12, 17, 20, 23, 26, 27, 28, 29 et 30 sont obtenus par la même procédure et les donnée~ pour leur identification ~ont expo~e3 dan~ les tableaux I et II.
Exemple 21.- Pr~paration du ~el p-tolu~nsulfonate de l'acide 7-[(2S,3R~-3-amino-2-méthyl-1-azétidinyll-1-(2,4-d i f l u o r o ph ény l) - 6 - f luoro-1,4-dihydro-4-oxo-3-quinoléincarboxylique. ~
A une 3u~pen~ion de 0.2 g (0.50 mmole ) de l'acide 7-[~2S,3R)-3-amino-2-méthy1-1-az6tidinyl~ 2,4-difluoroph6nyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoléincarboxylique dan~ 3 ml d'~thanol à ébullition, on ajoute une solution de l'acide p-toluensulfonique dan~ l'éthanol jusqu'~ un pa légerement acide ~6).
Aprè~ refroidissement, on filtre le solide précipit~, on lave avec de l'éthanol froid et on obtient 0.23 g (0.40 mmole~) du ~el p-toluensulfonate de l'acide 7-[~2S,3R)-3-amino-2-méthyl-1-azétidinyl]-1-~2,4-difluorophényl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylique de point de fusion 214-216-C.
[~1 ~ - 36.5 ~c = 1.0, DMSO~
O
RMN ~H (300 M~z) ~DMSO-d~): 1.26 et 1.32 ~2xd,J=6.1Hz,3H); 2.28 ~s,3H); 3.64-392 ~m,2H); 4.16-4.42 ~m,2H); 5.76 Id,J=7.3Hz,1H);
7.11 et 7.46 (~1st~me AB, J-7.98Hz,4H~; 7.72-7.84 ~m,4H(~=7.98, d,J=12.68Hz)); ~.16 ~é,3H); 8.81 et 8.85 ~2xs,1H).
IR ~XBr): 1729, 1630, 1507, 1460.
Exemple 24.- Préparation du chlorhidrate de l'acide 7-l~29,3R)-3-amino-2-méthyl-1-az6tidinyl]-1-~2,4-difluorophényl)-6-fluoro-1,4,dihydro-4-oxo-3-quinoléincarboxylique.
A une ~uspension de 1.0 9 ~2.48 mmoles) de l'acide 7-~2S,3R)-3-amino-2-methyl-1-az6tidinyll-1-~2,4-di~luorophényl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoléincarboxylique dans 20 ml d'éthanol ~ ebullition, on ajoute une solution de l'acide chlorhydrique dan~ l'éthanol ju~qu'à un pH l~gerement acide (6).

6 2~0~2 Apr~s refroidi~ement, on filtre le olide pr~cipité, on lave avec de l'~thanol froid et on obtient 0. a6 9 ( 1 . 9s mmole~) du sel chlorhydrate de l'acide 7-[(2S,3R)-3-amino-2-m~thyl-1-azétidinyl]-l-(2,4-difluorophényl)-6-fluoro-1,4-dihydro-4-oxo-3-~uinoléincarboxylique de point de fusion 211-214-C.

[l = - 54.8 ~c = 1.0, DMF) RMN lH (300 M~z) (DMSO-do), ~: 1.29 et 1.33 ~2xd,J=6.0Hz,3H);
3.70 (m,lH3; 3.89 (m,lH); 4.35 (m,2H); 5.77 ~d,J=6.9Hz,lH); 7.47 (m,1~); 7.57 ~m,lH); 7.89-8.00 (a.c.,2H,(t = 5.77, d,J=6.9Hz));
8.30-8.70 (é,2H); 8.79 et 8.82 (2x~,1HI
IR (KBr): 3700-2300 (é), 1721, 1630, 1507, 1466, 1335 cm~1.
Exemple 25.- Préparation du, méthylsulfonate de l'acide 7-[(2S,3R)-3-amino-2-m~thyl-1-azétidinyll-1-(2,4-difluorophényl)-6-5 f luoro-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
A une suspension de 2.0 g (4.96 mmoles) de l'acide 7-[(2S,3R)-3-amino-2-méthyl-1-azétidinyl~ 2,4-difluorophényl~-6-fluoro-1,4-dihydro-4-oxo-3-quinoléincarboxylique dans 40 ml d'éthanol ~ ~bullition, on ajoute une ~olution de l'acide m~thylsulfonique dans l'éthanol ~usqu'à un pH légèrement acide (6).
Apr~ refroidi~ement, on filtre le solide précipité, on lave avec de 1'6thanol froid et on obtient 1.50 9 ~3.00 mmoles~
du sel methylsulfonate de l'acide 7-[~2S,3R)-3-amino-2-méthyl-1-azétidinyll-1-(2,4-difluorophényl~-6-fluoro-1,4-dihydro-4-oxo-3-quinoléincarboxylique de point de fusion 190-194-C.
:.o [~ 45.6 ~c = 1.0, DMF) RMN lH ~300 M~s) (DMSO-d~), 6: 1.28 et 1.32 ~2xd,J=6.0Hz,3H~;
2.31 (s,3H); 3.29 (6,2H); 3.71 (m,lH); 3.84 (m,lH); 4.20-4.43 ~m,2H); 5.77 ~d,J=7.2Hz,lH); 7.45 Im,lH); 7.55 (m,lH); 7.88-8.00 (a.c.,2H,~6 - 7.96, d,J=12.6Hz)); B.79 et 8.82 ~2xs,1H) IR ~Br): 3700-2300 (~), 1720, 1631, 1505, 1465, 1331 cm~ .
Les compos6s identifié~ par les exemples 7, 8, 9, 13, 14, 15, 16, 18, 19, et 22 sont obtenus par la même proc~dure et les données pour leur identification sont exposées dans les tableaux I et II.

7 2~94~32 . ._ a I O n n N S n ~, d3 d3 d a' 13 d3 O ~ ~3 3 z-r ~~ ~

IL Z l .r l 1~ ~; ¦ R; I ~ 11; 1 ~; ¦
~ l N N N N N N

os' 3 3 =N 3 3 3 n a 3n d' N 3n 3n ~ D l I Z
~U =, ~ 1~--~--U, ~ ~ lL~3 ~ ~ ~;7 ~ ",J~

~ --n n _ _ _ 8 2 ~ 8 ~
~r 17 . . ~ I

o~4 ~ ~' ~3 tO ~ D r D ~_ ~ N D

'~o~z-e ~ ~ 1 -~ I ~^1 ~^1 A~` ~ ~ N N N N

~ a r _ O D
t~ ~ D D D D D
E~ C~ ~t ~N
~ ~ D ~ D D D

Orl ~7 i~ ~ 3~ J~3 ,, r _ ~

9 2~082 i -I

~cr _-- 3~ _ ~ -- a~
,t ~ ~ 3~ ,, _ ~_ . ~ ~ ~' .

r ~7 ~ _ ~7 ~3 V
~ _l ~ ~ 1~ Ir~l ~

- ' 2~408~

O ~ _ I N N N N N N
O~z_~ ~

~ N N N _ l N

,~ ' __ 3 ~ 1!1 r I~ ~ , ~ _ ~

~ a a a a :1~

~ 11' U I!N U U U
,~ ~ e~i3 -~¢3 ~7 ~ J~3 J ~ N N N N N

- 2~940~2 ~r 3" _ q9 g~ ~ _ ~ ~Y '_'J,~ ',;7_ 1 2 2094~82 r _ ~ 7 N 7 ~ I I ~
~ e~ a I I I ?U, l . .

~o=~ z~F I ~ 1 l l l .

f ;~ .;i' _~ 3 a ~N a ilN ~N
,~- ~--3' :: = 37 :1 ~7 37 _--_ __ N laN ~IN 3IN 5 IN I~IN 1~
~ U U U ~ ~ ~
~ .~ .~ ~ ~ ~
~ ~ r ~ ~ ~ r~

13 2 ~ 2 , TABLEA~ II

ExempleSolvant RMN- H (100 MHz) i.25 et 1.31 (2xd,J=6.50Hz,3H);
3.62-3.92 (m,2H); 4.20-4.42 (m,2H); ¦
1 DMSO-d~/TFA 5.76 (d,J=6.84Hz,lH); 7.41 (m,lH);
(300 MHz) 7.67 (m,lH); 7.84-7.98 (m,2H,(~=7.94,¦
J 12;7Hz)); 8.23 (~,3H); 8.77 et 8.80 _ 0.60-1.30 (m,4H); 1.49 (d,J=6.0Hz, 2 DMSO-d~/TFA 3H); 3.71 (m,lH); 3.90-4.45 (m,2H);
5.00 (m,2H); 7.80 (d,J= 13.9Hz,lH);
8.36 (~,3H); 8.75 (s,lH) 1.04 (m,4H); 1~49 (d,J=5.7Hz,3H);
3 DMSO-d~/TFA 3.66 (m,lH); 3.99 ~m,2H); 4.65 ~m,2H); 8,34 ~,3H); 8.44 ~s,lH) 1.15 Im,4H); 1.50 ~d,J=6.1Hz,3H); 3.62-3.92 ~ m, 2H); 4.20-4.42 (m, 2H); 5.76 ~ d, J = 6.84Hz, 1H); 7.41 (m, 1H); 7.67 5m, 1H); 7.84-7.98 (m, 2H, (~ = 7.94, J-12.7Hz)); 8.23 (~, 3H ~; 877 and 8.80 (2x ~, 1H).
IR ~ KBr): 1630, 1611, 1509.
The components identified by PA examples such as 2, 3, 4, 5, 6, 10, 11, 12, 17, 20, 23, 26, 27, 28, 29 and 30 are obtained by the same procedure and data ~ for identification ~ have expo ~ e3 in ~ Tables I and II.
EXAMPLE 21 Preparation of ~ el p-tolu ~ nsulfonate acid 7 - [(2S, 3R ~ -3-amino-2-methyl-1-azetidinyll-1- (2,4-difluoro ph eny l) - 6 - f luoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic. ~
At a 3u ~ pen ~ ion of 0.2 g (0.50 mmol) of acid 7-[~ 2S, 3R) -3-amino-2-methyl1-1-az6tidinyl ~ 2,4-difluoroph6nyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic dan ~ 3 ml of ~ thanol at boiling point, add a solution of the acid p-toluensulfonique dan ~ ethanol up to ~ slightly pa acid ~ 6).
After ~ cooling, the solid precipitates is filtered ~, wash with cold ethanol and 0.23 g (0.40 mmol ~) is obtained ~ el p-toluensulfonate acid 7- [~ 2S, 3R) -3-amino-2-methyl-1-azetidinyl] -1- ~ 2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic melting point 214-216-C.
[~ 1 ~ - 36.5 ~ c = 1.0, DMSO ~
O
NMR ~ H (300 M ~ z) ~ DMSO-d ~): 1.26 and 1.32 ~ 2xd, J = 6.1Hz, 3H); 2.28 ~ s, 3H); 3.64-392 ~ m, 2H); 4.16-4.42 ~ m, 2H); 5.76 Id, J = 7.3Hz, 1H);
7.11 and 7.46 (~ 1st ~ me AB, J-7.98Hz, 4H ~; 7.72-7.84 ~ m, 4H (~ = 7.98, d, J = 12.68Hz)); ~ .16 ~ é, 3H); 8.81 and 8.85 ~ 2xs, 1H).
IR ~ XBr): 1729, 1630, 1507, 1460.
EXAMPLE 24 Preparation of the acid hydrochloride 7 l ~ 29.3R) -3-amino-2-methyl-1-az6tidinyl] -1- ~ 2,4-difluorophenyl) -6-fluoro-1,4, dihydro-4-oxo-3-quinoleincarboxylic.
At a ~ uspension of 1.0 9 ~ 2.48 mmol) of acid 7-~ 2S, 3R) -3-amino-2-methyl-1-az6tidinyll-1- ~ 2,4-di ~ luorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic in 20 ml ethanol ~ boiling, add a solution of the acid hydrochloric dan ~ ethanol ju ~ only at a pH slightly acidic (6).

6 2 ~ 0 ~ 2 After it has cooled down, we filter the precipid olide, wash with cold ~ thanol and 0. a6 9 is obtained (1. 9s mmole ~) the hydrochloride salt of acid 7 - [(2S, 3R) -3-amino-2-m ~ thyl-1-azetidinyl] -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-~ moleoleincarboxylic melting point 211-214-C.

[l = - 54.8 ~ c = 1.0, DMF) 1 H NMR (300 M ~ z) (DMSO-do), ~: 1.29 and 1.33 ~ 2xd, J = 6.0Hz, 3H);
3.70 (m, 1H3; 3.89 (m, 1H); 4.35 (m, 2H); 5.77 ~ d, J = 6.9Hz, 1H); 7.47 (m, 1 ~); 7.57 ~ m, 1H); 7.89-8.00 (ac, 2H, (t = 5.77, d, J = 6.9Hz));
8.30-8.70 (é, 2H); 8.79 and 8.82 (2x ~, 1HI
IR (KBr): 3700-2300 (é), 1721, 1630, 1507, 1466, 1335 cm ~ 1.
EXAMPLE 25 Preparation of acid methylsulfonate 7 [(2S, 3R) -3-amino-2-m ~ thyl-1-azétidinyll-1- (2,4-difluorophenyl) -6-5 f luoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic.
To a suspension of 2.0 g (4.96 mmol) of acid 7-[(2S, 3R) -3-amino-2-methyl-1-azetidinyl ~ 2,4-difluorophenyl ~ -6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic in 40 ml ethanol ~ ~ bullition, we add a ~ olution of the acid m ~ thylsulfonic in ethanol ~ up to a slightly pH
acid (6).
After ~ cooled ~ ement, we filter the precipitated solid, we wash with cold ethanol and we obtain 1.50 9 ~ 3.00 mmol ~
7- [~ 2S, 3R) -3-amino-2-methyl-1- acid methylsulfonate salt azétidinyll-1- (2,4-difluorophenyl ~ -6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic melting point 190-194-C.
: .o [~ 45.6 ~ c = 1.0, DMF) 1 H NMR ~ 300 M ~ s) (DMSO-d ~), 6: 1.28 and 1.32 ~ 2xd, J = 6.0Hz, 3H ~;
2.31 (s, 3H); 3.29 (6.2H); 3.71 (m, 1H); 3.84 (m, 1H); 4.20-4.43 ~ m, 2H); 5.77 ~ d, J = 7.2Hz, 1H); 7.45 Im, 1H); 7.55 (m, 1H); 7.88-8.00 (ac, 2H, ~ 6 - 7.96, d, J = 12.6Hz)); B.79 and 8.82 ~ 2xs, 1H) IR ~ Br): 3700-2300 (~), 1720, 1631, 1505, 1465, 1331 cm ~.
The compounds identified by Examples 7, 8, 9, 13, 14, 15, 16, 18, 19, and 22 are obtained by the same hard process and the data for their identification are set out in the tables I and II.

7 2 ~ 94 ~ 32 . ._ a IO nn NS n ~, d3 d3 da '13 d3 O ~ ~ 3 3 zr ~~ ~

IL Z l .rl 1 ~ ~; ¦ R; I ~ 11; 1 ~; ¦
~ l NNNNNN

os' 3 3 = N 3 3 3 na 3n d 'N 3n 3n ~ D l IZ
~ U =, ~ 1 ~ - ~ --U, ~ ~ lL ~ 3 ~ ~ ~; 7 ~ ", J ~

~ --nn _ _ _ 8 2 ~ 8 ~
~ r 17. . ~ I

o ~ 4 ~ ~ '~ 3 tO ~ D r D ~ _ ~ ND

'~ o ~ ze ~ ~ 1 - ~ I ~ ^ 1 ~ ^ 1 A ~ `~ ~ NNNN

~ ar _ OD
t ~ ~ DDDDD
E ~ C ~ ~ t ~ N
~ ~ D ~ DDD

Orl ~ 7 i ~ ~ 3 ~ J ~ 3 ,, r _ ~

9 2 ~ 082 i -I

~ cr _-- 3 ~ _ ~ - a ~
, t ~ ~ 3 ~ ,, _ ~ _. ~ ~ ~ '.

r ~ 7 ~ _ ~ 7 ~ 3 V
~ _l ~ ~ 1 ~ Ir ~ l ~

- '2 ~ 408 ~

O ~ _ INNNNNN
O ~ z_ ~ ~

~ NNN _ l N

, ~ '__ 3 ~ 1! 1 r I ~ ~, ~ _ ~

~ aaaa: 1 ~

~ 11 'UI! NUUU
, ~ ~ e ~ i3 - ~ ¢ 3 ~ 7 ~ J ~ 3 J ~ NNNNN

- 2 ~ 940 ~ 2 ~ r 3 "_ q9 g ~ ~ _ ~ ~ Y '_'J, ~',; 7_ 1 2 2094 ~ 82 r _ ~ 7 N 7 ~ II ~
~ e ~ a III? U, l. .

~ o = ~ z ~ FI ~ 1 lll.

f; ~.; i ' _ ~ 3 a ~ N a ilN ~ N
, ~ - ~ --3 ':: = 37: 1 ~ 7 37 _ - _ __ N laN ~ IN 3IN 5 IN I ~ IN 1 ~
~ UUU ~ ~ ~
~. ~. ~ ~ ~ ~
~ ~ r ~ ~ ~ r ~

13 2 ~ 2 , TABLEA ~ II

Example NMR-H solvent (100 MHz) i.25 and 1.31 (2xd, J = 6.50Hz, 3H);
3.62-3.92 (m, 2H); 4.20-4.42 (m, 2H); ¦
1 DMSO-d ~ / TFA 5.76 (d, J = 6.84Hz, 1H); 7.41 (m, 1H);
(300 MHz) 7.67 (m, 1H); 7.84-7.98 (m, 2H, (~ = 7.94, ¦
J 12; 7Hz)); 8.23 (~, 3H); 8.77 and 8.80 _ 0.60-1.30 (m, 4H); 1.49 (d, J = 6.0Hz, 2 DMSO-d ~ / TFA 3H); 3.71 (m, 1H); 3.90-4.45 (m, 2H);
5.00 (m, 2H); 7.80 (d, J = 13.9 Hz, 1 H);
8.36 (~, 3H); 8.75 (s, 1H) 1.04 (m, 4H); 1 ~ 49 (d, J = 5.7Hz, 3H);
3 DMSO-d ~ / TFA 3.66 (m, 1H); 3.99 ~ m, 2H); 4.65 ~ m, 2H); 8.34 ~, 3H); 8.44 ~ s, 1H) 1.15 Im, 4H); 1.50 ~ d, J = 6.1Hz, 3H);

4 DMSO-d~/TFA 3.98 (m,lHI; 4.42 ~m,3H); 5.02 (m,lH); 7.71 (d,J=13.1Hz,lH); 8,45 ~,3H); 8.58 ~s,lH) 1.17 ~m,4H); 1.52 (d,J=6.1Hz,3H): 4 DMSO-d ~ / TFA 3.98 (m, 1HI; 4.42 ~ m, 3H); 5.02 (m, 1H); 7.71 (d, J = 13.1Hz, 1H); 8.45 ~, 3H); 8.58 ~ s, 1H) 1.17 ~ m, 4H); 1.52 (d, J = 6.1Hz, 3H):

5 DMSO-d~/TFA 4.00 (m,lH); 4.42 (m,3H); 5.03 (m,lH); 7.72 (d,J-13.1Hz,lH); 8.46 ~,3~

1.40 (m,3HI; 3.65 ~m,lHI: 3.90 5 DMSO-d ~ / TFA 4.00 (m, 1H); 4.42 (m, 3H); 5.03 (m, 1H); 7.72 (d, J-13.1Hz, 1H); 8.46 ~, 3 ~

1.40 (m, 3HI; 3.65 ~ m, lHI: 3.90

6 DMSO-~/TFA ~m,lH); 4.89 ~m,2H); 7.52 ~m,3H); 6 DMSO- ~ / TFA ~ m, 1H); 4.89 ~ m, 2H); 7.52 ~ m, 3H);

7.98 (d,J=12.8Hz,lH); 8.31 (~,3H);
__ .__ 14 2~082 TABLEA~ II (Suite~

~ r - l Exemple Solvant RMN-lH (100 MHz) 0.85-1.30 (m,4H); 1.59 (s,3H); 2.26 ~s,3H)i 4.30 ~m,lH); 4.54 ~,4H);
7 DMSO-d~ 7.08 et 7.46 ~istème AB,J=8.0Hz,4H), 7.78 ~d,J=13,6Hz,lH)i 8.42 ~e,3H); 7.98 (d, J = 12.8Hz, 1H); 8.31 (~, 3H);
__ .__ 14 2 ~ 082 TABLEA ~ II (Continued ~

~ r - l Example 1 H NMR solvent (100 MHz) 0.85-1.30 (m, 4H); 1.59 (s, 3H); 2.26 ~ s, 3H) i 4.30 ~ m, 1H); 4.54 ~, 4H);
7 DMSO-d ~ 7.08 and 7.46 ~ isteme AB, J = 8.0Hz, 4H), 7.78 ~ d, J = 13.6 Hz, 1H) i 8.42 ~ e, 3H);

8.75 ~-~,lH) . ,~ 11 1.48 (m,6H)i 2.24 (9,3H)i 3.75 a DMSO-d~ ~m,lHJi 4.00-5.00 (m,5~); 7.05 et 7.49 (~i~tème AB, J=7.63Hz,4H); 7.71 (d,J-12.7Hz,lH): 8.42 (e,3H); 8.78 I
1.27 (m,3H); 2.26 (s,3H); 3.75 8.75 ~ - ~, 1H) . , ~ 11 1.48 (m, 6H) i 2.24 (9.3H) i 3.75 a DMSO-d ~ ~ m, lHJi 4.00-5.00 (m, 5 ~); 7.05 and 7.49 (~ i ~ teme AB, J = 7.63Hz, 4H); 7.71 (d, J-12.7Hz, 1H): 8.42 (e, 3H); 8.78 I
1.27 (m, 3H); 2.26 (s, 3H); 3.75

9 DMSO-do (m,2H); 4.32 (m,2H); 5.75 (d,J=7.0Hz, lH); 7.08 et 7.45 ~Qist~me AB, J=7.6Hz,4H); 7.50-8.10 (m,4H); 8.28 (~e,3H); 8.79 et 8.83 (2x~,1H) I ..
1.49 (m,6H); 3.71 (m,lH); 4.20 10DMSO-do/TFA (m,lH); 4.40-5.00 (m,4H); 7.77 ~d,J=12.9Hz,lH); 8.36 (e,3H); 8.78 8 , lH) I
1.25 et 1.31 (2xd,J=6.50Hz,3H);
3.62-3.92 (m,2H); 4.20-4.42 (m,2H);
11DMSO-d~/TFA 5.76 (d,J=6.84Hz,lH); 7.41 ~m,lH)i ~300 MHz) 7.67 (m,lH); 7.84-7.98 (m,2H,~=7.94, J 12 7Hz~); 8.23 (é,3H); 8.77 et 8.80 1.21 (m,3H); 3.68 (m,lH); 4.21 12DMSO-do/TFA (m,3H); 7.10-7.90 (m,3H); 8.09 (d J 11.3Hz,lH); 8.17 (~,3H); 8.80 ~ _~, ,., , . . ~

2 ~ 2 TABLEAU II ( Suite ) ~ , ._ . I
Exemple Solvant RMN-lH (100 MHz) 1.15 (m,4H); 1.61 ~d,J=6.4Hz,3H);
2.26 ~,3H); 3.5 (m,2H)i 4.33 (m,lH~-13 DMSO-d~ 4.64 (m,2H); 7.07 et 7.45 (~ist~me AB, J=7.8Hz,4H); 8.06 (d,J=11.4Hz, lH); 8.33 ~é,3H); 8.60 ~s,lH) I -I
1.16 ~m,4H); 1.62 (d,J=6.4Hz,3H);
2.27 (s,3H); 3.5 ~m,2H); 4.34 tm,lH);
14 DMSO-d~ 4,64 (m,2H); 7.08 et 7.46 ~istème AB, J=7.8Hz, 4H); 8.07 (d,J=11.4Hz, lH); 8.35 ~é,3H); 8.61 ~s,lH) 1.01 ~m,4H); 1.63 ~s,3H); 2.26 ~s,3H); 3.65 (m,lH); 4.38 (é,4H);
DMSO-d~ 7.07 et 7.46 (sist~me A8, J=7.6Hz, 4H); 8.04 (d,J=11.6Hz,lH); 8.50 (é,3H); 8.59 ~s,lH) ~ .
1.13 (m,4H); 1.65 ~s,3H); 2.25 ~s,3H); 2.66 (s,3H); 3.75 (m,lH);
16 DMSO-d~ 4.28 et 4.55 ~sisteme AB, J=7.5Hz, 4H); 7.04 et 7.46 (si~tème AB, J=7.8Hz,4H); 8.02 (d,J~11.4Hz,lH);
8.58 (s,lH); 9.25 (6,2H) 1.20 ~m,3H); 3.67 ~m,lH); 4.23 17 DMSO-d~ ~m,3H); 7.05-7.75 (a.c.,3H); 7.75 la.c.,4H,16=8.04,J=11.4Hz); 8.75 ~g,lH) _ 1.16 (m,4H); 1.63 (d,J=6.3Hz,3H);
18 DMSO-d~ 2.32 (s,3H); 3.77 ~m,2H); 4.32 (m,lH); 4.64 (m,2H); 8.07 (d,J=11.4H
_ -v ~ ~ lH), 8.34 ~é,3H); 8.60 ~-,lN) - 16 ~0~4082 TABLEAU II (Suite) -'''1- _ I
Exemple¦ Solvant RMN-lH (100 MHz~
_- ..
1.16 (m,4H); 1.64 (d,J=6.4Hz,3H);
19 DMSO-d~ 3.77 (m,2H); 4.37 (m,lH); 4.69 ~m,2H) 8.07 (d,J=ll.SHz,lH); 8.60 (~,lH);
8.72 (é,3H) _ 1.36 (~,J=6.0Hz,3H); 3.59 (m,lH);
DMSO-d~/TFA 4.02 (m,lH); 4.54 (m,2H); 7.36 (t, J=8.7Hz,2H); 7.60-7.90 (a.c., 3H);
8.24 (~,3H); 8.40 (s,lH) ._._ _ __ 1.26 et 1.32 (2xd,J=6.1Hz,3H); 2.28 (s,3H); 3.64-3.92 (m,2H); 4.16-4.42 21 DMSO-d~ ~m,2H); 5.76 ~d,J=7.3Hz,lH); 7.11 et ~300 MHz) 7.46 ~sistème AB,J=7.98Hz,4H);
7.72-7.84 ~m,4H~=7.98,J=12.68Hz));
8.16 ~é,3H); 8.81 et 8.85 ~2xs,1H) 1.26 ~m,4H); 1.56 ~d,J=6,0Hz,3H);
22 DMSO-d~ 2.34 ~s,3H); 3.7 ~m,3H); 4.53 ~m,2H);
7.04 ~d,J-7.7Hz,lH); 7.83 (d,J=12.8Hz lH); 8.43 (e,3H); 8.60 (s,lH) .. _ ._ 23 DMSO-d~TPA 1.01 (m,4H); 3.70-4.60(m,6H); 8.30 (é,3H); 8.40 (~,lH) I
1.29 et 1.33 ~2xd,J=6.0Hz,3H); 3.70 ~m,lH); 3,89 (m,lH); 4.35 (m,2H);
24 DMso-da 5.77 ~d,J=6.9Hz,lH); 7.47 (m,lH);
~300 MHz) 7.57 ~m,lH); 7.89-8.00 (a.c.,2H,~=
7.95,d,J=12.9Hz)); 8.30-8.70 (~,2H);
. . ~

~ 17 ~ 082 TABLEAU II (Suite) ¦Exemple Solvant RMN- H (100 MHz~
. _ 1.28 et 1.32 (2xd,J=6.0Hz,3H); 2.31 (-~,3H); 3.29 (é,2H); 3.71 (m,lH~;
DMSO-d~ 3.84 (m,lH); 4.20-4.43 (m,2H); 5.77 ~300 MHz) (d,J=7.2Hz,l~); 7.45 (m,lH); 7.55 (m,lH); 7.88-8.00 (a.c.,2H,l~=7.96, d,J=12.6Hz)); 8.79 et 8.82 ~2x~,1H) 0.80-1.30 (m,4H); 3.90-4.95 (m,6H);
26 DMSO-d~/TFA 7.74 Id,J=13.7Hz,lH); 8.45 (e,3H);
8,73 ~,lH) _ 0.75-1.32 ~m,4H); 2.63 ~s,3H); 3.90-27 DMSO-da/TFA 4 90 ~ ,6H); 7.73 ~d,J=13.6Hz,lH);
__ 3.99 ~m,lH); 4.42 ~m,2H); 4.70 28 DMSO-d~ ~m,2H); 7.10-8.05 ~a.c.,4H,(~=7.91,d, J=13.9Hz~); 8.26 ~6,3H); 8.56 (~,lH) 2.50 (~,3H); 3.97 (m,lH); 4.51 29 DMSo-d~TeA (m,4H); 7.10-8.00 (a.c.,4H,~=7.90,d, J=13.8Hz)); 8.55 ~s,lH); 9.07 (é,2H) _ 0.78 (m,lH); 1.08 (m,2H); 1.30 DMSO-d~/TFA (m,lH); 1.50 (d,J=6.0Hz,3H); 3.71 (300 MHz) (m,lH); 4.09 (m,lH); 4.34 (m,lH~;
5.01 (m,2H); 7.81 (d,J=13.8Hz,lH);
~____.__ ~ 8.39 (6,3H), 8 76 ( 9 ~ ln ) 18 2~Q~2 TABLEAU II ~ Suite ) . , ~ .
Exemple Solvant RMN-lH tlOO MHz~
. ,~ .
31 DMSO-d~/TFA 1.49 (4, 3H); 4.20 (m,4H); 7.10-8.00 ~m,3H); 8.31 (é,4H) 1,33 (m,3H); 3.57 (m,lH); 3.89 32 DMSO-d~/TFA (m,lH); 4.50 (m,2H); 7.05-8.00 (m,3H); 8.20 (é,3H); 8.32 (~,lH) ._ 33 DMSO-do/TFA 3.90-4.80 (m,5H); 7.05-8.05 (m,3H);
8.30 (~,4H) ...
1.36 (t,J=6.6Hz,3H); 1.59 (~,3H);
34 DMSO-d~/TFA 4.40 ~m,6H); 8.34 (~,3H); 8.60 8,1~) 1.35 (t,J~6.8Hz,3H); 1.50 (d,J=6.0Hz, DMSO-da/TFA 3H); 3.5-4.90 ~m,6H); 8.31 ~,3H);
8.59 ~,lH) -- .
36 DMSO-d./TFA 1.36 (t,J=6.6Hz,3H); 4.38 ~m,SH);
,. , . _ _ 19 20~4082 ACTIVITE BIOLOGIQUX
L'activit~ pharmacologique antimicrobienne de ce~ compo~ a été étudi~e ~elon le~ r~férence~ expocée~ ci-de~sou~.
Activité pharmacologique antimicrobienne ~G.L. Daquet et Y.A. Chabbect, Techniques en bactérioloqie, Vol 3, Flammarion Médecine-Science~, Pari~ 1972,- et W.B. Hugo et A.D. Rusell, Pharmaceutical MicrobioloqY, Blackwell Scientific Publicationq, London, 1977.
Milieu de culture et ~olvant:
Agar d'antibiotique~ nQ 1 (Oxoid CM 327) Bouillon de triptone-~oja (Oxoid CM 129) Solution Physiologique Ringer ~ (Oxoid BR 52) Agar Dextrose ~BBL 11165) Microorganisme~:
"~acillu~ su~tilis~ ATCC 6633 ~Citrobacter freundii~ ATCC 112606 "Enterobacter aerogenes~ ATCC 15038 "Enterobacter cloacae~ ATCC 23355 "Bacillus cereusn ATCC 1178 nEscherichia coli~ ATCC 10799 "E~cherichia coli~ ATCC 23559 "Klebsiella pneumoniae~ ATCC 10031 "Proteus vulgaris~ ATCC 8427 "Morg, morganiin ATCC ~019 "PseudomonaJ aeruginosa~ ATCC 9721 "Pseudomona~ aeruginosa~ ATCC 10145 "Salmonella typhimurium~ ATCC 14028 nSalmonella typhimurium~ ATCC 6539 nScrratia marcescens~ ATCC 138~0 nShigella flexnerii~ ATCC 12022 "Staphylococcusepidermis ATCC 155-1 ~Staphylococcus aureus ATCC 25178 nStreptococcus faecali~ ATCC 10541 Préparation deJ inoculations Chacun de~ microorganismes est ensemencé par strie dan~ de~
tube~ d'Agar d'antibiotiques nQ 1, et mis en incubation pendant 35 20 heures à 37-C. Ensuite on prend une an~e de culture, on en~emence dan~ un bouillon de Triptone-soja et on incube pendant 20 heure~ à 37-C. On dilue a ~ la culture obtenue avec une 2 ~ 2 solution phy~iologique Ringer, de façon ~ obtenir une suspen~ion normalisée de 10'-109 ~fc/ml pour chaque organisme.
Pr~Paration du milieu contenant leq dérivéq de formule qénérale I:
A partir d'une solution de 100 ~g/ml dan3 de la soude 0,1 N, chaque produit est dilué dans l'Agar Dextrose (préalablement fondu et maintenu à 50-C) par dilution~ successive~ de fa~on à
obtenir le~ concentrations suivantes: 64-32-16-B-4-2-1-0,5-0,25-0,125 ~g de dérivé/ml du milieu.
Po~térieurement, chaque concentration de chaque produit est répartie dans de~ boîte~ de Petri de 10 cm de diamètre, ~ raison de 10 ml de milieu par boite et autant de boîtes que de microorganismes à tester.
Une foi~ le milieu refroidi, les boite~ sont ensemencée~
avec le~ inoculation~ a rai~on de 0,4 ml d'inoculation par boite.
On les ~tend avec une anse de Driglasky et on recueille le surnageant. Le~ boftes ensemencées sont incubée~ à 37'C pendant 20 heures.
Les résultats obtenus sont décrits dans les tableaux suivants, L'activité des composés n in vitro" y est comparée ~
celle de la ciprofloxacine. Les concentrations sont données en ~g/ml.

21 20~082 E X E M P L E S
MICROORGANISMES
xCapirnoelo 1 2 3 4 5 acillus subtilis 0.060.06sO.03 s0.030.03 0.25 ATCC 6633 _ _ _ Bacillus cereu~0.25 0.25s0~03s0.03 0.060.25 Strep. faecali Q 0.5 1 sO.03 0.12 0.5 2 Staph aureus 0.25 0.1250.03s0.03 0.060.25 Staph. epidermidi 8 0.5,0.1250.03 sO.030.12 P~. aerugino~a0.06 10.06 0.12 0.25 2 Ps. aeruginosa0.12 10.12 0.12 0.5 2 Citr. freundiis0.03 0.1250.03sO.03 0.030.25 Morg. morganii0.06 0.25S0.03s0.03 0.060.25 Proteus vulgari~ 0.060.5s0.03 0.060.12 ~leb. pneumoniae sO.03 0.06 S0.03sO.03 0.03 0.25 Sal. typhimurium 0.060.12sO.03 s0.030.06 0.25 Sal typhi 0.06 0.0650.03sO.03 0.120.25 Escherichia coli 0.12 0.1250.03 50.030.06 0.25 Escherichia coli s0.03 0.06 sO.03sO.03 0.03 0.25 Ent. aerogene~0.12 0.12 S0.03 s0.030.03 0.25 ~nt. cloacae s0.03 0.12 s0.03 s0.030.03 0.25 Serr. marce~cens 0.25 0.550.03 0.06 0.12 Shigella flexnerii 0.12 0.06sO.03 s0.030.03 0.25 22 2~082 A ..f _ ~ l E X E M P ~ E S
MICROORGA~SMES _ _ Bacillus subtili~ 0.12 0.06 1 0.25 0.12 0.25 Bacillu~ cereu-Y 1 0.12 1 0.5 0.25 0.5 Strep. faecali~ 2 0.5 2 2 2 4 ATCC 10541 _ Staph. aureu~ 0.25 0.12 1 0.25 0.25 0.25 Staph. epidermidis 0.5 0.12 1 0.5 0.25 0.25 Ps. aeruginosa 2 0.5 1 2 0.5 4 P~. aerugino~a 2 0.5 2 2 2 8 Citr. freundii 0.5 0.06 0.25 0.5 0.12 _ Morg. morganii 0.5 0.06 0.25 0.5 0.12 Proteus vulgari~ 1 0.12 1 1 0.5 2 ATCC 8427 .
Kleb. pneumoniae 0.5 s0.03 0.25 0.12 0.06 0.25 Sal. typhimurium 0.5 0.06 0.25 0.5 0.12 . __ Sal. typhi 0.12 sO.030.25 0.5 0.06 Eacherichi~ coli 0.5 0.06 0.25 0.5 0.12 Escherichia coli 0.25 sO.03 0.25 0.25 0.12 0.5 Ent. aerogenes0.25 0.06 0.25 0.5 0.12 0.5 Ent. cloacae 0.25 s0.030.25 0.5 0.12 .
Serr. marce~cen~ 1 0.06 0.5 1 0.12 2 ATCC 13a80 Shigella flexnerii 0.12 S0.03 0.25 0.12 0.06 0.5 AI~C ~ _______ _ _ ~

MICROORGA~ISMES _ _ sacillus -~ubtilis sO.03 0.12 0.12 0.12 0.12 0.25 .
Bacillus cereus0.060.25 0.25 0.5 0.25 0.5 ATCC 11778 .
._ Strep. faecalis0.5 2 2 2 2 4 I
Staph. aureus 0.06 0.5 0.5 0.5 0.25 0.5 _ -Staph. epidermidi~ 0.12 0.5 0.5 0.5 0.25 0.5 Ps. aeruginosa 0.5 1 1 1 2 4 P9 aeruginosa 0.5 1 1 2 2 8 ATCC 10145 _ _ Citr. freundii0.06 0.06 0.12 0.12 0.12 .. _ . _ Morg. morganii0.25 0.12 0.12 0.25 0.12 Proteus vulgaris 0.5 0.25 0.25 0.5 0.5 2 .. _ _ Kleb. pneumoniae 50.03 50.03 0.06 0.06 0.06 0.25 Sal. typhimurium 0.12 0.12 0.12 0.25 0.12 _ Sal. typhi s0.030.06 0.12 0.12 0.12 ATCC 6539 _ Escherichi~ coli 0.06 0.12 0.06 0.25 0.12 ATCC 1079~
Escherichia coli 0.06 0.06 0.12 0.12 0.12 ¦ 0.5 Ent. aerogene~0.06 0.06 0.12 0.12 0.12 0.5 Ent. cloacae 0.06 0.06 0.12 0.12 0.12 Serr. marce~cens 0.25 0.25 0.25 0.5 0.25 2 _ Shigella flexnerii s0.03 0.06 0.06 0.060.06 ~ 5 ` 24 2~9~82 .~ _ E X E M P L E S
MICROORGANISMES _ 18 ~9 20 21 22 23 Bacillus subtili-q0.12 0.12 0.06 0.120.03 S0.03 ¦ Bacil1u~ cereuQ 0.5 0.25 0.12 0.250.06 50.03 strep. faecali-~ 2 1 1 10.25 0.25 Staph. aureuQ0.5 0.25 0.12 0.12 0.120.06 ATCC 25178 _ _ Staph. epidermidi30.5 0. 250.25 0.120.12 0.12 _ _ __ __ I
Ps. aerugino~a 0. 5 0.25 1 1 0.250.12 ....
P~. aerugino~a 1 0. 5 0.5 1 0.250.25 ATC~C 10145 __ _ Citr. freundii 0.06 0.06 0.06 0.25 0.03sO. 03 .
Morg. morganii 0.25 0.12 0.12 0. 5 0.06sO. 03 Proteus vulgarisO.5 O. 25 O.25 O.5 O.03O.06 ATCC 842?
_ ~leb. pneumoniae0.06 S0.03 S0.03 0.12 0.06s0.03 ._ Sal. typhimurium0.12 0.06 0.12 0.12 0.06s0.03 ATCC 14028 _ Sal. typhi 0.06 0.06 S0. 03 0. 06 0.03s0.03 .
Escherichia coli0.12 0.12 0.06 0.12 0. 03s0.03 __ E~cherichia; coli 0.06 0.06 0.06 0.120.0 3 s0.03 Ent. aerogenes 0. 12 0.0 6 0.06 0. 12 0.0350.03 ATCC 15038 _ Ent. cloacae 0.06 0.06 S0.03 0.12 0.12s0.03 Serr. marcescens0. 250.25 0.5 0.030.06 Shigella flexnerii 0.06 0.06 s0.03 0.060.06 s0.03 ATCC 12022 _ ~ G__ ~ Y_~

_ _ _ 25 2~ , E X E M P L E S
MI~ROORGANISMES _ _ _ 24 25 26 27 28 29 ~acillus subtili~ 0.12 0.120.06s0.03s0.03 s0.03 l Bacillu~ cereu~ 0.25 0.50.120.12S0.03 0.06 Strep. faecali~ 0.5 0.250.120.250.06 0.12 Staph. aureu~ 0.120.25 0.120.06sO.0350.03 Staph. epidermidis 0.25 0.50.120.06s0.03 0.06 Ps. aeruginosa 1 1 0.120.120.120.25 Ps. aerugino~a 0.5 1 0.250.250.120.25 ATCC 10145 _ Citr. freundii 0.120.25 0.12 0.12S0.03 s0.03 Morg. morganii 0.25 0.5 S0.03 S0.03S0.03 0.12 Proteu~ vulgaris 0.25 1S0.03S0.03s0.03 0.12 Kleb. pneumoniae 0.25 0.06 0.060.12S0.03 0.12 ¦ ATCC 10031 Sal. typhimurium 0.25 0.25 0.06 0.12 50.03 0.12 ¦ ATCC 14028 Sal. typhi 0.25 0.5 S0.03 S0.03 S0.03 s0.03 E~cherichia coli 0.12 0.12 S0.03 S0.03 S0.03 50.03 E w herichia coli 0.120.12 50.03S0.03 S0.03 s0.03 Snt. aerogenes0.12 0.250.12 S0.03S0.03 0.06 ATCC 1503~
Ent. cloacae 0.25 0.12S0.03 S0.03S0.03 0.12 _ Serr. marcescens 1 1 0.12 0.12 0.25 0.5 Shigella flexnerii 0.250.12 S0.0350.03 50.03 sO.03 ATCC 12022 _______ 26 2~082 E X E M P L E S
MICROORGA~ISMES _ _ I
8acillus subtili~ 0.12 50.03 s0.03 s0.03 0.06 s0.03 ¦ Bacillu~ cereus 0.5 0.06 s0.03 s0.03 0.12 0.06 ¦ Strep. faecali~ 0.25 0.25 0.250.25 0.50 0.25 . . .
Staph. aureu~ 0.5 0.120.06 0.06 0.250.25 Staph. epidermidiQ 0.5 0.12 0.060.12 0.25 0.12 ATCC 155-1 , _ Ps. aeruginosa 4 0.50.25 0.25 1.0 1.0 Ps. aerugino~a 4 0.50.25 0.50 1.0 1.0 Citr. freundii0.5 s0.03S0.03S0.03 0.06s0.03 Morg. morganii0.25 0.06S0.03S0.03 0.06S0.03 Proteus vulgaris 0.25 0.12 0.250.12 0.25 0.12 Kleb. pneumoniae 2 O.06 s0.03 50.03 0.12 O.06 Sal. typhimuriu~ O.S SO.03 SO.03 50.03 O.12 O.06 Sal. typhi 0.25 0.06S0.03 0.06 0.120.06 Eschcrichia coli 0.25s0.03 sO.03 s0.03 0.06 s0.03 EschQrichia coli 0.25S0.03 S0.03 S0.03 0.12 s0.03 Ent. aerogenes 1 0.12 0.06 0.06 0.120.06 Ent. cloacae 0.25 0.06 0.06 0.06 0.120.12 Serr. marcescen~ 1 0.12 0.25 0.250.25 0.12 ATCC 13880 _ Shigella flexnerii0.12 0.12 0.06 0.060.25 0.06 E X E h ~
MICROORGANISMES

_ Bacillu~ Yubtilis 0.06 ¦ ATCC 6633 _ Bacillus cereu~0.06 ¦ ATCC 11778 I _ Strep. faecalis 0.25 I.. --~ _ ¦ Staph, aureuR 0.25 Staph. epidermidi~ 0.12 Ps. aerugino~a 1.0 Ps. aeruginosa 1.0 Citr. freundiisO.03 _ Morg. morganiis0.03 Proteus vulgaris 0.25 Kleb. pneumoniae 0.06 Sal. typhimurium 0.06 Sal. typhi 0.12 . ..
E~cherichi~ coli 50.03 Escherichia coli sO.03 Ent. aerogenes0.06 .
Ent. cloacae 0.06 Serr. marcescens 0.25 ATCC 13880 _ Shigella flexnerii 0.12 ATCC 12022 _ 28 2~ 82 En thérapeuti~ue humaine, la dose d'admini~tration e~t bien sûr fonction de la 4u8ceptibllité de la ~ouche infective, de la nature du composé admini~tr6 et de la voie d'admini~tration. Elle sera généralement compri~e entre environ 0,200 et environ 300 mg pour chaque kilogramme de poid~ et par jour. Les d6rivéY de l'invention seront, par exemple, admini3tré3 sous forme de comprimé~, de ~olution~ ou de ~uQpen~ions, ou bien de g61ule~.
On indiquera ci-après, ~ titre d'exemple~, deux forme~
galéniques particuliare3 des dérivés objet~ de la présente inventiOn.
Exemple de formule par comprimé:
Composé de l'exemple 1250 mg Cellule microcri~talline69 mg Povidone 15 mg Amidon de blé 36 mg Dioxyde de ~ilice colloidale 2 mg St6arate de magnésium 3 mg Poids comprimé 375 mg Exemple de formule par 961ule:
Composé de l'exemple 1250 mg Glycéride polyoxyéthylé~n6e85 mg Behenate de glycérinelS mg Excipient gélatine molle q. 8 450 mg 9 DMSO-do (m, 2H); 4.32 (m, 2H); 5.75 (d, J = 7.0Hz, 1H); 7.08 and 7.45 ~ Qist ~ me AB, J = 7.6Hz, 4H); 7.50-8.10 (m, 4H); 8.28 (~ e, 3H); 8.79 and 8.83 (2x ~, 1H) I ..
1.49 (m, 6H); 3.71 (m, 1H); 4.20 10DMSO-do / TFA (m, 1H); 4.40-5.00 (m, 4H); 7.77 ~ d, J = 12.9Hz, 1H); 8.36 (e, 3H); 8.78 8, 1H) I
1.25 and 1.31 (2xd, J = 6.50Hz, 3H);
3.62-3.92 (m, 2H); 4.20-4.42 (m, 2H);
11DMSO-d ~ / TFA 5.76 (d, J = 6.84Hz, 1H); 7.41 ~ m, 1H) i ~ 300 MHz) 7.67 (m, 1H); 7.84-7.98 (m, 2H, ~ = 7.94, J 12 7Hz ~); 8.23 (é, 3H); 8.77 and 8.80 1.21 (m, 3H); 3.68 (m, 1H); 4.21 12 DMSO-do / TFA (m, 3H); 7.10-7.90 (m, 3H); 8.09 (d J 11.3Hz, 1H); 8.17 (~, 3H); 8.80 ~ _ ~,,.,,. . ~

2 ~ 2 TABLE II (Continued) ~, ._. I
Example 1 H NMR solvent (100 MHz) 1.15 (m, 4H); 1.61 ~ d, J = 6.4Hz, 3H);
2.26 ~, 3H); 3.5 (m, 2H) i 4.33 (m, lH ~ -13 DMSO-d ~ 4.64 (m, 2H); 7.07 and 7.45 (~ ist ~ me AB, J = 7.8Hz, 4H); 8.06 (d, J = 11.4Hz, 1H); 8.33 ~ é, 3H); 8.60 ~ s, 1H) I -I
1.16 ~ m, 4H); 1.62 (d, J = 6.4Hz, 3H);
2.27 (s, 3H); 3.5 ~ m, 2H); 4.34 mt, 1H);
14 DMSO-d ~ 4.64 (m, 2H); 7.08 and 7.46 ~ system AB, J = 7.8Hz, 4H); 8.07 (d, J = 11.4Hz, 1H); 8.35 ~ é, 3H); 8.61 ~ s, 1H) 1.01 ~ m, 4H); 1.63 ~ s, 3H); 2.26 ~ s, 3H); 3.65 (m, 1H); 4.38 (é, 4H);
DMSO-d ~ 7.07 and 7.46 (system A8, J = 7.6Hz, 4H); 8.04 (d, J = 11.6Hz, 1H); 8.50 (é, 3H); 8.59 ~ s, 1H) ~.
1.13 (m, 4H); 1.65 ~ s, 3H); 2.25 ~ s, 3H); 2.66 (s, 3H); 3.75 (m, 1H);
16 DMSO-d ~ 4.28 and 4.55 ~ sisteme AB, J = 7.5Hz, 4H); 7.04 and 7.46 (if AB, J = 7.8Hz, 4H); 8.02 (d, J ~ 11.4Hz, 1H);
8.58 (s, 1H); 9.25 (6.2H) 1.20 ~ m, 3H); 3.67 ~ m, 1H); 4.23 17 DMSO-d ~ ~ m, 3H); 7.05-7.75 (ac, 3H); 7.75 la.c., 4H, 16 = 8.04, J = 11.4Hz); 8.75 ~ g, 1H) _ 1.16 (m, 4H); 1.63 (d, J = 6.3Hz, 3H);
18 DMSO-d ~ 2.32 (s, 3H); 3.77 ~ m, 2H); 4.32 (m, 1H); 4.64 (m, 2H); 8.07 (d, J = 11.4H
_ -v ~ ~ 1H), 8.34 ~ é, 3H); 8.60 ~ -, lN) - 16 ~ 0 ~ 4082 TABLE II (Continued) - '''1- _ I
Example¦ 1 H NMR solvent (100 MHz ~
_- ..
1.16 (m, 4H); 1.64 (d, J = 6.4Hz, 3H);
19 DMSO-d ~ 3.77 (m, 2H); 4.37 (m, 1H); 4.69 ~ m, 2H) 8.07 (d, J = 11.SHz, 1H); 8.60 (~, 1H);
8.72 (é, 3H) _ 1.36 (~, J = 6.0Hz, 3H); 3.59 (m, 1H);
DMSO-d ~ / TFA 4.02 (m, 1H); 4.54 (m, 2H); 7.36 (t, J = 8.7 Hz, 2H); 7.60-7.90 (ac, 3H);
8.24 (~, 3H); 8.40 (s, 1H) ._._ _ __ 1.26 and 1.32 (2xd, J = 6.1Hz, 3H); 2.28 (s, 3H); 3.64-3.92 (m, 2H); 4.16-4.42 21 DMSO-d ~ ~ m, 2H); 5.76 ~ d, J = 7.3Hz, 1H); 7.11 and ~ 300 MHz) 7.46 ~ AB system, J = 7.98Hz, 4H);
7.72-7.84 ~ m, 4H ~ = 7.98, J = 12.68Hz));
8.16 ~ é, 3H); 8.81 and 8.85 ~ 2xs, 1H) 1.26 ~ m, 4H); 1.56 ~ d, J = 6.0Hz, 3H);
22 DMSO-d ~ 2.34 ~ s, 3H); 3.7 ~ m, 3H); 4.53 ~ m, 2H);
7.04 ~ d, J-7.7Hz, 1H); 7.83 (d, J = 12.8Hz 1H); 8.43 (e, 3H); 8.60 (s, 1H) .. _ ._ 23 DMSO-d ~ TPA 1.01 (m, 4H); 3.70-4.60 (m, 6H); 8.30 (é, 3H); 8.40 (~, 1H) I
1.29 and 1.33 ~ 2xd, J = 6.0Hz, 3H); 3.70 ~ m, 1H); 3.89 (m, 1H); 4.35 (m, 2H);
24 DMso-da 5.77 ~ d, J = 6.9Hz, 1H); 7.47 (m, 1H);
~ 300 MHz) 7.57 ~ m, 1H); 7.89-8.00 (ac, 2H, ~ =
7.95, d, J = 12.9Hz)); 8.30-8.70 (~, 2H);
. . ~

~ 17 ~ 082 TABLE II (Continued) ¦ Example NMR-H Solvent (100 MHz ~
. _ 1.28 and 1.32 (2xd, J = 6.0Hz, 3H); 2.31 (- ~, 3H); 3.29 (é, 2H); 3.71 (m, 1H ~;
DMSO-d ~ 3.84 (m, 1H); 4.20-4.43 (m, 2H); 5.77 ~ 300 MHz) (d, J = 7.2Hz, l ~); 7.45 (m, 1H); 7.55 (m, 1H); 7.88-8.00 (ac, 2H, l ~ = 7.96, d, J = 12.6Hz)); 8.79 and 8.82 ~ 2x ~, 1H) 0.80-1.30 (m, 4H); 3.90-4.95 (m, 6H);
26 DMSO-d ~ / TFA 7.74 Id, J = 13.7Hz, 1H); 8.45 (e, 3H);
8.73 ~, 1H) _ 0.75-1.32 ~ m, 4H); 2.63 ~ s, 3H); 3.90-27 DMSO-da / TFA 4 90 ~, 6H); 7.73 ~ d, J = 13.6Hz, 1H);
__ 3.99 ~ m, 1H); 4.42 ~ m, 2H); 4.70 28 DMSO-d ~ ~ m, 2H); 7.10-8.05 ~ ac, 4H, (~ = 7.91, d, J = 13.9Hz ~); 8.26 ~ 6.3H); 8.56 (~, 1H) 2.50 (~, 3H); 3.97 (m, 1H); 4.51 29 DMSo-d ~ TeA (m, 4H); 7.10-8.00 (ac, 4H, ~ = 7.90, d, J = 13.8Hz)); 8.55 ~ s, 1H); 9.07 (é, 2H) _ 0.78 (m, 1H); 1.08 (m, 2H); 1.30 DMSO-d ~ / TFA (m, 1H); 1.50 (d, J = 6.0Hz, 3H); 3.71 (300 MHz) (m, 1H); 4.09 (m, 1H); 4.34 (m, 1H ~;
5.01 (m, 2H); 7.81 (d, J = 13.8Hz, 1H);
~ ____.__ ~ 8.39 (6.3H), 8 76 (9 ~ ln) 18 2 ~ Q ~ 2 TABLE II ~ Continued) . , ~.
Example 1 H NMR solvent 100 MHz ~
. , ~.
31 DMSO-d ~ / TFA 1.49 (4.3H); 4.20 (m, 4H); 7.10-8.00 ~ m, 3H); 8.31 (é, 4H) 1.33 (m, 3H); 3.57 (m, 1H); 3.89 32 DMSO-d ~ / TFA (m, 1H); 4.50 (m, 2H); 7.05-8.00 (m, 3H); 8.20 (é, 3H); 8.32 (~, 1H) ._ 33 DMSO-do / TFA 3.90-4.80 (m, 5H); 7.05-8.05 (m, 3H);
8.30 (~, 4H) ...
1.36 (t, J = 6.6Hz, 3H); 1.59 (~, 3H);
34 DMSO-d ~ / TFA 4.40 ~ m, 6H); 8.34 (~, 3H); 8.60 8.1 ~) 1.35 (t, J ~ 6.8Hz, 3H); 1.50 (d, J = 6.0Hz, DMSO-da / TFA 3H); 3.5-4.90 ~ m, 6H); 8.31 ~, 3H);
8.59 ~, 1H) -.
36 DMSO-d./TFA 1.36 (t, J = 6.6Hz, 3H); 4.38 ~ m, SH);
,. ,. _ _ 19 20 ~ 4082 BIOLOGICAL ACTIVITY
The antimicrobial pharmacological activity of this ingredient been studied ~ e ~ according to ~ r ~ ference ~ expocée ~ ci ~ de ~ sou ~.
Antimicrobial pharmacological activity ~ GL Daquet and YA Chabbect, Techniques in bacteriology, Vol 3, Flammarion Médecine-Science ~, Pari ~ 1972, - and WB Hugo and AD Rusell, Pharmaceutical MicrobioloqY, Blackwell Scientific Publicationq, London, 1977.
Culture medium and solvent:
Antibiotic agar ~ nQ 1 (Oxoid CM 327) Triptone broth - ~ oja (Oxoid CM 129) Ringer Physiological Solution ~ (Oxoid BR 52) Dextrose Agar ~ BBL 11165) Microorganism ~:
"~ acillu ~ su ~ tilis ~ ATCC 6633 ~ Citrobacter freundii ~ ATCC 112606 "Enterobacter aerogenes ~ ATCC 15038 "Enterobacter cloacae ~ ATCC 23355 "Bacillus cereusn ATCC 1178 nEscherichia coli ~ ATCC 10799 "E ~ cherichia coli ~ ATCC 23559 "Klebsiella pneumoniae ~ ATCC 10031 "Proteus vulgaris ~ ATCC 8427 "Morg, morganiin ATCC ~ 019 "PseudomonaJ aeruginosa ~ ATCC 9721 "Pseudomona ~ aeruginosa ~ ATCC 10145 "Salmonella typhimurium ~ ATCC 14028 nSalmonella typhimurium ~ ATCC 6539 nScrratia marcescens ~ ATCC 138 ~ 0 nShigella flexnerii ~ ATCC 12022 "Staphylococcusepidermis ATCC 155-1 ~ Staphylococcus aureus ATCC 25178 nStreptococcus faecali ~ ATCC 10541 Preparation of inoculations Each of ~ microorganisms is seeded by streak dan ~ of ~
tube agar of antibiotics nQ 1, and incubated for 35 8 p.m. at 37-C. Then we take a year of culture, we in ~ emence dan ~ a triptone-soy broth and incubated for 8 p.m. ~ at 37-C. The culture obtained is diluted with a 2 ~ 2 physiological solution Ringer, so as to obtain a suspension normalized from 10'-109 ~ fc / ml for each organism.
Pr ~ Paration of the medium containing the derivative of formula General I:
From a solution of 100 ~ g / ml dan3 of 0.1 N sodium hydroxide, each product is diluted in Agar Dextrose (previously melted and maintained at 50-C) by dilution ~ successive ~ so ~ on obtain the following concentrations: 64-32-16-B-4-2-1-0,5-0,25-0.125 ~ g of derivative / ml of the medium.
Po ~ térieurement, each concentration of each product is distributed in ~ 10 cm diameter Petri dish, ~ reason 10 ml of medium per box and as many boxes as microorganisms to be tested.
Faith ~ the cooled environment, the boxes ~ are sown ~
with the ~ inoculation ~ a rai ~ on 0.4 ml of inoculation per box.
We stretch them out with a Driglasky handle and collect the supernatant. The ~ seeded bots are incubated ~ at 37'C for 20 hours.
The results obtained are described in the tables following, The activity of compounds n in vitro "is compared to it ~
that of ciprofloxacin. The concentrations are given in ~ g / ml.

21 20 ~ 082 EXAMPLES
MICROORGANISMS
xCapirnoelo 1 2 3 4 5 acillus subtilis 0.060.06sO.03 s0.030.03 0.25 ATCC 6633 _ _ _ Bacillus cereu ~ 0.25 0.25s0 ~ 03s0.03 0.060.25 Strep. faecali Q 0.5 1 sO.03 0.12 0.5 2 Staph aureus 0.25 0.1250.03s0.03 0.060.25 Staph. epidermidi 8 0.5,0.1250.03 sO.030.12 P ~. aerugino ~ a0.06 10.06 0.12 0.25 2 Ps. Aeruginosa0.12 10.12 0.12 0.5 2 Citr. freundiis0.03 0.1250.03sO.03 0.030.25 Morg. morganii0.06 0.25S0.03s0.03 0.060.25 Proteus vulgari ~ 0.060.5s0.03 0.060.12 ~ leb. pneumoniae sO.03 0.06 S0.03sO.03 0.03 0.25 Sal. typhimurium 0.060.12sO.03 s0.030.06 0.25 Sal typhi 0.06 0.0650.03sO.03 0.120.25 Escherichia coli 0.12 0.1250.03 50.030.06 0.25 Escherichia coli s0.03 0.06 sO.03sO.03 0.03 0.25 Ent. aerogenic ~ 0.12 0.12 S0.03 s0.030.03 0.25 ~ nt. cloacae s0.03 0.12 s0.03 s0.030.03 0.25 Serr. marce ~ cens 0.25 0.550.03 0.06 0.12 Shigella flexnerii 0.12 0.06sO.03 s0.030.03 0.25 22 2 ~ 082 A ..f _ ~ l EXEMP ~ ES
MICROORGA ~ SMES _ _ Bacillus subtili ~ 0.12 0.06 1 0.25 0.12 0.25 Bacillu ~ cereu-Y 1 0.12 1 0.5 0.25 0.5 Strep. faecali ~ 2 0.5 2 2 2 4 ATCC 10541 _ Staph. aureu ~ 0.25 0.12 1 0.25 0.25 0.25 Staph. epidermidis 0.5 0.12 1 0.5 0.25 0.25 Ps. Aeruginosa 2 0.5 1 2 0.5 4 P ~. aerugino ~ a 2 0.5 2 2 2 8 Citr. freundii 0.5 0.06 0.25 0.5 0.12 _ Morg. morganii 0.5 0.06 0.25 0.5 0.12 Proteus vulgari ~ 1 0.12 1 1 0.5 2 ATCC 8427.
Kleb. pneumoniae 0.5 s0.03 0.25 0.12 0.06 0.25 Sal. typhimurium 0.5 0.06 0.25 0.5 0.12 . __ Sal. typhi 0.12 sO.030.25 0.5 0.06 Eacherichi ~ coli 0.5 0.06 0.25 0.5 0.12 Escherichia coli 0.25 sO.03 0.25 0.25 0.12 0.5 Ent. aerogenes 0.25 0.06 0.25 0.5 0.12 0.5 Ent. cloacae 0.25 s0.030.25 0.5 0.12 .
Serr. marce ~ cen ~ 1 0.06 0.5 1 0.12 2 ATCC 13a80 Shigella flexnerii 0.12 S0.03 0.25 0.12 0.06 0.5 AI ~ C ~ _______ _ _ ~

MICROORGA ~ ISMES _ _ sacillus - ~ ubtilis sO.03 0.12 0.12 0.12 0.12 0.25 .
Bacillus cereus 0.060.25 0.25 0.5 0.25 0.5 ATCC 11778.
._ Strep. faecalis0.5 2 2 2 2 4 I
Staph. aureus 0.06 0.5 0.5 0.5 0.25 0.5 _ -Staph. epidermidi ~ 0.12 0.5 0.5 0.5 0.25 0.5 Ps. Aeruginosa 0.5 1 1 1 2 4 P9 aeruginosa 0.5 1 1 2 2 8 ATCC 10145 _ _ Citr. freundii0.06 0.06 0.12 0.12 0.12 .. _. _ Morg. morganii0.25 0.12 0.12 0.25 0.12 Proteus vulgaris 0.5 0.25 0.25 0.5 0.5 2 .. _ _ Kleb. pneumoniae 50.03 50.03 0.06 0.06 0.06 0.25 Sal. typhimurium 0.12 0.12 0.12 0.25 0.12 _ Sal. typhi s0.030.06 0.12 0.12 0.12 ATCC 6539 _ Escherichi ~ coli 0.06 0.12 0.06 0.25 0.12 ATCC 1079 ~
Escherichia coli 0.06 0.06 0.12 0.12 0.12 ¦ 0.5 Ent. aerogenic ~ 0.06 0.06 0.12 0.12 0.12 0.5 Ent. cloacae 0.06 0.06 0.12 0.12 0.12 Serr. marce ~ cens 0.25 0.25 0.25 0.5 0.25 2 _ Shigella flexnerii s0.03 0.06 0.06 0.060.06 ~ 5 `24 2 ~ 9 ~ 82 . ~ _ EXAMPLES
MICROORGANISMS _ 18 ~ 9 20 21 22 23 Bacillus subtili-q0.12 0.12 0.06 0.120.03 S0.03 ¦ Bacil1u ~ cereuQ 0.5 0.25 0.12 0.250.06 50.03 strep. faecali- ~ 2 1 1 10.25 0.25 Staph. aureuQ0.5 0.25 0.12 0.12 0.120.06 ATCC 25178 _ _ Staph. epidermidi30.5 0. 250.25 0.120.12 0.12 _ _ __ __ I
Ps. Aerugino ~ a 0. 5 0.25 1 1 0.250.12 ....
P ~. aerugino ~ a 1 0. 5 0.5 1 0.250.25 ATC ~ C 10145 __ _ Citr. freundii 0.06 0.06 0.06 0.25 0.03sO. 03 .
Morg. morganii 0.25 0.12 0.12 0. 5 0.06sO. 03 Proteus vulgaris O.5 O. 25 O.25 O.5 O.03O.06 ATCC 842?
_ ~ leb. pneumoniae0.06 S0.03 S0.03 0.12 0.06s0.03 ._ Sal. typhimurium0.12 0.06 0.12 0.12 0.06s0.03 ATCC 14028 _ Sal. typhi 0.06 0.06 S0. 03 0. 06 0.03s0.03 .
Escherichia coli0.12 0.12 0.06 0.12 0. 03s0.03 __ E ~ cherichia; coli 0.06 0.06 0.06 0.120.0 3 s0.03 Ent. aerogenic 0.12 0.0 6 0.06 0.12 0.0350.03 ATCC 15038 _ Ent. cloacae 0.06 0.06 S0.03 0.12 0.12s0.03 Serr. marcescens0. 250.25 0.5 0.030.06 Shigella flexnerii 0.06 0.06 s0.03 0.060.06 s0.03 ATCC 12022 _ ~ G__ ~ Y_ ~

_ _ _ 25 2 ~, EXAMPLES
MI ~ ROORGANISMS _ _ _ 24 25 26 27 28 29 ~ acillus subtili ~ 0.12 0.120.06s0.03s0.03 s0.03 l Bacillu ~ cereu ~ 0.25 0.50.120.12S0.03 0.06 Strep. faecali ~ 0.5 0.250.120.250.06 0.12 Staph. aureu ~ 0.120.25 0.120.06sO.0350.03 Staph. epidermidis 0.25 0.50.120.06s0.03 0.06 Ps. Aeruginosa 1 1 0.120.120.120.25 Ps. Aerugino ~ a 0.5 1 0.250.250.120.25 ATCC 10145 _ Citr. freundii 0.120.25 0.12 0.12S0.03 s0.03 Morg. morganii 0.25 0.5 S0.03 S0.03S0.03 0.12 Proteu ~ vulgaris 0.25 1S0.03S0.03s0.03 0.12 Kleb. pneumoniae 0.25 0.06 0.060.12S0.03 0.12 ¦ ATCC 10031 Sal. typhimurium 0.25 0.25 0.06 0.12 50.03 0.12 ¦ ATCC 14028 Sal. typhi 0.25 0.5 S0.03 S0.03 S0.03 s0.03 E ~ cherichia coli 0.12 0.12 S0.03 S0.03 S0.03 50.03 E w herichia coli 0.120.12 50.03S0.03 S0.03 s0.03 Snt. aerogenes0.12 0.250.12 S0.03S0.03 0.06 ATCC 1503 ~
Ent. cloacae 0.25 0.12S0.03 S0.03S0.03 0.12 _ Serr. marcescens 1 1 0.12 0.12 0.25 0.5 Shigella flexnerii 0.250.12 S0.0350.03 50.03 sO.03 ATCC 12022 _______ 26 2 ~ 082 EXAMPLES
MICROORGA ~ ISMES _ _ I
8acillus subtili ~ 0.12 50.03 s0.03 s0.03 0.06 s0.03 ¦ Bacillu ~ cereus 0.5 0.06 s0.03 s0.03 0.12 0.06 ¦ Strep. faecali ~ 0.25 0.25 0.250.25 0.50 0.25 . . .
Staph. aureu ~ 0.5 0.120.06 0.06 0.250.25 Staph. epidermidiQ 0.5 0.12 0.060.12 0.25 0.12 ATCC 155-1, _ Ps. Aeruginosa 4 0.50.25 0.25 1.0 1.0 Ps. Aerugino ~ a 4 0.50.25 0.50 1.0 1.0 Citr. freundii0.5 s0.03S0.03S0.03 0.06s0.03 Morg. morganii0.25 0.06S0.03S0.03 0.06S0.03 Proteus vulgaris 0.25 0.12 0.250.12 0.25 0.12 Kleb. pneumoniae 2 O.06 s0.03 50.03 0.12 O.06 Sal. typhimuriu ~ OS SO.03 SO.03 50.03 O.12 O.06 Sal. typhi 0.25 0.06S0.03 0.06 0.120.06 Eschcrichia coli 0.25s0.03 sO.03 s0.03 0.06 s0.03 EschQrichia coli 0.25S0.03 S0.03 S0.03 0.12 s0.03 Ent. aerogenes 1 0.12 0.06 0.06 0.120.06 Ent. cloacae 0.25 0.06 0.06 0.06 0.120.12 Serr. marcescen ~ 1 0.12 0.25 0.250.25 0.12 ATCC 13880 _ Shigella flexnerii0.12 0.12 0.06 0.060.25 0.06 EXE h ~
MICROORGANISMS

_ Bacillu ~ Yubtilis 0.06 ¦ ATCC 6633 _ Bacillus cereu ~ 0.06 ¦ ATCC 11778 I _ Strep. faecalis 0.25 I .. - ~ _ ¦ Staph, aureuR 0.25 Staph. epidermidi ~ 0.12 Ps. Aerugino ~ a 1.0 Ps. Aeruginosa 1.0 Citr. freundiisO.03 _ Morg. morganiis0.03 Proteus vulgaris 0.25 Kleb. pneumoniae 0.06 Sal. typhimurium 0.06 Sal. typhi 0.12 . ..
E ~ cherichi ~ coli 50.03 Escherichia coli sO.03 Ent. aerogenes0.06 .
Ent. cloacae 0.06 Serr. 0.25 marcescens ATCC 13880 _ Shigella flexnerii 0.12 ATCC 12022 _ 28 2 ~ 82 In human therapy, the administration dose is good sure function of the 4u8ceptibllité of ~ infective ouche, of nature of the compound administered and the route of administration. She will generally be between about 0.200 and about 300 mg for each kilogram of weight ~ and per day. The derivatives of the invention will, for example, be administered in the form of tablet ~, ~ ~ solution ~ or ~ uQpen ~ ions, or capsule ~.
We will indicate below, ~ as an example ~, two forms ~
galenic particuliare3 of the derivatives object ~ of this invention.
Example of formula per tablet:
Compound of example 1250 mg Microcrystalline cell69 mg Povidone 15 mg Wheat starch 36 mg Dioxide of colloidal ilium 2 mg Magnesium st6arate 3 mg Tablet weight 375 mg Example of formula by 961ule:
Compound of example 1250 mg Polyoxyethylated glyceride ~ n6e85 mg Glycerin behenate mg Excipient soft gelatin q. 8,450 mg

Claims

1.- Les composés de la présente invention répondant à la formule générale I

I

dans laquelle A représente un atome un atome d'azote ou bien un atome de carbone avec un atome d'hydrogène attache (C-H), ou bien un atome de carbone avec un halogène attaché (C-X), dans ce cas X
représente un atome de chlore, de fluor ou de brome ou bien un atome de carbone avec un radical hydroxy (C-OH).
R2 représente un radical alkyle ou cycloalkyle inférieur, un radical halogénoalkyle inférieur, un radical aryle ou un radical aryle substitué, notamment par un ou plusieurs atome(s) de fluor.
R2 et R3 représentent un atome d'hydrogène, un radical alkyle inférieur, un radical hydroxyle, un radical amino, un radical aminoalkyle, un radical alkylamino, un radical dialkylamino, un radical hétérocyclique azoté de préférence aromatique pouvant être un cycle de trois à six maillons, un radical alkylaminoalkyle, un radical alkylcarboxamido, et dans ce dernier ca-, le radical alkyle pouvant être substitué par un ou plusieurs halogènes, un radical arylsulfonyloxy, un radical alkylsulfonyloxy, un radical carboxamido, pouvant être substitué
ou non sur l'azote, ou un radical cyano.
R4 et R5, égaux ou différents, représentent un atome d'hydrogène ou un radical alkyle inférieur.
R4 représente un atome d'hydrogène, un radical nitro, un radical amino ou amino substitué.
R7 représente un radical hydroxy ou un radical alkyloxy inférieur de C1 à C4.
A et R1 peuvent former ensemble une liaison représentée par un groupe C-CH2-CH2-CHR?- ou C-O-CH2-CHR?- dans lesquels R5 représente un atome d'hydrogène ou un radical alkyle inférieur, et dans ce dernier cas, on a un centre chiral avec une configuration "R" ou "S". 1.- The compounds of the present invention corresponding to the general formula I

I

in which A represents an atom, a nitrogen atom or an atom of carbon with one attached hydrogen atom (CH), or one atom carbon with attached halogen (CX), in this case X
represents a chlorine, fluorine or bromine atom or a carbon atom with a hydroxy radical (C-OH).
R2 represents a lower alkyl or cycloalkyl radical, a lower haloalkyl radical, an aryl radical or a radical aryl substituted, in particular by one or more fluorine atom (s).
R2 and R3 represent a hydrogen atom, a radical lower alkyl, a hydroxyl radical, an amino radical, a aminoalkyl radical, an alkylamino radical, a radical dialkylamino, preferably a heterocyclic nitrogen radical aromatic can be a cycle of three to six links, a alkylaminoalkyl radical, an alkylcarboxamido radical, and in this last ca-, the alkyl radical being able to be substituted by one or several halogens, an arylsulfonyloxy radical, a radical alkylsulfonyloxy, a carboxamido radical, which can be substituted or not on nitrogen, or a cyano radical.
R4 and R5, equal or different, represent an atom hydrogen or a lower alkyl radical.
R4 represents a hydrogen atom, a nitro radical, a amino or substituted amino radical.
R7 represents a hydroxy radical or an alkyloxy radical lower from C1 to C4.
A and R1 can together form a bond represented by a group C-CH2-CH2-CHR? - or CO-CH2-CHR? - in which R5 represents a hydrogen atom or a lower alkyl radical, and in the latter case, we have a chiral center with a "R" or "S" configuration.

2.- Les composés répondant à la formule générale I, selon la revendication 1, sélectionnés parmi le groupe suivant:
? Acide 7-[(2S,3R)-3-amino-2-méthyl-1-azétidinyl]-1-(2,4-di-fluorophényl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoléincarboxy-lique.
? Acide 7-[(2S,3R)-3-amino-2-méthyl-1-azétidinyl]-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
? Acide 5-amino-7-[(2S,3R)-3-amino-2-méthyl-1-azétidinyll-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoléincar-boxylique.
? Acide 7-[(2S,3S)-3-amino-2-méthyl-1-azétidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
? Acide 7-[(2R,3R)-3-amino-2-méthyl-1-azétidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
? Acide 7-[(2S,3R)-3-amino-2-méthyl-1-azétidinyl]-8-chloro-1-(2,4-difluorophényl)-6-fluoro-1,4-dihydro-4-oxo-3-guinoléin-carboxylique.
? p-toluènsulfonate de l'acide 7-(3-amino-3-méthyl-1-asétidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoléin-carboxylique.
? p-toluenaulfonate de l'acide 7-[(2RS,3SR)-3-amino-2-méthyl-1-azétidinyl]-6,8-difluoro-1-éthyl-1,4-dihydro-4-oxo-3-quinoléin-carboxylique.
? p-toluènsulfonate de l'acide 7-(2RS,3SR)-3-amino-2-méthyl-1-azétitinyl]-1-(2,4-difluorophényl)-6-fluoro-1,4-dihydro-4-oxo-2.- The compounds corresponding to the general formula I, according to the claim 1, selected from the following group:
? Acid 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -1- (2,4-di-fluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboxy-lique.
? Acid 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic.
? 5-amino-7 acid - [(2S, 3R) -3-amino-2-methyl-1-azetidinyll-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoléincar-boxylic.
? Acid 7 - [(2S, 3S) -3-amino-2-methyl-1-azetidinyl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic.
? Acid 7 - [(2R, 3R) -3-amino-2-methyl-1-azetidinyl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic.
? Acid 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -8-chloro-1-(2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-guinoline-carboxylic.
? 7- (3-amino-3-methyl-1-asetidinyl) acid p-toluensulfonate -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic.
? 7 - [(2RS, 3SR) -3-amino-2-methyl-1- acid p-toluenaulfonate azetidinyl] -6,8-difluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinoline-carboxylic.
? 7- (2RS, 3SR) -3-amino-2-methyl-1- acid p-toluensulfonate azetitinyl] -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-

3-quinoleincarboxylique.
? Acide 7-[(2S,3R)-3-amino-2-méthyl-1-azétidinyl]-6,8-difluoro-1-éthyl-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
? Acide 7-[(2R,3S)-3-amino-2-méthyl-1-azétidinyl]-1-(2,4-difluorophényl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoléin-carboxylique.
? Acide 7-[12S,3R)-3-amino-2-méthyl-1-azétidinyll-1-(2,4-difluorophényl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphtyritine-3-carboxylique.
? p-toluenèulfonate de l'acide 7-[(2RS,3SR)-3-amino-2-méthyl-1-azétidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphtyridine-3-carboxylique.

? p-toluènsulfonate de l'acide 7-[(2S,3R)-3-amino-2-méthyl-1-azétidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphtyridine-3-carboxylique.
? p-toluènsulfonate de l'acide 7-(3-amino-3-méthyl-1-azétidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphtyridine-3-carboxylique.
? p-toluènsulfonate de l'acide 1-cyclopropyl-6-fluoro-7-(3-méthyl-3-méthylamino-1-azétidinyl)-1,4-dihydro-4-oxo-1,8-naphtyridine-3-carboxylique.
? Acide 7-[(2R,3S)-3-amino-2-méthyl-1-azétidinyl]-1-(2,4-difluorophényl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphtyridine-3-carboxylique.
? Méthylsulfonate de l'acide 7-[(2S,3R)-3-amino-2-méthyl-1-azétidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphtyridine-3-carboxylique.
? Chlorhydrate de l'acide 7-[(2S,3R)-3-amino-2-méthyl-1-azétidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphtyridine-3-carboxylique.
? Acide 7-1(2S,3R)-3-amino-2-méthyl-1-azétidinyl]-6,8-difluoro-1-(2,4-difluorophényl)-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
p-toluènsulfonate de l'acide 7-[(2S,3R)-3-amino-2-methyl-1-azétidinyl]-1-(2,4-difluorophényl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylique.
? Méthylsulfonate de l'acide 7-[(2RS,3SR)-3-amino-2-méthyl-1-azétidinyl]-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoléincarboYylique.
? Acide 5-amino-7-(3-amino-1-azétidinyl]-1-cyclopropyl-6,8-tifluoro-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
? Chlorhydraté de l'acide 7-[(2S,38)-3-amino-2-méthyl-1-azédinyl]-1-(2,4-difluorophényl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
? Méthylsulfonate de l'acide 7-[(2S,3R)-3-amino-2-méthyl-1-azétidinyl]-1-(2,4-difluorophényl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylique.
? Acide 7-(3-amino-1-azétidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
? Acite 8-chloro-1-cyclopropyl-6 fluoro-7-(3-méthylamino-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
? Acide 7-(3-amino-1-azétidinyl)-8-chloro-1-(2,4-difluorophényl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
? Acide 8-chloro-1-(2,4-difluorophényl)-6-fluoro-7-(3-méthyl-amino-1-azétidinyl)-1-4-dihydro-4-oxo-3-quinoléincarboxylique.
? Acide 7-[(2R,3S)-3-amino-2-méthyl-1-azétidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoléin-carboxylique.
? Acide 5-amino-7-(3-amino-3-méthyl-1-azétidinyl)-6,8-difluoro-1-(2,4-difluorophényl)-1,4-dihydro-4-oxo-3-quinoléincarboxy-lique.
? Acide 5-amino-7-1(2S,3R)-3-amino-2-méthyl-1-azétidinyl]-6,8-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinoléin-carboxylique.
? Acide 5-amino-7-(3-amino-1-azétildinyl)-6,8-difluoro-1-12,4-difluorophényl)-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
? Acide 5-amino-7-(3-amino-3-méthyl-1-azétidinyl)-6,8-difluoro-1-éthyl-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
? Acide 5-amino-7-[(2S,3R)-3-amino-2-méthyl-1-azétidinyl]-6,8-difluoro-1-éthyl-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
? Acide 5-amino-7-(3-amino-1-azétidinyl)-6,8-difluoro-1-éthyl-1,4-dihydro-4-oxo-3-quinoléincarboxylique.
3.- Procédé de préparation de ces composés, selon l'une quelconque des revendications 1 et 2 et qui se caractérise par la réaction d'un composé de formule générale II

II

dans l'aquellè
A, R1, R6, et R7 ont les significations mentionnées précédemment et Z représente un atome d'halogène, de préférence un chlore ou un fluor, avec une azétidine, de formule générale III.

III

dans laquelle R2, R3, R4 et R5, ont les significations mentionnées précédemment. 3-quinoleincarboxylic.
? Acid 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -6,8-difluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinoleincarboxylic.
? Acid 7 - [(2R, 3S) -3-amino-2-methyl-1-azetidinyl] -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic.
? Acid 7- [12S, 3R) -3-amino-2-methyl-1-azetidinyll-1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyritin-3-carboxylic.
? 7 - [(2RS, 3SR) -3-amino-2-methyl-1- acid p-toluene sulfonate azetidinyl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic.

? 7 - [(2S, 3R) -3-amino-2-methyl-1- acid p-toluensulfonate azetidinyl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic.
? 7- (3-amino-3-methyl-1-azetidinyl) acid p-toluensulfonate -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic.
? 1-cyclopropyl-6-fluoro-7- (3- 3- p-toluensulfonate) methyl-3-methylamino-1-azetidinyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic.
? Acid 7 - [(2R, 3S) -3-amino-2-methyl-1-azetidinyl] -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic.
? Acid methylsulfonate 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic.
? Acid hydrochloride 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic.
? Acid 7-1 (2S, 3R) -3-amino-2-methyl-1-azetidinyl] -6,8-difluoro-1-(2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinoleincarboxylic.
7 - [(2S, 3R) -3-amino-2-methyl-1- acid p-toluensulfonate azetidinyl] -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic.
? Acid methylsulfonate 7 - [(2RS, 3SR) -3-amino-2-methyl-1-azetidinyl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboYyl.
? 5-amino-7- (3-amino-1-azetidinyl] -1-cyclopropyl-6,8- acid tifluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic.
? 7 - [(2S, 38) -3-amino-2-methyl-1- acid hydrochloride azedinyl] -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic.
? Acid methylsulfonate 7 - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic.
? 7- (3-amino-1-azetidinyl) -8-chloro-1-cyclopropyl-6-fluoro- acid-1,4-dihydro-4-oxo-3-quinoleincarboxylic.
? Acite 8-chloro-1-cyclopropyl-6 fluoro-7- (3-methylamino-1-azetidinyl) -1,4-dihydro-4-oxo-3-quinoleincarboxylic.
? 7- (3-amino-1-azetidinyl) -8-chloro-1- (2,4-difluorophenyl) acid -6-fluoro-1,4-dihydro-4-oxo-3-quinoleincarboxylic.
? 8-chloro-1- (2,4-difluorophenyl) -6-fluoro-7- (3-methyl-amino-1-azetidinyl) -1-4-dihydro-4-oxo-3-quinoleincarboxylic.
? Acid 7 - [(2R, 3S) -3-amino-2-methyl-1-azetidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic.
? 5-amino-7- (3-amino-3-methyl-1-azetidinyl) -6,8-difluoro- acid 1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinoléincarboxy-lique.
? 5-amino-7-1 (2S, 3R) -3-amino-2-methyl-1-azetidinyl] -6,8-difluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-3-quinoline-carboxylic.
? 5-amino-7- (3-amino-1-azetildinyl) -6,8-difluoro-1-12,4- acid difluorophenyl) -1,4-dihydro-4-oxo-3-quinoleincarboxylic.
? 5-amino-7- (3-amino-3-methyl-1-azetidinyl) -6,8-difluoro- acid 1-ethyl-1,4-dihydro-4-oxo-3-quinoleincarboxylic.
? 5-amino-7 acid - [(2S, 3R) -3-amino-2-methyl-1-azetidinyl] -6,8-difluoro-1-ethyl-1,4-dihydro-4-oxo-3-quinoleincarboxylic.
? 5-amino-7- (3-amino-1-azetidinyl) -6,8-difluoro-1-ethyl- acid 1,4-dihydro-4-oxo-3-quinoleincarboxylic.
3.- Process for the preparation of these compounds, according to one any of claims 1 and 2 and which is characterized by the reaction of a compound of general formula II

II

in which A, R1, R6, and R7 have the meanings mentioned previously and Z represents a halogen atom, preferably a chlorine or a fluorine, with an azetidine, of formula general III.

III

in which R2, R3, R4 and R5, have the meanings mentioned previously.

4.- A titre de médicaments, les dérivés de formule générale I et leurs sels thérapeutiquement acceptables, selon les revendications 1 à 2, en particulier à titre de médicaments destinés au traitement de certaines maladies infectieuses. 4.- As medicaments, the derivatives of general formula I and their therapeutically acceptable salts, according to the claims 1 to 2, in particular as medicaments intended for the treatment of certain infectious diseases.

5.- Compositions pharmaceutiques, caractérisées par le fait qu'elles contiennent, outre un support pharmaceutiquement acceptable, au moins un dérivé de formule générale I ou l'un de ses sels physiologiquement acceptables, selon l'une des revendications 1 à 2. 5.- Pharmaceutical compositions, characterized by the fact that they contain, in addition to a pharmaceutical carrier acceptable, at least one derivative of general formula I or one of its physiologically acceptable salts, according to one of claims 1 to 2.

6.- Utilisation des dérivés de formule générale I et leurs sels physiologiquement acceptables, selon l'une des revendications 1 à 2, pour la fabrication de médicaments destinés au traitement des infections microbiennes. 6.- Use of derivatives of general formula I and their physiologically acceptable salts, according to one of claims 1 to 2 for the manufacture of medicaments intended in the treatment of microbial infections.