FR2858324A1 - Composition used for treating microbial infections, effective particularly against rifampicin-resistant bacteria, contain new or known 5-(heterocyclylmethylene)-thiazolidine derivatives - Google Patents

Abstract

Composition contains 3-substituted 5-(heterocyclylmethylene)-thiazolidine-2,4-one derivatives (including thione and/or imine analogs) (I) as active agents. Compositions containsa at least one thiazolidine derivative of formula (I) (in E- or Z-form or as an E/Z-mixture and including thione and/or imine analogs)) as an active agent, together with a carrier. [Image] X, Y : O, S, NH or NR; R : 1-5C alkyl (optionally substituted (os) by N or O); Ra1-16C alkyl or 2-16C alkenyl (both os by halo, CHO, COOH, CN, COOM, SR1, SOR1, SO2R1, SO2, SO2OH, SO3M, CF3, CHF2, (CF2)mCF3 or (CF2)mCF3) or 5- or 6-membered heterocyclyl (specifically 2-furanyl, 2-tetrahydrofuranyl, morpholino, 3-pyridinyl, N-(R6)-piperazino), 2-oxo-pyrrolidino, 4-hydroxy-2-oxo-pyrrolidino, 2-carboxypyrroldino or 2-carboxy-4-hydroxypyrrolidino); M : alkali(ne earth) metal (specifically Na, Ca, Mg, Al (sic), Zn (sic) or Li); R1H or 1-16C alkyl (specifically Me, Et or tert. butyl); m : 1-3; A : 5- or 6-membered heterocyclyl containing at least one of N, O, S, P, Si and/or Se as heteroatoms and optionally fused with another 4-7 membered ring (optionally containing heteroatom(s) as above) (preferably thiophene, pyrrole, 2H-pyrrole, 2H- or 3H-pyrroline, pyrrolidine, oxazole, thiazole, imidazole, 2-imidazoline, imidazolidine, pyrazole, 2-pyrazoline, pyrazolidine, isoxazole, isothiazole, 1,2,3-, 1,2,4- or 1,3,4-oxadiazole, 1,2,3-, 1,2,4- or 1,3,4-triazole, 1,2,4- or 1,3,4-thiadiazole, 2H- or 4H-pyran, 3,4- or 3,6-dihydro-2H-pyran, tetrahydropyran, pyridine, 2,3-. 1,2- or 1,4-dihydropyridine, 1,2,3,4-, 1,2,3,6- or 2,3,4,5-tetrahydropyridine, piperidine, 1,4-dioxan, 1,4-dithian, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, 1,3,5-, 1,2,3- or 1,24-triazine or purine), all os (specifically by one or more groups Q); Q : 1-16C alkyl or 6-30C aryl (preferably phenyl) (both os by one or more groups, specifically by halo (preferably Cl, Br or F), COOR1, OR1, CF3, NO2, SO2NH2, COMe or CN), heterocyclyl as defined for A, or halo, OR1a, COOR2, CN, COOM, SR1, SOR1, SO2R1, SO2, SO2OH, SO3M, NR3R4, NO2, CF3, CHF2, (CF2)mCF3 or (CF2)mCF3; R1aR1, or 2-16C alkenyl, 2-16C alkynyl, 5C, 6C, 9C, 10C or 12C aryl, 5C, 6C, 9C, 10C or 12C heteroaryl (containing at least one N, O or S), 4-8C cycloalkyl or 4-8C cycloalkenyl; R2R1 or 2-16C alkenyl or 2-16C alkynyl; R3, R4H, 1-16C alkyl, 2-16C alkenyl, 2-16C alkynyl, 5C, 6C, 9C, 10C or 12C aryl, 5C, 6C, 9C, 10C or 12C heteroaryl (containing at least one N, O or S), 4-8C cycloalkyl or 4-8C cycloalkenyl, or R3 + R44-6 membered ring. An independent claim is included for (I; A = A') as new compounds. A' : 1,2,4- or 1,3,4-oxadiazole, 1,2,4- or 1,3,4-thiadiazole, 1,2,4- or 1,3,4-triazole, imidazole, oxazole or thiazole. ACTIVITY : Antibacterial; Tuberculostatic. In tests, (Z)-3-(furan-2-ylmethyl)-5-(5-(3-trifluoromethylphenyl)-furan-2-ylmethylene)-2-thioxothiazolidin-4-one (Ia) exhibited IC50 values of 1.17 mu g/ml against Staphylococcus aureus CIP 76.25, 0.58 mu g/ml against Streptococcus epidermidis CIP 68.21 and 1.17 mu g/ml against Bacteriodes megaterium, and showed no cytotoxicity towards Chinese hamster ovary cells at concentrations up to 200 mu g/ml. MECHANISM OF ACTION : Bacterial RNA polymerase transcription inhibitor.

Description

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NOVEL ANTIBIOTIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND USES THEREOF
The present invention relates to novel antibiotic compounds as well as pharmaceutical compositions containing them. The present invention also relates to the use of these pharmaceutical compositions, particularly in the context of the treatment of microbial infections.

 For several decades, the search for new antibacterial agents against new targets has become increasingly urgent because of the high risks of antibiotic resistance among bacterial pathogens.

The arrival of bacterial genomics has provided bioinformatics data and tools to enable the rational identification of new potential antibacterial targets. However, target validation remains a limiting step in the process of discovering antibacterial agents.

 RNA polymerase is a key enzyme that is essential for bacterial growth and has already been used as a target by rifampicin, a commercial antibiotic. Rifampicin binds in a pocket of the RNA polymerase subunit but at more than 12 of the active site (Campbell et al (2001) Cell, 104 (6): 901-12) and probably interferes with the extrusion of RNA. Other antibiotics that have no therapeutic application because they are too hydrophobic or do not allow to circumvent rifampicin resistance, also serve as targets for RNA polymerase (O'Neill et al (2000) Antimicrobial Agents and Chemotherapy, 44 (11): 3163-3166). These have identical or very similar binding sites (Severinov (1993) J. Biol Chem., 268 (20): 14820-14825) and sometimes also resistant mutants (O'Neill et al (2000) Antimicrobial agents and Chemotherapy, 44 (11): 3163-3166).

 Recently, efforts have been made to identify small molecules capable of inhibiting protein-protein interactions (Oneyama et al (2002) Oncogene, 21 (13): 2037-2050, Dragic et al (2000) PNAS 97 (10): 5639-5644, Welzenbach et al (2002) J. Biol Chem., 277 (12): 10590-10598). However, RNA polymerase is a target interacting with many proteins, among which are the factors that are proteins involved in transcription initiation. Among these factors is found

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 including Escherichia coli protein # 70, which initiates transcription from genes expressed in exponentially growing cells.

 Complete sequences of pathogens such as Escherichia coli, Haemophilus influenzae, Staphylococcus aureus and Enteroccus faecalis are now known.

Alignment of the α and RNA polymerase sequences indicates that the interface between # 70 # family factors and between RNA polymerase is highly conserved among bacteria. Thus, this feature shows the interest of identifying the specific inhibitors of the interaction between RNA polymerase and # 70.

 Rifampicin is one of the few bactericidal antibiotic molecules on growing Gram positive bacteria, non-multiplying bacteria and biofilms. However, rifampicin causes the appearance of many resistant which limits its use.

 The object of the invention is to provide novel antibiotic compounds for inhibiting transcription by inhibiting the binding between RNA polymerase and sigma 70.

 It is an object of the present invention to provide molecules that act on RNA polymerase and prevent the binding of # -factors, which is a novel mechanism for inhibiting transcription.

 The object of the present invention is to provide novel compounds aimed at another site on RNA polymerase than rifampicin, having the same bactericidal properties as rifampicin and making it possible to overcome the resistance of the mutants developed with respect in particular to rifampicin. .

dans laquelle : - X représente un atome d'oxygène, un atome de soufre, un groupe NH ou un groupe NR, R représentant un groupe alkyle comprenant de 1 à 5 atomes de carbone, éventuellement substitué par un atome d'azote ou d'oxygène, The present invention relates to a pharmaceutical composition containing, as active substance, at least one of the compounds corresponding to the following formula (I):

in which: X represents an oxygen atom, a sulfur atom, an NH group or a NR group, R representing an alkyl group comprising from 1 to 5 carbon atoms, optionally substituted by a nitrogen atom or oxygen,

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Y represents an oxygen atom, a sulfur atom, an NH group or an NR group, R representing an alkyl group comprising from 1 to 5 carbon atoms, optionally substituted with a nitrogen or oxygen atom, Ra represents an alkyl group comprising from 1 to 16 carbon atoms, an alkenyl group comprising from 2 to 16 carbon atoms, an alkynyl group comprising from 2 to 16 carbon atoms, an aryl group comprising 5.6, 9.10 or 12 carbon atoms, a heteroaryl group comprising 5.6, 9.10 or 12 carbon atoms, a cycloalkyl group comprising from 4 to 8 carbon atoms or a cycloalkenyl group comprising from 4 to 8 carbon atoms, said alkyl groups, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or cycloalkenyl which may be optionally substituted, in particular by one of the following groups: a halogen atom such as fluorine, chlorine, bromine or iodine, an OR group, R1 representing a hydrogen atom or an alkyl group comprising from 1 to 16 carbon atoms, preferably being a methyl, ethyl or tert-butyl group, or an alkenyl group comprising from 2 to 16 carbon atoms, an alkynyl group comprising from 2 to 16 carbon atoms, an aryl group comprising of 5,6, 9,10 or 12 carbon atoms, a heteroaryl group comprising 5,6, 9,10 or 12 carbon atoms and of which at least one of the atoms is selected from
N, O, S, a cycloalkyl group comprising from 4 to 8 carbon atoms, a cycloalkenyl group comprising from 4 to 8 carbon atoms, a COR2 group or a COOR2 group, R2 representing a hydrogen atom or an alkyl group comprising 1 to 16 carbon atoms, being preferably a methyl, ethyl or tert-butyl group, an alkenyl group comprising from 2 to 16 carbon atoms, an alkynyl group comprising from 2 to 16 carbon atoms, an aryl group comprising 5,
6, 9, 10 or 12 carbon atoms, a heteroaryl group comprising 5.6,
9,10 or 12 carbon atoms and of which at least one of the atoms is chosen from N, O, S, a cycloalkyl group comprising from 4 to 8 carbon atoms, a cycloalkenyl group comprising from 4 to 8 carbon atoms,

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a group CONR3R4 or CSNR3R4, R3 and R4, which are identical or different, or connected together to form a 4- or 6-membered ring, and independently of one another represent a hydrogen atom or an alkyl group comprising 1 to 16 carbon atoms, an alkenyl group comprising 2 to 16 carbon atoms, an alkynyl group comprising 2 to 16 carbon atoms, an aryl group comprising 5.6, 9.10 or
12 carbon atoms, a heteroaryl group comprising 5.6, 9.10 or
12 carbon atoms and of which at least one of the atoms is selected from N,
O, S, a cycloalkyl group comprising from 4 to 8 carbon atoms, a cycloalkenyl group comprising from 4 to 8 carbon atoms, a CN group, a COOM group, M representing an alkaline or alkaline earth metal, in particular chosen from : Na, Ca, Mg, Al, Zn, Li *, a group SR1, R1 being as defined above, a group SOR1, R1 being as defined above, a group SO2R1, R1 being as defined above, a group -SO2-, -SO2-OH, SO3M, M being as defined above, a group NR3R4, R3 and R4, which are identical or different, or connected together to form a 4-membered ring; , 5 or 6-membered, independently of one another, a hydrogen atom or an alkyl group comprising 1 to 16 carbon atoms, an alkenyl group comprising 2 to 16 carbon atoms, an alkynyl group comprising 2 at 16 carbon atoms, an aryl group comprising 5,6, 9,10 or 12 carbon atoms, a heteroaryl group comprising 5,6, 9,10 or 12 carbon atoms and wherein at least one of the atoms is selected from N, O, S, a cycloalkyl group of 4 to 8 carbon atoms, a cycloalkenyl group of 4 to 8 carbon atoms, a group of NO 2, an NHOR group R5 represents a hydrogen atom or an alkyl group comprising 1 to 16 carbon atoms or an alkenyl group comprising from 2 to 16 carbon atoms, an alkynyl group comprising from 2 to 16 carbon atoms, an aryl group comprising from 5 to , 6, 9, 10 or 12 carbon atoms, a heteroaryl group comprising 5.6, 9.10

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or 12 carbon atoms and of which at least one of the atoms is selected from
N, O, S, a cycloalkyl group comprising from 4 to 8 carbon atoms, a cycloalkenyl group comprising from 4 to 8 carbon atoms, a CF3 group, CHF2, CH2F, - [CF2] m-CF3, m varying from 1 to 3, or - [CF 2] n -CH 3, n ranging from 1 to 3, a heterocycle with 4.5 or 6 members, in particular chosen from:

R6 represents an alkyl group comprising from 1 to 30, in particular from 1 to 16 carbon atoms, - A represents a heterocycle with 4.5 or 6 members, comprising at least one heteroatom chosen from N, O, S, P, Si, Se, optionally attached to another cyclic radical with 4, 5, 6 or 7 members, with or without heteroatoms as defined above, in particular a heterocycle such as: oxetane; oxetan-2-one; azetidine; azetidin-2-one; furan; thiophene; pyrrole; 2H-pyrrole; 2H-pyrroline; 3H-pyrroline; pyrrolidine; 1,3-dioxolane; oxazole; thiazole; imidazole; 2-imidazoline; imidazolidine; pyrazole; 2-pyrazoline; pyrazolidine; isoxazole; isothiazole; 1,2,3-oxadiazole; 1,2,3-triazole; 1,2,4-oxadiazole; 1,2,4-thiadiazole; 1,2,4-triazole; 1,3,4-oxadiazole; 1,3,4-thiadiazole; 1,3,4-triazole; 2H-pyran; 4H-pyran; 3,6-dihydro-2H-pyran; 3,4-dihydro-2H pyran; tetrahydropyran; pyridine; 2,3-dihydropyridine; 1,2-dihydropyridine;
1,4-dihydropyridine; 1,2,3,4-tetrahydro-pyridine; 1,2,3,6-tetrahydro-pyridine;
2,3,4,5-tetrahydro-pyridine; piperidine; 1,4-dioxane; 1,4-dithiane; morpholine; thiomorpholine; pyridazine; pyrimidine; pyrazine; piperazine; 1,3,5-triazine; 1,2,3-triazine; 1,2,4-triazine; indolizine; indole; isoindole; 3H-indole; indoline; benzo [b] furan; benzo [b] thiophene; 2,3-dihydro-benzofuran; 2,3-dihydrobenzothiophene; isobenzofuran; isobenzothiophene; pyrazolo [l, 5-a] pyridine; imidazo [1,5-a] pyridine; imidazo [l, 2-a] pyridine; IH-indazole; benzimidazole;

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benzoxazole; benzothiazole, benzo [d] isoxazole; benzo [d] isothiazole; purine; 4Hquinilizine; quinoline; isoquinoline; cinnoline; phthalazine; quinazoline; quinoxaline; 1,8-naphthyridine; pteridine; quinuclidine; carbazole; dibenzofuran; acridine, phenazine; phenothiazine; phenoxazine; said heterocycle being optionally substituted with one or more substituents, especially chosen from the following groups: ## STR2 ## an alkyl group comprising from 1 to 16 carbon atoms, an aryl group comprising from 6 to 30 carbon atoms, in particular a phenyl group, a heterocyclic group chosen from the abovementioned heterocycles for A, said alkyl or aryl group, in particular phenyl, which may be optionally, it may itself be substituted with one or more substituents, in particular chosen from the following groups: a halogen atom, in particular a chlorine, bromine or fluorine atom, a COOR group, a group;
OR], a CF3 group, an NO2 group, a SO2NH2 group, a group
COCH 3 or a CN group, R 1 being as previously defined, # a halogen atom such as fluorine, chlorine, bromine or iodine, # a group OR 1, R 1 representing a hydrogen atom or an alkyl group comprising from 1 to 16 carbon atoms, preferably being a methyl, ethyl or tert-butyl group, or an alkenyl group comprising from 2 to 16 carbon atoms, an alkynyl group comprising from 2 to 16 carbon atoms, an aryl group comprising from 5.6, 9.10 or 12 carbon atoms, a heteroaryl group comprising 5.6; 9,10 or 12 carbon atoms and of which at least one of the atoms is selected from N, O, S, a cycloalkyl group comprising from 4 to 8 carbon atoms, a cycloalkenyl group comprising from 4 to 8 carbon atoms, COR2 group or a COOR2 group, R2 representing a hydrogen atom or an alkyl group comprising 1 to 16 carbon atoms, preferably being a methyl, ethyl or tert-butyl group, an alkenyl group comprising from 2 to 16 carbon atoms, a alkynyl group comprising from 2 to 16 carbon atoms, an aryl group comprising 5.6,
9, 10 or 12 carbon atoms, a heteroaryl group comprising 5.6, 9, 10

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or 12 carbon atoms and wherein at least one of the atoms is selected from N, O, S, a cycloalkyl group comprising from 4 to 8 carbon atoms, a cycloalkenyl group comprising from 4 to 8 carbon atoms, # a group CONR3R4 or CSNR3R4, R3 and R4, which are identical or different, or connected together to form a 4- or 6-membered ring, and independently of one another represent a hydrogen atom or an alkyl group comprising 1 to 16 atoms carbon, an alkenyl group comprising from 2 to 16 carbon atoms, an alkynyl group comprising from 2 to 16 carbon atoms, an aryl group comprising 5,6, 9,10 or 12 carbon atoms, a heteroaryl group comprising 5, 6, 9, 10 or 12 carbon atoms and of which at least one of the atoms is chosen from N, O, S, a cycloalkyl group comprising from 4 to 8 carbon atoms, a cycloalkenyl group comprising from 4 to 8 carbon atoms, # a CN group, # a COOM group, M representing an alkaline or alkaline earth metal, selected from: Na, Ca, Mg, Al, Zn, Li *, a group SRI, R1 being as defined above, a group SOR1, R1 being as defined above, a group SO2R1, R1 being as defined above, a -SO2-, -SO2-OH, SO3M group, M being as defined above,. a group NR3R4, R3 and R4, which are identical or different, or connected together to form a 4- or 6-membered ring, independently of one another representing a hydrogen atom or an alkyl group comprising 1 to
16 carbon atoms, an alkenyl group comprising 2 to 16 carbon atoms, an alkynyl group comprising 2 to 16 carbon atoms, an aryl group comprising 5.6, 9.10 or 12 carbon atoms, a heteroaryl group comprising 5,6, 9,10 or 12 carbon atoms and at least one of which is selected from N, O, S, a cycloalkyl group comprising from 4 to 8 carbon atoms, a cycloalkenyl group comprising from 4 to 8 carbon atoms. carbon, # a NO 2 group, # an NHOR 5 group, R 5 representing a hydrogen atom or an alkyl group comprising 1 to 16 carbon atoms or an alkenyl group

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comprising from 2 to 16 carbon atoms, an alkynyl group comprising
2 to 16 carbon atoms, an aryl group comprising 5,6, 9,10 or 12 carbon atoms, a heteroaryl group comprising 5,6, 9, 10 or 12 carbon atoms and of which at least one of the atoms is chosen from N, O, S, a cycloalkyl group comprising from 4 to 8 carbon atoms, a cycloalkenyl group comprising from 4 to 8 carbon atoms, # a group CF3, CHF2, CH2F, - [CF2] m-CF3, m variant from 1 to 3, or - [CF 2] n -CH 3, n ranging from 1 to 3, said composition containing the compound of formula (I) in E or Z form, or containing a mixture of its E form and its Z form in combination with a pharmaceutically acceptable carrier.

 Said pharmaceutical composition has an antibiotic activity and makes it possible to inhibit the binding between the RNA polymerase and the transcription factor #.

 In the preparation of the compounds of formula (1), a mixture of the E form and the Z form of said compound is generally obtained. To obtain the E-form or the Z-form alone, a separation is carried out by chromatography.

(II') suivantes : y Ra (II) r*k N " X Rj, <C\ / V (ir) \~~/ Y (II') dans laquelle : - X, Y et Ra sont tels que définis ci-dessus, - i représente un nombre entier variant de 0 à 5, - j représente un nombre entier variant de 1 à i, - les groupes Rj, identiques ou différents, représentent notamment un atome d'halogène, de préférence un atome de chlore ou de brome, un groupe COORI, R1 étant tel que défini ci-dessus, et étant de préférence un atome d'hydrogène, un An advantageous pharmaceutical composition according to the invention contains, as active substance, at least one of the compounds corresponding to one of the formulas (II) or

(II '): y Ra (II) r * k N "X Rj, <C \ / V (ir) \ ~~ / Y (II') in which: - X, Y and Ra are as defined herein above, - i represents an integer ranging from 0 to 5, - j represents an integer ranging from 1 to i, - the groups Rj, identical or different, especially represent a halogen atom, preferably a chlorine atom; or bromine, a COORI group, R1 being as defined above, and preferably being a hydrogen atom, a

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OR1 group, R1 being as defined above, and preferably being a methyl group, a CF3 group, an NO2 group, a SO2NH2 group or a group
COCH3, said composition containing the compound of formula (II) in E or Z form, or containing a mixture of its E form and its Z form.

 The compounds of formula (II) and (II ') are compounds of formula (I) wherein A represents a furan group substituted with a phenyl group.

 In the compounds of formula (II), the furan group may be substituted interchangably at its four carbon atoms. As regards the phenyl group attached to said furan group, it may not be substituted or substituted by 1 to 5 substituents, said substituents being as defined above with respect to the definition of RJ, and may be identical or different.

 In the compounds of formula (II '), the furan group bonded to the phenyl group may be substituted indifferently at its three free carbon atoms. As regards the phenyl group attached to said furan group, it may not be substituted or substituted by 1 to 5 substituents, said substituents being as defined above with respect to the definition of R 1, and may be identical or different.

(III') suivantes : (Ri), Rb )= " Ra (III) / \S Y Rb X Ra ==\ N (III') (R ) N "y (III') t ' R dans laquelle : - X, Y et Ra sont tels que définis ci-dessus, An advantageous pharmaceutical composition of the invention contains, as active substance, at least one of the compounds corresponding to one of the formulas (III) or

(III '): (R1), Rb) = "Ra (III) / \ SY Rb X Ra == \ N (III') (R) N" y (III ') t' R in which: - X , Y and Ra are as defined above,

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Rb and Rc, which may be identical or different, represent an alkyl group comprising
1 to 5 carbon atoms, especially a methyl group, or an aryl group comprising from 6 to 30 carbon atoms, and being especially a phenyl group, - i represents an integer ranging from 0 to 5, - j represents a whole number varying from 1 to 1, the groups R 1, which are identical or different, represent in particular a halogen atom, preferably a chlorine atom, a COORI group, R 1 being as defined above, and preferably being a hydrogen atom. hydrogen or a methyl group, or a CF3 group, said composition containing the compound of formula (III) in E or Z form, or containing a mixture of its E form and its Z form.

 The compounds of formula (III) and (III ') are compounds of formula (I) wherein A represents a pyran group substituted with a phenyl group.

(IV') suivantes : (IV') suivantes: CR ) J 1 (IV) ~Y (iv) (IV) R-N R-N "~-y (Rj) 1 i (IV') ! N- 1 Ra (IV') R-N i =='Y dans laquelle : - X, Y et Ra sont tels que définis ci-dessus, - Rb représente un atome d'hydrogène ou un groupe alkyle comprenant de 1 à 5 atomes de carbone, notamment un groupe méthyle, ledit groupe alkyle étant éventuellement substitué par un groupe CN ou un groupe COOH, ou un groupe aryle comprenant de 6 à 30 atomes de carbone, et étant notamment un groupe phényle, An advantageous pharmaceutical composition according to the invention contains, as active substance, at least one of the compounds corresponding to one of the formulas (IV) or

(IV ') following: (IV') following: CR) J 1 (IV) ~ Y (iv) (IV) RN RN "~ -y (Rj) 1 i (IV ')! N-1 Ra (IV') In which: X, Y and Ra are as defined above, Rb represents a hydrogen atom or an alkyl group comprising from 1 to 5 carbon atoms, in particular a methyl group, said alkyl group being optionally substituted by a CN group or a COOH group, or an aryl group comprising from 6 to 30 carbon atoms, and being in particular a phenyl group,

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i represents an integer varying from 0 to 5; j represents an integer ranging from 1 to i; the groups R 1, which are identical or different, represent in particular a halogen atom, preferably a fluorine or bromine atom; a group COOR 1, R 1 being as defined above, and being preferably a hydrogen atom, a group OR 1, R 1 being as defined above, and preferably being a methyl group, a CF 3 group, a group NO2, a group SO2NH2 or a group
COCH3, said composition containing the compound of formula (IV) in E or Z form, or containing a mixture of its E form and its Z form.

 The compounds of formula (IV) and (IV ') are compounds of formula (I) wherein A represents a pyrazole group substituted with a phenyl group.

 The present invention also relates to a pharmaceutical composition as defined above, characterized in that Y represents a sulfur atom.

Such compounds therefore correspond to the following formula (I-bis):

The present invention also relates to a pharmaceutical composition as defined above, characterized in that X represents an oxygen atom.

Such compounds therefore correspond to the following formula (I-ter):

The present invention also relates to a pharmaceutical composition as defined above, containing as active substance at least one of the compounds corresponding to the following formula (IIa):

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 wherein R 1, i, j and Ra are as defined above, said composition containing the compound of formula (Ilbis) in E or Z form, or containing a mixture of its E form and its Z form.

 The compounds of formula (IIbis) are compounds of formula (II ') in which X represents an oxygen atom and Y represents a sulfur atom.

dans laquelle Rj, i, j et Ra sont tels que définis ci-dessus, ladite composition contenant le composé de formule (Ilter) sous forme E ou Z, ou contenant un mélange de sa forme E et de sa forme Z. According to an advantageous embodiment, the present invention relates to a pharmaceutical composition as defined above, containing as active substance at least one of the compounds corresponding to the following formula (IIter):

wherein R 1, i, j and Ra are as defined above, said composition containing the compound of formula (IIter) in E or Z form, or containing a mixture of its E form and its Z form.

According to an advantageous embodiment, the pharmaceutical composition according to the invention contains as active substance at least one of the compounds corresponding to formula (II), (II '), (IIa) or (IIter) in which - Ra represents:

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dans laquelle Rj, i, j, Ra, Rb et Rc sont tels que définis ci-dessus, ladite composition contenant le composé de formule (IIIbis) sous forme E ou Z, ou contenant un mélange de sa forme E et de sa forme Z. The present invention also relates to a pharmaceutical composition as defined above, containing as active substance at least one of the compounds corresponding to the following formula (IIIbis):

wherein R 1, i, j, R a, R b and R c are as defined above, said composition containing the compound of formula (IIIbis) in E or Z form, or containing a mixture of its E form and its Z form .

 The compounds of formula (IIIbis) are compounds of formula (III ') in which X represents an oxygen atom and Y represents a sulfur atom.

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dans laquelle Rj, j , i, Ra, Rb et Rc sont tels que définis ci-dessus, ladite composition contenant le composé de formule (IIIter) sous forme E ou Z, ou contenant un mélange de sa forme E et de sa forme Z. The present invention also relates to a pharmaceutical composition as defined above, containing as active substance at least one of the compounds corresponding to the following formula (IIIter):

wherein R 1, j, i, R a, R b and R c are as defined above, said composition containing the compound of formula (IIIter) in E or Z form, or containing a mixture of its E form and its Z form .

According to an advantageous embodiment, the present invention relates to a pharmaceutical composition containing as active substance at least one of the compounds corresponding to formula (III), (III '), (IIIa) or (IIIter) in which: - Ra represents:

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dans laquelle Rj, j, i, Ra et Rb sont tels que définis ci-dessus, ladite composition contenant le composé de formule (IVbis) sous forme E ou Z, ou contenant un mélange de sa forme E et de sa forme Z. The present invention also relates to a pharmaceutical composition as defined above, containing as active substance at least one of the compounds corresponding to the following formula (IVbis):

wherein R 1, j, i, Ra and Rb are as defined above, said composition containing the compound of formula (IVbis) in E or Z form, or containing a mixture of its E form and its Z form.

 The compounds of formula (IVbis) are compounds of formula (IV ') in which X represents an oxygen atom and Y represents a sulfur atom.

dans laquelle Rj, j , i, Ra et Rb sont tels que définis ci-dessus, ladite composition contenant le composé de formule (IVter) sous forme E ou Z, ou contenant un mélange de sa forme E et de sa forme Z. The present invention also relates to a pharmaceutical composition as defined above, containing as active substance at least one of the compounds corresponding to the following formula (IVter):

wherein R 1, j, i, R a and R b are as defined above, said composition containing the compound of formula (IVter) in E or Z form, or containing a mixture of its E form and its Z form.

 According to an advantageous embodiment, the present invention relates to a pharmaceutical composition containing as active substance at least one of the compounds corresponding to formula (IV), (IV '), (IVa) or (IVter) in which: - Ra represents H, and

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Thus, the preferred compounds of the invention, corresponding respectively to formulas (IV), (IV '), (IVa) and (IVter), are as follows:

An advantageous pharmaceutical composition according to the invention is characterized in that it contains a compound of formula (II), (II '), IIbis) or (IIter) in which Ra represents in particular one of the following groups:

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-CHj # CH # Oi, ou un groupe -ch2# - y
Une composition pharmaceutique selon la présente invention est caractérisée en ce qu'elle contient un composé de formule (IV), (IV'), IVbis) ou (IVter) dans laquelle

Ra représente l'un des groupes suivants un atome d'hydrogène, -CH2-CH3, -(CH2)2-CH3,-CH2-COOH,-(CH2)2-OMe, ~( / , ou ( / -\S o 0 et Rb représente un atome de fluor ou un atome de chlore. -c 0 / Av:
La présente invention concerne également une composition pharmaceutique telle que définie ci-dessus, caractérisée en ce qu'elle contient, à titre de substance active, un composé répondant à l'une des formules suivantes :

A pharmaceutical composition according to the present invention is characterized in that it contains a compound of formula (III), (III '), IIIbis) or (IIIter) in which Ra represents one of the following groups: an atom of hydrogen, a group

-CHj # CH # Oi, or a group -ch2 # - y
A pharmaceutical composition according to the present invention is characterized in that it contains a compound of formula (IV), (IV '), IVbis) or (IVter) in which

Ra represents one of the following groups a hydrogen atom, -CH2-CH3, - (CH2) 2 -CH3, -CH2-COOH, - (CH2) 2-OMe, ~ (/, or (/ - \ S o 0 and Rb represents a fluorine atom or a chlorine atom.
The present invention also relates to a pharmaceutical composition as defined above, characterized in that it contains, as active substance, a compound corresponding to one of the following formulas:

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An advantageous pharmaceutical composition of the invention is characterized in that it contains, as active substance, the compound of the following formula:

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The present invention also relates to a pharmaceutical composition as defined above, characterized in that it contains, as active substance, a compound corresponding to one of the following formulas:

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An advantageous pharmaceutical composition according to the invention is characterized in that it contains, as active substance, the compound of the following formula:

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The present invention also relates to a pharmaceutical composition as defined above, characterized in that it contains, as active substance, the compound of the following formula:

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An advantageous pharmaceutical composition according to the invention is characterized in that it contains, as active substance, the compound of the following formula:

The present invention also relates to a pharmaceutical composition as defined above, characterized in that it comprises at least one of the compounds as defined above, in a proportion of about 0.1 to about 200 mg / kg / unit dose.

 The present invention also relates to the use of the compounds as defined above, for the preparation of a medicament for the treatment of microbial infections.

 Said infections are particularly related to bacteria Staphylococcus, Enterococcus, Bacillus, Streptococcus, Mycobacterium, Bacteroides, Clostridium, Prevotella, Propionibacterium, Peptococcus, Fusobacterium and Peptostreptococcus.

More specifically, the bacteria are: Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemoliticus, Enterococcus faecalis, Enterococcus faecium, Bacillus subtillis, Bacillus anthracis, Bacillus megaterium, Bacillus cereus, Streptococcus pyrogenes, Streptococcus agalactiae, Streptococcus CD group, Streptococcus adjacent, Streptococcus Mitis, Streptococcus oralis, Streptococcus sanguis, Mycobacterium avium, Mycobacterium tuberculosis and Bacteroides fragilis.

 The present invention also relates to the use of the compounds as defined above to prevent the colonization of biomaterials such as prostheses

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 by bacterial biofilms. In the context of the present invention, the compounds may be included in said biomaterials or adsorbed on their surface.

 The present invention also relates to compounds corresponding to formula (I) as defined above, in which: X, Y and Ra are as defined above, and A represents a 5-membered heterocycle chosen from 1,2,4-oxadiazole; 1,2,4-thiadiazole; 1,2,4-triazole; 1,3,4-oxadiazole; 1,3,4-thiadiazole; 1,3,4-triazole; imidazole; oxazole and thiazole.

/ \ /S\ /"n /S\ /N î) ON GN {? 1 S ÎI \1 N IÎ N N N N#N N#N N-N 1,2,4- 1,2,4- 1,2,4- 1,3,4- 1,3,4- 1,3,4oxadiazole thiadiazole triazole oxadiazole thiadiazole triazole NOS N# 'J N# J CN imidazole oxazole thiazole
La présente invention concerne également les composés tels que définis ci-dessus répondent à la formule suivante :

dans laquelle :
W représente CH ou N,
Z représente un atome d'oxygène, un atome de soufre ou un groupe NH ;

- Ra représente soit 1- o 1 soit Si COOH - Rf représente l'un des groupes suivants :

Preferred heterocycles for A thus correspond to the following formulas:

/ \ / S \ / "n / S \ / N) ON GN {? 1 S I I NNNNN # NN # N N 1,2,4 1,2,4 1,2,4 1,3,4-1,3,4-1,3,4-oxadiazole thiadiazole triazole oxadiazole thiadiazole triazole NOS N # 'JN # J CN imidazole oxazole thiazole
The present invention also relates to the compounds as defined above have the following formula:

in which :
W represents CH or N,
Z represents an oxygen atom, a sulfur atom or an NH group;

- Ra represents either 1 o 1 or Si COOH - Rf represents one of the following groups:

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dans laquelle : - Z représente un atome d'oxygène, un atome de soufre ou un groupe NH ; @

représente soit soit s - R., représente soit "'/0\ soit' COOH - Rf représente l'un des groupes suivants :

According to an advantageous embodiment of the invention, the compounds as defined above have the following formula (A):

in which: Z represents an oxygen atom, a sulfur atom or an NH group; @

is either s - R., is either COOH - Rf is one of the following groups:

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Processes for preparing the compounds of the invention
The compound of formula (I) can be obtained according to two distinct methods.

(I)
A, X, Y et Ra étant tels que définis à propos de la formule (I) ci-dessus. The first method (Method 1) can be represented by the following reaction scheme:

(I)
A, X, Y and Ra being as defined for formula (I) above.

 A compound of general structure (VI) is subjected to a carbonyl derivative such as an aldehyde of general structure (VII) to obtain a compound of general structure (VIII).

Then this compound of general structure (VIII) is converted into a compound of general structure (I) by a reaction with a halogenated compound of Ra-Hal type, Hal representing a halogen selected from bromine, chlorine or iodine . Compounds of general structure (VI) are commercial and their synthesis is widely described in the literature. Compounds of general structure (VII) are either commercial products or products whose synthesis is widely described in the literature. Ra-Hal structural products are also either commercial products or products whose synthesis is widely described in the literature.

 The first step of this process consists of a Knoevenagel-type condensation between an active methylene compound of general formula (VI), here 2-thioxothiazolidin-4-one (X = O, Y = S) or thiazolidine-2, 4-dione (X = O, Y = O) or 4-thioxothiazolidin-2-one (X = S, Y = O) or thiazolidine-2,4-dithione (X = S; Y = S) with a carbonyl compound of

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 general structure (VII) as an aldehyde to yield a compound of the general formula (VIII) of the 5-heteroarylylidene-2-thioxo-thiazolidin-4-one (X = O; Y = S) or 5-heteroarylylidene thiazolidin-2 type, 4-dione (X = Y = O) or 5-heteroarylylidene-4-thioxothiazolidin-2-one (X = S, Y = O) or 5-heteroarylylidene-thiazolidine-2,4-dithione (X = Y = S) .

This reaction is carried out under reflux in an organic solvent such as toluene or xylene, in the presence of an acid-base catalysis, such as any mixture of a carboxylic acid (acetic acid, propionic acid, etc.) with a secondary amine (morpholine, piperidine). , etc.) or a carboxylic acid salt (sodium acetate, ammonium acetate, etc.). This first step is described in particular in the following publications: J. Pharm. Belg. (1956) 3, 5-6; J Org. Chem. (1958) 23, 112-113; J. Am. Chem. Soc. (1948) 70, 503.

 The above-mentioned method also applies to compounds in which X or Y represents an NH group (see in particular Journal of Agricultural and Food Chemistry (1991) 39 (3), 580-3) or NMe (see in particular Zhonghua Yaoxue Zazhi (1992) 44 (6), 501-7). Alternatively, compounds wherein X or Y is NMe can be obtained by converting 2-thioxothiazolidin-4-one to 2-methylaminothiazolidin-4-one according to the document Archiv der Pharmazie (Weinheim, Germany, 320). (4), 329-337, 1987).

 The second step consists of a nucleophilic substitution. More exactly, it is a substitution reaction on a halogenated derivative of general formula Ra-Hal with an activated form of formula (VIII), namely any alkaline or alkaline-earth salt. This activated form can be obtained in the form of a new stable entity using an alkaline hydride (NaH, KH, CaH2, etc.) or momentarily in the reaction medium in the presence of a mineral base such as sodium carbonate, potassium carbonate, cesium carbonate, etc. This second step is described in particular in the following publications: Pak J Sci. Ind. Res. (1992) 35, 12, 489-491 and Collect. Czech. Chem. Comm. (1981) 46.2, 436-445.

The second method of preparation (Method 2) of compounds of formula (I) can be represented by the following reaction scheme:

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This second method is characterized in that a product of general formula (VII) is subjected to a product of general formula (IX) in a basic medium or in acid-base catalysis. This reaction is carried out under reflux in an organic solvent such as toluene or xylene, in the presence of an acid-base catalysis, such as any mixture of a carboxylic acid (acetic acid, propionic acid, etc.) with a secondary amine (morpholine, piperidine). , etc.) or a carboxylic acid salt (sodium acetate, ammonium acetate, etc.). It can also be carried out in the presence of piperidine, an ethanolic solution of ammonia, or in a solid medium under microwave radiation (KF / Al 2 O 3). This process is described in particular in the following publications: Bioorg. Med. Lett. (2001) 11, 2, 91-94; Chem. Europ. J (2001) 7, 20, 4395-4402 and J. Am. Chem. Soc. (1951) 73.2357.

The compounds of formula (IX) can be obtained in different ways:
1) by direct alkylation of rhodanine (compound of formula (VI) in which X = O and Y = S):
A compound of formula (VI) is subjected to a halogenated derivative or an alcohol in the presence of a base or a condensing agent such as DEAD (diethylazodicarboxylate) or DIAD (diisopropylazodicarboxylate) (Mitsonobu reaction Chem Abst. (1960) 21074, Gazz Chem., Ital (1942) 72, 525-518), or an amine in the presence of formaldehyde (Zh.Org.Khem (1970) 6, 1738-1744).

suivant : suivant: 0 N H R"I 0 -N Ra 0- #### vs
Ra étant tel que défini précédemment. An example of such a reaction with a halogenated derivative is described in the Khim publication. Geterotsikl. Soedin (1971) 7, 189-191, according to the reaction scheme

next: next: 0 NHR "I 0 -N Ra 0- #### vs
Ra being as defined previously.

 The preferred base in this reaction is a trialkylamine such as triethylamine (TEA).

2) from isothiocyanates or isocyanates:
A compound having the following formula (X): Ra-N # C # X wherein X 'is O or S, with a derivative of thioglycolic acid (acid or ester form) in the presence of a desiccant or a tertiary amine such as TEA,

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suivant : XI / Ra R-N=C=X' /SH ~~~ / 1 a crm S XY, Y
R représentant un atome d'hydrogène ou un groupe alkyle,
X' et Y' représentant indifféremment l'un de l'autre un atome d'oxygène ou de soufre. to lead directly to the compounds of structure (IX '), according to the reaction scheme

next: XI / Ra RN = C = X '/ SH ~~~ / 1 a crm S XY, Y
R representing a hydrogen atom or an alkyl group,
X 'and Y' represent indifferently one of the other an oxygen or sulfur atom.

 For this particular process, reference may be made to the following publications: Hel. Chim. Acta (1952) 35, 1744-1746; Bioorg. Med. Chem. Lett. (2001) 11, 2, 91-94.

3) more generally, from the compound of formula (XI) by reacting directly with a primary amine, according to the following reaction scheme:

This particular case corresponds to the specific case of thiazolones (X = O and Y = S).

 This reaction is carried out in an alcohol in the presence of a mineral base such as alkali metal and alkaline earth carbonates (Zh Obshch Kihm (1957) 27, 2177-2181, Chim Abst (1960) 6689).

 The aforementioned protocols can also be used to prepare the compounds corresponding to formulas (II), (II '), (IIbis), (IIter), as well as the compounds corresponding to formulas (III), (III'), (IIIbis) (IIIter) and the compounds of formulas (IV), (IV '), (IVa), (IVter).

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1) Méthode 1 0 CHO+ s"'y- bzz (R)), (R J), réaction avec Ra-Hal Hal Br, CI, Hat=Br,C),! X /Ra 10 N (R) 2) Méthode 2

More specifically, the compounds of formula (II) can be obtained according to one of the following reaction schemes:

1) Method CHO + s "y- bzz (R)), (RJ), reaction with Ra-Hal Hal Br, CI, Hat = Br, C), X / Ra 10 N (R) 2) Method 2

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2) Méthode 2

i, Rj, Ra, X et Y étant tels que définis ci-dessus pour la formule (II) The compounds of formula (II ') can be obtained according to one of the following reaction schemes:
1) Method 1

2) Method 2

i, Rj, Ra, X and Y being as defined above for formula (II)

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2) Méthode 2

The compounds of formula (III) can be obtained according to one of the following reaction schemes:
1) Method 1

2) Method 2

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2) Méthode 2

i, Rj, Ra, Rb, Rc, X et Y étant tels que définis ci-dessus pour la formule (III) The compounds of formula (III ') can be obtained according to one of the following reaction schemes:
1) Method 1

2) Method 2

i, R 1, R a, R b, R c, X and Y being as defined above for formula (III)

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2) Méthode 2

The compounds of formula (IV) can be obtained according to one of the following reaction schemes:
1) Method 1

2) Method 2

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2) Méthode 2

i, Rj, Ra, Rb, X et Y étant tels que définis ci-dessus pour la formule (IV) The compounds of formula (IV ') can be obtained according to one of the following reaction schemes:
1) Method 1

2) Method 2

i, R 1, R a, R b, X and Y being as defined above for formula (IV)

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Rj, Ra et i étant tels que définis ci-dessus pour la formule (II)

2) Méthode 2 Ruz \~~/ 0 CHO s \=X s '##\ z) (Ri)1 ; (Ilter) Rj, Ra et i étant tels que définis ci-dessus pour la formule (II) The compounds of formula (IIter) can be obtained according to one of the following reaction schemes:
1) Method 1

Rj, Ra and i being as defined above for the formula (II)

2) Method 2 Ruz \ ~~ / 0 CHO s \ = X s'## \ z) (Ri) 1; (Ilter) Rj, Ra and i being as defined above for formula (II)

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Rj, Ra, Rb, Rc et i étant tels que définis ci-dessus pour la formule (III) 2) Méthode 2

@ Rj, Ra, Rb, Rc et i étant tels que définis ci-dessus pour la formule (III) The compounds of formula (IIIter) can be obtained according to one of the following reaction schemes:
1) Method 1

R 1, R a, R b, R c and i being as defined above for formula (III) 2) Method 2

Rj, Ra, Rb, Rc and i being as defined above for formula (III)

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Rj, Ra, Rb et i étant tels que définis ci-dessus pour la formule (IV) 2) Méthode 2

Rj, Ra, Rb et i étant tels que définis ci-dessus pour la formule (IV) The compounds of formula (IVter) can be obtained according to one of the following reaction schemes:
1) Method 1

Rj, Ra, Rb and i being as defined above for formula (IV) 2) Method 2

Rj, Ra, Rb and i being as defined above for formula (IV)

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EXPERIMENTAL PART Preparation of Compounds Examples with Method 1 First Step

In a 125 ml flask, sequentially introduced into 60 ml of acetic acid: 5.19 g of 5- (4-nitro-phenyl) -furan-2-carbaldehyde; 3.18 g of 2-thioxothiazolidin-4-one and then 1.96 g of sodium acetate which has been dried under vacuum. The reaction medium is then refluxed for 4 hours. During the rise in temperature, the reaction medium gradually changes from a yellow suspension to a thick suspension of orange-red color. The reaction medium is diluted with ethyl acetate and then filtered to give 7.62 g of an orange-red solid with a melting point of greater than 300 ° C. (yield 94%).

1H NMR (# in ppm) solvent DMSO d6: 8.418-8.388 (doublet, J = 9 Hz, 2H); 8.072-8.042 (doublet, J = 9Hz, 2H); 7.609-7.596 (doublet, J = 3.75 Hz, 1H); 7.535 (singlet, 1H); 7.372-7.360 (doublet, J = 3.75 Hz, 1H)
13 C NMR (8 ppm) DMSO solvent d6 196.7 155.4; 151.2; 147.2; 134.7; 125.4; 125.2; 122.4; 116.9; 114.1
Note: 5- (4-Nitro-phenyl) -furan-2-carbaldehyde is commercially available from Aldrich or may be prepared according to the following: Austr. J Chem., 26, 1973, 1059-1065; Org. Lett., 3, 11, 2001, 1677-1680; Synthesis, 11, 2001, 1681-1685.

 2-thioxothiazolidin-4-one is marketed at Acros, Aldrich, etc.

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Second step

In a 50 ml flask sequentially introduced into 25 ml of DMF: 3.3 g of 5- [5- (4-nitro-phenyl) -furan-2-ylmethylene] -2-thioxo-thiazolidin-4-one obtained in the first step; 3.9 g of cesium carbonate; 5 ml of 1-bromo-2-methoxyethane. The reaction medium is then heated at 50 ° C. for 18 hours. The reaction medium is then extended with ice water and the precipitate is filtered to give 2.9 g of an orange solid (yield 74%)
1 H NMR (8 ppm) DMSO solvent d6: 8.418-8.388 (doublet, J = 9 Hz, 2H); 8.072-8.042 (doublet, J = 9Hz, 2H); 7.609-7.596 (doublet, J = 3.75 Hz, 1H); 7.535 (singlet, 1H); 7.372-7.360 (doublet, J = 3.75 Hz, 1H); 4.25 (triplet, J = 5.3 Hz, 2H); 3.64 (triplet, J = 5.3 Hz, 2H); (singlet, 3H)
The compound thus obtained is a compound of formula (IIter) in which i = 1, R 1 represents a group NO 2 and Ra represents a group -CH 2 -CH 2 -OCH 3.

Dans un ballon de 50 ml on introduit séquentiellement dans 25 ml de DMF : g de 5-[5-(4-nitro-phényl)-furan-2-ylméthylène]-2-thioxo-thiazolidin-4-one obtenu à la première étape ;0,48 g d'hydrure de sodium préalablement lavé au pentane et 5 ml de bromoacétate d'éthyle. Le milieu réactionnel est ensuite maintenu à température ambiante pendant 16 heures. Le milieu réactionnel est ensuite étendu avec de l'eau glacée puis le précipité est filtré pour donner 2,9 g d'un solide orange. Second step (another example)

In a 50 ml flask, 25 g of 5- [5- (4-nitro-phenyl) -furan-2-ylmethylene] -2-thioxo-thiazolidin-4-one, obtained in the first batch, are introduced sequentially into 25 ml of DMF. 0.48 g of sodium hydride previously washed with pentane and 5 ml of ethyl bromoacetate. The reaction medium is then maintained at room temperature for 16 hours. The reaction medium is then extended with ice water and the precipitate is filtered to give 2.9 g of an orange solid.

 1 H NMR (8 ppm) DMSO solvent d6: 8.418-8.388 (doublet, J = 9 Hz, 2H); 8.072-8.042 (doublet, J = 9Hz, 2H); 7.609-7.596 (doublet, J = 3.75 Hz, 1H); 7.535 (singlet, 1H), 7.372-7.360 (doublet, J = 3.75 Hz, 1H).

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 The compound thus obtained is a compound of formula (IIter) in which i = 1, R 1 represents a group NO 2 and Ra represents a group -CH 2 -CO-OCH 2 CH 3.

Examples with method 2
First stage

In a 250 ml three-necked flask equipped with magnetic stirring and under nitrogen, 16.32 g of methyl ester of DL methionine, 160 ml of ethyl acetate and 25.8 ml of triethyl amine are sequentially introduced. After cooling to 0 C 7.6 ml of thiophosgene are slowly introduced into 50 ml of ethyl acetate. A milky suspension forms quickly and then slowly turns to orange-brown. Once the addition is complete, the temperature is maintained at 20 ° C. for 18 hours. The reaction medium is then extensively diluted with water and extracted with ethyl acetate (2 × 150 ml). The combined organic phases are then dried over sodium sulfate, concentrated under vacuum and chromatographed to give 13.32 g of an orange-yellow oil which is used as for the next step.

 The orange-yellow oil obtained above is mixed with 6.88 g of methyl thioglycolate and 200 ml of toluene. To the solution thus obtained are added 1.49 g of metallic sodium. The reaction medium is then refluxed for 6 hours and then concentrated in vacuo. The solid thus obtained is washed with water and recrystallized from ethanol. 14.5 g of an orange powder corresponding to the expected result are obtained.

 1H NMR (# in ppm) solvent DMSO d6: 5.98 (broad singlet, 1H); 4.27 (singlet, 2H); 3.25 (singlet, 3H); (multiplet, 7H); (singlet 3H).

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Second step

In a 125 ml flask, sequentially introduced into 60 ml of acetic acid: 5.19 g of 5- (4-nitro-phenyl) -furan-2-carbaldehyde; g of the compound as obtained in the preceding step and then 1.96 g of sodium acetate which had been dried beforehand in vacuo. The reaction medium is then refluxed for 4 hours. During the rise in temperature, the reaction medium gradually changes from a yellow suspension to a thick suspension of orange-red color. The reaction medium is diluted with ethyl acetate and then filtered to give 10.5 g of an orange-red solid. It is then hydrolysed with an alcoholic solution of 5 N potassium hydroxide to give after acidification 9.23 g of a yellow solid in accordance with the expected structure.

1 H NMR (# in ppm) solvent DMSO d6: 8.42 (doublet, J = 9 Hz, 2H); 8.09 (doublet, J = 9 Hz, 2H); (singlet, 1H); 7.67 (doublet, J = 3.8 Hz, 1H); 7.61 (doublet, J = 3.8 Hz, 1H); 5.98 (broad singlet, 1H); 2.54-2.37 (multiplet, 7H); 2.05 (singlet, 3H)
The compound thus obtained is named 5850330 (see below) and corresponds to a compound of formula (IIter) in which i = 1, Rj is a NOz group and Ra is -CH (COOH) - (CH2) 2 -CHS3.

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Other examples with the method 1 Formula IIIter First step

In a 125 ml flask was added sequentially in 60 ml of acetic acid: 6.38 g of 2,5-dimethyl-1- (3-trifluoromethyl-phenyl) -1H-pyrrole-3-carbaldehyde (Aldrich); 3.18 g of 2-thioxothiazolidin-4-one and then 1.96 g of sodium acetate which has been dried under vacuum. The reaction medium is then refluxed for 4 hours. During the rise in temperature, the reaction medium thickens considerably while staining. The reaction medium is spread with water and then filtered to give 7.75 g of an orange-yellow solid.

Dans un ballon de 50 ml on introduit séquentiellement dans 25 ml de DMF : g de 5-[2,5-diméthyl-1 -(3-trifluorométhyl-phényl)- 1 H-pyrrol-3-ylméthylène]-2-thioxo- thiazolidin-4-one obtenu à la première étape ; 0,48 g d'hydrure de sodium préalablement lavé au pentane et 5 ml de bromure d'allyle. Le milieu réactionnel est ensuite maintenu à température ambiante pendant 16 heures. Le milieu réactionnel est ensuite étendu concentré sous vide puis lavé avec de l'eau glacée. Le précipité est filtré pour donner 3,94 g d'un solide orange. 1 H NMR (3 in ppm) solvent DMSO d6: 8.08 (doublet, J = 9.8 Hz, 1H); 7.807 (expanded singlet); 7.604 (triplet, 9.8 Hz, 1H); 7.41 (expanded doublet, J = 9.2 Hz, 1H); 6.29 (singlet, 1H); 2.2 (singlet, 3H); (singlet, 3H)
Second step

In a 50 ml flask was sequentially introduced into 25 ml of DMF: 5- [2,5-dimethyl-1- (3-trifluoromethyl-phenyl) -1H-pyrrol-3-ylmethylene] -2-thioxo thiazolidin-4-one obtained in the first step; 0.48 g of sodium hydride previously washed with pentane and 5 ml of allyl bromide. The reaction medium is then maintained at room temperature for 16 hours. The reaction medium is then concentrated concentrated under vacuum and then washed with ice water. The precipitate is filtered to give 3.94 g of an orange solid.

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 1H NMR (8 ppm) DMSO solvent d6: 8.08 (doublet, J = 9.8 Hz, 1H), 7.807 (expanded singlet); 7.604 (triplet, J = 9.8 Hz, 1H); 7.41 (expanded doublet, J = 9.2 Hz, 1H); 6.29 (singlet, 1H); 5.85 (multiplet, 1H); 5.19 (multiplet, 2H); (multiplet, 2H); 2.2 (singlet, 3H); (singlet, 3H).

 The compound thus obtained is a compound of formula (IIIter) in which i = 1, Rj is CF3, Rb and Rc are methyl and Ra is -CH2-CH = CH2.

Formula IVter

In a 125 ml flask is added sequentially in 60 ml of acetic acid: 4.1 g of 5-phenyl-2H-pyrazole-4-carbaldehyde; 3.18 g of 2-thioxothiazolidin-4-one and then 1.96 g of sodium acetate which has been dried under vacuum. The reaction medium is then refluxed for 4 hours. During the rise in temperature, the reaction medium thickens considerably while staining. The reaction medium is spread with water and then filtered to give 4.8 g of a yellow solid in the form of a mixture E + Z (50/50).

 1H NMR (# in ppm) solvent DMSO d6: 13.85-13.7 (2 broad singlets, 1H); 13.5 (expanded singlet, 1H); 8.15-7.77 (2 extended singlet, 1H); 7.63-7.38 (multiplet, 6H).

 Mass Spectrum: m / z: 287; m / z = 201; m / z = 200 (base peak); m / z = 172, m / z = 171, m / z = 168.

 The compound thus obtained corresponds to the compound named 7105786 (see below) and is a compound of formula (IVter) in which i = 0 and Rb and Ra represent a hydrogen atom.

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s Synthèse des composés préférés de structure générale R- / S N -1-01 R/ '0 I / à partir de composés de structure S N 0 Première étape

Synthesis of Preferred Compounds of General Structure R- / SN -1-01 R / '0 I / From Compounds of Structure SN 0 First Step

27.8 g of 2-furfuryl isothiocyanate (Provenance: Avocado) are mixed with 21.9 g of methyl thioglycolate and 300 ml of toluene. 4.6 g of metallic sodium are added to the solution thus obtained. The reaction medium is then refluxed for 8 hours and then concentrated in vacuo. The solid thus obtained is washed with water and recrystallized from ethanol. 31.45 g of a powder corresponding to the expected result are obtained with a melting point of 74.degree.

Second step (standard operating mode)
In a 125 ml flask, 0.023 mol of aldehyde is introduced sequentially into 60 ml of acetic acid; 5.09 g of the compound as obtained in the preceding step and then 1.96 g of sodium acetate which had been dried under vacuum. The reaction medium is then refluxed for 4 hours. The reaction medium is spread with ethyl acetate and then filtered, washed with water and then dried to give a solid, generally colored, in accordance with the expected structure.

<Desc / Clms Page number 48>

ANALYTICAL DATA
Compound 5529625

1H NMR (8 in ppm) solvent DMSO d6: 8.17 (expanded singlet, 1H); 8.16-8.10 (multiplet, 1H); 7.89-7.45 (multiplet, 2H); 7.73 (singlet, 1H); 7.57 (expanded singlet, 1H); 7.53 (doublet, J = 3.8 Hz, 1H); 7.39 (doublet, J = 3.8 Hz, 1H); 6.85 (singlet, 2H); 5.25 (singlet, 2H)
Compound 5535058

1 H NMR (# in ppm) solvent DMSO d6: 7.91 (doublet expanded, 1H); 7.68-7.50 (multiplet, 2H); (singlet, 1H); 7.49 (doublet, J = 3.8 Hz, 1H); 7.39 (doublet, J = 3.8 Hz, 1H); 6.85 (singlet, 2H); 5.25 (singlet, 2H)
Compound 5573416

1H NMR (# in ppm) solvent DMSO d6: 8.21-8.05 (multiplet, 4H); 7.73 (singlet, 1H); 7.53 (doublet, J = 3.8 Hz, 1H); 7.39 (doublet, J = 3.8 Hz, 1H); 6.85 (singlet, 2H); (singlet, 2H)

<Desc / Clms Page number 49>

Compound 5572135

1H NMR (8 ppm) solvent DMSO d6: 8.15-7.86 (multiplet, 4H) 7.73 (singlet, 1H); 7.53 (doublet, J = 3.8 Hz, 1H); 7.39 (doublet, J = 3.8 Hz, 1H); 6.85 (singlet, 2H); 5.25 (singlet, 2H)
Compound 5854209

1H NMR (8 in ppm) solvent DMSO d6: 8.24-7.48 (multiplet, 3H); 7.73 (singlet, 1H); 7.53 (doublet, J = 3.8 Hz, 1H), 7.39 (doublet, J = 3.8 Hz, 1H), 6.85 (singlet, 2H); (singlet, 2H)
Compound 8042021

1H NMR (8 in ppm) solvent DMSO d6: 7.58-7.13 (multiplet, 5H); 7.73 (singlet, 1H); 7.53 (doublet, J = 3.8 Hz, 1H); 7.39 (doublet, J = 3.8 Hz, 1H); 6.85 (singlet, 2H); 5.25 (singlet, 2H)

<Desc / Clms Page number 50>

Compound 8029051

1 H NMR (# in ppm) solvent DMSO d6: 8.24-7.48 (multiplet, 3H) 7.73 (singlet, 1H); 7.53 (doublet, J = 3.8 Hz, 1H), 7.39 (doublet, J = 3.8 Hz, 1H); 6.85 (singlet, 2H); 5.25 (singlet, 2H)
Compound 8042022

1H NMR (8 ppm) DMSO solvent d6: 8.21-8.05 (multiplet, 4H); 7.73 (singlet, 1H); 7.53 (doublet, J = 3.8 Hz, 1H), 7.39 (doublet, J = 3.8 Hz, 1H); 6.85 (singlet, 2H); 5.25 (singlet, 2H)
The other preferred compounds are synthesized from the various methods described above. Only the analytical data of the products are included here.

Compound 80811727

1H NMR (8 in ppm) solvent DMSO d6: 8.10 (expanded singlet, 1H); 7.85-7.71 (multiplet, 2H); (singlet, 1H); 7.45 (doublet, J = 3.8 Hz, 1H); 7.35 (doublet, J = 3.8 Hz, 1H); 4.4 - 4.25 (multiplet, 2H); (multiplet, 2H)

<Desc / Clms Page number 51>

Compound 5681435

1H NMR (# in ppm) solvent DMSO d6 8.41 (expanded singlet, 1H); 8.08 (expanded doublet, 1H); 7.99 (expanded doublet, 1H); 7.69 (singlet, 1H); 7.75-7.64 (multiplet, 1H); 7.42 (doublet, J = 3.8 Hz, 1H), 7.37 (doublet, J = 3.8 Hz, 1H); 6.0-5.8 (multiplet, 1H); 5.25-5.1 (multiplet, 2H); 4.68 (singlet, 2H)
Composed 6327701

1H NMR (8 ppm) DMSO solvent d6: 8.06 (doublet, J = 12H, 2H); 7.88 (doublet, J = 12H, 2H); 7.807 (singlet, 1H); 7.275 (doublet, J = 3.8 Hz, 1H); 7.205 (doublet, J = 3.8 Hz, 1H); 4.42 (singlet, 2H)
Compound 6327700

1H NMR (8 ppm) DMSO solvent d6: 8.08 (doublet, J = 9.8 Hz, 1H); 7.807 (expanded singlet); 7.604 (triplet, 9.8 Hz, 1H), 7.41 (doublet expanded, 9.2 Hz, 1H); 6.29 (singlet, 1H); 5.85 (multiplet, 1H); 5.19 (multiplet, 2H); 4.63 (multiplet, 2H); 2.2 (singlet, 3H); 2.05 (singlet, 3H)

<Desc / Clms Page number 52>

Compound 6699808

1 H NMR (# in ppm) solvent DMSO d6: 8.23 (doublet, J = 4H, 1H); 7.94 (doublet, doublet, J = 12 Hz, J = 4 Hz, 1H); 7.70 (expanded singlet, 1H); 7.67 (singlet, 1H); 7.39 (doublet, J = 3.8 Hz, 1H); 7.32 (doublet, J = 3.8 Hz, 1H); 4.28 (multiplet, 2H); 3.70 (multiplet, 2H); 3.30 (singlet, 3H)
Compound 5920787

1H NMR (# in ppm) solvent DMSO d6: 8.39 (doublet, J = 12 Hz, 2H); 8.09 (doublet, J = 12 Hz, 2H); 7.73 (singlet, 1H); 7.57 (doublet, J = 3.8 Hz, 1H); 7.39 (doublet, J = 3.8 Hz, 1H); 5.9 (expanded singlet, 1H); 3.42 to 2.95 (unresolved peak)

<Desc / Clms Page number 53>

Preparation of new compounds First step

In a 125 ml flask was sequentially introduced into 60 ml of acetic acid: 4.52 g of 2-phenyl-thiazole-4-carbaldehyde (commercially available from Maybridge or obtained according to the procedure described in Tetrahedron, 56.5, 2000). , 811-816), 3.18 g of 2-thioxo-thiazolidin-4-one and then 1.96 g of sodium acetate previously dried under vacuum. The reaction medium is then refluxed for 2 hours. During the rise in temperature, the reaction medium thickens considerably while staining. The reaction medium is spread with water and then filtered to give 5.94 g of an orange solid.

1H NMR (# in ppm) solvent DMSO d6: 7.58-7.13 (multiplet, 6H); 7.73 (singlet, 1H)
Second step

In a 50 ml flask was sequentially introduced into 25 ml of DMF: 3.0 g of 5- (2-phenyl-thiazol-4-ylmethylene) -2-thioxo-thiazolidin-4-one in the first step; 0.48 g of sodium hydride previously washed with pentane and 5 ml of allyl bromide. The reaction medium is then maintained at room temperature for 16 hours. The reaction medium is then extended concentrated under vacuum then

<Desc / Clms Page number 54>

 washed with ice water. The precipitate is filtered and then chromatographed on silica gel to give 2.05 g of an orange solid.

1H NMR (8 ppm) DMSO solvent d6: 7.58-7.13 (multiplet, 6H), 7.73 (singlet, 1H), 5.85 (multiplet, 1H); 5.19 (multiplet, 2H), 4.63 (multiplet, 2H)
Preparation of compounds of formula (A)
Example with a 1,2,4-thiadiazole heterocycle
First stage

In a three-necked 500 ml equipped with a mechanical stirring and under slight pressure of nitrogen is introduced 26.8 g of ethyl ester of 5- (4-chloro-phenyl) - [1,2,4] thiadiazole-3-carboxylic acid (obtained according to the procedure described in Monsanto US Pat. No. 4,115,095) in 250 ml of anhydrous THF. The reaction medium is then cooled to -78 ° C. using an acetone-dry ice solution. Once the temperature is stabilized, 125 ml of a 1M solution of diisobutyl aluminum hydride dissolved in toluene are slowly introduced. The temperature is maintained at -78 ° C. for 4 hours, then another 4 hours at -20 ° C. The reaction medium is then treated with a solution of sodium and potassium double tartrate. Once the aluminum-tartaric complex has been formed, the medium is extracted twice with methylene chloride. The organic phases are combined, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. 25 g of a colorless, thick oil which is purified by chromatography on silica gel (toluene / AcOEt: 9/1) are then obtained. 16.23 g of a colorless oil corresponding to the expected structure and used for the next step are then obtained.

<Desc / Clms Page number 55>

Second step s - {N CHO NINNN - \ N s N 1 \\ N 0 NIN 1 S 0 # CI CI / 0 III CI) l) MW = 224.67 MW = 213.28 MW = 419.93 C, Fi, CIN20S C8H, N02S2 C17H1OCINP2S3
In a 125 ml flask was sequentially introduced into 60 ml of acetic acid: 5.36 g of aldehyde obtained in the first step; 5.09 g of 3-furan-2-ylmethyl-2-thioxo-thiazolidin-4-one and 1.96 g of sodium acetate which had previously been dried under vacuum. The reaction medium is then refluxed for 3.5 hours. The reaction medium is spread with ethyl acetate and then filtered, washed with water and then dried to give 7.62 g of an orange-yellow solid in accordance with the expected structure.

0 atome de chlore et Ra représente un groupe de formule \0/ Exemple avec un hétérocycle 1,2,4-oxadiazole Première étape

1 H NMR (# in ppm) solvent DMSO d6: 8.15-7.86 (multiplet, 4H) 7.79 (singlet, 1H); 6.85 (singlet, 2H); (singlet, 2H)
The compound thus obtained is a compound of formula (A) in which Z represents a sulfur atom, Rf represents a phenyl group substituted in para by a

0 atom of chlorine and Ra represents a group of formula 0 0 / Example with a heterocycle 1,2,4-oxadiazole First step

In a three-necked 500 ml provided with mechanical stirring and under a slight excess of nitrogen, 24.8 g of ethyl ester of 5- (4-methoxyphenyl) - [1,2,4 ] oxadiazole-3-carboxylic acid (obtained according to the procedure described in the patent Glaxo DE 2224338) in 250 ml of anhydrous THF. The reaction medium is then cooled to -78 ° C. using an acetone-dry ice solution. Once

<Desc / Clms Page number 56>

 stabilized temperature, 125 ml of a 1M solution of diisobutyl aluminum hydride dissolved in toluene are slowly introduced. The temperature is maintained at -78 ° C. for 4 hours, then another 4 hours at -20 ° C. The reaction medium is then treated with a solution of sodium and potassium double tartrate. Once the aluminum-tartaric complex has been formed, the medium is extracted twice with methylene chloride. The organic phases are combined, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. 20.2 g of a colorless oil are obtained which is purified by chromatography on silica gel (toluene / AcOEt: 9/1). 12.33 g of a colorless oil conforming to the expected structure and used for the next step are then obtained.

Second step

In a 125 ml flask is introduced sequentially into 60 ml of acetic acid: 4.8 g of aldehyde obtained in the first step; 5.09 g of 2-thioxothiazolidin-4-one and 1.96 g of sodium acetate which had been dried under vacuum. The reaction medium is then refluxed for 4 hours. The reaction medium is spread with ethyl acetate and then filtered, washed with water and then dried to give 6.93 g of an orange solid in accordance with the expected structure. Melting point> 300 C
1H NMR (# in ppm) solvent DMSO d6: 8.21-8.05 (multiplet, 4H); 7.73 (singlet, 1H); 3.23 (singlet, 3H)
The compound thus obtained is a compound of formula (A) in which Z represents an oxygen atom, Rf represents an OCH3 group and Ra represents a hydrogen atom.

<Desc / Clms Page number 57>

Biological tests
All these compounds have been subjected to various biological tests.

Cytotoxicity measurement
The cytotoxicity of the products is measured in 96-well dishes on CHO cells.

The cells are diluted the day before in 100 l at 20 000 cells / well in RPMI supplemented with 5% of fetal calf serum. The cells are incubated for 24 hours at 37 ° C. in the presence of product concentrations of between 100 g / ml and 0.062 g / ml and the cytotoxicity is measured by the colorimetric test "cell cytotoxicity kit I" (Roche Applied Sciences). The results are given in the table below. A compound exhibiting a toxicity value equal to 100 g / ml corresponds to a toxic compound from the dose of 100 g / ml; a compound having a toxicity value greater than 200 g / ml corresponds to a toxic compound above the dose of 200 g / ml.

Identification of molecules displacing the link between # 70 and RNA polymerase
To identify molecules that displace the binding between # 70 and RNA polymerase, the ELISA assay was used as described in International Application WO 02/44735.

Measurement of minimal inhibitory concentrations
Minimum inhibitory concentrations (MIC) are measured according to NCCLS guidelines. The following strains were used: Staphylococcus aureus (CIP 76.25), Staphylococcus epidermidis (CIP 68.21), Streptococcus pneumoniae (CIP 103566), Bacillus cereus (ATCC 14579), Escherichia coli (CIP 76.24) and Pseudomonas aeruginosa. (CIP 76.110). The MICs are determined in a liquid medium, in a 96-well box, on two independent experiments. The inoculum is prepared from colonies grown to confluency and then diluted in MHB (Mueller and Hinton's medium, Sigma: M-9677) to 105 bacteria / ml. The products are tested at concentrations of 100 g / ml to 0.062 μg / ml.

<Desc / Clms Page number 58>

CMI (Ilglml) Composé Staphylococcus Staphylococcus Bacteroides IC50 Toxicité aureus epidermidis megatrium (Ilglml) (Ilglml) C) /'\/ 0 1,17 0,58 1,17 1,26 >200 p-Rli g S 1,17 . 0,58 1,17 1,26 > 200 S FS F F 5529625 H,C o 9,4 77 4,7 10,1 100 Sus 5681435 OH ô N ' / 0 0 0 s s 4 4 4 1,32 100 5850330 H30N 0 s /p 1 I \ 18,75 4,69 o 1'\ 18,75 4,69 >200 s 18,75 4,69 HO 5888656 /=="N-CH, 0 0 S-\s 8 8 6 0,32 100 HO 6258097 Results

CMI (Ilglml) Compound Staphylococcus Staphylococcus Bacteroides IC50 Toxicity aureus epidermidis megatrium (IIgml) (IIgml) C) / 1.17 0.58 1.17 1.26> 200 p-R1g S 1.17. 0.58 1.17 1.26> 200 S FS FF 5529625 H, C o 9.4 77 4.7 10.1 100 Sus 5681435 OH o N '/ 0 0 0 ss 4 4 4 1.32 100 5850330 H30N 0 s / p 1 I \ 18.75 4.69 o 1 '18.75 4.69> 200 s 18.75 4.69 HO 5888656 / == "N-CH, 0 0 S- \ s 8 8 6 0.32 100 HO 6258097

<Desc / Clms Page number 59>

/ rô H,C 0 0-bN s Ns CH, 1,83 / Vy s~4g 18 18 10 1,83 100 H,C 6327700 N={ y-N' 18 . 18 10 3,21 50 7105786 o 0 N j~/#s 1 0,3 0,78 43,5 100 8042021 o 0 .J'\s-s 200 10 5 11,2 100 H2N~s s 0 8042022 1 OH ION )SO 1,04 Cil 0 N 1,04 >200 ci 80811727

## STR2 ## wherein: embedded image 18 3.21 50 7105786 o 0 N j ~ / # s 1 0.3 0.78 43.5 100 8042021 o 0 .J '\ ss 200 10 5 11.2 100 H2N ~ ss 0 8042022 1 OH ION) N / A 1.04 Cil 0 N 1.04> 200 c 80811727

<Desc / Clms Page number 60>

Test of a molecule included in a plastic film
500 mg of polyurethane (Ref .: 81367 Fluka), 200 mg of polyethylene glycol (average molecular weight: 8000 daltons, Ref .: P-5413 sigma) and 10 mg of a compound of the invention of formula (I) are placed in solution in 50 ml of dimethylformamide.

After complete dissolution, 10 ml of the liquid thus obtained is transferred to a 50 ml polypropylene tube and the solvent is evaporated by lyophilization. A plastic film containing the compound of formula (I) then covers the bottom of the tube.

 Confluent S. epidermidis bacteria (CIP 105777) are diluted to 1.108 bacteria / ml in Mueller and Hinton medium (MHB) and are incubated overnight in this tube covered by the plastic film containing the above compound. The next day, the bacterial culture is removed, the bacteria are washed in MHB and are counted by spreading. No viable bacteria are detected in the plastic-coated tube with said compound. 108 to 109 bacteria are detected in a tube covered with polyurethane.

Claims (28)

A pharmaceutical composition containing, as active ingredient, at least one of the compounds of formula (I) below:

 in which: X represents an oxygen atom, a sulfur atom, an NH group or a NR group, R representing an alkyl group comprising from 1 to 5 carbon atoms, optionally substituted by a nitrogen atom or oxygen, Y represents an oxygen atom, a sulfur atom, an NH group or a NR group, R representing an alkyl group comprising from 1 to 5 carbon atoms, optionally substituted by a nitrogen or oxygen atom; Ra represents an alkyl group comprising from 1 to 16 carbon atoms, an alkenyl group comprising from 2 to 16 carbon atoms, said alkyl or alkenyl groups possibly being substituted, in particular by one of the following groups: halogen such as fluorine, chlorine, bromine or iodine, a COR2 group or a COOR2 group, R2 representing a hydrogen atom, a CN group, a COOM group, M representing an alkali metal or alkaline earth, especially chosen from: Na, Ca, Mg, Al, Zn, Li * a group SR1, R1 representing a hydrogen atom or an alkyl group comprising from 1 to 16 carbon atoms, and preferably being a methyl, ethyl or tert-butyl group, a SOR1 group, Ri being as defined above, a group SO2R, R1 being as defined above, a group -SO2-, -SO2-OH, SO3M, M being as defined above, a group CF3, CHF2, CH2F, - [CF2] m-CF3, m varying from 1 to 3, or - [CF2] n-CH3, n varying from 1 to 3, <Desc / Clms Page number 62>

 a heterocycle with 4.5 or 6 members, in particular chosen from: 2,3,4,5-tetrahydro-pyridine; piperidine; 1,4-dioxane; 1,4-dithiane; morpholine; thiomorpholine; pyridazine; pyrimidine; pyrazine; piperazin; 1,3,5-triazine; 1,2,3-triazine; 1,2,4-triazine; purine; said heterocycle being optionally substituted by one or more substituents chosen in particular from the following groups: # an alkyl group comprising from 1 to 16 carbon atoms, an aryl group comprising from 6 to 30 carbon atoms, in particular a phenyl group, a heterocyclic group selected from the heterocycles mentioned above for A, said alkyl or aryl group, in particular phenyl, which may optionally itself be substituted with one or more substituents, in particular 1,4-dihydropyridine; 1,2,3,4-tetrahydro-pyridine; 1,2,3,6-tetrahydro-pyridine; R6 represents an alkyl group comprising from 1 to 30, especially from 1 to 16 carbon atoms, - A represents a 5- or 6-membered heterocycle comprising at least one heteroatom chosen from N, O, S, P, Si, Se, optionally coupled to another cyclic radical with 4, 5, 6 or 7 members, with or without heteroatoms as defined above, in particular a heterocycle such as: thiophene; pyrrole; 2H-pyrrole; 2H-pyrroline; 3H-pyrroline; pyrrolidine; oxazole; thiazole; imidazole; 2-imidazoline; imidazolidine; pyrazole; 2-pyrazoline; pyrazolidine; isoxazole; isothiazole; 1,2,3-oxadiazole; 1,2,3-triazole; 1,2,4-oxadiazole; 1,2,4-thiadiazole; 1,2,4-triazole; 1,3,4-oxadiazole; 1,3,4-thiadiazole; 1,3,4-triazole; 2H-pyran; 4H-pyran; 3,6-dihydro-2H-pyran; 3,4-dihydro-2H pyran; tetrahydropyran; pyridine; 2,3-dihydropyridine; 1,2-dihydropyridine; <Desc / Clms Page number 63> COCH 3 or a CN group, R 1 being as previously defined, a halogen atom such as fluorine, chlorine, bromine or iodine, a group OR 1, R 1 representing a hydrogen atom or an alkyl group comprising from 1 to 16 carbon atoms, preferably being a methyl, ethyl or tert-butyl group, or an alkenyl group comprising from 2 to 16 carbon atoms, a group alkynyl comprising from 2 to 16 carbon atoms, an aryl group comprising 5.6, 9.10 or 12 carbon atoms, a heteroaryl group comprising 5, 6, 9, 10 or 12 carbon atoms and at least one of which atoms is selected from N, O, S, a cycloalkyl group having 4 to 8 carbon atoms, a cycloalkenyl group comprising from 4 to 8 carbon atoms, # a COOR2 group, R2 representing a hydrogen atom or an alkyl group comprising 1 to 16 carbon atoms, being preferably a methyl, ethyl or tert-butyl group, an alkenyl group comprising from 2 to 16 carbon atoms, or an alkynyl group comprising from 2 to 16 carbon atoms, a CN group,. a COOM group, M representing an alkali metal or alkaline earth metal, in particular chosen from: Na, Ca, Mg, Al, Zn, Li * a group SR1, R1 being as defined above, a group SOR1, R1 being as defined above, a group SO2R1, wherein R1 is as defined above, a group -SO2-, -SO2-OH, SO3M, M being as defined above, a group NR3R4, R3 and R4, which are identical or different, or connected together to form a 4-, 5- or 6-membered ring, independently of one another representing a hydrogen atom or an alkyl group comprising 1 to 16 carbon atoms, an alkenyl group comprising from 2 to 16 carbon atoms, an alkynyl group comprising from 2 to 16 carbon atoms, an aryl group comprising 5,6, 9,10 or 12 carbon atoms, a heteroaryl group comprising 5 , 6, 9, 10 or 12 carbon atoms and of which at ORi, CF3 group, NO2 group, SO2NH2 group, a group  selected from the following groups: a halogen atom, especially a chlorine, bromine or fluorine atom, a COORi group, a group <Desc / Clms Page number 64>  at least one of the atoms is selected from N, O, S, a cycloalkyl group comprising from 4 to 8 carbon atoms, a cycloalkenyl group comprising from 4 to 8 carbon atoms, a group N02,. a group CF3, CHF2, CH2F, - [CF2] m-CF3, m ranging from 1 to 3, or - [CF2] n-CH3, n ranging from 1 to 3, said composition containing the compound of formula (I) under E or Z form, or containing a mixture of its E form and its Z form, in combination with a pharmaceutically acceptable vector.  2. Pharmaceutical composition according to claim 1, containing, as active ingredient, at least one of the compounds corresponding to one of formulas (II) or (II ')

 following: x Ra / T "\\ - *" \ y # N Q'OIZS 0 y (il) (Ri), XS, N / Ra (il ') N (II') \ ~ \ / <\ Y ( Wherein: X, Y and Ra are as defined in claim 1, - i represents an integer ranging from 0 to 5, - j represents an integer ranging from 1 to i, - the groups RJ, identical or different from different, in particular represent a halogen atom, preferably a chlorine or bromine atom, a COORI group, R 1 being as defined in claim 1, and preferably being a hydrogen atom, a group OR 1, R 1 being as defined in claim 1, and preferably being methyl group, CF3 group, NO2 group, SO2NH2 group or COCH3 group, said composition containing the compound of formula (II) in E or Z form, or containing a mixture of its E form and its Z shape. <Desc / Clms Page number 65>  3. Pharmaceutical composition according to claim 1, containing, as active substance, at least one of the compounds corresponding to one of the formulas (III) or

 (III '): (R) Rb Rb XA (III) N HN N $ J s "Iy RRXA / = \ N (iii') (., / Fs (II ') (R1), in which: X , Y and Ra are as defined in claim 1, - Rb and Rc, identical or different, represent an alkyl group comprising 1 to 5 carbon atoms, especially a methyl group, or an aryl group comprising from 6 to 30 carbon atoms, and being especially a phenyl group, - i represents an integer ranging from 0 to 5, - j represents a whole number varying from 1 to 1, the groups R 1, which are identical or different, represent in particular a halogen atom, preferably a chlorine atom, a COORI group, R 1 being as defined in claim 1, and preferably being an atom of hydrogen or a methyl group or a CF3 group, said composition containing the compound of formula (III) in E or Z form, or containing a mixture of its E form and its Z form.  4. Pharmaceutical composition according to claim 1, containing, as active substance, at least one of the compounds corresponding to one of formulas (IV) or

 (fiv) following: (IV ') srnvantes: (R, J, (IV) x Ra R-N / ZN / \ <Desc / Clms Page number 66> S02NH2 or a COCH3 group, said composition containing the compound of formula (IV) in E or Z form, or containing a mixture of its E form and its Z form.  in which: X, Y and Ra are as defined in claim 1; Rb represents a hydrogen atom or an alkyl group comprising from 1 to 5 carbon atoms, in particular a methyl group, said alkyl group being optionally substituted; by a CN group or a COOH group, or an aryl group comprising from 6 to 30 carbon atoms, and being especially a phenyl group, - i represents an integer ranging from 0 to 5, - j represents an integer varying from 1 at i, the groups R 1, which are identical or different, represent in particular a halogen atom, preferably a fluorine or bromine atom, a COOR 1 group, R 1 being as defined in claim 1, and preferably being an atom of hydrogen, a group OR 1, R 1 being as defined in claim 1, and preferably being a methyl group, a CF 3 group, a NO 2 group, a group

 5. Pharmaceutical composition according to one of claims 1 to 4, characterized in that Y represents a sulfur atom.  6. Pharmaceutical composition according to one of claims 1 to 5, characterized in that X represents an oxygen atom. <Desc / Clms Page number 67>  7. Pharmaceutical composition according to one of claims 1 to 6, containing as active ingredient at least one of the compounds of formula

 (IIbis) wherein Ra, i, j and Ra are as defined in claim 2, said composition containing the compound of formula (IIbis) in E or Z form, or containing a mixture of its E form and its Z shape.  8. Pharmaceutical composition according to one of claims 1 to 6, containing as active ingredient at least one of the compounds of formula

 (IIter) wherein Ra, i, j and Ra are as defined in claim 2, said composition containing the compound of formula (IIter) in E or Z form, or containing a mixture of its E form and its Z shape.  9. Pharmaceutical composition according to one of claims 1 to 8, containing as active ingredient at least one of the compounds of formula (II), (IIa) or (IIter) in which

 Ra represents:., O 3>> -SO, H <Desc / Clms Page number 68>

 especially :

10. Pharmaceutical composition according to one of claims 1 to 6, containing as active ingredient at least one of the compounds of formula

 (IIIbis) Rb 0 Il (RA ~ Y S (ilibis) in which RJ, i, j, Ra, Rb and Rc are as defined in claim 3, <Desc / Clms Page number 69>  said composition containing the compound of formula (IIIa) in E or Z form, or containing a mixture of its E form and its Z form.  11. Pharmaceutical composition according to one of claims 1 to 6, containing as active ingredient at least one of the compounds of formula

 (illiterate): ## STR2 ## wherein R 1, R 1, R 1, Rb and Rc are as defined in claim 1. 3, said composition containing the compound of formula (IIIter) in E or Z form, or containing a mixture of its E form and its Z form.  12. Pharmaceutical composition according to one of claims 1 to 6, 10 or 11, containing as active ingredient at least one of the compounds of formula (III), (IIIa) or (IIIter) wherein: Ra represents:

<Desc / Clms Page number 70> 13. Pharmaceutical composition according to one of claims 1 to 6, containing as active ingredient at least one of the compounds of the formula

 (IVa) following: CR) 1 (R 1 RbN 1 Ra R # N. / SS (IVa)) wherein R 1, j, i, Ra and Rb are as defined in claim 4, said composition containing the compound of formula (IVbis) in E or Z form, or containing a mixture of its E form and its Z form.  14. Pharmaceutical composition according to one of claims 1 to 6, containing as active ingredient at least one of the compounds of formula

 (IVter) ## STR2 ## wherein R 1, R 1, R 1 and R b are as defined in claim 4, said composition containing the compound of formula (IVter) in E or Z form, or containing a mixture of its E form and its Z form.  15. Pharmaceutical composition according to one of claims 1 to 6, 13 or 14, containing as active ingredient at least one of the compounds of formula (IV), (IVa) or (IVter) wherein: Ra represents H, and

 - <-. '> # represents y # <Desc / Clms Page number 71> 16. Pharmaceutical composition according to one of claims 2 or 5 to 9, characterized in that Ra represents in particular one of the following groups:

17. Pharmaceutical composition according to one of claims 3, 5, 6 or 10 to 12, characterized in that Ra represents one of the following groups: an atom

 of hydrogen, a group -cH, - # = CH, or a group ~ Tj ~ // / # \ 18. Pharmaceutical composition according to one of claims 4 to 6 or 13 to 15, characterized in that Ra represents one of the following groups: an atom

 of hydrogen, -CH 2 -CH 3, - (CH 2) 2 -CH 3, -CH 2 -COOH, - (CH 2) 2-OMe, / or, - CS ", / 00 -CH 2 p and that Rb represents a fluorine atom or a chlorine atom. <Desc / Clms Page number 72>  19. Pharmaceutical composition according to claims 1, 2,5 to 9, or 16, characterized in that it contains, as active substance, a compound corresponding to one of the following formulas:

<Desc / Clms Page number 73>

<Desc / Clms Page number 74>

<Desc / Clms Page number 75>

<Desc / Clms Page number 76> 20. Pharmaceutical composition according to claim 19, characterized in that it contains, as active substance, the compound of the following formula:

<Desc / Clms Page number 77>

21. Pharmaceutical composition according to claims 1, 3, 5, 6, 10 to 12 or 17, characterized in that it contains, as active substance, a compound corresponding to one of the following formulas: <Desc / Clms Page number 78>

22. Pharmaceutical composition according to claim 21, characterized in that it contains, as active substance, the compound of the following formula:

23. Pharmaceutical composition according to claims 1, 4 to 6, 13 to 15, or 18, characterized in that it contains, as active substance, the compound of the following formula:

<Desc / Clms Page number 79>

<Desc / Clms Page number 80>

24. Pharmaceutical composition according to claim 23, characterized in that it contains, as active substance, the compound of the following formula: 25. Pharmaceutical composition according to any one of claims 1 to 24, characterized in that it comprises at least one of the compounds as defined in any one of claims 1 to 24, at about 0, 1 to about 200 mg / kg / unit dose.  26. Use of the compounds as defined in any one of claims 1 to 24, for the preparation of a medicament for the treatment of microbial infections.  Compounds according to formula (I) as defined in claim 1, wherein: - X, Y and Ra are as defined in claim 1, and - A represents a 5-membered heterocycle selected from the following: 1,2,4-oxadiazole; 1,2,4-thiadiazole; 1,2,4-triazole; 1,3,4-oxadiazole; 1,3,4-thiadiazole; 1,3,4-triazole; imidazole; oxazole and thiazole.  28. Compounds according to claim 27, having the following formula (A):

<Desc / Clms Page number 81>

 Ra represents either AA or Si COOH - Rf represents one of the following groups:

 in which: Z represents an oxygen atom, a sulfur atom or an NH group;