WO2000066573A2

WO2000066573A2 - Oxa combinatorial library, production and use thereof

Info

Publication number: WO2000066573A2
Application number: PCT/FR2000/001138
Authority: WO
Inventors: Xavier Williard; Juliana Pop-Botez; Benoît Deprez
Original assignee: Cerep
Priority date: 1999-04-30
Filing date: 2000-04-28
Publication date: 2000-11-09
Also published as: AU4306300A; WO2000066573A3; FR2792936A1

Abstract

The invention relates to a combinatorial library of compounds, characterized in that it comprises substituted derivatives of oxadiazolinone and/or oxadiazolinthione. The invention also relates to novel synthesis paths, such as automated synthesis, for said libraries and compounds. The invention also relates to the use of said libraries in the identification or optimization of compounds which can be used in chemistry, pharmacy or in the agro-food industry.

Description

OXA COMBINATORIAL BANKS, PREPARATION AND USES

The present invention relates to the field of combinatorial chemistry. It relates in particular to new product libraries, their constitution, and their uses, in particular for the identification or optimization of products of interest. The present invention can be implemented in the pharmaceutical (in particular therapeutic or vaccine), chemical, agro-food (insecticides, herbicides), textile, etc. fields.

Combinatorial chemistry is a rapidly developing technological field. It makes it possible to generate banks of synthetic molecules of very varied structures and compositions, useful in the development of new industrial products. Combinatorial chemistry therefore involves appropriate methods of producing libraries of compounds, as well as efficient methods of screening such libraries. The present invention now relates to new methods and compositions for the preparation of combinatorial libraries.

One aspect of the invention lies more particularly in new combinatorial libraries of compounds. Another aspect of the invention lies in optimized methods of synthesis of such banks. The invention also relates to the use of banks, in particular for the search and / or optimization of "leads", as well as screening and / or profiling methods using the banks of the invention. The invention further relates to kits or supports comprising compounds or libraries defined in the present application.

A first object of the invention therefore relates to new combinatorial libraries of compounds. More particularly, a first subject of the invention relates to a combinatorial library of compounds, characterized in that it comprises substituted derivatives of oxadiazolinones and / or oxadiazolinthiones. The present invention derives in particular from the development of advantageous synthesis methods making it possible to produce, efficiently and industrially, substituted derivatives of oxadiazolinones 2

and / or oxadiazolinthiones. The invention therefore resides in the use of such derivatives for the generation of combinatorial, diverse or focused libraries. The banks of the invention have an original composition, linked to the original structure of the monomers ("building blocks") used, and also particularly advantageous properties. Thus, in fact, oxadiazolinones have been described as carrying interesting biological properties, such as tuberculostatic, antibacterial (Sherman WR, J. Org. Chem. 26 (1961) 88), insecticidal (Rufenacht K. Helv. Chim. Acta) properties. 55 (1972) 1174), or also inhibitor of type B monoamine oxidases (Mazouz et al., Eur. J. Med. Chem. 25 (1990) 659), for example. The libraries of the invention therefore constitute a new rich source for the identification of compounds of interest.

A library (or library) more particularly designates, within the meaning of the present invention, a composition comprising a collection of compounds of diverse structure. More particularly, the banks of the invention comprise at least 50 compounds of different structure, preferably at least 100, even more preferably, at least 500. Particular banks can comprise more than 1000, in particular more than 5000 products of various structure, for example up to 500,000, or more.

In addition, the banks according to the invention can be primary banks or focused banks. A primary bank is a bank produced essentially at random, without any particular structural or conformational constraints. Primary banks are therefore often very diverse, and contain a large number of products. A focused bank, on the other hand, is a "secondary" bank composed of products with a common characteristic (structural, conformational, etc.), or supposed to be such. This type of library is generally less diverse than primary banks, and has a lower number of compounds. These banks are more often used to optimize active products, in particular to search for analogues of active products. More particularly, the invention relates to a combinatorial library of compounds, characterized in that it comprises a plurality of compounds of general formula (I) below:

Ri K

"V \

(D

wherein R ₁ is a hydrogen atom (H) or a first substituent; and A is chosen from the groups:

R2 X S-R3

I II I

- NC— ^or - N = C—

in which R2 represents a hydrogen atom (H) or a second substituent; R3 represents a hydrogen atom (H) or a third substituent, and X represents O or S.

More particularly, in the general formula (I) above, at least one of the substituents R1, R2 and R3 is different from H.

The combinatorial libraries of the invention therefore comprise compounds having a common nucleus, derived from oxadiazolinones or oxadiazolinthiones, on which 1 or more substituents are introduced. Preferably, the compounds comprise 2 substituents, of different structure. In this regard, the di-substituted compounds entering more preferably in the composition of the banks of the invention therefore carry a substituent R1 and a substituent R2 or, a substituent R1 and a substituent R3.

Even more preferably, the invention relates to a combinatorial library of compounds, characterized in that it comprises a plurality of compounds of general formula (II):

wherein R is a hydrogen atom or a first substituent; R ₂ is a hydrogen atom or a second substituent, and X is an oxygen or sulfur atom, at least one of the groups R1 and R2 being different from H.

More preferably, in the general formula (II), X is an oxygen atom (see for example the final compound described in Figures 2A, 3 and 4). Even more preferably, in the general formula (II), R1 and R2 are different from H. A preferred embodiment is that in which X is an oxygen atom and R1 and R2 are different from H.

In another preferred embodiment, the invention relates to a combinatorial library of compounds, characterized in that it comprises a plurality (i) of compounds of general formula (III):

in which R is a hydrogen atom or a first substituent and R ₃ is a hydrogen atom or a second substituent, at least one of the groups R1 and R3 being different from H (see for example the final compound described in FIGS. 2C and 5B) and, optionally (ii) of compounds of general formula (II) as defined above, in which R., is a hydrogen atom or a first substituent; R ₂ is a hydrogen atom or a second substituent, X is a sulfur atom and at least one of the groups R1 and R2 is different from H (see for example the final compound described in Figures 2B, 3, 4 and 5A). More preferably, in the general formulas (II) and (III), R1, R2 and R3 are different from H. The term "plurality" as used in the present application designates the fact that the banks of the invention comprise at least 2 compounds of different structure corresponding to the formula (I) above. In this regard, as indicated above, a preferred bank within the meaning of the invention advantageously comprises more than 50 different products, and can include up to 500,000 products, or more. The libraries of the invention may comprise, in addition to the compounds of formula (I), other compounds of different structure, derived from combinatorial chemistry or from other synthetic routes.

In a particular embodiment, the invention relates to a combinatorial library of compounds as defined above, in which each compound is a substituted derivative of oxadiazolinone or of oxadiazolinthione, in particular in which each compound corresponds to the general formula (I) above.

In another particular embodiment, the invention relates to a combinatorial library of compounds as defined above, in which each compound corresponds to the general formula (II) above, in particular to the formula (II) in which X is an oxygen or sulfur atom, preferably oxygen and or R1 and R2 are substituent groups.

In another particular embodiment, the invention relates to a combinatorial library of compounds as defined above, in which each compound corresponds to the general formula (III) above, in particular in which R1 and R3 are groups substituents.

In another particular embodiment, the invention relates to a combinatorial library of compounds as defined above, in which each compound corresponds to the general formula (II) or (III) above, in particular in which R1, R2 and R3 are substituent groups and X is a sulfur atom. Substitutes

Within the meaning of the present invention, the term “substituent” designates any atom, radical or chemical group capable of being covalently linked with the nucleus of the molecule of formula (I). It may especially be any neutral or charged chemical group, linear, branched or cyclic, hydrophobic or hydrophilic, acceptor or donor of electron (s) or proton (s), aromatic or not, halogenated or not, a protective group, of an arm which can be used for example to immobilize the compound (or the bank) on a support, etc. Generally, the substituents used in the context of the present invention comprise one or more aromatic, heterocyclic, alkyl (saturated or unsaturated), acyl, alcohol, phenol, (thio) ether, acid, ester, nitrile, amino, ammonium, nitro groups. , aldehyde, ketone and / or halogen. More particularly, a substituent group of the invention can comprise from 1 to 30 carbon atoms, preferably from 1 to 20 carbon atoms.

Preferably, the substituent R1 can consist of any side chain of a hydrazide (ie, of formula R1-CO-NH-NH2). In this regard, it may be a substituent comprising one or more aromatic, heterocyclic, alkyl (saturated or unsaturated), acyl, secondary or tertiary alcohol, phenol, (thio) ether, ester, nitrile, tertiary amine groups, ammonium, nitro, aldehyde, ketone and / or halogen, preferably containing from 1 to 30 carbon atoms, more preferably from 1 to 20 carbon atoms. To this end, for the synthesis of the libraries and compounds of the invention, the substituent R1 can come from any commercial hydrazide. Table 1 gives an illustrative list of hydrazides which can be used to provide the substituent group R1 in the constitution of the libraries of the invention. These hydrazides are commercial and can easily be obtained by a person skilled in the art. If necessary, they can also be synthesized according to conventional methods. Other commercial hydrazides are also described in the base of ACD ("Available Chemical Directory") data, usable in the context of the present invention. All these hydrazides are therefore capable of being used to produce compounds of the invention. Furthermore, any other hydrazide (ie, non-commercial) can also be used to obtain and introduce the substituent R1. In this regard, hydrazides carrying a desired side chain R1 can be synthesized from carboxylic acids according to conventional techniques of chemistry. There are approximately 18,000 commercial carboxylic acids, of which at least 10,000 can be used to synthesize hydrazides. R1 can therefore consist of any lateral grouping of a hydrazide, a carboxylic acid or any activated form of carboxylic acid (for example acyl halide or anhydride). The level of diversity of R1 is therefore high, since at least more than 10,000 different substituents can be used.

Preferably, however, in order to limit the side reactions which may occur during the synthesis phase with a reactive function other than the hydrazide present on the substituent R1, in particular when the (thio) carbonyldiimidazole is used, it is preferable in this case to use substituents R1 which do not carry a primary or secondary amino function, primary alcohol or carboxylic acid.

Preferably, the substituent R2 may consist of any side chain of a halogen derivative, of a carboxylic acid or any activated form of carboxylic acid (for example acyl halide or anhydride) or of a primary amine or secondary, for example. In this regard, it may be an alkyl, alkyl, linear or branched group, cyclic or not, aromatic or not, a group COR ₄ , CH ₂ -NR ₅ R ₆ or CH ₂ -CH (OH ) -R ₄ , in which R4, R5 and R6, independently of one another, are hydrogen atoms, alkyl or acyl groups, linear or branched, cyclic or not, saturated or not, aromatic or not, heterocyclic, alcohol, phenol, (thio) ether, acid, ester, nitrile, amino, ammonium, nitro, aldehyde, ketone and / or halogen. The substituent R2 preferably contains from 1 to 30 carbon atoms, more preferably from 1 to 20 carbon atoms.

Preferably, the substituent R3 can consist of any side chain of a halogen derivative, of an epoxide, of a carboxylic acid or any activated form of carboxylic acid (for example acyl halide or anhydride), for example. In this regard, it may be an alkyl, alkyl, linear or branched group, cyclic or not, aromatic or not, a group CO-R ₄ , CH ₂ -NR ₅ R ₆ , or CH ₂ - CH (OH) -R ₄ , in which R4, R5 and R6, independently of one another, are hydrogen atoms, alkyl or acyl groups, linear or branched, cyclic or not, saturated or not, aromatic or not , heterocyclics, alcohol, phenol, (thio) ether, acid, ester, nitrile, amino (tertiary), ammonium, nitro, aldehyde, ketone and / or halogen. The substituent R3 preferably contains from 1 to 30 carbon atoms, more preferably from 1 to 20 carbon atoms.

Given the diversity of the substituents R1, R2 and R3, the libraries of the invention can comprise a large quantity of individual compounds of different structure, and thus allow a better search for molecules of interest.

Synthesis

The compounds and libraries of the invention are generally synthesized, by preparation, in a first step, of a monosubstituted oxadiazolinone or oxadiazolinthione carrying the substituent R1. Then, as the case may be, the substituent R2 or R3 can be introduced, by conventional chemistry methods, to generate an oxadiazolinone or a di-substituted oxadiazolinthione.

In this regard, the present invention also relates to a process for preparing a library of compounds as defined above, comprising a first synthesis step, preferably at high throughput, preferably automated, of a monosubstituted oxadiazolinone or oxadiazolinthione carrying the substituent R1 and, where appropriate, a second combinatorial step of substitution of the products monosubstituted by R2 or R3.

In the first stage, the oxadiazolinone or the monosubstituted oxadiazolinthione (carrying the substituent R1) can be synthesized in different ways. Thus, the synthesis can be carried out in the context of the present invention, by thermal cyclization of carboxylic derivatives of acylhydrazines, or also by reaction of acylhydrazine and phosgene (Dornow et al., Ber. 82

(1949) 121). The Applicant has also shown that this synthesis can also be carried out by reaction of acylhydrazine and triphosgene. A preferred method of synthesis of the monosubstituted compounds and of the corresponding libraries of the invention nevertheless consists in using, as starting material, (thio) carbonyldiimidazole. These compounds are first reacted with a hydrazide having a side chain R1, to generate the oxadiazolinone or the monosubstituted oxadiazolinthione. The corresponding reaction scheme is shown in Figure 1A for oxadiazolinones and in Figure 1B for oxadiazolinthiones.

In a particularly preferred embodiment, this synthesis step is carried out in the presence of dimethylformamide ("DMF"). Thus, surprisingly and particularly advantageously, the applicants have demonstrated that when these syntheses are carried out in the presence of DMF, the reactions are quantitative, can be carried out at ambient temperature, and very high yields (which may exceed 95%) are obtained. On the contrary, the reaction represented in FIG. 1A, carried out under the conditions of the prior art (in particular in the presence of THF only), gave rise to much lower yields, imposed temperature conditions which are difficult to use industrially. (Firoozi et al., J. Heterocycl. Chem. 32 (1995) 123; Boschelli et al., J. Med. Chem. 36 (1993) 1802) and did not allow the dissolution of the starting hydrazides to reach the desired concentrations for hydrazides in solution. Of 10

even, the finished product represented in FIG. 1B was obtained, under the conditions of the prior art, in the presence of carbon sulphide, CS ₂ , under conditions which are difficult to automate (Young et al., J. Am. Chem. Soc. 77 (1955) 400; Goswami et al., Indian J. Chem. 23B (1984) 796). The present invention therefore also describes an advantageous process for the synthesis of substituted oxadiazolinone (or oxadiazolinthion) compounds, comprising the reaction of a hydrazide and (thio) carbonyldiimidazole in the presence of DMF. The synthesis reaction is advantageously carried out in the presence of an excess of (thio) carbonyldiimidazole, under temperature conditions adaptable by a person skilled in the art, in particular close to ambient temperature. Even more preferably, the reaction is carried out in the presence of approximately 1 equivalent of hydrazide (in DMF) and of approximately 2 equivalents of (thio) carbonyldiimidazole (in a solvent such as THF or DMF). The ratio between the reactants as well as the temperature and the duration of the reaction can obviously be adapted by a person skilled in the art. In particular, it is possible to use from 1 to 5 equivalents of (thio) carbonyldiimidazole per equivalent of hydrazide. However, the best performance of the process is generally obtained under the conditions indicated above.

It is understood that this mode of synthesis constitutes the preferred embodiment of the invention, since it makes it possible to synthesize, on a large scale, under industrializable and economic conditions, large quantities of oxadiazolinone derivatives (or oxadiazolinthiones) diversified. In addition, this synthetic route can be automated, which constitutes another major advantage in the field of combinatorial chemistry. Examples of implementation of this synthesis method are given in the experimental part.

The compounds thus obtained therefore carry a diversity site which, taking into account the large number of usable structures (substituent R1) can already be used for the constitution of product banks. Indeed, as 11

indicated above, particular libraries according to the present invention are those in which R1 is a substituent and R2 or R3 represent a hydrogen atom.

More preferably, however, it is preferred to increase the level of diversity of the inventive banks and introduce a new degree of substitution in the individual molecules. For this, an additional substituent R2 or R3 is introduced into the molecules of formula (I). In this case, the second step of the combinatorial synthesis process can be carried out immediately after the first, without first isolating the mono-substituted products obtained, or, on the contrary, after an intermediate step of separation (or isolation) of these. In this regard, the process for the synthesis of oxadiazolinones or oxadiazolinthiones according to the invention using DMF is particularly advantageous since it makes it possible to make the separation or filtration step optional. Indeed, the reaction being essentially quantitative, it is possible to carry out the additional substitution directly in the same receptacle (plate well, in particular).

For the preparation of oxadiazolinones or di-substituted oxadiazolinthiones, the substituent R2 can be introduced by (i) an alkylation reaction (ii) an acylation reaction or (iii) a Mannich reaction, for example.

For the alkylation reaction, the monosubstituted oxadiazolinone or oxadiazolinthione is incubated in the presence of a halogen derivative of formula R2-Y, in which Y is a halogen atom (Cl, Br or I), under conditions classics known to those skilled in the art (Milcent et al., J. of Heterocyclic Chemistry 28 (1991) 1511; Gogoi et al., Indian J. of Chemistry Sect B29 (1990) 1159). The corresponding reaction scheme is shown in FIG. 2A for the synthesis of di-substituted oxadiazolinones and in FIG. 2B for the synthesis of di-substituted oxadiazolones. The reaction product can be easily isolated from excess reagents, if necessary, by conventional chromatographic methods or by simple filtration, for example.

For the acylation reaction, the monosubstituted oxadiazolinone or oxadiazolinthione is incubated in the presence of an acid chloride of formula CICOR ₄ , in which R4 is defined as above, under conventional conditions known to man of the profession (Gogoi et al., Indian J. of Chemistry Sect B29 (1990) 1159). The corresponding reaction scheme is shown in Figure 3. The reaction product can be easily isolated from excess reagents, if necessary, by conventional chromatographic methods or by simple filtration, for example.

For the Mannich reaction, the monosubstituted oxadiazolinone or oxadiazolinthione is incubated in the presence of a primary or secondary amine of formula HNR ₅ R _f5 , in which R5 and R6 are defined as above, and of formaldehyde CH ₂ 0 The reaction is carried out under conventional conditions known to a person skilled in the art (Sherman WS, J. Organic Chemistry 26 (1961) 88; Vakula et al., Indian J. Chem. 7 (1969) 583; Goswami et al. , Indian J. Chem. 23B (1984) 796). The corresponding reaction scheme is shown in Figure 4. The reaction product can be easily isolated from excess reagents, if necessary, by conventional chromatographic methods or by simple filtration, for example.

The substituent R2 can also be introduced on the monosubstituted oxadiazolinthione by opening of epoxides, according to the reaction represented in FIG. 5A (see for example Saski et al., J. Org. Chem. 47 (1982) 2757).

The substituents R2 and R3 can be introduced on the monosubstituted oxadiazolinthione for example by (i) alkylation reaction, (ii) epoxide opening reaction, or (iii) acylation reaction. For the alkylation reaction, the monosubstituted oxadiazolinthione is incubated in the presence of a halogen derivative of formula R3-Y, in which Y is a halogen atom (Cl, Br or I), under the conditions described above for the substituent R2. The Corresponding reaction scheme is shown in Figure 2C. Thus, the alkylation of unsubstituted oxadiazolinthiones can be carried out by different types of halogen derivatives (halides), in particular in the presence of halides which are slightly, moderately or reactive. Preferred halides for carrying out this step are in particular the compounds whose structure is shown in FIG. 6A, in which Ar represents a heterocyclic aromatic group or not, X represents a halogen atom, preferably Cl or Br, and R denotes a linear or branched hydrocarbon group, saturated or not, cyclic or not. Preferably, the groups Ar and R have one or more other functions, for example alcohol, phenol, (thio) ether, acid, ester, nitrile, amino, ammonium, nitro, aldehyde, ketone and / or halogen.

Other preferred halides for implementing the invention are the reactive halides of the α-halo amide type, as represented in FIG. 6B, where X denotes a halogen, preferably Cl or Br, and Ar denotes a group aromatic heterocyclic or not. More preferred examples of such α-halo amide compounds are given in Figure 6C. Also preferred are α-haloamides having linear or branched aliphatic groups, saturated or not, cyclic or not, preferably carrying one or more other functions, for example alcohol, phenol, (thio) ether, acid, ester, nitrile, amino, ammonium, nitro, aldehyde, ketone and / or halogen.

The alkylation can be carried out by incubating the oxadiazolinthione in the presence of the alkylating agent (alkyl halide, benzyl halide, α-haloamide (α-bromamide), α-haloketone, for example), for a period which may reach 3 p.m. for example (preferably from 20 'to 12 p.m.). The reaction can be carried out in the presence of a solvent, such as for example ethanol, acetone, etc. (see in particular Sen Gupta et al., Indian J. Chem. 16B (1978) 629; Sasaki et al., J. Org. Chem. 47 (1982) 2757). The applicants have shown that, in a particularly preferred mode of implementation, this reaction is carried out in a solvent such as DMF which 14

provides high yields and the dissolution of a maximum of products reacted, the temperature and the reaction time can be adapted by the skilled person.

For the synthesis by opening of epoxide, the monosubstituted oxadiazolinthione is incubated in the presence of an epoxide carrying a side chain R4 in the presence of glacial acetic acid (see in particular Vakula et al, Indian J.

Chem 7 (1969) 583), according to the reaction scheme presented in Figure 5B.

The applicants have shown that, in a particularly preferred mode of implementation, this reaction is carried out in a solvent such as DMF which makes it possible to obtain high yields as well as the dissolution of a maximum of products reacted, the temperature and reaction time can be adapted by those skilled in the art. The Mannich reaction can also be carried out under the conditions described above (see also Goswami et al., Indian J. of Chemistry 23B (1984) 796). The reaction product (i.e., di-substituted oxadiazolinthione) can be easily isolated from excess reagents, if necessary, by standard chromatographic methods or by simple filtration, for example.

It should be noted that the conversions of the alkylation step are similar, with or without prior evaporation of the solvent used for the formation of the mono-substituted oxadiazolinthiones. In addition, it should be noted that the reactions shown in FIGS. 2B and 2C can lead, depending on the reaction conditions used, to a mixture of the N- and S-alkylated products. These can essentially be separated, or used as such for the constitution of a library of the invention. The same applies to the reactions presented in FIGS. 5A and 5B, which can produce mixtures of N- and S- substituted compounds.

The synthesis by combinatorial chemistry can be carried out in the form of a mixture and, in this case, the identification of the individual compounds, having proved to be active during a screening test, is then carried out subsequently. The combinatorial synthesis can also be carried out in parallel and, in this case, the syntheses are carried out simultaneously but in separate compartments (or wells). For example, parallel synthesis can be carried out in microplates, in which the reagents are introduced sequentially, manually or by means of suitable robots. The synthesis can in particular be carried out using reagents immobilized on supports, in order to facilitate the optional intermediate separation step. In general, the combinatorial synthesis is carried out from a first bank of selected reagents (hydrazides), which is distributed, for example by means of an automaton, in an appropriate support (preferably microplates having high numbers of wells, for example up to 1000 wells / plate). Preferably, each hydrazide is used at several points. Then (or beforehand), the (thio) carbonyldiimidazole is introduced, in the chosen quantities, into the support, preferably by means of an automatic machine. The reaction is continued for the selected time (5 to 15 hours generally), at the chosen temperature (generally room temperature). The products obtained can then be harvested to constitute banks, or, more simply, the supports used directly as a bank in screening tests. When an additional degree of substitution is sought, the products obtained are optionally isolated (for example by suction and / or filtration), distributed again in supports, and subjected to a second substitution reaction, as indicated above, by example by contacting with halogen derivatives. Another advantage of the present invention is that it can make it possible to carry out the second substitution step directly on the products of the first, without resorting to intermediate separation / filtration. The resulting products can also be isolated or used directly as a support. In the combinatorial library described in the examples, a first synthesis was carried out by incubation of thiocarbonyidiimidazole in the presence of a first bank of 80 commercial hydrazides, distributed in the wells of a microplate. 84 identical plates are produced. In a second step, in each of these 84 plates are distributed a halogen derivative or a different epoxide, leading to the synthesis of 6720 different compounds.

Uses

The present invention can be implemented in any type of industry, for research and / or optimization of products. In particular, it can be implemented in the pharmaceutical industry, for research and / or optimization of active products. Thus, in the process of finding active products, the pharmaceutical industry increasingly uses combinatorial chemistry, that is to say banks of synthetic products, diversified or focused, which are screened by different batteries of tests (biological, physical, pharmacological, etc.). Thanks to the development of particularly effective methods, the present invention now makes it possible to widen the field of diversity of combinatorial banks, and thus to access new active molecules. As indicated above, the libraries of the invention can be of variable diversity, and thus serve in primary screening or for research of analogues, during optimization phases.

In this regard, another object of the invention resides in a process for searching for active products, characterized in that it comprises a step during which a bank as defined above is tested.

Another particular object of the invention resides in a method for optimizing active products, characterized in that it comprises a step during which a focused bank as defined above is tested.

In these methods of the invention, the banks can be tested in different ways, essentially with the aim of identifying leads exhibiting activity on a target, that is to say the ability to interact physically or functionally with a target. 17

The present invention therefore also relates to the use of the banks described above for the identification or optimization of active compounds. It also relates to the active compounds themselves, obtained by the methods of the invention and / or by means of the banks of the invention. The invention relates in this regard to the individual individual compounds constituting the libraries described above exhibiting a given biological activity.

The present invention also relates to any support comprising a library of compounds as defined above, in particular to a microplate comprising at least part of a library as defined above.

Other applications and advantages of the present invention will appear on reading the examples which follow, which should be considered as illustrative and not limiting.

Legend of Figures

Figure 1: Reaction diagram of the synthesis of oxadiazolinone (1A) or oxadiazolinthiones (1B) derivatives substituted from a hydrazide and (thio) carbonyldiimidazole.

Figure 2: Reaction diagram of the substitution of oxadiazolinone derivatives by alkylation reaction (2A), oxadiazolinthiones by N-alkylation (2B) and oxadiazolinthiones by S-alkylation (2C).

Figure 3: Reaction diagram of the substitution of oxadiazolinone / oxadiazolinthiones derivatives by acylation reaction.

Figure 4: Reaction diagram of the substitution of oxadiazolinone / oxadiazolinthiones derivatives by Mannich reaction. 18

Figure 5: Reaction diagram of the substitution, on the nitrogen atom, of the oxadiazolinthion derivatives by opening reaction of epoxides (5A) and of the substitution, on the sulfur atom, of the oxadiazolinthion derivatives by reaction of opening of epoxides (5B).

Figure 6: Structure of halides for the alkylation of mono-substituted oxadiazolinthiones.

EXAMPLES

Example 1 Synthesis of Monosubstituted Oxadiazolinones

Protocol

To a solution of 0.1 M acylhydrazine (0.5 mmol in 5 ml of DMF), 1, 1'-carbonyldiimidazole 0.25M (1 mmol in 4 ml of THF) was added. After 12 hours at room temperature, the reaction was stopped with water (1 mL) and evaporated in vacuo at 40 ° C, until dry residues were obtained. 10 to 40 ml of ethyl acetate were then added to the residues, washed with a saturated aqueous NaCl solution (4 × 10 ml), and the residual aqueous phase was extracted with ethyl acetate (10 mL) and washed with a saturated aqueous NaCl solution (4 X 10 mL). The organic phases were extracted with water (10 mL) and evaporated to dryness under vacuum at 40 ° C. When they are soluble in water, the products obtained were purified by reverse phase HPLC or by chromatography on silica gel.

Results

The structure of the acylhydrazines used for the synthesis is given in Table 2. This Table also gives the yields of the reactions, and shows the high efficiency of the method of synthesis of the invention using DMF. The NMR spectrum of the products obtained is given below: Product 3a: Η-NMR (300 MHz, CDCl ₃ / DMSO (d ₆ ) 5/1): δ 7.46 (3H, m), δ 7.97 (3H, m), δ 9 (IH, d, J = 8.44 Hz ), δ 12 (IH, s), EI-MS (m / z) 212 (M +, 100%), 168 (42%), 153 (47%), 128 (57%), 127 (63%).

Product 3b: Η-NMR (300 MHz, CDCl ₃ / DMSO (d ₆ ) 5/1): δ 3.65 (IH, s), δ 6.75 (2H, d, J = 8.96 Hz), δ 7.55 (2H, d , J = 8.96 Hz), δ 11.75 (IH, s), EI-MS (m / z) 192 (M +, 91%), 148 (38%), 135 (53%), 133 (100%), 105 (14%).

Product 3c: Η-NMR (600 MHz, CDCl ₃ / DMSO (d ₆ ) 5/1): δ 7.39 (IH, dd, J = 8, 4.9 Hz), δ 8.05 (IH, ddd, J = 8, 1.74 , 1.74 Hz), δ 8.65 (IH, dd, J = 4.6, 0.9 Hz), δ 9 (IH, s), δ 12.3 (IH, s), EI- MS (m / z) 163 (M +, 100% ), 119 (72%), 106 (25%), 104 (12%).

Product 3d: Η-NMR (300 MHz, CDC1 ₃ ): δ. 6.61 (IH, dd J = 3.54, 1.78 Hz), δ 7.06 (IH, dd J = 3.52, 0.56 Hz), δ 7.65 (IH, dd, J = 1.75, 0.71 Hz), δ 10 (IH, s), EI-MS (m / z) 152 (M +, 100%), 108 (36%).

Product 3rd: Η-NMR (300 MHz, CDCl ₃ / DMSO (d ₆ ) 5/1): δ 6.16 (IH, dd, J = 3.5, 2.6 Hz), δ 6.65 (IH, dd, J = 3.7, 1.4 Hz), δ 6.86 (IH, dd, J = 2.6, 1.4 Hz), δ 11.1 (IH, s), δ 11.7 (IH, s), EI-MS (m / z) 151 (M +, 100%), 149 (17%), 107 (11%).

Product 3f: Η-NMR (300 MHz, CDC1 ₃ + D ₂ 0): δ 7.18 (IH, dd, J = 5.07, 3.7 Hz), δ 7.56 (IH, dd, J = 5.07, 1.18 Hz), δ 7.66 (IH, dd, J = 3.76, 1.15 Hz), EI-MS (m / z) 168 (M +, 100%), 124 (26%), 111 (55%), 109 (12%).

Product 3g: Η-NMR (600 MHz, CDCl ₃ / DMSO (d ₆ ) 5/1): δ 5.08 (2H, s), δ 6.42 (IH, d, J = 3.5 Hz), δ 6.79 (IH, d , J = 3.5 Hz), δ 7.46 (IH, s), EI-MS (mz) 302 (0.8%), 300 (M +, 1.2%), 165 (100), 121 (1 1%), 109 (33 %), 106 (12%).

Product 3h: 'H-NMR (300 MHz, DMSO (d ₆ )): δ 4.83 (2H, s), δ 5.16 (2H, s), δ 6.53 (IH, s), δ 6.68 (IH, d, J = 2.8 Hz), δ 7.75 (IH, s), δ 8.43 (IH, s), δ 12.75 (IH, s), EI-MS (m / z) 327 (M +, 6%), 263 (49%), 183 (100%), 165 (44%), 149 (53%), 139 (18 %), 126 (32%), 125 (33%), 124 (24%), 109 (19%).

s Product 3i: Η-NMR (300 MHz, DMSO (d ₆ )): δ 3.96 (2H, s), δ 7.07 (IH, dd, .7 = 4.9, 0.9 Hz), δ 7.41 (IH, m), δ 7.54 (IH, dd, 7 = 4.9, 3 Hz), δ 12.24 (IH, s), EI-MS (m / z) 182 (M +, 100%), 140 (37%), 125 (40%) , 112 (10%), 111 (11%), 110 (11%).

EXAMPLE 2 Synthesis of a Bank of Di-Substituted Oxadiazolinthiones

0 This example describes the conditions for the synthesis of a bank of alkylated oxadiazolinthiones. This bank constitutes a source of products allowing the identification of active compounds.

2.1. Solutions used.

The following solutions were used:

5 - solution S: solution of thiocarbonyl-diimidazole at approximately 0.25 M in DMF.

solutions N: distinct solutions of hydrazides of different structures (80 hydrazides chosen in part from the hydrazides listed in Table 1) at 0.1 M in DMF, at neutrality.

0 - solutions A: distinct solutions of alkylating agents of different structures (78 halides and 6 epoxides) at 0.5 M in DMF, neutral.

2.2. Procedure

5 μmoles of thiocarbonyidiimidazole per well are distributed in “deep-wells” plates (with deep wells) (ie approximately 20 μl of solution S per well, the 5 precise volume of solution S is calculated prior to synthesis, by reactivity test of solution S). Preferably, the distribution is carried out by means of an automatic machine. 84 96-well plates are thus prepared, within of which, only the first 80 wells are used (80 different products synthesized per plate).

Then, on each plate, 50 μl of solutions N are distributed, each solution N being distributed, on the same plate, in a different well (i.e., one hydrazide per well).

The plates are then stirred for 3 to 12 hours at room temperature. At the end of this first phase, a bank of mono-substituted oxadiazolinthiones is obtained. This first bank includes 80 compounds with different structures. At this stage, quality control is carried out. For this, 5 μl are withdrawn from each well and evaporated under reduced pressure. The products obtained are dissolved with 300 μl of acetonitrile and injected (10 μl) on a chromatographic column and analyzed by LC / MS (liquid chromatography coupled to mass spectrometry).

For the creation of a combinatorial bank, the oxadiazolinthiones obtained are subjected to an additional substitution. For this, 10 μl of solutions A are added to each well (1 whole plate for each solution A). The plates are then placed in ovens and heated (target temperature 95 ° C), under nitrogen, for 6 hours. After this incubation, the heating and the flow of nitrogen are stopped, and the plates are cooled for 30 minutes. Each of the above steps is preferably carried out automatically. The plates are then removed from the oven, and 5 μl are taken from each well and distributed in a blank plate, for quality control (QC). The "synthesis" plates and the QC plates are then placed under reduced pressure for 4 hours to 24 hours, until the solvents have evaporated. The QC products are then dissolved with 300 μl of acetonitrile and injected on a LC / MS chromatographic column. The "synthesis" plates constitute a combinatorial library of substituted oxadiazolinthiones, usable for the search for active compounds, for example by screening and / or high throughput profiling.

TABLE 1: LIST OF HYDRAZIDES

HYDRt ZIDES MDL NUMBER

2-FUROIC ACID HYDRAZIDE MFCD00003235

3-HYDROXY-2-NAPHTHOIC ACID HYDRAZIDE MFCD00004097

2-THIOPHENECARBOXYLIC ACID HYDRAZIDE MFCD00005435

INDOLE-3-ACETIC ACID HYDRAZIDE MFCD00005634

NICOTINIC ACID HYDRAZIDE MFCD00006383

ISONICOTINIC ACID HYDR \ ZIDE MFCD00006426

BENZHYDRAZIDE MFCD00007596

2-CHLOROBENZHYDRAZIDE MFCD00007597

2-NITROBENZHYDRAZIDE MFCD00007598

SALICYLHYDRAZIDE MFCD00007599

3-BROMOBENZHYDRAZIDE MFCD00007600

3- ETHOXYBENZHYDRAZIDE MFCD00007601

4-BROMOBENZHYDRAZIDE MFCD00007602

4-CHLOROBENZHYDRAZIDE MFCD00007603

4-NITROBENZHYDRAZIDE MFCD00007604

4-HYDROXYBENZHYDRAZIDE MFCD00007605

P-TOLUIC HYDRAZIDE MFCD00007607

OXALYL DIHYDR / \ ZIDE MFCD00007608

ACETIC HYDRAZIDE MFCD00007610

CYANOACETOHYDRAZIDE MFCD00007611

PHENYLACETIC HYDRAZIDE MFCD00007612

SUCCINIC DIHYDRAZIDE MFCD00007613

ADIPIC DIHYDRAZIDE MFCD00007614

OCTANOIC HYDRAZIDE MFCD00011588

2,5-DICHLOROBENZHYDRAZIDE MFCD00014754

2-METHOXYBENZHYDRAZIDE MFCD00014755

O-TOLUIC HYDRAZIDE MFCD00014756

3-CHLOROBENZHYDRAZIDE MFCD00014757

3,4,5-TRIMETHOXYBENZHYDRAZIDE MFCD00014758

3-HYDROXYBENZHYDRAZIDE MFCD00014759

3-TOLUIC HYDRAZIDE MFCD00014760

4-DIMETHYLAMINOBENZHYD.RAZIDE MFCD00014761

TEREPHTHALIC DIHYDRAZIDE MFCD00014762

4-TERT-BUTYLBENZHYDRAZIDE MFCD00014763

STEARIC HYDRAZIDE MFCD00014764

SUBERIC DIHYDRAZIDE MFCD00014765

ALPH A-N APHTHOYLHYDRAZI N E MFCD00016804

BETA-NAPHTHOYLHYDRAZINE MFCD00016810

2-CHLORO-4-NITROBENZHYDRAZIDE MFCD00017047

2-PHENOXYBENZHYDRAZIDE MFCD00017048

2,5-DIMETHOXYBENZHYDRAZIDE MFCD00017049

2-ETHOXYBENZHYDF AZIDE MFCD00017050

2-HYDROXY-3-METHYLBENZHYDRAZIDE MFCD00017052

2,4-DIHYDROXYBENZHYDRAZIDE MFCD00017053

6-HYDROXY-3-ANISIC ACID HYDRAZIDE MFCD00017054

2-HYDROXY-5-METHYLBENZHYDRAZIDE MFCD00017055

3.5-DNODO-4-METHOXYBENZHYD.RAZIDE MFCD00017058

3-NITROBENZHYDRAZIDE MFCD00017059

3,5-DINITROBENZHYDRAZIDE MFCD00017060

3,4-DIMETHOXYBENZHYDRAZIDE MFCD00017061

3,5-DIMETHOXYBENZHYDRAZIDE MFCD00017062

3-ETHOXYBENZHYDRAZIDE MFCD00017063 24

3,4-DIHYDROXYBENZHYDRAZIDE MFCD00017064

3,4,5-TRIHYDROXYBENZHYDRAZIDE MFCD00017065

3,5-DIHYDROXYBENZHYDRAZIDE MFCD00017066

4-CHLORO-3-NITROBENZHYDRAZIDE MFCD00017072

4-METHOXYBENZHYDRAZIDE MFCD00017073

4-ETHOXYBENZHYDRAZIDE MFCD00017074

3,5-DIIODO-4-HYDROXY BENZHYDRAZIDE MFCD00017075

VANILLIC ACID HYDRAZIDE MFCD00017076

3,5-DIMETHOXY-4-HYDROXYBENZHYDRAZIDE MFCD00017077

4-BIPHENYLCARBOXYLIC ACID HYDRAZIDE MFCD00017078

4,4'-BISBENZHYDRAZIDE MFCD00017079

BENZILIC HYDRAZIDE MFCD00017082

CINNAMIC ACID HYDF AZIDE MFCD00017083

3,5-DINITRO-4-HYDROXYPHENYLPROPIONIC ACID HYDRAZIDE MFCD00017084

5-BROMO-2-HYDROXYBENZHYDRAZIDE MFCD00017567

2- (FURFURYLUREIDO) ACETIC ACID HYDRAZIDE MFCD00020957

2-NAPHTHYLACETIC HYDF AZIDE MFCD00021652

3-INDOLEPROPIONIC ACID HYDRAZIDE MFCD00022777

5 _F 6-DIMETHYLBENZIMID, AZOLE-1-ACETHYDRAZIDE MFCD00022841

NICOTINIC HYDRAZIDE N-OXIDE MFCD00023409

2-FLUOROBENZHYDRAZIDE MFCD00025112

2,4-DICHLOROBENZHYDRAZIDE MFCD00025113

2-IODOBENZHYD.RAZIDE MFCD00025114

2- (METHYLUREIDO) BENZOIC ACID HYDRAZIDE MFCD00025115

ISOPHTHALIC DIHYDRAZIDE MFCD00025117

4- (TERT-BUTYLUREIDO) BENZOIC ACID HYDRAZIDE MFCD00025118

BENZOYL-L-TYR HYDF AZIDE MFCD00025120

N-ACETYL-L-TYROSINE HYDRAZIDE MFCD00025121

ISOBUTYRIC ACID HYDRAZIDE MFCD00025122

((2-ETHOXYPHENYL) UREIDO) ACETIC ACID HYDRAZIDE MFCD00025123

((3-CHLOROPHENYL) UREIDO) ACETIC ACID HYDRAZIDE MFCD00025124

2- (3,4-DICHLOROPHENYLUREIDO) ACETIC ACID HYDRAZIDE MFCD00025125

2- (3- (3-NITROPHENYL) UREIDO) ACETIC ACID HYDRAZIDE MFCD00025126

CBZ-GLY HYDRAZIDE MFCD00025127

2- (2-HYDROXYPHENYL) ACETHYDRAZIDE MFCD00025128

MALEIC ACID DIHYDRAZIDE MFCD00025130

3- (3,5-DI-TERT-BUTYLPHENYL) -3-HYDROXYPROPIONIC ACID MFCD00025131

HYDI AZIDE

HEXANOIC HYDRAZIDE MFCD00025133

BUTYRIC ACID HYDRAZIDE MFCD00025135

GLUTARIC DIHYDRAZIDE MFCD00025136

VALERIC ACID HYDRAZIDE MFCD00025137

PIMELIC DIHYD.RAZIDE MFCD00025138

DECANOIC HYDRAZIDE MFCD00025139

4,4-DIPHENYL-1- (N- MFCD00031402

(HYDRAZINOCARBONYLMETHYL) CARBAMOYL) SEMICARBAZIDE

2- (4-FLUOROPHENYLUREIDO) ACETHYDRAZIDE MFCD00031403

2- (4-METHYLPHENYLCARBOXAMIDO) BENZOIC HYDRAZIDE MFCD00031404

4- (3-CHLOROPHENYLUREIDO) BENZHYDRAZIDE MFCD00031405

2-HYDROXY-2-METHYLPROPIONIC HYDRAZIDE MFCD00031406

O-ANISIC ACID HYDRAZIDE HYDROCHLORIDE MFCD00035461

MANDELIC ACID HYDRAZIDE MFCD00038133

LACTHYDRAZIDE MFCD00038134

Z-HIS-NHNH2 MFCD00038621

SEBACIC DIHYDRAZIDE MFCD00039763 25

MALONIC ACID DIHYDRAZIDE MFCD00041268

1, 4-CYCLOHEXANEDICARBOHYDRAZIDE MFCD00043475

N-TRITYLGLYCINE HYDRAZIDE MFCD00043618

DODECANEDIOIC DIHYDRAZIDE MFCD00043619

N-BUTYL HYDRAZINE OXALATE MFCD00047823

5-BROMO-2-CHLOROBENZHYDRAZIDE MFCD00051528

, AZELAIC DIHYDRAZIDE MFCD00051529

2-BROMOBENZHYDRAZIDE MFCD00051577

3,4-DIMETHOXYPHENYLACETIC ACID HYDRAZIDE MFCD00051701

4- (TRIFLUOROMETHYL) BENZHYDRAZIDE MFCD00051703

3,5-BIS (TRIFLUOROMETHYL) BENZHYDRAZIDE MFCD00051848

2,4-DICHLOROPHENOXYACETIC ACID HYDRAZIDE MFCD00051972

4-NITROPHENOXYACETIC ACID HYDRAZIDE MFCD00051973

(4- (TRIFLUOROMETHOXY) PHENOXY) ACETIC ACID HYDRAZIDE MFCD00052355

BOC-HIS-NHNH2 MFCD00055954

Z-TYR-NHNH2 MFCD00057641

2-IMINOBIOTIN HYDRAZIDE HYDROCHLORIDE MFCD00058114

2-PICOLINYL HYDRAZIDE MFCD00059782

3-FLUOROBENZHYDRAZIDE MFCD00060561

4-FLUOROBENZHYDFJAZIDE MFCD00060562

4- (CYCLOHEXYLUREIDO) BENZOIC ACID HYDRAZIDE MFCD00065311

BIOTIN-XX-HYDRAZIDE MFCD00065501

PALMITIC ACID HYDRAZIDE MFCD00066357

2- (4-CHLOROPHENYL) -3- (TRIFLUOROMETHYL) PYRAZOLE-4- MFCD00068154

CARBOXYLIC ACID HYDRAZIDE

BIOTINAMIDOCAPROYL HYDRAZIDE MFCD00077659

BIOTIN HYDRAZIDE MFCD00078532

4-FLUOROPHENOXYACETIC ACID HYDRAZIDE MFCD00082651

2-METHYL-4-CHLOROPHENOXYACETIC ACID HYDRAZIDE MFCD00082720

2-CHLOROPHENOXYACETIC ACID HYDRAZIDE MFCD00082786

N- [3,5-BIS (TRIFLUOROMETHYL) BENZENESULFONYL] -L- MFCD00084900

METHIONYL HYDF AZIDE

N- [4- (TRIFLUOROMETHYL) BENZOYL] -L-METHIONYLHYD.RAZIDE MFCD00085179

5-OXO-1-PHENYL-2-PYRAZOLINE-3-CARBOXYLIC ACID MFCD00085802

HYDRAZIDE

2.5-DIMETHOXYTETRAHYDRO-2-FUROIC ACID HYDRAZIDE MFCD00086221

ORTHO- (DIMETHYLAMINO) -BENZOIC ACID HYDRAZIDE MFCD00087186

3-HYDROXYBUTYRIC ACID HYDRAZIDE MFCD00087370

4-CHLORO-2.6-PYRIDINEDICARBOXYLIC HYDRAZIDE MFCD00091142

ETHYLMALONIC ACID, DIHYDRAZIDE MFCD00093418

4-CYCLOHEXEN-1, 2-DICARBOXYLIC DIHYD.RAZIDE MFCD00094417

4- (3- (2-FLUOROPHENYL) UREIDO) BENZOIC HYDRAZIDE MFCD00094571

4- (3- (3- (TRIFLUOROMETHYL) PHENYL) UREIDO) BENZOIC MFCD00094600

HYDRAZIDE

2-METHYLPENTANOIC HYDRAZIDE MFCD00094913

4- (3-PHENYL-2-THIOUREIDO) BENZOIC HYDRAZIDE MFCD00095482

9-XANTHENECARBOXYLIC HYDFJAZIDE MFCD00100677

4- (TRIFLUOROMETHYL) PYRIDINE-3-CARBOXYLIC MFCD00101567

ACIDHYDRAZIDE

3-METHYL-5- [4- (TRIFLUOROMETHYL) PHENYL] ISOXAZOLE-4- M FCD00102588

CARBOXYLIC ACID HYDRAZIDE

BIONET 10B-013 MFCD00110397

3-PHENYL-5-METHYLISOXAZOLE-4-CARBOHYDRAZIDE MFCD00119108

ETHYL 3-HYDRAZINO-3-OXOPROPIONATE M FCD00134484

N-BENZYLOXYCARBONYL-L-VALYL-L-TYROSINE HYDRAZIDE MFCD00136446 26

CARBOBENZYLOXY-L-LEUCINE HYDRAZIDE M FCD00136780

4- (4-CHLOROPHENOXY) -3-NITROBENZHYDRAZIDE MFCD00138750

3-CARBOXYHYDRAZONO-1- (3,4-DICHLOROBENZYL) -2- MFCD00140455

PYRIDONE

3-CARBOXYHYDRAZONO-1- (3-TRIFLUOROMETHYLBENZYL) -2- MFCD00140456

PYRIDONE

3-CARBOXYHYDRAZONO-1- (2,4-DICHLOROBENZYL) -2- MFCD00140461

PYRIDONE

3-CARBOXYHYDRAZONO-1-BENZYL-2-PYRIDONE MFCD00140469

3-CARBOXYHYDRAZONO-1- (3-TRIFLUOROMETHYLBENZYL) -6- MFCD00140548

PYRIDONE

1-BENZYL-3-CARBOXYHYDRAZONO-6-PYRIDONE MFCD00140619

1- (4-METHOXYPHENYL) 4- (4-METHYLPHENYLTHIO) 6- MFCD00141164

PYRIDAZINONE 3-CARBOXYLICACID HYDRAZI

1-PHENYL 4-PHENOXY 6-PYRIDAZINONE-3-CARBOXYLIC ACID MFCD00141172

HYDRAZIDE

1, 2,4-TRIAZOL-1-YL-ACETIC ACID HYDRAZIDE MFCD00141553

1-PHENYL-1, 2,4-TRIAZOL-3-YLOXY ACETIC ACID HYD.RAZIDE MFCD00141608

1- (2- (3-CHLORO-5-TRIFLUOROMETHYL) PYRIDYL) -4- (2-ACETIC MFCD00141696

ACID HYDRAZIDO) PIPERAZINE

1-METHYL-4- (2,4-DICHLOROBENZOYL) PYRROLE-2- MFCD00141855

CARBOHYDRAZIDE

4- (2,4-DICHLOROBENZOYL) PYRROLE-2-CARBOHYDRAZIDE MFCD00141933

Z-THR-NHNH2 MFCD00153343

4-PHENOXYBENZHYDRAZIDE MFCD00153894

1-ADAMANTANECARBOXYLIC ACID HYDR ^ ZIDE M FCD00154679

2,4-DIMETHYLPHENOXYACETIC ACID HYDRAZIDE MFCD00156144

1- (NAPHTHOXY) ACETIC ACID HYDRAZIDE MFCD00156157

9,10-DIHYDRO-9,10-ETHANOANTHRACENE-11, 12-DICARBOXYLIC MFCD00157914

DIHYDRAZIDE

HYDROCINNAMIC HYDRAZIDE MFCD00157933

9, 10-DIHYDRO-11 -METHYL-9, 10-ETHANOANTHRACENE-11 - MFCD00157935

CARBOXYLIC HYDRAZIDE

N- (5-CHLORO-2-THIAZOLYL) OXAMIC HYDRAZIDE M FCD00159777

2-PHENYL-4-QUINOLINECARBOXYLIC HYDRAZIDE MFCD00160604

2- (BENZIMID.AZOLYLTHIO) ACETIC ACID HYDRAZIDE MFCD00171027

N- (2- (4-METHYLPYRIMIDYL) -2-AMINOMETHYLENE HIPPURIC MFCD00171914

ACID HYDRAZIDE

1- (2 '- (3'-CHLORO-5-TRIFLUOROMETHYL) PYRIDYL) ISONIPECOTIC MFCD00172276

ACID HYDRAZIDE

N- (2- (3-CHLORO-5-TRIFLUOROMETHYL) PYRIDYL) - -AMINO MFCD00172610

BUTYRIC ACID HYDRAZIDE

OXALIC ACID, MONOHYDRAZIDE, N- (4-METHOXYPHENYL) AMIDE MFCD00173090

OXALIC ACID, MONOHYDF AZIDE, MONO- (4- MFCD00173093

TRIFLUOROMETHOXYPHENYL) AMIDE

OXALIC ACID, MONOHYD.RAZIDE, MONO PHENYLAMIDE MFCD00173094

1- (6-CHLORO-2-PYRIDYL) -3- (2- MFCD00173102

HYDRAZINOCARBONYL) PHENOXYMETHYL

2-METHYL-2- (1, 2,4-TRIAZOL-1-YL) PROPIONIC ACID HYDRAZIDE MFCD00173108

3- (4-CHLOROBENZYLOXY) THIOPHENE-2-CARBOHYDRAZIDE MFCD00173482

2,4-DIFLUOROBENZOIC ACID HYDRAZIDE MFCD00173685

1- (4-NITROPHENYL) -4 - ((EXO-DEHYDRO) PIPERIDINE) ACETIC MFCD00180778

ACID HYDRAZIDE

HZ- '-CHLORO-δ'-TRIFLUOROMETHYLpYRIDYLJPIPERAZINE- MFCD00180800

4-HYDRAZIDO ETHYLENE 2- (PYRIMIDIN-2-YLSULFANYL) -ACETIC ACID HYDRAZIDE MFCD00181554

2- (2-METHYLSULFANYL-PYRIMIDIN-4-YLSULFANYL) -ACETIC MFCD00181568

ACID HYDRAZIDE

2- (4,6-DIMETHYL-PYRIMIDIN-2-YLSULFANYL) -ACETIC ACID MFCD00181595

HYDRAZIDE

(BENZOYLAMINO-2-HYDRAZINOCARBONYL-1-PH-VINYL) - MFCD00181901

TRIPHENYL-PHOSPHONIUM, PERCHLORATE

2- (1-HYDRAZINOCARBONYL-1-METHYL-ETHYLAZO) -2-METHYL- MFCD00181929

PROPIONIC ACID HYDRAZIDE

2,2-DICHLORO-N- (4-HYDRAZINOCARBONYL-BENZYL) - MFCD00182660

ACETAMIDE

4.6-DIPHENYL-PYRIMIDINE-2-CARBOXYLIC ACID HYDFJAZIDE M FCD00184890

3-BENZYLOXY-4,5-DIMETHOXY-BENZOIC ACID HYDRAZIDE MFCD00185565

1-ADAMANTANEACETIC HYDRAZIDE MFCD00185799

2- (3-HYDRAZINOCARBONYLMETHYL-ADAMANTAN-1-YL) -ACETIC MFCD00186490

ACID HYDRAZIDE

2- (4-PHENYL-5-PHENYLAMINO-4H- (1, 2,4) TRIAZOL-3- MFCD00186735

YLSULFANYL) -ACETIC ACID HYDFAZIDE

2- (4-ISOPROPYL-3-METHYL-PHENOXY) -ACETIC ACID MFCD00187115

HYDRAZIDE

2-BENZENESULFONYL-2 - ((4-CHLORO-PHENYL) -HYDRAZONO) - MFCD00187922

ACETIC ACID HYDRAZIDE

AC-PHE-NHNH2 MFCD00190721

BOC-THR-NHNH2 MFCD00190834

Z-GLY-HIS-NHNH2 MFCD00191101

Z-HIS-NHNH2 HCL MFCD00191105

2 - ((4-BROMO-PHENYL) -HYDRAZONO) -2- (TOLUENE-4- MFCD00193669

SULFONYL) -ACETIC ACID HYDRAZIDE

2- (TOLUENE-4-SULFONYL) -2- (P-TOLYL-HYDRAZONO) -ACETIC M FCD00193670

ACID HYDRAZIDE

2- (TOLUENE-4-SULFONYL) -2- (0-TOLYL-HYDRAZONO) -ACETIC M FCD00193672

ACID HYDRAZIDE

2 - ((4-CHLORO-PHENYL) -HYDRAZONO) -2- (TOLUENE-4- M FCD00193673

SULFONYL) -ACETIC ACID HYDRAZIDE

2-BENZENESULFONYL-2 - ((3-CHLORO-PHENYL) -HYDRAZONO) - M FCD00193676

ACETIC ACID HYDRAZIDE

2-BENZENESULFONYL-2 - ((3-NITRO-PHENYL) -HYDRAZONO) - MFCD00193677

ACETIC ACID HYDRAZIDE

2-BENZENESULFONYL-2 - ((4-FLUORO-PHENYL) -HYDRAZONO) - MFCD00193678

ACETIC ACID HYDRAZIDE

2-BENZENESULFONYL-2- (P-TOLYL-HYDRAZONO) -ACETIC ACID M FCD00193679

HYDF AZIDE

2-BENZENESULFONYL-2- (M-TOLYL-HYDRAZONO) -ACETIC ACID M FCD00193680

HYDRAZIDE

2-BENZENESULFONYL-2- (0-TOLYL-HYDRAZONO) -ACETIC ACID MFCD00193681

HYDRAZIDE

2-BENZENESULFONYL-2- (PHENYL-HYDI AZONO) -ACETIC ACID MFCD00193682

HYDI AZIDE

2- (4-CL-BENZENESULFONYL) -2 - ((2-METHOXY-PHENYL) - MFCD00193683

HYDFÎy ZONO) -ACETIC ACID HYDFîAZIDE

2- (4-CL-BENZENESULFONYL) -2 - ((4-CHLORO-PHENYL) - MFCD00193684

HYDI AZONO) -ACETIC ACID HYDRAZIDE

2- (4-CHLORO-BENZENESULFONYL) -2- (P-TOLYL-HYDRAZONO) - M FCDO0193685 ACETIC ACID HYDRAZIDE

2- (4-CHLORO-BENZENESULFONYL) -2- (PHENYL-HYDRAZONO) - MFCD00193686

ACETIC ACID HYDRAZIDE

1- (BIS-PHENOXY-PHOSPHORYL) -4-HYDRAZINOCARBONYL- M FCD00194827

PYRIDINIUM, CHLORIDE

5-CHLORO-2-METHYL-PYRIMIDINE-4-CARBOXYLIC ACID MFCD00195316

HYDRAZIDE

3- (4-BENZYLOXY-3-METHOXY-PHENYL) -PROPIONIC ACID MFCD00195544

HYDRAZIDE

HYDRAZINOCARBONYL-1- (OXO-TETRAOXA-PHOSPHA- MFCD00196024

BENZOCYCLOUNDECEN-9-YL) -PYRIDINIUM, CL

2-OXO-2H-CHROMENE-3-CARBOXYLIC ACID HYDRAZIDE MFCD00197340

5-ALPHA-ANDROSTANE-17-BETA-CARBOXYLIC ACID HYDRAZIDE MFCD00200754

3-BETA-HYDROXYANDROST-5-ENE-17-BETA-CARBOXYLIC ACID MFCD00200773

HYDRAZIDE

2-METHYL-4-TRIFLUOROMETHYLTHIAZOLE-5- MFCD00202351

CARBOHYDRAZIDE

5- (2 '- (3'-CHLORO-5'- MFCD00202621

TRIFLUOROMETHYL) PYRIDYLAMINO) METHYL-3,4-DIHYDRO

ISOXAZOLE-2-

5- (TRIFLUOROMETHYL) THIENO [3,2-B] PYRIDINE-6-CARBOXYLIC MFCD00203163

ACID, HYDRAZIDE

2- (2,4-DICHLOROPHENOXY) PROPIONIC ACID HYDRAZIDE MFCD00204152

2- (TRIFLUOROMETHOXY) BENZOIC ACID HYDRAZIDE MFCD00204180

4- (TRIFLUOROMETHOXY) BENZOIC ACID HYDRAZIDE MFCD00204234

QUINOXALINE-6-CARBOXYLIC ACID HYDRAZIDE MFCD00210172

9, 10-DIHYDRO-9, 10-ETHANOANTHRACENE-11 -CARBOXYLIC MFCD00213638

HYDRAZIDE

4-CYANO-5-METHYL-3-ISOTHIAZOLYLTHIOACETIC HYDRAZIDE MFCD00214720

3- (4-FLUOROBENZYLOXY) THIOPENE-2-CARBOHYDRt \ ZIDE MFCD00215161

3- (BENZYLOXY) THIOPENE-2-CARBOHYDRAZIDE MFCD00215166

3- (4-METHYLBENZYLOXY) THIOPENE-2-CARBOHYDRAZIDE MFCD00215167

3- (2,4-DICHLOROBENZYLOXY) THIOPENE-2-CARBOHYDRAZIDE MFCD00215168

3- (3-TRIFLUOROMETHYLBENZYLOXY) THIOPENE-2- MFCD00215180

CARBOHYDRAZIDE

0- (2,4-DICHLOROBENZYL) MALONIC HYDRAZIDE ALDOXIME MFCD00215353

2- (5-PHENYLTETRAZOLO) ACETHYDRAZIDE MFCD00215520

M-MALEIMIDOBENZOIC ACID HYDRAZIDE HCL MFCD00216008

3- (4-HYDROXYPHENYL) PROPIONIC ACID HYDRAZIDE HCL MFCD00216009

2- [2- (TRIFLUOROMETHYL) QUINOL-4-YLTHIO] ACETIC MFCD00219658

ACIDHYDRAZIDE

3-METHYL-4-NITROBENZHYDRAZIDE MFCD00220059

2,5-BIS (2,2,2-TRIFLUOROETHOXY) BENZOIC ACIDHYDRAZIDE MFCD00221192

TRIFLUOROACETIC ACID HYDRAZIDE MFCD00221440

2- (TRIFLUOROMETHYL) BENZOIC ACID HYDRAZIDE MFCD00221473

3- (TRIFLUOROMETHYL) BENZOIC ACID HYDRAZIDE MFCD00221476

2- (5,7-DIBROMO-QUINOLIN-8-YLOXY) -ACETIC ACID HYDRAZIDE MFCD00222142

1-HYDRAZINOCARBONYLMETHYL-4-METHYL-QUINOLINIUM, MFCD00222339

CHLORIDE

2-METHYL-PYRIMIDINE-5-CARBOXYLIC ACID HYDRAZIDE MFCD00223569

5-METHOXY-PYRIMIDINE-2-CARBOXYLIC ACID HYDRAZIDE MFCD00223629

2-METHYL-PYRIMIDINE-4-CARBOXYLIC ACID HYDRAZIDE MFCD00223633

2- (6-METHYL-2-METHYLSULFANYL-PYRIMIDIN-4-YLOXY) -ACETIC MFCD00224466

ACID HYDRAZIDE

2- (2-BENZYLSULFANYL-6-METHYL-PYRIMIDIN-4-YLOXY) -ACETIC MFCD00224467 ACID HYDRAZIDE

2- (2-BENZYLAMINO-6-METHYL-PYRIMIDIN-4-YLOXY) -ACETIC MFCD00224469

ACID HYDRAZIDE

2- (6-METHYL-2-PIPERIDIN-1-YL-PYRIMIDIN-4-YLOXY) -ACETIC MFCD00224470

ACID HYDRAZIDE

2- (6-METHYL-2-MORPHOLIN-4-YL-PYRIMIDIN-4-YLOXY) -ACETIC MFCD00224471

ACID HYDRAZIDE

3-HYDRAZINOCARBONYL-1-METHYL-PYRIDINIUM, IODIDE MFCD00225323

2- (2-METHYL-BENZOIMID.AZOL-1-YL) -ACETIC ACID HYDf AZIDE MFCD00227235

(3-HYDRAZINOCARBONYL-PROPIONYL) -CARBAMIC ACID ETHYL MFCD00229278

ESTER

2- (4-FLUOROPHENYLSULPHONAMIDO) ACETIC HYDRAZIDE MFCD00232501

Z-SER (TBU) -NHNH2 MFCD00237365

Z-HIS-LYS (BOC) -NHNH2 MFCD00238465

3- (N, N-DIMETHYLAMINO) BENZHYDRAZIDE MFCD00238588

2- (3-CHLORO-5-TRIFLUOROMETHYL-2-PYRIDYL) PROPIONIC MFCD00244378

HYDRAZIDE

3- (3,5-DIOXO-2,3,4,5-4H- (1, 2,4) TRIAZIN-6-YLAMINO) -PROPIONIC MFCD00267697

ACID HYDRz-λZIDE

2- (3,5-DIOXO-2,3,4,5-TETRAHYDRO- (1, 2,4) TRIAZIN-6-YLAMINO) - MFCD00267698

ACETIC ACID HYDRAZIDE

3-BROMO-4-CHLOROBENZHYDRAZIDE MFCD00270094

4-BROMO-2-CHLOROBENZHYDRAZIDE MFCD00270095

4-BROMO-3-CHLOROBENZHYDRAZIDE MFCD00270096

3-IODOBENZHYDRAZIDE MFCD00270106

4-IODOBENZHYDRAZIDE MFCD00270107

2-PHENYLBENZHYDRAZIDE MFCD00270122

ACETHYDRAZIDE PYRIDINIUM CHLORIDE

MFCD00272258

CBZ-DL-PHE-GLY-GLY HYDRAZIDE MFCD00272795

CBZ-L-LEU GLY HYDRAZIDE MFCD00272856

9,10-DIHYDROXY STEARIC HYDRAZIDE MFCD00272898

1-PYRENEBUTANOIC ACID, HYDRAZIDE MFCD00467260

2-ACETAMIDO-4-MERCAPTOBUTANOIC ACID HYDRAZIDE MFCD00467314

3- (2-PYRIDYLDITHIO) PROPIONIC ACID HYDRAZIDE HCL MFCD00467348

4,4-DIFLUORO-5,7-DIMETHYL-4-BORA-3A, 4A-DIAZA-S-INDACENE- MFCD00467387

3-PROPIONIC ACID, HYDRAZ

4,4-DIFLUORO-5J-DIPHENYL-4-BORA-3A, 4A-DIAZA-S-INDACENE- MFCD00467394

3-PROPIONIC ACID, HYDRAZ

7-DIETHYLAMINOCOUMARIN-3-CARBOXYLIC ACID, HYDRAZIDE MFCD00467583

MALEIMIDOPROPIONIC ACID HYDRAZIDE HCL MFCD00467760

2- (2-NAPHTHOXY) ACETIC HYDRAZIDE MFCD00553736

1, 4,5,6-TETRAHYDRO-CYCLOPENTAPYRAZOLE-3-CARBOXYLIC MFCD00611174

ACID HYDRAZIDE

4,5,6,7-TETRAHYDRO-1 H-INDAZOLE-3-CARBOXYLIC ACID MFCD00611197

HYDRAZIDE

3- (4-CYANOPYRAZOLE) CARBOXYLIC ACID HYDRAZIDE MFCD00663749

[4,5-BIS- (HYDROXYMETHYL) -4,5-DIHYDROISOXAZOLE-3- MFCD00664160

CARBOXLIC ACID HYDRAZIDE] [1- (4-N

4,5-BIS (HYDROXYMETHYL) -3-HYDRAZIDO-4,5- MFCD00664178

DIHYDROISOXAZOLE-1- (2- (3-CHLORO-5-TRIFLUO

4,5-BIS (HYDROXYMETHYL) -3-HYDRAZIDO-4,5- MFCD00664179

DIHYDROISOXAZOLE-1- (2-PYRIMIDYL) PIPERID-4

4,5-BIS (HYDROXYMETHYL) -3-HYDRAZIDO-4,5- MFCD00664180

DIHYDROISOXAZOLE-1- (2,6-DINITRO-4-TRIFLUO 3-CHLORO-5-TRIFLUOROMETHYL-2-PYRIDYLTHIO ACETIC MFCD00664272

HYDRAZIDE

1- (2- (3-CHLORO-5-TRIFLUOROMETHYL) PYRIDYL] INDOLE-3- MFCD00664547

ACETAHYDRAZIDE-N'-PHENYLTHIOSE

5-DIMETHYLAMINOTETRAZOLE-1-ACETHYDRAZIDE MFCD00664557

5-METHYL-4- [N- (2- (3-CHLORO-5-TRIFLUOROMETHYL) PYRIDYL)] MFCD00664740

CARBOXYAMIDO-3-ISOXAZOLE

3-ACETHYDRAZIDO-4- MFCD00664748

(DIPHENYLMETHYLPIPERAZINO) CARBONYL-5-METHYL

ISOXAZOLE

3-CYANO-5-METHOXY-2-METHYL-BENZOIC ACID HYDRAZIDE MFCD00666525

BICYCLO [5.2.0] NONANE-2-CARBOXYLIC ACID HYDRAZIDE MFCD00666528

N-HYDRAZINOCARBONYLMETHYL-2-PHENOXY-ACETAMIDE MFCD00667228

2-CHLORO-N- (4-HYDRAZINOCARBONYL-PHENYL) -ACETAMIDE MFCD00667230

4-BROMO-N-HYDRAZINOCARBONYLMETHYL-BENZAMIDE MFCD00667241

2- (BENZOTHIAZOL-2-YLSULFANYL) -N- (4-HYDRAZINOCARBONYL- MFCD00667249

ME-THIAZOL-2-YL) -ACETAMIDE

PENT-3-ENOIC ACID HYDRAZINOCARBONYLMETHYL-AMIDE MFCD00667262

3BETA-HYDROXY-DELTA5-ETIOCHOLANIC ACID HYDRAZIDE MFCD00670863

4-BROMO-3-METHYLBENZOIC HYDRAZIDE MFCD00672945

2,5-DIBROMOBENZOIC HYDRAZIDE MFCD00672991

3,4-DIFLUOROBENZOIC HYDRAZIDE MFCD00672992

3.5-DIBROMO-4-METHYLBENZOIC HYDRAZIDE MFCD00672993

1- (6-CHLORO-3-PYRIDAZINYL) -4-PIPERIDINECARBOHYDRAZIDE MFCD00794640

N1- (2 - [[3-CHLORO-5- (TRIFLUOROMETHYL) -2- MFCD00794671

PYRIDYL] AMINO] ETHYL) -N1 - [[3- (HYDRAZINOCAR

3 - [[(4-CHLOROPHENYL) SULFONYL] METHYL] -4-NITRO-1- MFCD00794694

BENZENECARBOHYDRAZIDE

5-HEX-1-YN-YLPYRIDINE-3-CARBOXHYDRAZIDE MFCD00830971

CIS-CYCLOPROPANE-1.2-DICARBOXYLIC ACID HYDRAZIDE MFCD00831969

3,4-DICHLOROPHENYLACETIC ACID HYDRAZIDE MFCD00833407

3,5-DICHLOROBENZOIC ACID HYDRAZIDE MFCD00833411

3-PHENYL-1 H-INDOLE-2-CARBOHYDRAZIDE MFCD00974217

BENZYL N- [2-HYDRAZINO-1- (1 H-IMIDAZOL-2-YLMETHYL) -2- MFCD00974982

OXOETHYL] CARBAMATE

5-OXO-5,6,7,8-TETRAHYDROIMIDAZO [1, 2-C] PYRIMIDINE-7- MFCD00974983

CARBOHYDRAZIDE

TRANS CYCLOPROPYL-1, 2-DICARBOXYLIC ACID HYDRAZIDE MFCD01073574

HYDRATE

1-METHYLCYCLOPROPYL-1, 2-DIBENZOIC ACID HYDRAZIDE M FCD01073578

HYDRATE

1-METHYL-2.3-TRANS-CYCLOPROPANEDICARBOXYLIC ACID M FCD01073596

HYDRAZIDE

5 - (((2- (CARBOHYDRAZINO) METHYL) THIO) ACETYL) AMINOEOSIN M FCD01073636

5-BENZYLOXYINDOLE-3-ACETIC ACID HYDRAZIDE MFCD01074492

5-BROMOINDOLE-3-ACETIC ACID HYDRAZIDE MFCD01074493

5-FLUOROINDOLE-3-ACETIC ACID HYDRAZIDE MFCD01074504

5-METHOXYINDOLE-3-ACETIC ACID HYDRAZIDE MFCD01074508

5-METHOXY-2-METHYLINDOLE-3-ACETIC ACID HYDRAZIDE MFCD01074511

5-METHYLINDOLE-3-ACETIC ACID HYDRAZIDE MFCD01074516

ISONIAZID, [CARBONYL-14C] -

MFCD01075914

3-PHENOXYBENZHYDRAZIDE M FCD01090945 TABLE 2: SUMMARY OF SUBSTITUTED OXADIAZOLINONES

Claims

1. Combinatorial library of compounds, characterized in that it comprises substituted derivatives of oxadiazolinones and / or oxadiazolinthiones.

2. Combinatorial bank according to claim 1, characterized in that it comprises a plurality of compounds of general formula (I) below:

in which R, is a hydrogen atom or a first substituent; and A is chosen from the groups:

R2 X S-R3

I II I -N-C— or - N = C—

in which R2 represents a hydrogen atom or a second substituent; R3 represents a hydrogen atom or a third substituent, and X represents O or S, at least one of the substituents R1, R2 and R3 being other than H.

3. Combinatorial library of compounds according to claim 2, characterized

in that it comprises a plurality of compounds of general formula (II):

(H) wherein R ₁ is a hydrogen atom or a first substituent; R ₂ is a hydrogen atom or a second substituent, and X is an oxygen or sulfur atom, at least one of the groups R1 and R2 being different from H.

4. Combinatorial library of compounds according to claim 3, characterized in that, in the general formula (II), R1 and R2 are different from H.

5. Combinatorial library of compounds according to claim 3 or 4, characterized in that, in the general formula (II), X is an oxygen atom.

6. Combinatorial library of compounds according to claim 2, characterized in that it comprises a plurality of compounds of general formula (III):

wherein R ₁ is a hydrogen atom or a first substituent and R ₃ is a hydrogen atom or a third substituent, at least one of the groups R1 and R3 being different from H.

7. combinatorial library of compounds according to claim 6, characterized in that, in the general formula (III), R1 and R3 are different from H.

8. Combinatorial bank according to any one of claims 2 to 7, characterized in that the first, second and / or third substituent comprises one or more aromatic, heterocyclic groups, alkyl (saturated or not), acyl, alcohol, phenol, (thio) ether, acid, ester, nitrile, amino, ammonium, nitro, aldehyde, ketone and / or halogens.

9. Combinatorial library of compounds according to claim 2, in which each compound corresponds to the general formula (I).

10. Combinatorial library of compounds according to claim 3, in which each compound corresponds to the general formula (II).

11. Combinatorial library of compounds according to claim 6, in which each compound corresponds to the general formula (III).

12. Bank according to any one of the preceding claims, characterized in that it comprises up to 500,000 different compounds

13. Bank according to any one of the preceding claims, characterized in that it is a focused bank.

14. Method for preparing a library of compounds according to any one of the preceding claims, comprising a first step for the synthesis of a monosubstituted oxadiazolinone or oxadiazolinthione carrying the substituent R1 and, where appropriate, a second combinatorial step of substitution of the monosubstituted products with R2 or R3.

15. Method for searching for active products, characterized in that it comprises a step during which a bank according to claim 1 is tested.

16. Method for optimizing active products, characterized in that it comprises a step during which a bank according to claim 13 is tested.

17. Use of substituted derivatives of oxadiazolinones and / or oxadiazolinthiones for the generation of various or focused combinatorial libraries.

18. Process for the synthesis of substituted oxadiazolinone (or oxadiazolinthion) compounds, comprising the reaction of a hydrazide and (thio) carbonyldiimidazole in the presence of dimethylformamide.

19. Support comprising a library of compounds according to one of claims 1 to 13.