FR2792936A1 - OXA COMBINATORIAL BANKS, PREPARATION AND UTILIZATION. - Google Patents

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

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

Combinatorial chemistry is a rapidly developing field of technology. It makes it possible to generate libraries 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 compound libraries, as well as efficient methods of screening such libraries. The present invention now relates to novel methods and compositions for the preparation of combinatorial libraries.

One aspect of the invention resides more particularly in new combinatorial libraries of compounds. Another aspect of the invention resides in optimized methods for synthesizing such libraries. The invention also relates to the use of banks, particularly for research and / or optimization of "leads", as well as screening and / or profiling methods using the libraries 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 novel 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 results in particular from the development of advantageous synthesis methods making it possible to produce,

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 efficient and industrially usable, substituted derivatives of oxadiazolinones and / or oxadiazolinthiones. The invention therefore lies in the use of such derivatives for the generation of combinatorial, diverse or focused libraries.

The libraries of the invention have an original composition, related to the original structure of the monomers ("building blocks") used, and also particularly interesting properties. Thus, in fact, oxadiazolinones have been described as carrying interesting biological properties, such as tuberculostatic, antibacterial properties (Sherman W. R., J. Org Chem 26 (1961) 88), insecticide (Rufenacht K. Helv.

Chim. Acta 55 (1972) 1174), or a monoamine oxidase type B inhibitor (Mazouz et al., Eur J Med Chem (1990) 659), for example. The libraries of the invention therefore constitute a rich new source for the identification of compounds of interest.

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

In addition, the libraries according to the invention can be primary banks or focused banks. A primary bank is a bank produced mainly at random, without particular structural or conformational constraints. Primary banks are therefore often very diverse and have a large number of products. A focused bank, on the other hand, is a "secondary" bank composed of products having a common characteristic (structural, conformational, etc.), or supposed to be such. This type of bank is generally less diverse than primary banks, and has fewer compounds. These banks

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 are used more often to optimize active products, in particular to look for analogues of active products.

dans laquelle R1 est un atome d'hydrogène (H) ou un premier substituant ; et A est choisi parmi les groupes :

dans lesquels R2 représente un atome d'hydrogène (H) ou un second substituant ; R3 représente un atome d'hydrogène (H) ou un troisième substituant, et X représente 0 ou S. 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:

wherein R1 is a hydrogen atom (H) or a first substituent; and A is selected from the groups:

wherein R2 represents a hydrogen atom (H) or a second substituent; R3 represents a hydrogen atom (H) or a third substituent, and X represents 0 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 thus comprise compounds having a common ring, 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 more preferably entering the composition of the libraries of the invention therefore carry a substituent R 1 and a substituent R 2 or, a substituent R 1 and a substituent R 3.

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dans laquelle R1 est un atome d'hydrogène ou un premier substituant ; R2 est un atome d'hydrogène ou un deuxième substituant, et X est un atome d'oxygène ou de soufre, l'un au moins des groupes R1 et R2 étant différent de H. Even more preferentially, the invention relates to a combinatorial library of compounds, characterized in that it comprises a plurality of compounds of general formula (II):

wherein R1 is a hydrogen atom or a first substituent; R2 is a hydrogen atom or a second substituent, and X is an oxygen or sulfur atom, at least one of 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 preferentially, 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.

dans laquelle R1 est un atome d'hydrogène ou un premier substituant et R3 est un atome d'hydrogène ou un deuxième substituant, l'un au moins des groupes R1 et R3 étant différent de H (voir par exemple le composé final décrit dans les Figures 2C et 5B) et, éventuellement (ii) de composés de formule générale (II) telle que définie ci-dessus, dans laquelle R1 est un atome d'hydrogène ou un premier substituant ; R2 est un atome d'hydrogène ou un deuxième In another preferred embodiment, the invention relates to a combinatorial library of compounds, characterized in that it comprises a plurality of (i) compounds of general formula (III):

in which R 1 is a hydrogen atom or a first substituent and R 3 is a hydrogen atom or a second substituent, at least one of R 1 and R 3 being different from H (see, for example, the final compound described in US Pat. Figures 2C and 5B) and optionally (ii) compounds of general formula (II) as defined above, wherein R1 is a hydrogen atom or a first substituent; R2 is a hydrogen atom or a second

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 substituent, X is a sulfur atom and at least one of 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 this application refers to the fact that the libraries of the invention comprise at least 2 compounds of different structure having the formula (1) above. In this respect, as indicated above, a preferred library within the meaning of the invention advantageously comprises more than 50 different products, and can comprise up to 500,000 products, or more. The libraries of the invention may comprise, in addition to the compounds of formula (1), other compounds of different structure, resulting from combinatorial chemistry or other synthetic routes.

In a particular embodiment, the invention relates to a combinatorial library of compounds as defined above, wherein each compound is a substituted oxadiazolinone or oxadiazolinthione derivative, in particular wherein each compound has the general formula (1) 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 R 1 and R 3 are groups substituents.

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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 R 1, R2 and R3 are substituent groups and X is a sulfur atom.

Substituents For the purpose of the present invention, the term "substituent" denotes any atom, radical or chemical group likely to be covalently bonded to the nucleus of the molecule of formula (1). It may be in particular any neutral or charged chemical group, linear, branched or cyclic, hydrophobic or hydrophilic, acceptor or donor of electron (s) or proton (s), or not, halogenated or not, of a protecting group, an arm that 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, amine, ammonium, nitro groups. , aldehyde, ketone and / or halogen. More particularly, a substituent group of the invention may comprise from 1 to 30 carbon atoms, preferably from 1 to 20 carbon atoms.

Preferably, the substituent R 1 may consist of any side chain of a hydrazide (i.e., of formula R 1 -CO-NH-NH 2). In this respect, 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, ammonium, nitro, aldehyde, ketone and / or halogen, preferably having 1 to 30 carbon atoms, more preferably 1 to 20 carbon atoms. For this purpose, for the synthesis of the libraries and compounds of the invention, the substituent R1

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 can come from any commercial hydrazide. Table 1 gives an illustrative list of hydrazides that can be used to provide the substituent group R 1 in the constitution of the libraries of the invention. These hydrazides are commercial and can easily be obtained by those skilled in the art. Where appropriate, they can also be synthesized according to conventional methods.

Other commercial hydrazides are also described in the ACD ("Available Chemical Directory") database, which can be used in the context of the present invention. All these hydrazides are therefore likely to be used to produce compounds of the invention. On the other hand, any other hydrazide (i.e., non-commercial) may also be used to obtain and introduce the substituent R1. In this regard, hydrazides carrying a desired R1 side chain can be synthesized from carboxylic acids according to conventional chemistry techniques. There are about 18,000 commercial carboxylic acids, of which at least 10,000 are useful for synthesizing hydrazides. R1 may therefore consist of any side group 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 10,000 different substituents can be used.

Preferably, however, in order to limit the secondary reactions that may occur during the synthesis phase with a reactive function other than the hydrazide present on the substituent R 1, especially when the (thio) carbonyldiimidazole is used, it is preferable in this case to use substituents R 1 not carrying a primary or secondary amine function, primary alcohol or carboxylic acid.

Preferably, the substituent R2 can consist of any side chain of a halogenated derivative, a carboxylic acid or any activated form of carboxylic acid (acyl halide or anhydride for example) or a primary amine or secondary, for example. In this respect, it may be a question of

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 alkyl group, linear or branched, cyclic or otherwise, aromatic or otherwise, of a group COR4, CH2-NR5R6 or CH2-CH (OH) -R4, in which R4, R5 and R6, independently of each other, are hydrogen atoms, alkyl, acyl, linear or branched, cyclic or otherwise, saturated or unsaturated, aromatic or non-aromatic, heterocyclic, alcohol, phenol, (thio) ether, acid, ester, nitrile, amine, ammonium, nitro , aldehyde, ketone and / or halogen. The substituent R2 preferably comprises from 1 to 30 carbon atoms, more preferably from 1 to 20 carbon atoms.

Preferably, the substituent R3 may consist of any side chain of a halogenated derivative, an epoxide, a carboxylic acid or any activated form of carboxylic acid (acyl halide or anhydride, for example), for example. In this regard, it may be a linear or branched alkyl, alkyl, cyclic or non-cyclic group, aromatic or otherwise, of a CO-R 4, CH 2 -NR 5 R 6 or CH 2 -CH (OH) -R 4 group. , in which R4, R5 and R6, independently of one another, are hydrogen atoms, alkyl, acyl, linear or branched, cyclic or otherwise, saturated or unsaturated, aromatic or non-aromatic, heterocyclic, alcohol, phenol, (thio) ether, acid, ester, nitrile, amine (tertiary), ammonium, nitro, aldehyde, ketone and / or halogen. The substituent R3 preferably comprises from 1 to 30 carbon atoms, more preferably from 1 to 20 carbon atoms.

Given the diversity of substituents R 1, R 2 and R 3, the libraries of the invention may comprise a large amount 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 synthesized in a general manner, by preparation, in a first step, of an oxadiazolinone or monosubstituted oxadiazolinthione carrying the substituent R 1. Then, according to the

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 In this case, the substituent R2 or R3 can be introduced, by conventional chemistry, to generate an oxadiazolinone or a di-substituted oxadiazolinthione.

In this regard, the subject of the present invention is also a method for preparing a library of compounds as defined above, comprising a first step of synthesis, preferably at high speed, preferably automated, of an oxadiazolinone or monosubstituted oxadiazolinthione bearing the substituent R1 and, where appropriate, a second combinatorial step of substitution of the monosubstituted products by R2 or R3.

In the first step, the monosubstituted oxadiazolinone or 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 by reaction of acylhydrazine and phosgene (Domow et al., Ber., 82 (1949) 121). The Applicant has also shown that this synthesis can also be carried out by reacting acylhydrazine and triphosgene. A preferred method for synthesizing monosubstituted compounds and corresponding libraries of the invention, however, is to use (thio) carbonyldiimidazole as starting material. These compounds are first reacted with a hydrazide having an R 1 side chain to generate the mono-substituted oxadiazolinone or oxadiazolinthione. The corresponding reaction scheme is shown in Figure 1A for oxadiazolinones and Figure 1B for oxadiazolinthiones.

In a particularly preferred mode of implementation, 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 room temperature, and very high yields (possibly exceeding 95%) are obtained.

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 obtained. On the contrary, the reaction shown 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, required temperature conditions that were 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. Similarly, the finished product represented in FIG. 1B was obtained, under the conditions of the prior art, in the presence of carbon disulfide, CS2, under conditions that 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 method for synthesizing substituted oxadiazolinone (or oxadiazolinthion) compounds, comprising reacting 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 that can be adapted by those skilled in the art, especially close to ambient temperature. Even more preferably, the reaction is carried out in the presence of about 1 equivalent of hydrazide (in DMF) and about 2 equivalents of (thio) carbonyldiimidazole (in a solvent such as THF or DMF). The ratio between the reagents as well as the temperature and the duration of the reaction may of course be adapted by those skilled in the art. In particular, it is possible to use from 1 to 5 equivalents of (thio) carbonyldiimidazole per equivalent of hydrazide. Nevertheless, the best performance of the process is generally obtained under the conditions indicated above.

It is understood that this method of synthesis is the preferred embodiment of the invention, since it allows to synthesize, on a large scale, under industrializable and economic conditions, significant amounts of oxadiazolinone derivatives (or oxadiazolinthiones) diversified. In

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 in addition, this synthetic route can be automated, which is another major advantage in the field of combinatorial chemistry. Examples of implementation of this method of synthesis are given in the experimental part.

The compounds thus obtained thus carry a site of diversity which, taking into account the large number of usable structures (substituent R1) can already be used for the constitution of product banks. Indeed, as 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 libraries of the invention 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 (1). 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, conversely, after an intermediate step of separation (or isolation) thereof. In this respect, the process for synthesizing the 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, since the reaction is essentially quantitative, it is possible to perform the additional substitution directly in the same receptacle (plate well, in particular).

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

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 For the alkylation reaction, the monosubstituted oxadiazolinone or oxadiazolinthione is incubated in the presence of a halogenated derivative of formula R2Y, in which Y is a halogen atom (Cl, Br or I) under known conventional conditions. 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 Figure 2A for the synthesis of di-substituted oxadiazolinones and in Figure 2B for the synthesis of di-substituted oxadiazolinthiones. The reaction product can be easily isolated from excess reagents, if desired, by conventional chromatographic methods or by simple filtration, for example.

For the acylation reaction, the oxadiazolinone or monosubstituted oxadiazolinthione is incubated in the presence of an acid chloride of formula CICOR4, in which R4 is defined as above, under standard conditions known to the person of the occupation (Gogoi et al., Indian J. of Chemistry Sect B29 (1990) 1159). The corresponding reaction scheme is shown in FIG. 3. The product of the reaction can be easily isolated from the 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 HNR5R6, in which R5 and R6 are defined as above, and of formaldehyde CH2O. The reaction is carried out under standard conditions known to those skilled in the art (Sherman WS, J. Organic Chemistry 26 (1961) 88, Vakula et al., Indian J. Chem., 7 (1969) 583, et al., Indian J. Chem 23B (1984) 796). The corresponding reaction scheme is shown in FIG. 4. The product of the reaction can be easily isolated from excess reagents, if appropriate, by conventional chromatographic methods or by simple filtration, for example.

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Substituent R2 may be further introduced to the monosubstituted oxadiazolinthione by epoxide opening, depending on the reaction shown in Figure 5A (see, for example, Saski et al., J. Org Chem 47 (1982) 2757).

The substituents R 2 and R 3 may 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 halogenated derivative of formula R 3 -Y, in which Y is a halogen atom (Cl, Br or 1), under the conditions described above. for the substituent R2. The corresponding reaction scheme is shown in Figure 2C. Thus, the alkylation of the unsubstituted oxadiazolinthiones can be carried out by different types of halogenated derivatives (halides), especially in the presence of low, medium or reactive halides.

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 a Cl or Br atom, and R denotes a linear or branched hydrocarbon group, saturated or unsaturated, cyclic or otherwise. Preferably, the groups Ar and R have one or more other functions, for example alcohol, phenol, (thio) ether, acid, ester, nitrile, amine, ammonium, nitro, aldehyde, ketone and / or halogen.

Other preferred halides for carrying out the invention are the α-haloamide reactive halides, as shown 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-haloamide compounds are given in Figure 6C. Also preferred are α-haloamides having linear or branched, saturated or unsaturated, cyclic or non-cyclic aliphatic groups, preferably bearing one or

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 several other functions for example alcohol, phenol, (thio) ether, acid, ester, nitrile, amine, ammonium, nitro, aldehyde, ketone and / or halogen.

The alkylation can be carried out by incubation of the oxadiazolinthione in the presence of the alkylating agent (alkyl halide, benzyl halide, ahaloamide (α-bromamide), α-haloketone, for example) for a period of up to 15 hours. h for example (preferably from 20 'to 12 h). 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 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 makes it possible to obtain high yields as well as the dissolution of a maximum of products which are reacted, the temperature and the reaction time may be adapted by those skilled in the art.

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

Chem 7 (1969) 583), according to the reaction scheme shown 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 which are reacted, the temperature and the reaction time may 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., the di-substituted oxadiazolinthione) can be easily isolated from excess reagents, if desired, by conventional chromatographic methods or by simple filtration, for example.

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 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 mono-substituted oxadiazolinthiones. In addition, it should be noted that the reactions shown in FIGS. 2B and 2C can lead, according to 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 is true of the reactions shown 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 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 performed in microplates, in which reagents are introduced sequentially, manually or by means of suitable robots. In particular, the synthesis can 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 a suitable support (preferably microplates with high numbers of well, for example up to 1000 wells / plate). Preferably, each hydrazide is used at several points. Then (or previously), the (thio) carbonyldiimidazole is introduced, in the quantities chosen, into the support, preferably by means of an automaton. The reaction is continued for the selected time (usually 5 to 15 hours) at the selected temperature (usually room temperature). The products obtained can then be harvested to form banks, or, more simply, the

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 media 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 contact with the halogenated 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 carrier. In the combinatorial library described in the examples, a first synthesis was carried out by incubation of thiocarbonyldiimidazole in the presence of a first bank of 80 commercial hydrazides, distributed in the wells of a microplate. 84 identical plates are made. In a second step, in each of these 84 plates are distributed a different halogenated derivative or 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 product optimization. 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 is increasingly calling on 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 broaden the range of diversity of combinatorial libraries, and thus to access new active molecules. As indicated above, the libraries of the invention can be of variable diversity, and thus serve

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 in a primary screening or for a search for 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 process for optimizing active products, characterized in that it comprises a step during which a focused library as defined above is tested.

In these methods of the invention, the libraries can be tested in a variety of ways, essentially for the purpose of identifying leads having activity on a target, i.e., the ability to physically or functionally interact with a target. target.

The present invention therefore also relates to the use of the libraries 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 libraries of the invention.

The invention relates in this regard to the novel compounds constituting the libraries described above having 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 a portion 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.

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

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

 Figure 3: Schémaréactionnel substitution of oxadiazolinones derivatives / oxadiazolinthiones by acylation reaction.

 4: Schemareeaction of the substitution of the oxadiazolinone / oxadiazolinthion derivatives by Mannich reaction.

 FIG. 5: Schemeolarization of the substitution, on the nitrogen atom, of the oxadiazolinthion derivatives by reaction of opening of epoxides (5A) and of the substitution, on the sulfur atom, of the oxadiazolinthion derivatives by an opening reaction epoxides (5B).

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

EXAMPLES Example 1 Synthesis of Mono-Substituted Oxadiazolinones Protocol To a solution of 0.1 M acylhydrazine (0.5 mmol in 5 ml of DMF) was added 0.25M-1,1'-carbonyldiimidazole (1 mmol in 4ml of THF). After 12 hours at room temperature, the reaction was quenched with water (1 mL) and evaporated under vacuum at 40 C until dry residues were obtained. 10 to 40 mL of ethyl acetate was then added to the residues, washed with

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 saturated aqueous NaCl solution (4 X 10 mL), and the residual aqueous phase was extracted with ethyl acetate (10 mL) and washed with 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 soluble in water, the products obtained have been purified by
Reverse phase HPLC or by silica gel chromatography.

Results
The structure of acylhydrazines used for synthesis is given in
Table 2. This Table also gives the yields of the reactions, and shows the high efficiency of the synthesis method of the invention using DMF. The NMR spectrum of the products obtained is given below:
Product 3a: H-NMR (300 MHz, CDCl3 / DMSO (d6) 5/1): # 7.46 (3H, m),
7. 97 (3H, m), 89 (1H, d, J = 8.44Hz), # 12 (1H, s), EI-MS (m / z) 212 (M +, 100%), 168 (42%). ), 128 (57%), Product 3b: H-NMR (300 MHz, CDCl 3 / DMSO (d 6) 5/1): 3.65 (1H, s), 8
6. 75 (2H, d, 7 = 8.96 Hz), 8.75 (2H, d, J = 8.96 Hz), 11.75 (1H, s), EI-MS (m / z) 192 (M +, 91%), 148 (38%), 135 (53%), 133 (100%), 105 (14%).

Product 3c: H-NMR (600MHz, CDCl3 / DMSO (d6) 5/1): 8.75 (1H, dd, J = 8.4.9 Hz), 8.85 (1H, ddd, J = 8, 1. 74, 1. 74 Hz), 8. 8. 65 (1H, dd, J = 4.6,
0.9 Hz), 89 (1H, s), 8 12.3 (1H, s), EI-MS (m / z) 163 (M +, 119 (72%), 106 (25%), 104 (12%). ).

3d product: H-NMR (300 MHz, CDCl3): δ6.61 (1H, dd J = 3.54, 1.78 Hz), δ8.06 (1H, dd J = 3.52, 0.5 Hz) , 7.55 (1H, dd, J = 1.75, 0.71Hz), δ (1H, s), EI-MS (m / z) 152 (M +, 108 (36%).

Product 3e: 1H-NMR (300 MHz, CDCl3 / DMSO (d6) 5/1): 8.66 (1H, dd, J = 3.5, 2.6Hz), 8.66 (1H, dd, J) = 3.7, 1.4 Hz), 8 6. 86 (1H, dd, J = 2.6, 1. 4

<Desc / Clms Page number 20>

 Hz), δ 11.1 (1H, s), δ 11.7 (1H, s), EI-MS (m / z) 151 (M +, 100%), 149 (17%), 107 (11%).

Product 3f: 1H-NMR (300 MHz, CDCl 3 + D 2 O): # 7. 18 (1H, dd, J = 5.07, 3. 7 Hz), 8.75 (1H, dd, 7 = 5.07, 1. 18 Hz), 8.76 (1H, dd, J = 3.76, 1.5 Hz), EI-MS (m / z) 168 (M +, 100%), 124 (26%), 111 (55%) , 109 (12%).

Product 3g: H-NMR (600MHz, CDCl3 / MDSO (d6) 5/1): 5.8 (2H, s), 8.62 (1H, d, 7 = 3.5Hz), 8.66. (1H, d, 7 = 3.5Hz), 8.76 (1H, s), EI-MS (m / z) 302 (0.8%), 300 (M +, 1.2%), 165 (100), 121 ( 11%), 109 (33%),
106 (12%).

Product 3h: H-NMR (300MHz, DMSO (d6)): # 4.83 (2H, s), 5.8 (2H, s), # 6.53 (1H, s), 8.68. (1H, d, 7 = 2.8 Hz), 7.75 (1H, s), 8.84 (1H, s), 8
12. 75 (1H, 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%).

Product 3i: H-NMR (300MHz, DMSO (d6)): 3.96 (2H, s), 8.77 (1H, dd, 7 = 4.9, 0.9Hz), 8.71. (1H, m), 8.74 (1H, dd, 7 = 4.9, 3Hz), 812.24 (1H, s), EI-MS (m / z) 182 (M +, 100%), 140 (37%), 125 (40%), 112 (10%), 111 (11%), 110 (11%).

 EXAMPLE 2 Synthesis of a Di-Substituted Oxadiazolinthiones Bank This example describes the synthesis conditions of an alkylated oxadiazolinthiones library. This bank is a source of products for the identification of active compounds.

2. 1. Solutions used.

The following solutions were used: solution S: solution of thiocarbonyl diimidazole at about 0.25 M in DMF.

<Desc / Clms Page number 21>

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

solutions A: separate solutions of alkylating agents of different structures (78 halides and 6 epoxides) at 0.5 M in DMF, with neutrality.

2. 2. Procedure 5 moles of thiocarbonyldiimidazole per well are distributed in "deep-wells" plates (approximately 20 l of solution S per well, the precise volume of solution S is calculated prior to synthesis. by reactivity test of the solution S). Preferably, the distribution is performed by means of an automaton. 84 plates of 96 wells are thus prepared, in which only the first 80 wells are used (80 different products synthesized per plate).

Then, on each plate, 50 l of N solutions are dispensed, each N solution being dispensed, on the same plate, into 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 mono-substituted oxadiazolinthiones library is obtained. This first bank comprises 80 compounds of different structures. At this stage, a quality control is performed. For this, 5 l are taken from each well and evaporated under reduced pressure. The products obtained are solubilized with 300 l of acetonitrile and injected (10 l) on a chromatographic column and analyzed by LC / MS (liquid chromatography coupled to mass spectrometry).

For the realization of a combinatorial library, the oxadiazolinthiones obtained are subjected to an additional substitution. For this, 10 l of A solutions are added to each well (1 full plate for each

<Desc / Clms Page number 22>

 solution A). The plates are then placed in incubators and heated (set temperature of 95 C), under nitrogen, for 6 hours. After this incubation, the heating and nitrogen flow are stopped, and the plates are cooled for 30 minutes. Each of the above steps is preferably performed in an automated manner. The plates are then removed from the oven, and 5 l are taken from each well and distributed in a blank plate, for quality control (QC). The "synthesis" plates and the CQ plates are then placed under reduced pressure for 4 hours to 24 hours, until the solvents evaporate. The products of CQ are then solubilized with 300 l of acetonitrile and injected on an LC / MS chromatographic column. The "synthesis" plates constitute a combinatorial library of substituted oxadiazolinthiones, which can be used to search for active compounds, for example by screening and / or high-throughput profiling.

<Desc / Clms Page number 23>

TABLE 1: LIST OF HYDRAZIDS

<Tb>
<tb> HYDRAZIDES <SEP> NUMBER <SEP> MDL
<tb> 2-FUROIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00003235
<tb> 3-HYDROXY-2-NAPHTHOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00004097
<tb> 2-THIOPHENECARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00005435
<tb> INDOLE-3-ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00005634
<tb> NICOTINIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00006383
<tb> ISONICOTINIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00006426
<tb> BENZHYDRAZIDE <SEP> MFCD00007596
<tb> 2-CHLOROBENZHYDRAZIDE <SEP> MFCD00007597
<tb> 2-NITROBENZHYDRAZIDE <SEP> MFCD00007598
<tb> SALICYLHYDRAZIDE <SEP> MFCD00007599
<tb> 3-BROMOBENZHYDRAZIDE <SEP> MFCD00007600
<tb> 3-METHOXYBENZHYDRAZIDE <SEP> MFCD00007601
<tb> 4-BROMOBENZHYDRAZIDE <SEP> MFCD00007602
<tb> 4-CHLOROBENZHYDRAZIDE <SEP> MFCD00007603
<tb> 4-NITROBENZHYDRAZIDE <SEP> MFCD00007604
<tb> 4-HYDROXYBENZHYDRAZIDE <SEP> MFCD00007605
<tb> P-TOLUIC <SEP> HYDRAZIDE <SEP> MFCD00007607
<tb> OXALYL <SEP> DIHYDRAZIDE <SEP> MFCD00007608
<tb> ACETIC <SEP> HYDRAZIDE <SEP> MFCD00007610
<tb> CYANOACETOHYDRAZIDE <SEP> MFCD00007611
<tb> PHENYLACETIC <SEP> HYDRAZIDE <SEP> MFCD00007612
<tb> SUCCINIC <SEP> DIHYDRAZIDE <SEP> MFCD00007613
<tb> ADIPIC <SEP> DIHYDRAZIDE <SEP> MFCD00007614
<tb> OCTANOIC <SEP> HYDRAZIDE <SEP> MFCD00011588
<tb> 2,5-DICHLOROBENZHYDRAZIDE <SEP> MFCD00014754
<tb> 2-METHOXYBENZHYDRAZIDE <SEP> MFCD00014755
<tb> O-TOLUIC <SEP> HYDRAZIDE <SEP> MFCD00014756
<tb> 3-CHLOROBENZHYDRAZIDE <SEP> MFCD00014757
<tb> 3,4,5-TRIMETHOXYBENZHYDRAZIDE <SEP> MFCD00014758
<tb> 3-HYDROXYBENZHYDRAZIDE <SEP> MFCD00014759
<tb> 3-TOLUIC <SEP> HYDRAZIDE <SEP> MFCD00014760
<tb> 4-DIMETHYLAMINOBENZHYDRAZIDE <SEP> MFCD00014761
<tb> TEREPHTHALIC <SEP> DIHYDRAZIDE <SEP> MFCD00014762
<tb> 4-TERT-BUTYLBENZHYDRAZIDE <SEP> MFCD00014763
<tb> STEARIC <SEP> HYDRAZIDE <SEP> MFCD00014764
<tb> SUBERIC <SEP> DIHYDRAZIDE <SEP> MFCD00014765
<tb> ALPHA-NAPHTHOYLHYDRAZINE <SEP> MFCD00016804
<tb> BETA-NAPHTHOYLHYDRAZINE <SEP> MFCD00016810
<tb> 2-CHLORO-4-NITROBENZHYDRAZIDE <SEP> MFCD00017047
<tb> 2-PHENOXYBENZHYDRAZIDE <SEP> MFCD00017048
<tb> 2,5-DIMETHOXYBENZHYDRAZIDE <SEP> MFCD00017049
<tb> 2-ETHOXYBENZHYDRAZIDE <SEP> MFCD00017050
<tb> 2-HYDROXY-3-METHYLBENZHYDRAZIDE <SEP> MFCD00017052
<tb> 2,4-DIHYDROXYBENZHYDRAZIDE <SEP> MFCD00017053
<tb> 6-HYDROXY-3-ANISIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00017054
<tb> 2-HYDROXY-5-METHYLBENZHYDRAZIDE <SEP> MFCD00017055
<tb> 3,5-DIIODO-4-METHOXYBENZHYDRAZIDE <SEP> MFCD00017058
<tb> 3-NITROBENZHYDRAZIDE <SEP> MFCD00017059
<tb> 3,5-DINITROBENZHYDRAZIDE <SEP> MFCD00017060
<tb> 3,4-DIMETHOXYBENZHYDRAZIDE <SEP> MFCD00017061
<tb> 3,5-DIMETHOXYBENZHYDRAZIDE <SEP> MFCD00017062
<tb> 3-ETHOXYBENZHYDRAZIDE <SEP> MFCD00017063
<Tb>

<Desc / Clms Page number 24>

<Tb>
<tb> 3,4-DIHYDROXYBENZHYDRAZIDE <SEP> MFCD00017064
<tb> 3,4,5-TRIHYDROXYBENZHYDRAZIDE <SEP> MFCD00017065
<tb> 3,5-DIHYDROXYBENZHYDRAZIDE <SEP> MFCD00017066
<tb> 4-CHLORO-3-NITROBENZHYDRAZIDE <SEP> MFCD00017072
<tb> 4-METHOXYBENZHYDRAZIDE <SEP> MFCD00017073
<tb> 4-ETHOXYBENZHYDRAZIDE <SEP> MFCD00017074
<tb> 3,5-DIIODO-4-HYDROXY <SEP> BENZHYDRAZIDE <SEP> MFCD00017075
<tb> VANILLIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00017076
<tb> 3,5-DIMETHOXY-4-HYDROXYBENZHYDRAZIDE <SEP> MFCD00017077
<tb> 4-BIPHENYLCARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00017078
<tb>4,4'-BISBENZHYDRAZIDE<SEP> MFCD00017079
<tb> BENZILIC <SEP> HYDRAZIDE <SEP> MFCD00017082
<tb> CINNAMIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00017083
<tb> 3,5-DINITRO-4-HYDROXYPHENYLPROPIONIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00017084
<tb> 5-BROMO-2-HYDROXYBENZHYDRAZIDE <SEP> MFCD00017567
<tb> 2- (FURFURYLUREIDO) ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00020957
<tb> 2-NAPHTHYLACETIC <SEP> HYDRAZIDE <SEP> MFCD00021652
<tb> 3-INDOLEPROPIONIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00022777
<tb> 5,6-DIMETHYLBENZIMIDAZOLE-1-ACETHYDRAZIDE <SEP> MFCD00022841
<tb> NICOTINIC <SEP> HYDRAZIDE <SEP> N-OXIDE <SEP> MFCD00023409
<tb> 2-FLUOROBENZHYDRAZIDE <SEP> MFCD00025112
<tb> 2,4-DICHLOROBENZHYDRAZIDE <SEP> MFCD00025113
<tb> 2-IODOBENZHYDRAZIDE <SEP> MFCD00025114
<tb> 2- (METHYLUREIDO) BENZOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00025115
<tb> ISOPHTHALIC <SEP> DIHYDRAZIDE <SEP> MFCD00025117
<tb> 4- (TERT-BUTYLUREIDO) BENZOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00025118
<tb> BENZOYL-L-TYR <SEP> HYDRAZIDE <SEP> MFCD00025120
<tb> N-ACETYL-L-TYROSINE <SEP> HYDRAZIDE <SEP> MFCD00025121
<tb> ISOBUTYRIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00025122
<tb> ((2-ETHOXYPHENYL) UREIDO) ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00025123
<tb> ((3-CHLOROPHENYL) UREIDO) ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00025124
<tb> 2- (3,4-DICHLOROPHENYLUREIDO) ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00025125
<tb> 2- (3- (3-NITROPHENYL) UREIDO) ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00025126
<tb> CBZ-GLY <SEP> HYDRAZIDE <SEP> MFCD00025127
<tb> 2- (2-HYDROXYPHENYL) ACETHYDRAZIDE <SEP> MFCD00025128
<tb> MALEIC <SEP> ACID <SEP> DIHYDRAZIDE <SEP> MFCD00025130
<tb> 3- (3,5-DI-TERT-BUTYLPHENYL) -3-HYDROXYPROPIONIC <SEP> ACID <SEP> MFCD00025131
<tb> HYDRAZIDE
<tb> HEXANOIC <SEP> HYDRAZIDE <SEP> MFCD00025133
<tb> BUTYRIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00025135
<tb> GLUTARIC <SEP> DIHYDRAZIDE <SEP> MFCD00025136
<tb> VALERIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00025137
<tb> PIMELIC <SEP> DIHYDRAZIDE <SEP> MFCD00025138
<tb> DECANOIC <SEP> HYDRAZIDE <SEP> MFCD00025139
<tb> 4,4-DIPHENYL-1- (N- <SEP> MFCD00031402
<tb> (HYDRAZINOCARBONYLMETHYL) CARBAMOYL) SEMICARBAZIDE
<tb> 2- (4-FLUOROPHENYLUREIDO) ACETHYDRAZIDE <SEP> MFCD00031403
<tb> 2- (4-METHYLPHENYLCARBOXAMIDO) BENZOIC <SEP> HYDRAZIDE <SEP> MFCD00031404
<tb> 4- (3-CHLOROPHENYLUREIDO) BENZHYDRAZIDE <SEP> MFCD00031405
<tb> 2-HYDROXY-2-METHYLPROPIONIC <SEP> HYDRAZIDE <SEP> MFCD00031406
<tb> O-ANISIC <SEP> ACID <SEP> HYDRAZIDE <SEP> HYDROCHLORIDE <SEP> MFCD00035461
<tb> MANDELIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00038133
<tb> LACTHYDRAZIDE <SEP> MFCD00038134
<tb> Z-HIS-NHNH2 <SEP> MFCD00038621
<tb> SEBACIC <SEP> DIHYDRAZIDE <SEP> MFCD00039763
<Tb>

<Desc / Clms Page number 25>

<Tb>
<tb> MALONIC <SEP> ACID <SEP> DIHYDRAZIDE <SEP> MFCD00041268
<tb> 1,4-CYCLOHEXANEDICARBOHYDRAZIDE <SEP> MFCD00043475
<tb> N-TRITYLGLYCIN <SEP> HYDRAZIDE <SEP> MFCD00043618
<tb> DODECANEDIOIC <SEP> DIHYDRAZIDE <SEP> MFCD00043619
<tb> N-BUTYL <SEP> HYDRAZINE <SEP> OXALATE <SEP> MFCD00047823
<tb> 5-BROMO-2-CHLOROBENZHYDRAZIDE <SEP> MFCD00051528
<tb> AZELAIC <SEP> DIHYDRAZIDE <SEP> MFCD00051529
<tb> 2-BROMOBENZHYDRAZIDE <SEP> MFCD00051577
<tb> 3,4-DIMETHOXYPHENYLACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00051701
<tb> 4- (TRIFLUOROMETHYL) BENZHYDRAZIDE <SEP> MFCD00051703
<tb> 3,5-BIS (TRIFLUOROMETHYL) BENZHYDRAZIDE <SEP> MFCD00051848
<tb> 2,4-DICHLOROPHENOXYACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00051972
<tb> 4-NITROPHENOXYACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00051973
<tb> (4- (TRIFLUOROMETHOXY) PHENOXY) ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00052355
<tb> BOC-HIS-NHNH2 <SEP> MFCD00055954
<tb> Z-TYR-NHNH2 <SEP> MFCD00057641
<tb> 2-IMINOBIOTIN <SEP> HYDRAZIDE <SEP> HYDROCHLORIDE <SEP> MFCD00058114
<tb> 2-PICOLINYL <SEP> HYDRAZIDE <SEP> MFCD00059782
<tb> 3-FLUOROBENZHYDRAZIDE <SEP> MFCD00060561
<tb> 4-FLUOROBENZHYDRAZIDE <SEP> MFCD00060562
<tb> 4- (CYCLOHEXYLUREIDO) BENZOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00065311
<tb> BIOTIN-XX-HYDRAZIDE <SEP> MFCD00065501
<tb> PALMITIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00066357
<tb> 2- (4-CHLOROPHENYL) -3- (TRIFLUOROMETHYL) PYRAZOLE-4- <SEP> MFCD00068154
<tb> CARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE
<tb> BIOTINAMIDOCAPROYL <SEP> HYDRAZIDE <SEP> MFCD00077659
<tb> BIOTIN <SEP> HYDRAZIDE <SEP> MFCD00078532
<tb> 4-FLUOROPHENOXYACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00082651
<tb> 2-METHYL-4-CHLOROPHENOXYACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00082720
<tb> 2-CHLOROPHENOXYACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00082786
<tb> N- [3,5-BIS (TRIFLUOROMETHYL) BENZENESULFONYL] -L- <SEP> MFCD00084900
<tb> METHIONYL <SEP> HYDRAZIDE
<tb> N- [4- (TRIFLUOROMETHYL) BENZOYL] -L-METHIONYLHYDRAZIDE <SEP> MFCD00085179
<tb> 5-OXO-1-PHENYL-2-PYRAZOLIN-3-CARBOXYLIC <SEP> ACID <SEP> MFCD00085802
<tb> HYDRAZIDE
<tb> 2,5-DIMETHOXYTETRAHYDRO-2-FUROIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00086221
<tb> ORTHO- (DIMETHYLAMINO) -BENZOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00087186
<tb> 3-HYDROXYBUTYRIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00087370
<tb> 4-CHLORO-2,6-PYRIDINEDICARBOXYLIC <SEP> HYDRAZIDE <SEP> MFCD00091142
<tb> ETHYLMALONIC <SEP> ACID, <SEP> DIHYDRAZIDE <SEP> MFCD00093418
<tb> 4-CYCLOHEXEN-1,2-DICARBOXYLIC <SEP> DIHYDRAZIDE <SEP> MFCD00094417
<tb> 4- (3- (2-FLUOROPHENYL) UREIDO) BENZOIC <SEP> HYDRAZIDE <SEP> MFCD00094571
<tb> 4- (3- (3- (TRIFLUOROMETHYL) PHENYL) UREIDO) BENZOIC <SEP> MFCD00094600
<tb> HYDRAZIDE
<tb> 2-METHYLPENTANOIC <SEP> HYDRAZIDE <SEP> MFCD00094913
<tb> 4- (3-PHENYL-2-THIOUREIDO) BENZOIC <SEP> HYDRAZIDE <SEP> MFCD00095482
<tb> 9-XANTHENECARBOXYLIC <SEP> HYDRAZIDE <SEP> MFCD00100677
<tb> 4- (TRIFLUOROMETHYL) PYRIDINE-3-CARBOXYLIC <SEP> MFCD00101567
<tb> ACIDHYDRAZIDE
<tb> 3-METHYL-5- [4- (TRIFLUOROMETHYL) PHENYL] ISOXAZOLE-4- <SEP> MFCD00102588
<tb> CARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE
<tb> BIONET <SEP> 10B-013 <SEP> MFCD00110397
<tb> 3-PHENYL-5-METHYLISOXAZOLE-4-CARBOHYDRAZIDE <SEP> MFCD00119108
<tb> ETHYL <SEP> 3-HYDRAZINO-3-OXOPROPIONATE <SEP> MFCD00134484
<tb> N-BENZYLOXYCARBONYL-L-VALYL-L-TYROSINE <SEP> HYDRAZIDE <SEP> MFCD00136446
<Tb>

<Desc / Clms Page number 26>

<Tb>
<tb> CARBOBENZYLOXY-L-LEUCINE <SEP> HYDRAZIDE <SEP> MFCD00136780
<tb> 4- (4-CHLOROPHENOXY) -3-NITROBENZHYDRAZIDE <SEP> MFCD00138750
<tb> 3-CARBOXYHYDRAZONO-1- (3,4-DICHLOROBENZYL) -2- <SEP> MFCD00140455
<tb> PYRIDONE
<tb> 3-CARBOXYHYDRAZONO-1- (3-TRIFLUOROMETHYLBENZYL) -2- <SEP> MFCD00140456
<tb> PYRIDONE
<tb> 3-CARBOXYHYDRAZONO-1- (2,4-DICHLOROBENZYL) -2- <SEP> MFCD00140461
<tb> PYRIDONE
<tb> 3-CARBOXYHYDRAZONO-1-BENZYL-2-PYRIDONE <SEP> MFCD00140469
<tb> 3-CARBOXYHYDRAZONO-1- (3-TRIFLUOROMETHYLBENZYL) -6- <SEP> MFCD00140548
<tb> PYRIDONE
<tb> 1-BENZYL-3-CARBOXYHYDRAZONO-6-PYRIDONE <SEP> MFCD00140619
<tb> 1- (4-METHOXYPHENYL) 4- (4-METHYLPHENYLTHIO) 6- <SEP> MFCD00141164
<tb> PYRIDAZINONE <SEP> 3-CARBOXYLICACID <SEP> HYDRAZI
<tb> 1-PHENYL <SEP> 4-PHENOXY <SEP> 6-PYRIDAZINONE-3-CARBOXYLIC <SEP> ACID <SEP> MFCD00141172
<tb> HYDRAZIDE
<tb> 1,2,4-TRIAZOL-1-YL-ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00141553
<tb> 1-PHENYL-1,2,4-TRIAZOL-3-YLOXY <SEP> ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00141608
<tb> 1- (2- (3-CHLORO-5-TRIFLUOROMETHYL) PYRIDYL) -4- (2-ACETIC <SEP> MFCD00141696
<tb> ACID <SEP> HYDRAZIDO) PIPERAZINE
<tb> 1-METHYL-4- (2,4-DICHLOROBENZOYL) PYRROLE-2- <SEP> MFCD00141855
<tb> CARBOHYDRAZIDE
<tb> 4- (2,4-DICHLOROBENZOYL) PYRROLE-2-CARBOHYDRAZIDE <SEP> MFCD00141933
<tb> Z-THR-NHNH2 <SEP> MFCD00153343
<tb> 4-PHENOXYBENZHYDRAZIDE <SEP> MFCD00153894
<tb> 1-ADAMANTANECARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00154679
<tb> 2,4-DIMETHYLPHENOXYACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00156144
<tb> 1- (NAPHTHOXY) ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00156157
<tb> 9,10-DIHYDRO-9,10-ETHANOANTHRACENE-11,12-DICARBOXYLIC <SEP> MFCD00157914
<tb> DIHYDRAZIDE
<tb> HYDROCINNAMIC <SEP> HYDRAZIDE <SEP> MFCD00157933
<tb> 9,10-DIHYDRO-11-METHYL-9,10-ETHANOANTHRACENE-11- <SEP> MFCD00157935
<tb> CARBOXYLIC <SEP> HYDRAZIDE
<tb> N- (5-CHLORO-2-THIAZOLYL) OXAMIC <SEP> HYDRAZIDE <SEP> MFCD00159777
<tb> 2-PHENYL-4-QUINOLINECARBOXYLIC <SEP> HYDRAZIDE <SEP> MFCD00160604
<tb> 2- (BENZIMIDAZOLYLTHIO) ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00171027
<tb> N- (2- (4-METHYLPYRIMIDYL) -2-AMINOMETHYLENE <SEP> HIPPURIC <SEP> MFCD00171914
<tb> ACID <SEP> HYDRAZIDE
<Tb>

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

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

<Tb>
<tb> ACID <SEP> HYDRAZIDE
<tb> N- (2- (3-CHLORO-5-TRIFLUOROMETHYL) PYRIDYL) - <SEP> -AMINO <SEP> MFCD00172610
<tb> BUTYRIC <SEP> ACID <SEP> HYDRAZIDE
<tb> OXALIC <SEP> ACID, <SEP> MONOHYDRAZIDE, <SEP> N- (4-METHOXYPHENYL) AMIDE <SEP> MFCD00173090
<tb> OXALIC <SEP> ACID, <SEP> MONOHYDRAZIDE, <SEP> MONO- (4- <SEP> MFCD00173093
<tb> TRIFLUOROMETHOXYPHENYL) AMIDE
<tb> OXALIC <SEP> ACID, <SEP> MONOHYDRAZIDE, <SEP> MONO <SEP> PHENYLAMIDE <SEP> MFCD00173094
<tb> 1- (6-CHLORO-2-PYRIDYL) -3- (2- <SEP> MFCD00173102
<tb> HYDRAZINOCARBONYL) PHENOXYMETHYL
<tb> 2-METHYL-2- (1,2,4-TRIAZOL-1-YL) PROPIONIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00173108
<tb> 3- (4-CHLOROBENZYLOXY) THIOPHENE-2-CARBOHYDRAZIDE <SEP> MFCD00173482
<tb> 2,4-DIFLUOROBENZOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00173685
<tb> 1- (4-NITROPHENYL) -4- ((EXO-DEHYDRO) PIPERIDINE) ACETIC <SEP> MFCD00180778
<tb> ACID <SEP> HYDRAZIDE
<Tb>

1 -(2'-(3'-CHLORO-5'-TR)FLUOROMETHYL)PYR)DYL)P)PERAZ!NE- MFCD00180800

1 - (2 '- (3'-CHLORO-5'-TR) FLUOROMETHYL) PYR) DYL) P) PERAZ! NE- MFCD00180800

<Tb>
<tb> 4-HYDRAZIDO <SEP> ETHYLENE
<Tb>

<Desc / Clms Page number 27>

<Tb>
<tb> 2- (PYRIMIDIN-2-YLSULFANYL) -ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00181554
<tb> 2- (2-METHYLSULFANYL-PYRIMIDIN-4-YLSULFANYL) -ACETIC <SEP> MFCD00181568
<tb> ACID <SEP> HYDRAZIDE
<tb> 2- (4,6-DIMETHYL-PYRIMIDIN-2-YLSULFANYL) -ACETIC <SEP> ACID <SEP> MFCD00181595
<tb> HYDRAZIDE
<tb> (BENZOYLAMINO-2-HYDSRAZINOCARBONYL-1-PH-VINYL) - <SEP> MFCD00181901
<tb> TRIPHENYL-PHOSPHONIUM, <SEP> PERCHLORATE
<tb> 2- (1-HYDRAZINOCARBONYL-1-METHYL-ETHYLAZO) -2-METHYL- <SEP> MFCD00181929
<tb> PROPIONIC <SEP> ACID <SEP> HYDRAZIDE
<tb> 2,2-DICHLORO-N- (4-HYDRAZINOCARBONYL-BENZYL) - <SEP> MFCD00182660
<tb> ACETAMIDE
<tb> 4,6-DIPHENYL-PYRIMIDINE-2-CARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00184890
<tb> 3-BENZYLOXY-4,5-DIMETHOXY-BENZOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00185565
<tb> 1-ADAMANTANEACETIC <SEP> HYDRAZIDE <SEP> MFCD00185799
<tb> 2- (3-HYDRAZINOCARBONYLMETHYL-ADAMANTAN-1 <SEP> -YL) -ACETIC <SEP> MFCD00186490
<tb> ACID <SEP> HYDRAZIDE
<tb> 2- (4-PHENYL-5-PHENYLAMINO-4H- (1,2,4) TRIAZOL-3- <SEP> MFCD00186735
<tb> YLSULFANYL) -ACETIC <SEP> ACID <SEP> HYDRAZIDE
<tb> 2- (4-ISOPROPYL-3-METHYL-PHENOXY) -ACTIC <SEP> ACID <SEP> MFCD00187115
<tb> HYDRAZIDE
<tb> 2-BENZENESULFONYL-2 - ((4-CHLORO-PHENYL) -HYDRAZONO) - <SEP> MFCD00187922
<tb> ACETIC <SEP> ACID <SEP> HYDRAZIDE
<tb> AC-PHE-NHNH2 <SEP> MFCD00190721
<tb> BOC-THR-NHNH2 <SEP> MFCD00190834
<tb> Z-GLY-HIS-NHNH2 <SEP> MFCD00191101
<tb> Z-HIS-NHNH2 <SEP> HCL <SEP> MFCD00191105
<tb> 2 - ((4-BROMO-PHENYL) -HYDRAZONO) -2- (TOLUENE-4- <SEP> MFCD00193669
<tb> SULFONYL) -ACETIC <SEP> ACID <SEP> HYDRAZIDE
<tb> 2- (TOLUENE-4-SULPHONYL) -2- (P-TOLYL-HYDRAZONO) -ACETIC <SEP> MFCD00193670
<tb> ACID <SEP> HYDRAZIDE
<tb> 2- (TOLUENE-4-SULPHONYL) -2- (O-TOLYL-HYDRAZONO) -ACETIC <SEP> MFCD00193672
<tb> ACID <SEP> HYDRAZIDE
<tb> 2 - ((4-CHLORO-PHENYL) -HYDRAZONO) -2- (TOLUENE-4- <SEP> MFCD00193673
<tb> SULFONYL) -ACETIC <SEP> ACID <SEP> HYDRAZIDE
<tb> 2-BENZENESULFONYL-2 - ((3-CHLORO-PHENYL) -HYDRAZONO) - <SEP> MFCD00193676
<tb> ACETIC <SEP> ACID <SEP> HYDRAZIDE
<tb> 2-BENZENESULFONYL-2 - ((3-NITRO-PHENYL) -HYDRAZONO) - <SEP> MFCD00193677
<tb> ACETIC <SEP> ACID <SEP> HYDRAZIDE
<tb> 2-BENZENESULFONYL-2 - ((4-FLUORO-PHENYL) -HYDRAZONO) - <SEP> MFCD00193678
<tb> ACETIC <SEP> ACID <SEP> HYDRAZIDE
<tb> 2-BENZENESULFONYL-2- (P-TOLYL-HYDRAZONO) -ACTIC <SEP> ACID <SEP> MFCD00193679
<tb> HYDRAZIDE
<tb> 2-BENZENESULFONYL-2- (M-TOLYL-HYDRAZONO) -ACTIC <SEP> ACID <SEP> MFCD00193680
<tb> HYDRAZIDE
<tb> 2-BENZENESULFONYL-2- (O-TOLYL-HYDRAZONO) -ACTIC <SEP> ACID <SEP> MFCD00193681
<tb> HYDRAZIDE
<tb> 2-BENZENESULFONYL-2- (PHENYL-HYDRAZONO) -ACTIC <SEP> ACID <SEP> MFCD00193682
<tb> HYDRAZIDE
<tb> 2- (4-CL-BENZENESULFONYL) -2 - ((2-METHOXY-PHENYL) - <SEP> MFCD00193683
<tb> HYDRAZONO) -ACTIC <SEP> ACID <SEP> HYDRAZIDE
<tb> 2- (4-CL-BENZENESULFONYL) -2 - ((4-CHLORO-PHENYL) - <SEP> MFCD00193684
<tb> HYDRAZONO) -ACTIC <SEP> ACID <SEP> HYDRAZIDE
<tb> 2- (4-CHLORO-BENZENESULFONYL) -2- (P-TOLYL-HYDRAZONO) - <SEP> MFCD00193685
<Tb>

<Desc / Clms Page number 28>

<Tb>
<tb> ACETIC <SEP> ACID <SEP> HYDRAZIDE
<tb> 2- (4-CHLORO-BENZENESULFONYL) -2- (PHENYL-HYDRAZONO) - <SEP> MFCD00193686
<tb> ACETIC <SEP> ACID <SEP> HYDRAZIDE
<tb> 1- (BIS-PHENOXY-PHOSPHORYL) -4-HYDRAZINOCARBONYL- <SEP> MFCD00194827
<tb> PYRIDINIUM, <SEP> CHLORIDE
<tb> 5-CHLORO-2-METHYL-PYRIMIDIN-4-CARBOXYLIC <SEP> ACID <SEP> MFCD00195316
<tb> HYDRAZIDE
<tb> 3- (4-BENZYLOXY-3-METHOXY-PHENYL) -PROPIONIC <SEP> ACID <SEP> MFCD00195544
<tb> HYDRAZIDE
<tb> HYDRAZINOCARBONYL-1- (OXO-TETRAOXA-PHOSPHA- <SEP> MFCD00196024
<tb> BENZOCYCLOUNDECEN-9-YL) -PYRIDINIUM, <SEP> CL
<tb> 2-OXO-2H-CHROMENE-3-CARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00197340
<tb> 5-ALPHA-ANDROSTANE-17-BETA-CARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00200754
<tb> 3-BETA-HYDROXYANDROST-5-ENE-17-BETA-CARBOXYLIC <SEP> ACID <SEP> MFCD00200773
<tb> HYDRAZIDE
<tb> 2-METHYL-4-TRIFLUOROMETHYLTHIAZOLE-5- <SEP> MFCD00202351
<tb> CARBOHYDRAZIDE
<tb> 5- (2 '- (3'-CHLORO-5'- <SEP> MFCD00202621
<tb> TRIFLUOROMETHYL) PYRIDYLAMINO) METHYL-3,4-DIHYDRO
<tb> ISOXAZOLE-2-
<tb> 5- (TRIFLUOROMETHYL) THIENO [3,2-B] PYRIDINE-6-CARBOXYLIC <SEP> MFCD00203163
<tb> ACID, <SEP> HYDRAZIDE
<tb> 2- (2,4-DICHLOROPHENOXY) PROPIONIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00204152
<tb> 2- (TRIFLUOROMETHOXY) BENZOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00204180
<tb> 4- (TRIFLUOROMETHOXY) BENZOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00204234
<tb> QUINOXALINE-6-CARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00210172
<Tb>

9,10-DIHYDRO-9,10-ETHANOANTHRACENE-1 1-CARBOXYLIC MFCD00213638

9,10-DIHYDRO-9,10-ETHANOANTHRACENE-1-CARBOXYLIC MFCD00213638

<Tb>
<tb> HYDRAZIDE
<tb> 4-CYANO-5-METHYL-3-ISOTHIAZOLYLTHIOACETIC <SEP> HYDRAZIDE <SEP> MFCD00214720
<tb> 3- (4-FLUOROBENZYLOXY) THIOPENE-2-CARBOHYDRAZIDE <SEP> MFCD00215161
<tb> 3- (BENZYLOXY) THIOPENE-2-CARBOHYDRAZIDE <SEP> MFCD00215166
<tb> 3- (4-METHYLBENZYLOXY) THIOPENE-2-CARBOHYDRAZIDE <SEP> MFCD00215167
<tb> 3- (2,4-DICHLOROBENZYLOXY) THIOPENE-2-CARBOHYDRAZIDE <SEP> MFCD00215168
<tb> 3- (3-TRIFLUOROMETHYLBENZYLOXY) THIOPENE-2- <SEP> MFCD00215180
<tb> CARBOHYDRAZIDE
<tb> O- (2,4-DICHLOROBENZYL) MALONIC <SEP> HYDRAZIDE <SEP> ALDOXIME <SEP> MFCD00215353
<tb> 2- (5-PHENYLTETRAZOLO) ACETHYDRAZIDE <SEP> MFCD00215520
<tb> M-MALEIMIDOBENZOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> HCL <SEP> MFCD00216008
<tb> 3- (4-HYDROXYPHENYL) PROPIONIC <SEP> ACID <SEP> HYDRAZIDE <SEP> HCL <SEP> MFCD00216009
<tb> 2- [2- (TRIFLUOROMETHYL) QUINOL-4-YLTHIO] ACETIC <SEP> MFCD00219658
<tb> ACIDHYDRAZIDE
<tb> 3-METHYL-4-NITROBENZHYDRAZIDE <SEP> MFCD00220059
<tb> 2,5-BIS (2,2,2-TRIFLUOROETHOXY) BENZOIC <SEP> ACIDHYDRAZIDE <SEP> MFCD00221192
<tb> TRIFLUOROACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00221440
<tb> 2- (TRIFLUOROMETHYL) BENZOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00221473
<tb> 3- (TRIFLUOROMETHYL) BENZOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00221476
<tb> 2- (5,7-DIBROMO-QUINOLIN-8-YLOXY) -ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00222142
<tb> 1-HYDRAZINOCARBONYLMETHYL-4-METHYL-QUINOLINIUM, <SEP> MFCD00222339
<tb> CHLORIDE
<tb> 2-METHYL-PYRIMIDINE-5-CARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00223569
<tb> 5-METHOXY-PYRIMIDINE-2-CARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00223629
<tb> 2-METHYL-PYRIMIDINE-4-CARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00223633
<tb> 2- (6-METHYL-2-METHYLSULFANYL-PYRIMIDIN-4-YLOXY) -ACETIC <SEP> MFCD00224466
<tb> ACID <SEP> HYDRAZIDE
<tb> 2- (2-BENZYLSULFANYL-6-METHYL-PYRIMIDIN-4-YLOXY) -ACETIC <SEP> MFCD00224467
<Tb>

<Desc / Clms Page number 29>

<Tb>
<tb> ACID <SEP> HYDRAZIDE
<tb> 2- (2-BENZYLAMINO-6-METHYL-PYRIMIDIN-4-YLOXY) -ACETIC <SEP> MFCD00224469
<tb> ACID <SEP> HYDRAZIDE
<tb> 2- (6-METHYL-2-PIPERIDIN-1-YL-PYRIMIDIN-4-YLOXY) -ACETIC <SEP> MFCD00224470
<tb> ACID <SEP> HYDRAZIDE
<tb> 2- (6-METHYL-2-MORPHOLIN-4-YL-PYRIMIDIN-4-YLOXY) -ACETIC <SEP> MFCD00224471
<tb> ACID <SEP> HYDRAZIDE
<tb> 3-HYDRAZINOCARBONYL-1-METHYL-PYRIDINIUM, <SEP> IODIDE <SEP> MFCD00225323
<tb> 2- (2-METHYL-BENZO-IMIDAZOL-1-YL) -ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00227235
<tb> (3-HYDRAZINOCARBONYL-PROPIONYL) -CARBAMIC <SEP> ACID <SEP> ETHYL <SEP> MFCD00229278
<tb> ESTER
<tb> 2- (4-FLUOROPHENYLSULPHONAMIDO) ACETIC <SEP> HYDRAZIDE <SEP> MFCD00232501
<tb> Z-SER <SEP> (TBU) -NHNH2 <SEP> MFCD00237365
<tb> ZHIS-LYS (BOC) -NHNH2 <SEP> MFCD00238465
<tb> 3- (N, N-DIMETHYLAMINO) BENZHYDRAZIDE <SEP> MFCD00238588
<tb> 2- (3-CHLORO-5-TRIFLUOROMETHYL-2-PYRIDYL) PROPIONIC <SEP> MFCD00244378
<tb> HYDRAZIDE
<tb> 3- (3,5-DIOXO-2,3,4,5-4H- (1,2,4) TRIAZIN-6-YLAMINO) -PROPIONIC <SEP> MFCD00267697
<tb> ACID <SEP> HYDRAZIDE
<tb> 2- (3,5-DIOXO-2,3,4,5-TETRAHYDRO- (1,2,4) TRIAZIN-6-YLAMINO) - <SEP> MFCD00267698
<tb> ACETIC <SEP> ACID <SEP> HYDRAZIDE
<tb> 3-BROMO-4-CHLOROBENZHYDRAZIDE <SEP> MFCD00270094
<tb> 4-BROMO-2-CHLOROBENZHYDRAZIDE <SEP> MFCD00270095
<tb> 4-BROMO-3-CHLOROBENZHYDRAZIDE <SEP> MFCD00270096
<tb> 3-IODOBENZHYDRAZIDE <SEP> MFCD00270106
<tb> 4-IODOBENZHYDRAZIDE <SEP> MFCD00270107
<tb> 2-PHENYLBENZHYDRAZIDE <SEP> MFCD00270122
<tb> ACETHYDRAZIDE <SEP> PYRIDINIUM <SEP> CHLORIDE
<tb> MFCD00272258
<tb> CBZ-DL-PHE-GLY-GLY <SEP> HYDRAZIDE <SEP> MFCD00272795
<tb> CBZ-L-LEU <SEP> GLY <SEP> HYDRAZIDE <SEP> MFCD00272856
<tb> 9,10-DIHYDROXY <SEP> STEARIC <SEP> HYDRAZIDE <SEP> MFCD00272898
<tb> 1-PYRENEBUTANOIC <SEP> ACID, <SEP> HYDRAZIDE <SEP> MFCD00467260
<tb> 2-ACETAMIDO-4-MERCAPTOBUTANOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00467314
<tb> 3- (2-PYRIDYLDITHIO) <SEP> PROPIONIC <SEP> ACID <SEP> HYDRAZIDE <SEP> HCL <SEP> MFCD00467348
4,4-DIFLUORO-5,7-DIMETHYL-4-BORA-3A, 4A-DIAZA-S-INDACENE- SEP MFCD00467387
<tb> 3-PROPIONIC <SEP> ACID, <SEP> HYDRAZ
<tb> 4,4-DIFLUORO-5,7-DIPHENYL-4-BORA-3A, 4A-DIAZA-S-INDACENE- <SEP> MFCD00467394
<tb> 3-PROPIONIC <SEP> ACID, <SEP> HYDRAZ
<tb> 7-DIETHYLAMINOCOUMARIN-3-CARBOXYLIC <SEP> ACID, <SEP> HYDRAZIDE <SEP> MFCD00467583
<tb> MALEIMIDOPROPIONIC <SEP> ACID <SEP> HYDRAZIDE <SEP> HCL <SEP> MFCD00467760
<tb> 2- (2-NAPHTHOXY) ACETIC <SEP> HYDRAZIDE <SEP> MFCD00553736
<tb> 1,4,5,6-TETRAHYDRO-CYCLOPENTAPYRAZOLE-3-CARBOXYLIC <SEP> MFCD00611174
<tb> ACID <SEP> HYDRAZIDE
<tb> 4,5,6,7-TETRAHYDRO-1 <SEP> H-INDAZOLE-3-CARBOXYLIC <SEP> ACID <SEP> MFCD00611197
<tb> HYDRAZIDE
<tb> 3- (4-CYANOPYRAZOLE) CARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00663749
<tb> [4,5-BIS- (HYDROXYMETHYL) -4,5-DIHYDROISOXAZOLE-3- <SEP> MFCD00664160
<tb> CARBOXLIC <SEP> ACID <SEP> HYDRAZIDE] [1- (4-N)
<tb> 4,5-BIS (HYDROXYMETHYL) -3-HYDRAZIDO-4,5- <SEP> MFCD00664178
<tb> DIHYDROISOXAZOLE-1- (2- (3-CHLORO-5-TRIFLUO
<tb> 4,5-BIS (HYDROXYMETHYL) -3-HYDRAZIDO-4,5- <SEP> MFCD00664179
<tb> DIHYDROISOXAZOLE-1- (2-PYRIMIDYL) PIPERID-4
<tb> 4,5-BIS (HYDROXYMETHYL) -3-HYDRAZIDO-4,5- <SEP> MFCD00664180
<tb> DIHYDROISOXAZOLE-1- (2,6-DINITRO-4-TRIFLUO
<Tb>

<Desc / Clms Page number 30>

<Tb>
<tb> 3-CHLORO-5-TRIFLUOROMETHYL-2-PYRIDYLTHIO <SEP> ACETIC <SEP> MFCD00664272
<tb> HYDRAZIDE
<tb> 1- (2- (3-CHLORO-5-TRIFLUOROMETHYL) PYRIDYL] INDOLE-3 <SEP> MFCD00664547
<tb>ACETAHYDRAZIDE-N'-PHENYLTHIOSE
<tb> 5-DIMETHYLAMINOTETRAZOLE-1-ACETHYDRAZIDE <SEP> MFCD00664557
<Tb>

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

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

<Tb>
<tb> CARBOXYAMIDO-3-ISOXAZOLE
<tb> 3-ACETHYDRAZIDO-4- <SEP> MFCD00664748
<tb> (DIPHENYLMETHYLPIPERAZINO) CARBONYL-5-METHYL
<tb> ISOXAZOLE
<tb> 3-CYANO-5-METHOXY-2-METHYL-BENZOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00666525
<tb> BICYCLO [5.2.0] NONANE-2-CARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00666528
<tb> N-HYDRAZINOCARBONYLMETHYL-2-PHENOXY-ACETAMIDE <SEP> MFCD00667228
<tb> 2-CHLORO-N- (4-HYDRAZINOCARBONYL-PHENYL) -ACETAMIDE <SEP> MFCD00667230
<tb> 4-BROMO-N-HYDRAZINOCARBONYLMETHYL-BENZAMIDE <SEP> MFCD00667241
<tb> 2- (BENZOTHIAZOL-2-YLSULFANYL) -N- (4-HYDRAZINOCARBONYL- <SEP> MFCD00667249
<tb> ME-THIAZOL-2-YL) -ACETAMIDE
<tb> PENT-3-ENOIC <SEP> ACID <SEP> HYDRAZINOCARBONYLMETHYL-AMIDE <SEP> MFCD00667262
<tb> 3BETA-HYDROXY-DELTA5-ETIOCHOLANIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00670863
<tb> 4-BROMO-3-METHYLBENZOIC <SEP> HYDRAZIDE <SEP> MFCD00672945
<tb> 2,5-DIBROMOBENZOIC <SEP> HYDRAZIDE <SEP> MFCD00672991
<tb> 3,4-DIFLUOROBENZOIC <SEP> HYDRAZIDE <SEP> MFCD00672992
<tb> 3,5-DIBROMO-4-METHYLBENZOIC <SEP> HYDRAZIDE <SEP> MFCD00672993
<tb> 1- (6-CHLORO-3-PYRIDAZINYL) -4-PIPERIDINECARBOHYDRAZIDE <SEP> MFCD00794640
<tb> N1- (2 - [[3-CHLORO-5- (TRIFLUOROMETHYL) -2- <SEP> MFCD00794671
<tb> PYRIDYL] AMINO] ETHYL) -N1- <SEP> [[3- (HYDRAZINOCAR
<tb> 3 - [[(4-CHLOROPHENYL) SULFONYL] METHYL] -4-NITRO-1- <SEP> MFCD00794694
<tb> BENZENECARBOHYDRAZIDE
<tb> 5-HEX-1 <SEP> -YN-YLPYRIDINE-3-CARBOXHYDRAZIDE <SEP> MFCD00830971
<tb> CIS-CYCLOPROPANE-1,2-DICARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00831969
<tb> 3,4-DICHLOROPHENYLACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00833407
<tb> 3,5-DICHLOROBENZOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD00833411
<tb> 3-PHENYL-1 <SEP> H-INDOLE-2-CARBOHYDRAZIDE <SEP> MFCD00974217
<tb> BENZYL <SEP> N- [2-HYDRAZINO-1- (1H-IMIDAZOL-2-YLMETHYL) -2- <SEP> MFCD00974982
<tb> OXOETHYL] CARBAMATE
<tb> 5-OXO-5,6,7,8-TETRAHYDROIMIDAZO [1,2-C] PYRIMIDINE-7- <SEP> MFCD00974983
<tb> CARBOHYDRAZIDE
<tb> TRANS <SEP> CYCLOPROPYL-1,2-DICARBOXYLIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD01073574
<tb> HYDRATE
<tb> 1-METHYLCYCLOPROPYL-1,2-DIBENZOIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD01073578
<tb> HYDRATE
<tb> 1-METHYL-2,3-TRANS-CYCLOPROPANEDICARBOXYLIC <SEP> ACID <SEP> MFCD01073596
<tb> HYDRAZIDE
<tb> 5 - (((2- (CARBOHYDRAZINO) METHYL) THIO) ACETYL) AMINOEOSIN <SEP> MFCD01073636
<tb> 5-BENZYLOXYINDOLE-3-ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD01074492
<tb> 5-BROMOINDOLE-3-ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD01074493
<tb> 5-FLUOROINDOLE-3-ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD01074504
<tb> 5-METHOXYINDOLE-3-ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD01074508
<tb> 5-METHOXY-2-METHYLINDOLE-3-ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD01074511
<tb> 5-METHYLINDOLE-3-ACETIC <SEP> ACID <SEP> HYDRAZIDE <SEP> MFCD01074516
<tb> ISONIAZID, <SEP> [CARBONYL-14C] MFCD01075914
<tb> 3-PHENOXYBENZHYDRAZIDE <SEP> MFCD01090945
<Tb>

<Desc / Clms Page number 31>

y6 i 9G R, 9G cmmpou Rdt compos6 Rdt compos Rdt 3a-3c: 3cI-3f 2s, 3 a T11 95 2d, 3d V~ 50 2gg 3S si 2a,3a 2d,3d 2.31 2b. 3b 89 2c, 3e 83 2h, 3h 92 2c, 3c 86 21. 3f 76 2i, 3i 90TABLE 2: SYNTHESIS OF SUBSTITUTED OXADIAZOLINONES

y6 i 9G R, 9G cmmpou Composed Rdt compos Ytd 3a-3c: 3cI-3f 2s, 3a T11 95 2d, 3d V ~ 50 2gg 3S if 2a, 3a 2d, 3d 2.31 2b. 3b 89 2c, 3e 83 2h, 3h 92 2c, 3c 86 21. 3f 76 2i, 3i 90

Claims (19)

 1. Combinatorial library of compounds, characterized in that it comprises substituted derivatives of oxadiazolinones and / or oxadiazolinthiones. 2. Combinatorial library according to claim 1, characterized in that it comprises a plurality of compounds of general formula (I) below:

 wherein R1 is a hydrogen atom or a first substituent; and A is selected from the groups:

 wherein R2 represents a hydrogen atom or a second substituent; R3 represents a hydrogen atom or a third substituent, and X represents 0 or S, at least one of the substituents R1, R2 and R3 being different from H. 3. Combinatorial library of compounds according to claim 2, characterized in that it comprises a plurality of compounds of general formula (II):

<Desc / Clms Page number 33>  wherein R1 is a hydrogen atom or a first substituent; R2 is a hydrogen atom or a second substituent, and X is an oxygen or sulfur atom, at least one of 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 R 1 and R 3 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. <Desc / Clms Page number 34> 8. Combinatorial library according to any one of claims 2 to 7, characterized in that the first, second and / or third substituent comprises one or more aromatic groups, heterocyclic, alkyl (saturated or unsaturated), acyl, alcohol, phenol, (thio) ether, acid, ester, nitrile, amine, ammonium, nitro, aldehyde, ketone and / or halogen. The combinatorial library of compounds according to claim 2, wherein each compound has the general formula (I). The combinatorial library of compounds according to claim 3, wherein each compound has the general formula (II). The combinatorial library of compounds according to claim 6, wherein each compound has 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. <Desc / Clms Page number 35>  A process for the preparation of a library of compounds according to any one of the preceding claims, comprising a first step of synthesis of a mono-substituted oxadiazolinone or oxadiazolinthione carrying the substituent R 1 and, if appropriate, a second combinatorial step of substitution of the products monosubstituted by R2 or R3. 15. A method of searching for active products, characterized in that it comprises a step in which a library according to claim 1 is tested. 16. Process for optimizing active products, characterized in that it comprises a step in which a library according to claim 13 is tested. 17. Use of substituted derivatives of oxadiazolinones and / or oxadiazolinthiones for the generation of combinatorial, diverse or focused 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 compound library according to one of claims 1 to 13.