EP2069345A2 - Pyridazin- und pyrrolverbindungen, verfahren zu ihrer gewinnung und verwendung - Google Patents

Pyridazin- und pyrrolverbindungen, verfahren zu ihrer gewinnung und verwendung

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Publication number
EP2069345A2
EP2069345A2 EP07823344A EP07823344A EP2069345A2 EP 2069345 A2 EP2069345 A2 EP 2069345A2 EP 07823344 A EP07823344 A EP 07823344A EP 07823344 A EP07823344 A EP 07823344A EP 2069345 A2 EP2069345 A2 EP 2069345A2
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European Patent Office
Prior art keywords
bis
pyridin
group
formula
pyridine
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EP07823344A
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French (fr)
Inventor
Didier Max Dubreuil
Muriel Geneviève PIPELIER
Jean Paul Pradere
Hicham Bakkali
Patrice Lepape
Thierry Delaunay
Alexandra Tabatchnik
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Centre National de la Recherche Scientifique CNRS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/22—Tin compounds
    • C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B57/00—Other synthetic dyes of known constitution
    • C09B57/10—Metal complexes of organic compounds not being dyes in uncomplexed form

Definitions

  • the present invention relates to nonlinear oligopyridazine compounds, processes for obtaining them, their applications, as well as their regression in oligopyrroles and to the applications of the pyridazinyl-pyrrole and oligopyrrole compounds obtained.
  • oligopyridazine and oligopyrrole denote compounds comprising a series of nitrogen rings of pyridazine or pyrrole type, said sequence being composed of two symmetrical or non-symmetrical parts, connected by a heterocyclic spacer group (s) or a heteroatom. In the present application, these terms will be further limited to the compounds according to the invention, which have a strictly defined structure.
  • Oligopyridines are polydentate ligands which can also be classified according to the number of nitrogen atoms involved in the metal chelation in the complex: bidentates (bipyridines), tridentates (terpyridines), tetradentates (quaterpyridines), etc., of structure
  • the 2, 2'-bipyridines have long been the most used ligands in coordination chemistry, especially when they express asymmetric induction properties related to the presence of groups inducing a chirality factor. More recently, the 2,2 ': 6', 2 '' -terpyridines (tpy) have opened an investigation field by the expression of polydentate sites favoring the formation of complexes with transition metals of higher oxidation state. . This property has been exploited, for example, for the oxidation of alcohols and the carbonylation of aromatic compounds. More recently, the chemistry of this type of polydentate ligand has been developed for catalytic activation in the context of the decontamination of radioactive waste.
  • 6,6'-bis (6-methyl-pyridin-2-yl) -3,3'-bipyridazine 2 has also shown a high potential for supramolecular organization in the presence of various metals, such as silver (I (Baxter, PNW, Lehn, J. -M., Fisher, J., Youinou, M, -T Angew Chem 1994, 106, 2432).
  • this tetramer preferentially leads to a supramolecular arrangement of square grid type, as is the case for bipyridazine 2.
  • the elongation of the pyridazine chain also allows in this case a self-assembly of four monomers leading to a helical organization formed of a tetramer in equilibrium with the square grid.
  • oligopyridazine compounds could be feasible under conditions to be determined, despite the presence of several pyridazine rings within the same molecule, said cycles being capable of considerably modifying its structure and its electronic properties.
  • a second step the reduction of pyridazine sequences in oligopyrroles could be attempted.
  • this reduction is not only effective under specific conditions developed and optimized by the inventors, but in addition, it does not give rise to a cyclization between the pyridazine residues or any other potential side reactions.
  • the reduction can also take place pyridazine ring by pyridazine cycle to obtain a single or more site (s) of reduction on the molecule, thus opening the way to the preparation of mixed pyridazinyl-pyrrole compounds.
  • the inventors have also sought to identify the potential biological applications of these novel compounds. These compounds were then found to have therapeutic properties of great interest, in particular anti-parasitic, anti-cancer and antibacterial.
  • the present invention therefore relates to non-linear oligopyridazine compounds, to their processes for their applications, as well as their reduction in oligopyrroles and the applications of the pyridazinyl-pyrrole and oligopyrrole compounds obtained.
  • the invention relates to compounds of formula
  • the groups A identical or different, represent a grouping
  • n is an integer equal to 1 or 2
  • Y represents an oxygen atom, sulfur atom, a methylene, hydroxymethylene, carbonyl, thiocarbonyl group or a group of formula
  • the groups R which may be identical or different, represent a hydrogen, an alkyl, alkylamine, hydroxyalkyl or alkyloxy chain of 1 to 6 carbons, a -COOH group, -CONH 2 group , COOR 2 group , -CONHR 2 group in which R 2 is an alkyl chain of 1 with 6 carbons or when the substituents R are identical in the 2-pyridinyl groups, the substituents R 2 may together form an etheric cyclic alkyl chain, with the exception of the compounds:
  • the alkyl, alkylamine, hydroalkyl and alkyloxy chains are methyl, methylamine, hydroxymethyl and methoxy
  • the etheric cyclic chain is of the -C 2 H 5 - (O-C 2 H 5 -) p / p type which can be between 1 and 4, terminals included.
  • Y will represent an oxygen atom, sulfur atom or a group of formula
  • R which are identical or different, will represent a hydrogen, an alkyl or alkyloxy chain of 1 to 6 carbons, a -COOH group, -COOR 2, in which R 2 is an alkyl chain of 1 to 6 carbons.
  • R1 represents a hydrogen, an alkyl or alkyloxy chain of 1 to 6 carbons
  • Z 1 represents a mercapto group or a group SnE 3 , in which E represents a methyl, butyl or phenyl chain, or, when n is an integer equal to 2, the groups A, which are identical or different, represent a grouping
  • R1 represents a hydrogen, an alkyl or alkyloxy chain of 1 to 6 carbons - Z 1 represents a halogen, an alkyl or alkyloxy chain of 1 to 6 carbons, a hydroxyl, mercapto or SnE 3 group , in which E is as defined herein; beforehand, with the exception of 3-chloro-6- [6- (6-methyl-pyridin-2-yl) -pyridazin-3-yl] -pyridazine.
  • the precursors will have identical A groups, and Z 1 will be halogen or alkoxy, SnE 3 , hydroxy or mercapto.
  • the invention relates to processes for preparing said precursors.
  • a first process for the preparation of precursors makes it possible to prepare the compounds of general formula
  • G represents a halogen
  • D is as defined above and m is an integer between 1 and 3 inclusive
  • a stoichiometric mixture of zinc, dibromobis (triphenylphosphine) nickel and iodide of tetrabutylammonium in dimethylformamide distilled and degassed in which G represents a halogen, D is as defined above and m is an integer between 1 and 3 inclusive
  • This method has the advantage of allowing incrementation of the number of pyridazine rings in the molecule.
  • the purification step is necessary in order to decomplex the reaction product from the reaction medium.
  • This purification process can be carried out according to two distinct procedures:
  • the process for purifying the compounds is carried out by decomplexing said compounds in a saturated aqueous solution of potassium cyanide or cold sodium for about 1H30 to 4H, preferably of the order of 2h to 3h.
  • Cold means temperatures ranging from 0 to 25 0 C, preferably of the order of 18 to 20 0 C.
  • the process for purifying the compounds is carried out by decomplexing said compounds in a saturated aqueous solution of potassium halide or of tetrabutylammonium halide, preferably potassium fluoride, or in a saturated solution of ammonia, the organic phase being then washed with sodium hydrogencarbonate or potassium, and then extracted with chloroform, dichloromethane, ethyl acetate or ether ...
  • n2 is an integer between 1 and 4 inclusive
  • the groups X 1, identical or different, represent an alkyl or alkyloxy chain of 1 to 6 carbons, or a group selected from the following groups:
  • R is hydrogen, alkyl or alkyloxy chain of 1 to 6 carbons or phenyl.
  • Z 2 , Z 3 different, represent either a halogen or a stannyl group of formula SnE 3 , wherein E represents a methyl, butyl or phenyl chain, and X 1 is as defined above in connection with the formula (XXIa).
  • This process allows the coupling of end groups on oligopyridazine compounds.
  • the inventors therefore propose a process for electrochemically homocoupling a pyridazine pyridine with the formula
  • n 1 or 2
  • G is halogen and X 2 is a halogen, an alkyl or alkyloxy chain of 1 to 6 carbons, a group selected from the following groups: in which R represents a hydrogen, an alkyl or alkyloxy chain of 1 to 6 carbons or a phenyl, the conditions of the electrolysis being as follows: the anode consists of at least 50% iron,
  • the electrolysis medium comprises nickel, an element chosen from halogens, and pyridine or its derivatives.
  • the anode used is a Fe / Ni anode (64/36).
  • the solvent of the reaction advantageously comprises at least 50% of DMF and a polar co-solvent.
  • a polar co-solvent for example, it is possible to use a mixture of dimethylformamide (DMF) and pyridine, in a ratio ranging from 90/10 to 50/50 inclusive, preferably 80/20.
  • the catalyst used is preferably a nickel complex, such as a hydrated nickel halide.
  • a nickel-bipyridine halide may advantageously be used as catalyst.
  • the support electrolyte is preferably a tetrabutylammonium halide or an equivalent such as tetrabutylammonium tetrafluoroborate, advantageously in amounts ranging from about 10 to 20 mol% inclusive, preferably 13 to 17%, with respect to the pyridazine substrate. .
  • the intensity used during the reaction is for example of the order of 0.05A to 0.2A, inclusive limits, of preferably 0.06A to 0.1A.
  • the reaction can be carried out at ambient temperature (of the order of 18-25 ° C.).
  • the inventors also propose a process for the electrochemical heterocoupling of a pyridazine pyridine with the formula
  • n is an integer of 1 or 2
  • G is halogen
  • G is an alkyl or alkyloxy chain of 1 to 6 carbons or a carbonyl group of the following groups:
  • R represents hydrogen, an alkyl or alkyloxy chain of 1 to 6 carbons, with an aromatic halide of formula Ar-G, wherein X is as defined previously and Ar represents an aromatic ring of 5 or 6 optionally substituted, the conditions of the electrolysis being as follows:
  • the anode is made of iron.
  • the catalyst is chosen from nickel bipyridine halides.
  • the solvent used is DMF while the supporting electrolyte is a tetrabutylammonium halide or an equivalent such as tetrabutylammonium tetrafluoroborate in amounts ranging from about 10 to 20 mol%, inclusive, preferably from 13 to 20%. at 17%, relative to the pyridazine substrate.
  • the intensity implemented during the reaction is from 0.15 to 0.35A inclusive, preferably of the order of 0.2A.
  • the reaction can be carried out at ambient temperature (of the order of 18-25 ° C.).
  • the aromatic ring is preferably a phenyl, pyridinyl or thiophenyl ring, optionally monosubstituted.
  • J represents halogen or methoxy
  • the compounds of formula (XV) may alternatively be prepared from 3-acetyl-6- (pyridin-2-yl) -pyridazine, itself obtained from 3-chloro (Pyridin-2-yl) pyridazine.
  • glyoxylic acid is then condensed on 3-acetyl-6- (pyridin-2-yl) -pyridazine in the presence of potassium carbonate, and then the intermediate obtained is treated in acetic acid medium and in the presence of hydrazine monohydrate.
  • n is an integer equal to 1 or 2
  • the groups R 1, which are identical or different, represent a hydrogen, an alkyl or alkyloxy chain of 1 to 6 carbons, are obtained by reacting phosphorus pentasulfide with the compound of formula
  • the invention also relates to the process for preparing compounds of formula
  • R 1 which are identical or different, represent a hydrogen, an alkyl or alkyloxy chain of 1 to 6 carbons
  • E represents a methyl, butyl or phenyl chain
  • Another precursor of interest synthesized by the inventors is 6, 6'-bis-tributylstannyl-2,2'-bipyridine.
  • This compound is obtained by reaction of 6, 6'-dihalogeno-2,2'-bipyridine with hexabutyldistannate in the presence of palladium (0) at a temperature of approximately 90-110 ° C.
  • La 6, 6 '- dihalo-2, 2 '- bipyridine has been described in Nakhmanovich et al., Synthetic Metal, 1997, 84: 883-884.
  • the pyrrole precursors can be obtained by pyrrole reduction of the corresponding pyridazine compounds.
  • ni is an integer between 2 and 4 inclusive terminals
  • the groups X 1 identical or different, represent an alkyl or alkyloxy chain of 1 to 6 carbons or a group chosen from the following groups:
  • R represents a hydrogen, an alkyl or alkyloxy chain of 1 to 6 carbons, or a phenyl, electrochemically, by extrusion of a nitrogen atom on one or more pyridazine ring (s), wherein the conditions of electrolysis are as follows:
  • the anode is a large surface electrode, -
  • the electrolysis medium is a proton - donating polar medium.
  • the compounds according to the invention can be synthesized. According to a fourth aspect of the invention, it relates to the processes for preparing the compounds according to the invention using the precursors described above.
  • the invention thus proposes, in particular, a process for the preparation of compounds of formula
  • n is an integer equal to 1 or 2
  • Y 1 represents an oxygen or a sulfur
  • the groups X 3 which are identical or different, represent a hydrogen or a substituent of formula
  • the temperature of the reaction is preferably between 80-110 0 C inclusive.
  • the following strong bases will be used: NaH, NaOH, and as a solvent, DMF or DMSO.
  • Y 1 represents an oxygen or a sulfur
  • n is an integer equal to 1 or 2
  • the groups R 1, which are identical or different, represent a hydrogen, an alkyl or alkyloxy chain of 1 to 6 carbons
  • the groups A are identical.
  • the invention further provides a process for the preparation of the compounds of formula
  • Y 2 represents a group of formula
  • n is an integer equal to 1 or 2
  • the groups R 1, which are identical or different, represent a hydrogen, an alkyl or alkyloxy chain of 1 to 6 carbons, by coupling Stille between a compound of formula
  • Z 2 and Z 3 represent either a halogen or a stannyl group of formula SnE 3 , in which E represents a methyl, butyl or phenyl chain and Y 2 , R 1, n as defined above.
  • the invention provides a process for the preparation of compounds of formula
  • Y 3 represents a methylene, hydroxymethylene, carbonyl or thiocarbonyl group n is an integer equal to 1 or 2, the groups R 1, which are identical or different, represent a hydrogen, an alkyl or alkyloxy chain of 1 to 6 carbons, by coupling of two organomagnesium compounds or organocuprates of formula
  • Z 4 represents MgG or Cu, G being halogen, in the presence of methylformate, carbonyldiimidazole or thiocarbonyldiimidazole.
  • organomagnesium and organocuprate derivatives is well known to those skilled in the art.
  • the conventional reaction uses the halogenated compound corresponding to the desired organomagnesium / organocuprate compound.
  • the insertion of magnesium or copper in the compound is carried out by adding magnesium or copper halide (CuI, CuCl) in the reaction medium, in the presence of solvent such as, for example, Et 2 O or THF.
  • solvent such as, for example, Et 2 O or THF.
  • This reaction preferably implements two equivalents of glyoxylic acid.
  • the base may be selected from potassium carbonate or potassium hydroxide. This reaction is preferably carried out at ambient temperature (of the order of 18-25 ° C.).
  • 2,6-bis (6-halo-pyridazin-3-yl) -pyridine is obtained by halogenation with phosphorus oxyhalide of the 2,6-bis (6-2H-pyridazine) compound. 3-one) - pyridine. This reaction is advantageously carried out at a temperature of the order of 80 to 110 ° C.
  • 2,6-bis (pyridazin-3-yl) pyridine is prepared by reducing the halogen functions of 2,6-bis (6-halopyridazin-3-yl) pyridine by catalytic hydrogenation.
  • This latter reaction is catalyzed by palladium on carbon under a dihydrogen atmosphere.
  • the solvent used is ethanol. This reaction can be carried out at room temperature.
  • the invention also relates to a method of condensation-aldolization in a basic medium of glyoxylic acid on the compound of formula
  • R 3 represents a hydrogen, an alkyl chain of 1 to 6 carbons, a -COCH 3 group, characterized in that the base used is potassium carbonate, introduced in an amount of at least three equivalents of said carbonate relative to the compound of formula (XIV).
  • the weak bases may be chosen from calcium carbonate or potassium carbonate.
  • the reaction can be conducted at room temperature.
  • the invention further provides a process for preparing a compound
  • n is an integer equal to 1 or 2
  • Y represents an oxygen atom, sulfur atom, a methylene, hydroxymethylene, carbonyl, thiocarbonyl group or a group of formula
  • the groups T identical or different, represent a hydrogen, an alkyl chain of 1 to 6 carbons,
  • the solvent will be THF or ether, the zinc reagent, ZnCl 2 and palladium (o) (Pd (Ph 3 ) 4 ) or palladium dibenzylidene acetone (Pd 2 dba 3 ).
  • this relates to a process for oligopyrrole reduction of oligopyridazines according to the invention.
  • Y 4 represents a methylene group or a group of formula
  • V n is an integer equal to 1 or 2
  • the groups X 4 which are identical or different, represent a hydrogen, a hydroxyl group, a mercapto group or a substituent of formula
  • the groups R which are identical or different, represent a hydrogen, an alkyl or alkyloxy chain of 1 to 6 carbons, or a phenyl, electrochemically, by extrusion of a nitrogen atom over one or more rings pyridazine (s), the conditions of the electrolysis being as follows:
  • the anode is a large surface electrode
  • the electrolysis medium is a polar proton donor medium.
  • Y 4 is
  • R1 is methyl or methoxy
  • the polar proton donor medium may consist of an organic polar solvent (such as
  • a proton donor such as phenol, acetic acid, etc.
  • a carrier electrolyte such as quaternary ammonium salts or an aqueous alcoholic acid medium.
  • the quaternary ammonium salts are chosen from tetrabutylammonium hexafluorophosphate or tetrabutylammonium hydrogensulfate and.
  • the alcoholic acid medium is constituted by a sulfuric acid or acetic acid mixture supplemented with ethanol.
  • the cathode is chosen from mercury layer electrodes with a diameter of 4.5 cm, large surface carbon electrodes or screen printed carbon electrodes.
  • the intensity used is of the order of 10 to 5OmA.
  • the reaction is carried out at ambient temperature (of the order of 18-25 ° C.).
  • the imposed reduction potential which varies according to the substrates studied must be controlled, in order to control the quantity of Coulomb consumed during the electrolysis, ie the number of electrons used: 4 for the monopyrrole and 8 for the bipyrrole, etc.
  • the aim was to evaluate the influence of the possible formation of a first pyrrole or a dihydropyridazine intermediary on the reduction potential of the systems. mixed then generated.
  • regression we mean two acid reduction steps, regression being the mechanistic result of electrochemical reductions.
  • the work of the inventors has made it possible to establish a protocol adapted to the reduction of oligopyridazine compounds and to demonstrate the sequential character of this reduction being simultaneous according to the number of electrons and the potential applied during the electroreduction.
  • alkyl and alkyloxy chains having 1 to 6 carbons contain 1 to 3 carbons, preferably they are methyl, ethyl, methoxy or ethoxy.
  • the invention aims to cover the multiple applications of the synthesized compounds.
  • the alkyl, alkylamine, hydroalkyl and alkyloxy chains are methyl, methylamine, hydroxymethyl and methoxy
  • the etheric cyclic chain is of the type -C 2 H 5 - (O-C 2 H 5 -Jp, p being such that previously defined.
  • Y will represent an oxygen atom, sulfur atom or a group of formula
  • R which are identical or different, will represent a hydrogen, an alkyl or alkyloxy chain of 1 to 6 carbons, a -COOH group, -COOR 2, in which R 2 is an alkyl chain of 1 to 6 carbons.
  • the compounds according to the invention are ligands which complex particularly well metal ions, in particular the iron, copper, ruthenium, europium, silver and bismuth type cations. They can be used alone or alternatively, several identical ligands can be used in combination with each other. Examples of non-limiting ligands are metallocatenanes formed from compounds according to the invention.
  • the inventors have also researched the possible biological properties of their compounds and demonstrated therapeutic properties of interest.
  • the invention therefore relates to the compounds according to the invention for use as a medicament, and their use as active principle in therapeutic compositions.
  • the compounds according to the invention have several biological applications that can lead to therapeutic applications.
  • the compounds according to the invention can be used for obtaining a medicament intended to treat parasitic diseases.
  • the parasitic diseases targeted by the invention are in particular leishmaniases, aspergillosis and candidiasis.
  • Y represents a sulfur atom, or a group of formula
  • R which are identical or different, represent a hydrogen, an alkyl chain of 1 to 6 carbons, a -COOH group, -COOR 2, in which R 2 is an alkyl chain of 1 to 6 carbons.
  • these compounds according to the invention exhibit a cytotoxic activity with respect to cancer cells. They are therefore particularly suitable for the preparation of anticancer drugs.
  • the cancer targeted by the invention is a carcinoma, for example an ENT carcinoma, lungs, uterus, digestive (esophagus, colon, liver), skin, breast, prostate, ovaries.
  • a carcinoma for example an ENT carcinoma, lungs, uterus, digestive (esophagus, colon, liver), skin, breast, prostate, ovaries.
  • group A represents a grouping
  • Y represents a group of formula
  • R represents a hydrogen, an alkyl or alkyloxy chain of
  • the compounds according to the invention are suitable for the preparation of antibacterial drugs, for example for the treatment of dysentery or meningitis.
  • some of the compounds according to the invention are vectors of radioactive metals of great interest in the context of radioligands. Therefore, when complexed to the appropriate metal, such as bismuth or europium, they allow to obtain a drug for radioimmunotherapy.
  • the groups R which may be identical or different, represent a group -COOR 2 or -CONHR 2 in which the substituents R 2 together form an ether cyclic alkyl chain, if the groups A represent a grouping
  • the groups R which are identical or different, represent a hydrogen, an alkyl, alkylamine, hydroxyalkyl or alkyloxy chain of 1 to 6 carbons, a -COOH group, -CONH 2 group , -COOR 2 group , -CONHR 2 group in which R 2 is an alkyl chain of 1 with 6 carbons or when the substituents R are identical in the X 7 groups, the substituents R 2 may together form an etheric cyclic alkyl chain.
  • the ethereal cyclic alkyl chain is a chain of the -C 2 H 5 - (O-C 2 H 5 -) P , p type as defined above.
  • These compounds are tridentate or tetradentate, mixed N, O or N-donor ligands. They are therefore particularly suitable for complexing metal ions.
  • the compounds according to the invention can selectively complex nucleic acids.
  • they can be used as selective complexing agents of DNA and RNA, including that of HIV. They act on the reverse transcriptase of cells, by inhibiting its primer on viral RNA. They are therefore particularly suitable for the preparation of anti-viral drugs.
  • These compounds can also be used as DNA cleavage agents (metallo-nuclease, particularly when complexed to a Cu-type metal, for example).
  • the inventors have also defined applications in the field of the environment, materials and electronics.
  • the invention therefore also relates to the use of the compounds according to the invention for the depollution of cations in liquid media.
  • the groups A identical or different, represent a grouping
  • n is an integer equal to 1 or 2
  • Y represents a group of formula
  • the groups R identical or different, represent a hydrogen, an alkyl or alkyloxy chain of 1 to 6 carbons, a group -COOH 7 -CONH 2 , -COOR 2 , -CONHR 2 in which R 2 is an alkyl chain of 1 to 6 carbons or when the R substituents are identical in the X groups, the R2 substituents may together form an etheric cyclic alkyl chain.
  • these compounds are particularly suitable for complexing metal ions. They may optionally be used alone or alternatively, several identical ligands may be used in combination with each other.
  • the compound will be selected from the following group: - 2,9-bis [5- (pyridin-2-yl) -pyrrol-2-yl)] -1,10-phenanthroline,
  • the above compounds will advantageously be used in combination with a carboxylic acid, in particular ⁇ -bromocapric acid.
  • a carboxylic acid in particular ⁇ -bromocapric acid.
  • the inventors have indeed found a synergy in the depollution activity when this specific combination was implemented with respect to the actinide cations particularly.
  • the invention also covers materials composed of a supramolecular organization of compounds according to the invention.
  • some of the compounds according to the invention possess self-assembly properties. Others can self-assemble around metal cations.
  • the invention also aims as such subgroups of compounds defined for different applications / uses as products.
  • FIG. 2 cyclic voltammograms during the preparative electrolysis of the 6, 6 '-bis (6 2-methylpyridin-2-yl) -3,
  • FIG. 8 is a 1 H NMR analysis of di- (6-pyridin-2-yl) -pyridazine thioether 11,
  • FIG. 11 is a voltammogram of the preparative electrolysis reaction of 6, 6 '-bis (4,6-dimethylpyridin-2-yl) - 3, 3'-bipyridazine 105
  • FIG. 12 shows the UV-Visible and fluorescence absorption spectra of 2,6-bis [6- (6-methyl-pyridin-2-yl) -pyridazin-3-yl). ] -pyridine 49
  • FIG. 13 shows the UV-Visible and fluorescence absorption spectra of 2,6-bis (5- (6-methylpyridin-2-yl) pyrrol-2-yl) pyridine 206
  • FIG. 14 shows the UV-Visible and fluorescence absorption spectra of 2,6-bis [6- (pyridin-2-yl) -pyridazin-3-yl] -pyridine 33
  • FIG. 12 shows the UV-Visible and fluorescence absorption spectra of 2,6-bis [6- (pyr
  • UV-Visible absorption spectra were recorded on a UV-240IPC Shimadzu spectrometer. Fluorescence spectra were recorded on an SPEX Fluoromax fluorometer. All spectra recorded by the devices described above were carried out in a UV-Visible quartz cell (lcm).
  • Mass Spectroscopy Mass spectra were recorded on a Thermoelectron DSQ instrument by electronic impact (70 eV), chemical ionization (ammonia), direct insertion or GC-MS coupling.
  • the compound to be reduced is dissolved either in a system of three solvents (THF / acetic buffer / CH 3 CN: 5/4/1), or in a solution of H 2 SO 4 at 0.5M and placed in the anode compartment of the electrochemical cell.
  • An identical solvent system is placed in the cathode compartment and the appropriate voltage is imposed until the passage of 8 electrons.
  • the organic phase is evaporated under vacuum if necessary.
  • the aqueous phase is then treated with a saturated solution of Na 2 CO 3 until an alkaline pH is obtained.
  • the medium is extracted with DCM, the organic phase is dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • the residue is purified by chromatography on a silica column (EP / AcOEt: the ratio depends on the compounds).
  • the synthetic route used also corresponds to route 4 of point 1.
  • the addition of an additional methyl substituent on the 6-methylpyridinyl group makes it possible to increase the solubility of the compound and thus to facilitate the electrochemical cycle regression.
  • This molecule has a high cytotoxic potential on KB cancer cells with an IC 50 of 0.3 ⁇ g / ml and also affects the tonB protein involved in the iron transport process used for the growth of bacteria.
  • the coupling of aromatic halides is possible thanks to an indirect electrolysis process catalyzed by nickel complexes.
  • the process employed is the consumable anode process.
  • the precursor of the catalyst is introduced in the form of nickel salts (NiBr 2 , xH 2 0) or by oxidation of a nickel-containing metal bar (stainless steel or Fe / Ni steel 64/36)
  • the material used is as follows:
  • the electrochemical cell consists of a glass wall terminating in its lower part by a screw thread on which is screwed a Bakelite base (black, SVL40) containing a seal. sealing.
  • SVL40 Bakelite base
  • four inputs type SVL 15 are placed around a central entrance SVL22 for adapting a metal bar that will play the role of anode.
  • the cathode consisting of a nickel foam (40 cm 2 ), is placed concentrically around the anode. The agitation of the solvent within the cell is provided by a magnetic bar.
  • the function of the various lateral inputs is to allow the electrical connection of the cathode by means of a stainless steel wire, to allow the entry and exit of a gas such as argon ensuring an inert atmosphere in the cell. electrochemical.
  • the fourth entry makes it possible to take samples or to add reagents into the reaction medium during electrolysis.
  • One of the inputs can, if useful, be used to place a reference electrode to measure the evolution of the potential of the cell during the reaction.
  • the cell is placed on a magnetic oil-stirrer bath, allowing possible heating, if necessary.
  • DMF is the solvent used in the process.
  • the medium is made conductive through the introduction of carrier electrolytes such as quaternary ammonium salts.
  • the power supply of the cell is ensured by a stabilized power supply which makes it possible to work under an intensiostatic regime of 10 to 300 mA.
  • the two reactions involved during electrolysis take place simultaneously.
  • the cathodic reaction concerns the reduction of the most easily reducible species which is in this case the catalyst precursor (nickel II salts). Nickel (II) is thus reduced to nickel (0) stabilized by ligands present in the medium (pyridine or bipyridine).
  • the counter-reaction is the oxidation of the metallic bar, made of iron or an iron / nickel alloy of composition 64/36.
  • the metal salts generated in the medium thus contribute to the smooth progress of the reaction.
  • the process involved around nickel (0) is presented in diagrams 1 and 2, according to the intensity imposed: strong (diagram 1) or weak (diagram 2).
  • the precursor of the catalyst used is the NiBr 2 Bipy complex (10%), and in the case of a Fe / Ni anode (64/36) the precursor of the catalyst is NiBr 2 (5 to 10%) and the ligand placed as co-solvent is pyridine.
  • 6,6'-Dimethoxy-3,3'-bipyridazine is the key intermediate for the synthesis of 6,6'-bisubstituted 3,3'-bipyridazine.
  • a simple and effective original synthesis of this intermediate has been developed electrochemically. This synthesis uses the consumable anode method described above and involves the homocoupling of 3-chloro-6-methoxypyridazine 14 through catalysis by the nickel complexes (Scheme I ').
  • the equipment used is that described in paragraph 1.
  • the anode is a Fe / Ni bar (64/36) and the cathode is a nickel foam (Goodfellow supplier).
  • the solvent is a DMF / pyridine 50/50 mixture and the carrier electrolyte consists of a mixture NBu 4 Br / NBu 4 I 1/1.
  • the reaction is conducted at room temperature under an argon atmosphere.
  • Pre-electrolysis in the presence of dibromoethane (300 ⁇ l) is carried out for 15 min at an intensity of 0.1 A in the absence of nickel (NiBr 2 , xH 2 0, 10%) and reagent (3-chloro-6-methoxypyridazine) .
  • N-N DMF N N X
  • FIG 4 The heterocouples were conducted, unlike homocoupling, at an intensity of 0.2 A.
  • the precursor of the catalyst is the NiBr 2 bipy complex added in a catalytic amount (10%).
  • the anode is iron (XClO, 0.1% carbon).
  • the solvent is DMF.
  • Table 1 Heterocoupling of aromatic halides with 3-chloro-6-methoxypyridazine.
  • R X or Aryl or other groupings
  • R ' R' e-, [Ni] e-, [Ni]
  • the first wave could correspond to a potential of a simultaneous reduction to two electrons (per pyridazine cycle), of the two symmetrical pyridazine groups of dimer 2 (4 electrons in total).
  • the formation of a bis-dihydropyridazine intermediate 68 could thus be envisaged and its regression in dipyrrole 71 should logically still require a contribution of at least four electrons per mole (two electrons per dihydro ring), for a total of eight electrons / mol from bipyridazine 2
  • This alternative offers the possibility of access to alternating pyridazine-pyrrole systems.
  • the preferred mechanism seems in fact to be the formation of a bis-1,2-dihydropyridazine 68 (resulting from a reduction to 4 electrons) which rearranges in an acidic medium in the pyrrole-pyridazine 70 mixed system.
  • the bipyrrole 71 results from a further 4-electron reduction of the remaining pyridazine.
  • the preparative electrolysis is carried out in a sulfuric acid medium (0.5 mol / l) / ethanol (proportion: 0.5 / 0.5) in a cell with two compartments separated by a sintered glass.
  • a sulfuric acid medium 0.5 mol / l
  • ethanol proportion: 0.5 / 0.5
  • anode compartment In the anode compartment is placed the anode, a plate stainless steel surface 15 cm 2 .
  • the cathode compartment are introduced the cathode a surface mercury layer 16 cm 2 and the reference electrode, the saturated calomel electrode.
  • the volume of solvent in the two compartments is 9OmL
  • the substrate is introduced into the cathode compartment (194 mg or 5.7 10-4 mol) and the potential applied at the beginning of electrolysis is -0.5V / ECS (potential reduction of the substrate), the corresponding intensity is 35 mA.
  • the bipyrroleic compound 112 was obtained with a yield close to 10%, as well as the monopyrrolic compound 107 and the tetrahydropyridazine compound 108.
  • the low yield obtained for the bipyrrole can be explained by its partial degradation in a concentrated H 2 SO 4 medium and by difficulties of purification by flash chromatography on silica gel.
  • the first four electron peaks are well defined and appear at potentials between -0.9 V and -1.1
  • the first bielectronic transfer makes it possible to generate the dihydropyridazine intermediates (1,2 or 1,4-dihydropyridazines according to their relative stability) and the second bielectronic transfer causes atom extrusion. of nitrogen by evolution of ammonia.
  • the potential to be imposed for the preparative electrolyses must therefore be at the level of the reduction waves corresponding at least to a reduction to four electrons.
  • the preparative electrolyses of the different pyridazines were carried out respectively at a working potential corresponding to the potential of the second wave of reduction of the precursors. These were continued until the total disappearance of the precursors and until the consumption of a quantity of charges (number of Coulombs) corresponding to the minimum quantity of electrons necessary to induce their rearrangement in pyrrole (four electrons per mole of the reduced substrate).
  • the decrease in the intensity of the precursor reduction wave (-1.08V) during preparative electrolysis is correlated with the transformation during electrosynthesis. In addition, it disappears completely at the end of the electrolysis thus making it possible to check the total consumption of the precursor.
  • the ligand 33 was synthesized via a double coupling of Stille, according to two different protocols (Rtrisyn ceremonies 2).
  • Lane A by the action of two equivalents of 2-tributylstannylpyridine 18 on the 2,6-bis (3-chloro-pyridazin-6-yl) -pyridine precursor 32.
  • Lane B by condensation of two residues of 3-tributylstannyl-6- (pyridin-2-yl) -pyridazine on 2,6-dibromo-pyridine 31.
  • a third path, c, alternative to path A, has also been developed, using Negishi coupling instead of Stille coupling.
  • the dicarboxylate precursor 35 was generated in situ by condensation of 2,6-diacetylpyridine 34 with two moles of glyoxylic acid (Scheme 13). The addition of two equivalents of hydrazine to the intermediate at the reflux of acetic acid leads by double cyclization, followed by dehydration, to 2,6-bis (6-2H-pyridazin-3-one). pyridine 36 with a yield of 75%.
  • Dipyridazinone 36 can be in equilibrium in its tautomeric form.
  • the 1 H NMR analysis (300 MHz) shows a broad singlet towards 11.38 ppm corresponding to the NH protons of the dione 36 form.
  • Dipyridazinone 36 was then treated with an excess of POCl 3 at 95 ° C to yield bis (chloropyridazinyl) pyridine 32 in 72% yield.
  • the bis (chloropyridazine) -pyridine 32 obtained is an ⁇ , ⁇ '-bifunctional, tridentate ligand which allows an extension of the arrangement of the "pyridine-pyridazine" strand by coupling reactions. This opportunity obviously offers the possibility of preparing, subsequently, a variety of new heterocyclic chains.
  • the monosubstituted intermediate, 3- (2-bromo-pyridin-6-yl) -6- (pyridin-2-yl) -pyridazine 43, can also be predominantly isolated with a yield of 72%, starting from an equimolar mixture of the starting reagents (Scheme 17).
  • Condensation is first carried out between 2,6-diacetylpyridine (34) and two moles of glyoxylic acid.
  • the addition of two moles of hydrazine and acetic acid allows a double cyclization followed by dehydration and leads to 2,6-bis (6-2H-pyridazin-3-one) -pyridine (36) with 91% yield.
  • This compound is then treated with an excess of POCl 3 under reflux for 15 hours to give bis (chloropyridazine) -pyridine (32) in 48% yield.
  • the coupling of Stille is replaced by a coupling of Negishi.
  • chloro (pyridyl) -pyridazine 8a was selected as a precursor in Stille coupling to react with methylated stannylpyridine 22 (Scheme 19), in the presence of equimolar palladium tetrakistriphenylphosphine, to exclusively supply the coupling product. 44 with a yield of 90%.
  • the diacid pyridazine ligand 48 can be obtained by oxidation of bis (dimethylpyridyl) pyridazine 47 (Scheme 21).
  • the latter was prepared via a double Stille coupling between 6-methyl-2-tributylstannylpyridine 22 and 3,6-dichloropyridazine 46 in the presence of palladium tetrakistriphenylphosphine. In this case, a slight excess of stannylated pyridine (3 eq.) was used.
  • 3,6-bis (2-carboxyl-pyridin-6-yl) -pyridazine acid 48 is isolated with 68% yield.
  • the pyridazine diacid 48 obtained is a bis-tridentate ligand: N-donor (pyridine and pyridazine) and O-donors (diacid).
  • N-donor pyridine and pyridazine
  • O-donors diacid
  • the bis (chloropyridazinyl) -pyridine precursor 32 can lead, by a double coupling of Stille [Pd (PPh 3 ) 2 Cl 2 , DMF, 110 0 C], in the presence of two moles of 6-methyl-2-tributylstannylpyridine 22, to 2,6-di [6- (6-methyl-pyridin-2-yl) pyridazin-3-yl] -pyridine ( Figure 22).
  • the dimethyl ligand 49 was obtained with 53% yield.
  • bipyridazine 49 with selenium dioxide makes it possible to isolate 2,6-di [3- (2-carboxyl-pyridin-6-yl) pyridazin-6-yl] -pyridine-50 with 71%. yield.
  • the diacid 50 obtained is a ligand which has three coordination sites, a central site only W-donor and two symmetrical terminal sites tridentate (N, O) -donneurs.
  • This compound can be converted into a cyclic ligand by introduction of an ethereal alkyl chain from both acidic functions (via the ester or acid chloride) (Compound A below).
  • This transformation generalizable to all the compounds according to the invention having two terminal acid functions, allows a direct application in radioimmunotherapy where heterogeneous cyclic ligands (N 1 O donors) are in great demand.
  • the diacid 50 exhibited cation selective complexing abilities, for example lanthanide type cations.
  • hydrophobic (alkyl) chains also makes it possible to improve the solubility in an organic medium after complexation, for example in the context of a liquid-liquid extraction (compound B above).
  • a hydrophilic chain makes it possible to use these same ligands in an aqueous medium optionally.
  • Retrosynthesis 3 The first approach (Route A) was attempted via homocoupling, 2-bromo-6- [3- (pyridin-2-yl) -pyridazin- ⁇ -yl] -pyridine 43, in the presence of a catalytic amount. NiBr 2 (PPh 3 ) 2 / Zn and nBu 4 NI in DMF. This procedure did not produce the expected product. Such a result can be explained by the strong coordination potential of the polyazotrized precursor which traps the catalytic complex in situ.
  • the second method consisted in performing a double Stille coupling of two equivalents of pyridylpyridazine 39 or 8a, respectively, on ⁇ , ⁇ '-multifunctional bipyridine precursors 52b or 60.
  • 6,6'-Dichloro-2,2'-bipyridine 52a was synthesized by reacting 2-chloropyridine with a mixture of BuLi / Me 2 N (CH 2 ) 2 OLi as a base to ensure the regioselective lithiation in C- 6 (Scheme 23).
  • the 6-lithio-2-chloropyridine obtained seems to react on the starting chloropyridine to yield the corresponding coupling product 52a with a yield of 47%.
  • 6,6'-Dibromo-2,2'-bipyridine 52b was also obtained according to a similar procedure via monolithiation of 2,6-dibromopyridine 42, followed by oxidative coupling, with a yield of 50% (Scheme 24).
  • 6,6'-Dichloro-2,2'-bipyridine 52a may also be prepared via Stille heterocoupling between 2-bromo-6-chloro-pyridine 55 and 2-chloro-6-tributylstannyl-pyridine 56 with a yield of 35% (Scheme 25).
  • 6,6'-di [6- (pyridin-2-yl) pyridazin-3-yl] -2,2'-bipyridine 61 was prepared in seven steps in an overall yield of 30%.
  • N, N'-bonded dione 64 is the precursor of 2,9-dihalo-1, 10-phenanthroline 65a and 65b. It can be prepared by regioselective oxidation of 1,10-phenanthroline 62 after prior protection of the nitrogen doublets.
  • 1, 10-phenontroline 63 with a yield of 81%.
  • Oxidation of salt 63 was carried out by potassium hexacyanoferate in an aqueous alkaline solution of sodium hydroxide at 0 ° C.
  • the N, N '-pontée 64 dione formed was isolated by chromatography on silica gel with 52% yield .
  • the ⁇ , ⁇ '-halogenation of dione 64 follows the same halogenation mechanism as in the case of pyridazinone 16, or pyridinone 59, with a spontaneous opening of the [N- (CH 2 ) 3 -N bridge. ] by aromaticity effect.
  • the 2,9-dichloro and 2,9-dibromo-l, 10-phenanthroline 65a and 65b were obtained by heating at 95 ° C., respectively, in an excess of corresponding phosphorus oxyhalide in a yield of 72 and 79%.
  • the 2,9-dihalo-l, 10-phenontroline 65a and 65b are precursors of choice for the synthesis of many ligand-like rigid ligands prepared from 2,2'-bipyridine.
  • Rigid ligand 66 was obtained by bis-coupling of Stille, by condensing two tributylstannylpyridazine residues 39 on 2,9-dibromo-1,10-phenanthroline 65b, in a yield of 91%, while its dichlorinated homologue 65a only yields a more modest return of 62% ( Figure 31).
  • the bipyridazine structure 66 has been subjected to electrochemical cycle regression conditions.
  • the electroreduction experiment was carried out in a sulfuric acid medium.
  • the voltammogram of 2,9-di [6- (pyridin-2-yl) -pyridazin-3-yl) -1,1,10-phenanthroline 66 clearly indicates a very marked reduction peak at a potential of -0.63V.
  • the wave corresponds to a potential of a simultaneous reduction to 4 electrons (per pyridazine cycle).
  • the formation of the corresponding dipyrrole 67 thus logically requires the addition of at least 8 electrons per mole of bipyridazine 66.
  • the reaction is monitored by cyclic voltammetry and TLC.
  • the preparative electrolysis of bipyridazine 49 made it possible to isolate bipyrrole 206 as the only reaction product with an optimum yield of 45%.
  • Example 16 Preparation of di- (6-pyridin-2-yl) pyridazine ethers via 6- (pyridin-2-yl) -2H-pyridazin-3-one 4, and 6- (pyridin-2-yl) pyridazine 2-yl) 2H-pyridazin-3-thione
  • the condensation of glyoxylic acid with 2-acetylpyridine 4 is carried out according to an aldolization in a basic medium (potassium carbonate) (Scheme 3) (Coates and McKillop, 1992). This step has been optimized from 31% to 65% in simply increasing the number of equivalents of the base to 3 eq. , while the yield of this condensation falls in a more basic medium of potassium hydroxide (Coates and McKillop 1992).
  • 2-hydroxy-4-oxo-4- (pyridin-2-yl) potassium butanoate 5 obtained is then cyclized, under reflux of acetic acid in the presence of hydrazine monohydrate r, to form the intermediate 6 which dehydrates in situ to give 6- (pyridin-2-yl) -2H-pyridazin-3-one 7 with an overall yield of 65%.
  • Chlorination, or bromination, of pyridazinone 7 is a conventional reaction carried out, respectively, in an excess of phosphorus oxychloride and of phosphorus oxybromide, at 100 ° C., to give 3-halopyridazines 8a and 8b with virtually quantitative yields
  • the 1 H NMR (300 MHz) analyzes surprisingly show a resolution of all the signals that seem to indicate a distribution of 12 distinct protons (FIG 8). This observation could possibly be related to the existence in solution of a dimeric, non-symmetrical structure induced by intermolecular hydrogen bonds, via a molecule of water for example. This argument can only be verified from the crystal structure of the molecule because the electron impact mass spectrum of the product 9 confirms the characterization of an ether-oxide monomer 9 (M + 328).
  • 3,3'-Di [6- (pyridin-2-yl)] pyridazine thioether 11 was also prepared by coupling 6- (pyridin-2-yl) -2H-pyridazin-3-thione and 3- chloro-6- (pyridin-2-yl) pyridazine 8a, in the presence of a strong base (NaOH) in DMSO (Scheme 6).
  • Pyridazine thione 10 was prepared beforehand by the action of phosphorus pentasulfide on 6- (pyridin-2-yl) -2H-pyridazin-3-one 7 with a yield of 92%.
  • the purification of the product 2 can be obtained by decomplexing in a saturated aqueous solution of cold potassium cyanide or EDTA for at least two hours, after the 24h of heating mentioned above.
  • This decomplexation can also be carried out by mixing the product 2 to 40 ml of a saturated aqueous solution of potassium fluoride.
  • the organic phase is then washed with NaHCO 3 and followed by extraction with CHCl 3 .
  • the organic phase is dried over MgSO 4, filtered and concentrated. Washing with 3 times 150 ml of 1 M HCl is applied and the aqueous phases are pooled. After filtration, the mixture is neutralized with Na 2 CO 3 and the precipitate formed 2 is then filtered.
  • 1 H NMR (CDCl 3 ) ⁇ ppm: 7.45 (m, 2H, Pyr i dine); 7.94 (dt, J " is
  • the mixture is kept two hours at -78 ° C. After returning to ambient temperature, the solvent is evaporated in vacuo. The residue is taken up in dichloromethane and then washed with water. The organic phase is dried over MgSO 4 and evaporated to dryness.
  • reaction medium After cooling to room temperature, the reaction medium is diluted with 80 ml of dichloromethane, then poured into a saturated solution of KF, after filtration, the filtrate is washed with a saturated aqueous solution of NaHCO 3 , the organic phase is dried over MgSO 4 and concentrated under reduced pressure. The residue obtained is chromatographed on silica gel (eluting a mixture of ethyl acetate / petroleum ether (20/80). ethoxyvinyl) -3,3'-bipyridazine (18) is isolated in 66% yield.
  • This compound is obtained in the form of a brown powder according to procedure C from 6,6 '- (pyridine-2, 6-diyl) dipyridazin-3 (2H) -one 36 (1.9 g, 6.247 mmol) and POCl 3 (15mL). The residue is purified by silica column chromatography (AcOEt) to give the desired product in 48% yield.
  • This compound is synthesized according to procedure E from 2,6-bis (6-chloropyridazin-3-yl) pyridine 32 (0.50 g, 1.65 mmol), 2-bromopyridine (0.537 g, 4.13 mmol), zinc chloride (0.69g, 4.13mmol), butyllithium (2.5M in hexane, 3.6mL, 4.13mmol), tetrakis (triphenylphosphine) palladium (0) (0.19g, 0.165mmol) and THF (8OmL) . Chromatography on silica (EP / AcOEt: gradient from 80/20 to 0/100) gives the pure product in the form of a pale yellow powder with a yield of 17%.
  • the 3,6-bis (6-methyl-pyridin-2-yl) -pyridazine 47 is obtained according to the general procedure of Stille, starting from a reaction mixture of 1.55 g (4.06 mmol) of 6-methyl-2- tributylstannyl-pyridine 22, 300 mg (2.03 mmol) of 3,6-dichloropyridazine 46, 231 mg (0.20 mmol) of tetrakis (triphenylphosphine) palladium (0) and 50 mL of freshly distilled toluene.
  • the diacid 48 is obtained according to a procedure similar to the preparation of the acid 45, from a mixture of 230 mg (0.88 mmol) of pyridazine 47, 126 mg (1.14 mmol) of selenium dioxide, and 7 ml of o-dichlorobenzene. The mixture is heated at 150 ° C. for 12 hours, to yield diacid 48 with a yield of 68%.
  • the diacid 50 is obtained according to the procedure used for the preparation of the acid (48), from a mixture of 300 mg
  • 2,6-dibromopyridine (2.32 g, 10 mmol) is solubilized in 25 ml of diethyl ether cooled to -78 ° C.
  • the assembly is equipped with a solid ampoule containing copper chloride.
  • (2) previously dried, 2g, 14.9mmol.
  • Butyllithium (2.4M in hexane, 4.6mL, 11mmol) is added dropwise and the reaction mixture is stirred for 2 hours at -78 ° C.
  • the copper chloride is added slowly over 30 minutes and the mixture is stirred for an additional 30 minutes at -78 ° C. Dry oxygen bubbling is carried out for 1 hour at -78 ° C.
  • the reaction medium is treated with 20OmL of water and 50 mL of 1M HCl solution and a precipitate appears.
  • the solution is filtered and the resulting solid is recrystallized from THF.
  • the brownish solid is then solubilized in THF and filtered on Millipore.
  • the solution is concentrated under vacuum and the desired product is obtained in the form of a white powder with a yield of 79%.
  • bipyridine 58 The synthesis of bipyridine 58 is carried out according to the procedure used for the preparation of bipyridazinone 15, by preparing a catalytic mixture of 7.77 g (10.5 mmol) of dichlorobis (triphenylphosphine) nickel (II), 2.27 g (35 mmol) of zinc and 11.235 g (35 mmol) tetrabutylammonium bromide in 100 mL of DMF to couple 5 g (35 mmol) of 2-chloro-6-methoxypyridine (12 hours). Bipyridine 58 was isolated with 94% yield.
  • the solution is refluxed for 24 hours.
  • the solvent is evaporated off under reduced pressure, and the residue is purified by chromatography on a neutral alumina gel.
  • 6,6'-bis [6- (pyridin-2-yl) -pyridazin-3-yl] -2,2'-bipyridine 61 was prepared according to the general procedure of coupling Stille, starting from a mixture reaction of 1.17 g (6.15 mmol) of chloropyridazine 8a, 1.50 g (2.05 mmol) of 6,6'-ditributylstannyl-2,2'-bipyridine 60, 238 mg (0.20 mmol) of tetrakis (triphenylphosphine) palladium (0), and 60 mL of freshly distilled toluene.
  • the disubstituted product 61 is isolated in 68% yield.
  • Phenanthroline 62 (2.51 g, 13.9 mmol) is placed in a flask and is solubilized in the minimum of freshly distilled nitrobenzene, 1,3-dibromopropane (6.3mL, 61.9 mmol) is then added to the solution. The medium is heated at 120 ° C. for 2 hours, the color of the solution changes from yellow to orange. After cooling to room temperature, the precipitate formed is filtered and washed with toluene and recrystallized from a 5/1 mixture of ethanol / water. After filtration and drying, the quaternary bis-salt is isolated with a yield of 81%.
  • glyoxylic acid monohydrate (2.27 g, 30.67 mmol) is added to a solution of K 2 CO 3 (6.83g, 49.43mol) in 4OmL of water.
  • 2,6-diacetylpyridine (34) (2 g, 12.26 mmol) is added and the solution is heated at 50 ° C. for 2.5 hours.
  • the medium is then cooled to 0 ° C., glacial acetic acid (10.5 ml) and then hydrazine monohydrate (5 ml) are added dropwise.
  • the solution is refluxed for 2 hours.
  • the medium is then cooled to 0 ° C.
  • the IC50 values at the promastigote stage for the reference molecules given above are of the order of 0.4 ⁇ g / ml for Amphotericin B, 0.3 ⁇ g / ml for ketoconazole and greater than 2 ⁇ g / ml for Miltefosine.
  • the compounds according to the invention have IC 50 of the order of 0.05 to 0.1 ⁇ g / ml.

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EP07823344A 2006-07-26 2007-07-26 Pyridazin- und pyrrolverbindungen, verfahren zu ihrer gewinnung und verwendung Withdrawn EP2069345A2 (de)

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FR0606842A FR2904315B1 (fr) 2006-07-26 2006-07-26 Composes pyridaziniques et pyrroliques, procedes d'obtention et applications
PCT/FR2007/001287 WO2008012440A2 (fr) 2006-07-26 2007-07-26 Composes pyridaziniques et pyrroliques, procedes d'obtention et applications

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EP2186810A1 (de) 2008-10-31 2010-05-19 Institut Curie Poly-Heteroaryl-Derivate zur Behandlung von Krebs
WO2010088268A1 (en) 2009-01-28 2010-08-05 Smartcells, Inc. Exogenously triggered controlled release materials and uses thereof
WO2010088286A1 (en) 2009-01-28 2010-08-05 Smartcells, Inc. Synthetic conjugates and uses thereof
WO2010088300A1 (en) 2009-01-28 2010-08-05 Smartcells, Inc. Crystalline insulin-conjugates
BRPI1007457A2 (pt) 2009-01-28 2015-08-25 Smartcells Inc Conjungado, formulação de liberação prolongada, e, sistema de distribuição de bomba.
WO2010107520A1 (en) 2009-03-20 2010-09-23 Smartcells, Inc. Soluble non-depot insulin conjugates and uses thereof
US8623345B2 (en) 2009-03-20 2014-01-07 Smartcells Terminally-functionalized conjugates and uses thereof
KR20120102649A (ko) 2009-10-30 2012-09-18 막스-플랑크-게젤샤프트 츄어 푀르더룽 데어 비쎈샤프텐 에.파우. 질소 함유 방향족 화합물 및 금속 착체
JP2013535467A (ja) 2010-07-28 2013-09-12 スマートセルズ・インコーポレイテツド 組換えにより発現されたインスリンポリペプチドおよびその使用
EP2598522A4 (de) 2010-07-28 2014-11-12 Smartcells Inc Rekombinante lektine, bindungsstellenmodifizierte lektine und anwendungen davon
AU2011282977A1 (en) 2010-07-28 2013-02-21 Smartcells, Inc. Drug-ligand conjugates, synthesis thereof, and intermediates thereto
JP2014156402A (ja) * 2011-05-27 2014-08-28 Nippon Soda Co Ltd ビピリジン化合物および殺菌剤
WO2013033018A2 (en) 2011-08-30 2013-03-07 Drexel University Dihydroxybipyridine complexes of ruthenium and iridium for water oxidation and hydrogenation
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CN110437206B (zh) * 2019-03-13 2022-06-10 上海大学 吡啶-吡咯交替的分子折叠体及其制备方法

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CA2658624A1 (fr) 2008-01-31
US9034873B2 (en) 2015-05-19
FR2904315A1 (fr) 2008-02-01
WO2008012440A3 (fr) 2008-05-29
FR2904315B1 (fr) 2012-12-14
US20100298562A1 (en) 2010-11-25
JP5564252B2 (ja) 2014-07-30
JP2009544671A (ja) 2009-12-17

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