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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • 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
  • 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
  • C07D401/12—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 linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H1/00—Processes for the preparation of sugar derivatives
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  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
  • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
  • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/06—Pyrimidine radicals
• • C—CHEMISTRY; METALLURGY
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  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/06—Pyrimidine radicals
  • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical

Definitions

• the present invention relates to a method of manufacturing pyrazoles, new pyrazoles impossible to manufacture to date, and their applications.
• a first solution consists in using the cyclo-condensation of 1,3-dielectrophiles, such as beta-diketones, with hydrazines.
• This solution has been known for many years and is probably the most widely used today for the synthesis of pyrazoles.
• this method has a number of limitations. In particular, it can not be applied to all the substrates, in particular the hydrazine substrates having nucleophilic groups such as amines can not be used.
• dielectrophilic substrates having other electrophilic centers, such as aldehydes, ketones or Michael acceptors are to be avoided.
• the reaction conditions most often require the use of acids and / or high temperatures.
• the second solution is to prepare the pyrazoles by 1,3-dipolar cycloaddition from alkynes and dipoles such as diazoalkanes, nitrilimines or sydnones.
• alkynes and dipoles such as diazoalkanes, nitrilimines or sydnones.
• the reaction with the diazo alkanes and the nitrilimines requires strong base conditions and the use of organic solvents which is a significant disadvantage when fragile substrates and / or solely soluble in aqueous medium must be employed.
• these reactions generate two regioisomers that need to be separated.
• a first solution is to prepare the pyrazoles thermally.
• Thermal sydnone / alkyne cycloaddition has been known for many years and has been described in particular by Kirsi Harju, Johanna Vesterinen and Jari Yli-Kauhaluoma, Org. Lett. 2009, 10, 2219-2221 and by Duncan L. Browne, Matthew D. Helm, Andrew Plant, and Joseph PA Harrity, Angew. Chem. Int. Ed. 2007, 46, 8656-8658.
• the temperatures required for the reaction are typically greater than 120 ° C.
• Another solution consists of preparing the pyrazoles from very reactive alkynes.
• the sydnone / alkyne cycloaddition can then be carried out at room temperature when aromatic compounds called arynes having an extremely reactive triple bond are used.
• Arynes are not stable and must be prepared in situ from appropriate precursors.
• the disadvantages of the first solution are related to the drastic conditions of preparation. High temperatures, typically of the order of 150 ° C, are incompatible with many fragile substrates. The thermal reaction does not tolerate the presence of many reaction functions. More regioisomeric products are formed, which reduces the synthesis yields and requires tedious purifications.
• the second solution uses very particular alkynes. It is therefore inherently limited in terms of the diversity of substrates that can be used. Only pyrazoles called 2H-lndazoles can be synthesized by this reaction.
• R represents a hydrogen atom, a halogen atom, a thio or thioalkyl group, a hydroxyl or alkoxy group, an amino or aminoalkyl group, an alkyl radical containing from 1 to 8 carbon atoms which is unsubstituted; or substituted one or more times with F, Cl, Br, I, CN, OH, NH 2 , NH-C 1 -C 8 alkyl, N- (C 1 -C 8 alkyl) 2 , SH, an aryl radical containing 6 to 10 carbon atoms.
• R ' represents a hydrogen atom, a halogen atom, a thio or -thioalkyl group, a hydroxyl or alkoxy group, an amino or -aminoalkyl group, an alkyl radical containing from 1 to 8 carbon atoms which is not substituted or substituted one or more times with F, Cl, Br, I, CN, OH, NH 2 , NH-C 1 -C 8 alkyl, N- (C 1 -C 8 alkyl) 2 , SH, an aryl radical containing 6 to 10 atoms of carbon which is unsubstituted or substituted one or more times with an alkyl or alkoxy radical containing 1 to 8 carbon atoms, a heterocycle,
• R represents a hydrogen atom, a halogen atom, a thio group, a hydroxyl group, an amino group, a hydrocarbon group or a hydrocarbon group containing from 1 to 100 heteroatoms, R" particularly representing an atom of hydrogen, a halogen atom, a thio or thioalkyl group, a hydroxy or alkoxy group, an amino or -aminoalkyl group, an alkyl radical containing from 1 to 8 carbon atoms which is unsubstituted or substituted one or more times with Substituted or unsubstituted F, Cl, Br, I, CN, OH, O-heterocycle, NH 2 , -NH-C 1 -C 8 alkyl, -N- (C 1 -C 8 alkyl) 2 , -NH-R '", or - Alkyl C1 -C3-NH-R '"where R'" represents a sulfonated group
• the halogen atom may be a bromine or iodine atom, and preferably a chlorine atom.
• the alkyl radical is straight chain or branched chain and may contain 1 to 8 carbon atoms and preferably 1 to 5 carbon atoms. Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. It is the same for the alkyl radical of the alkylthio group, alkoxy or alkylamino.
• aryl refers to an aromatic carbocyclic radical containing 6 to 10 carbon atoms unless otherwise indicated.
• Suitable aryl groups include phenyl, naphthyl and biphenyl.
• the substituted aryl groups include the aryl groups described above which are substituted one or more times, preferably once with halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy.
• the heterocycle may be a saturated, partially saturated and fully unsaturated heterocyclic group having one, two or three rings and a total number of 5 to 10 ring atoms wherein at least one of the ring atoms is an N, O atom. or S.
• the heterocyclic group contains from 1 to 3 ring heteroatoms selected from N, O and S.
• Suitable saturated and partially saturated heterocyclic rings include tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxoazolinyl, isoxazolinyl, and the like.
• Suitable heteroaryl groups include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, benzopyranyl, indolyl, quinolinyl, isoquinolinyl, naphthyridinyl, and the like.
• heterocyclic rings are 2-quinolinyl, 1,3-benzodioxyl, 2-thienyl, 2-benzofuranyl, 2-benzothiophenyl, 3-thienyl, 2,3-benzenediyl, 5-dihydro-5-benzofuranyl, 4-indoyl, 4-pyridyl, 3-quinolinyl, 4-quinolinyl, 1,4-benzodioxan-6-yl, 3-indoyl, 2-pyrrolyl, benzopyran, 6-yl, a 5-indolyl, a 1,5-benzoxepin-8-yl, a 3-pyridyl, a 6-coumarinyl, a 5-benzofuranyl, a 2-isoimidazol-4-yl, a 3-pyrazolyl, a 3-carbazolyl, 2-thiazolyl, 2-oxazolyl, 1-imidazolyl and 2-imidazolyl.
• the heterocycle may be substituted in one or more substitutable sites with, for example, halogen, aryl, C1-C5 alkyl, hydroxy, C1-C5 alkoxy, cyano, trifluoromethyl, nitro, an oxo, a amino, a C1-C5 alkyl amino or a C1-C5 amino dialkyl or even another heterocycle which itself may also be substituted.
• radicals which are substituted one or more times preferably contain 1 to 3 substituents.
• a polypeptide may for example be angotensin II, substance P, neurokine A, calcitonin, oxytocin.
• a protein may be for example an antibody, an enzyme, hemoglobin, transferrin, streptavidin.
• a nucleic acid may be for example a molecule consisting of DNA or RNA.
• a polysaccharide may be for example chitosan, cellulose, alginates, dextran.
• a polymer may be for example polyethylene glycol (PEG), polystyrene, polypropylene, polyethylene, polyacrylamide.
• PEG polyethylene glycol
• polystyrene polystyrene
• polypropylene polypropylene
• polyethylene polyacrylamide
• a nanoparticle may be selected for example parm i quantum dots, carbon nanotubes, metal nanoparticles (Au, Fe 3 O 4, Cr 2 O 3, Al 2 O 3, BaFei 2 Oi 9).
• a dendrimer may be chosen for example from PAMAM dendrimers and Cyclotriphosphazene-PMMH.
• R '" represents a sulfonated group, it is preferably one of the sulfonated groups illustrated by the examples.
• hydrocarbon group designates a linear, branched, cyclic or polycyclic hydrocarbon group, these cycles being able to be fused or not, containing from 1 to 100 heteroatoms, these groups being able to be unsubstituted or substituted by one or more atoms or groups such as those mentioned for the radicals R 'and R ".
• sydnones of formula II are dipoles existing in several tautomeric forms. Only one of the forms is represented above.
• R represents an optionally substituted aryl or heteroaryl radical, in particular an optionally substituted aryl radical, particularly an optionally substituted phenyl radical, these different radicals and substituent having in particular the meanings indicated above.
• R ' represents a hydrogen atom.
• R represents a heteroaryl radical or an aryl radical or an alkyl radical containing 1 to 8 carbon atoms, preferably one of the last two .
• R and R ', R' and R ", R and R”, and R, R 'and R " have the preferred values indicated above.
• the catalyst metal of the reaction is copper.
• Copper forms that can be used in the process are, for example, and preferably either copper (I) salts such as Cul, CuOTf, CuCl, CuOAc, etc. and preferably Cul, or copper (II) salts such as CuSO 4 , CuOTf 2 , CuOAc 2 , ... and preferably CuSO 4 reduced in situ to Cu (1) salts by a reducing agent such as ascorbic acid, sodium bisulfite, zinc or metallic copper, and preferably ascorbic acid.
• a reducing agent such as ascorbic acid, sodium bisulfite, zinc or metallic copper, and preferably ascorbic acid.
• the copper salts can either be used as such or preferably in complexed form with ligands, preferably nitrogenous, such as the phenanthroline compounds such as IV below, triazoles such as V or VII below, pyridines such as IX and X below, of imidazoles such as VI II below, benzimidazoles such as VI below and phosphines, preferably nitrogen ligands such as those mentioned above, particularly phenanthrolines.
• nitrogen ligands allow an increase in the catalytic activity of the copper but also the regioselectivity of the reaction, in particular in the case where R 'is different from H.
• the above copper salts are preferably reduced in situ to salts having a lower oxidation state.
• the solvents which can be used for the implementation of the present process can be organic solvents, water or organo-aqueous mixtures. It should be noted that quite remarkably, an optionally complex physiological fluid such as plasma, urine, cell lysates or cell culture media can be used as a solvent medium in the present invention, without disturbing the reaction.
• the present process is insensitive to the pH of the editorial medium. However, it is preferred to operate in a neutral medium, or particularly in an alkaline medium.
• a neutral medium or particularly in an alkaline medium.
• an organic base such as triethylamine or triethanolamine can be used.
• the reaction of a sydnone of formula II with an alkyne of formula III is preferably carried out between 10 ° C and 120 ° C, preferably between 15 ° C and 100 ° C, particularly between 15 ° C and 70 ° C.
• pyrazole compounds of formula I which are sensitive or fragile such as a polypeptide, a protein, a nucleic acid, a DNA molecule, a polysaccharide, a nanoparticle or a dendrimer
• the procedure is preferably carried out between 15 ° and 50 °. C, preferably between 20 and 40 ° C.
• the pyrazole compound of formula I is not particularly sensitive or fragile, it is preferably carried out between 45 and 72 ° C, preferably between 55 and 65 ° C.
• the methods that are the subject of the present invention possess very interesting properties. They notably enjoy remarkable reaction yields, generally greater than 95%. They benefit from total regioselectivity, ie only one regioisomer is formed during the reaction.
• reaction is applicable regardless of the structure of the reagents defined above implemented.
• the reaction is carried out under mild reaction conditions, compatible in particular with fragile molecules or biomolecules such as proteins, enzymes, DNA molecules, etc. These properties are illustrated below in the experimental part.
• R represents a polypeptide such as, for example, angiotensin II, substance P, neurokine A, calcitonin, oxytocin, a protein such as an antibody, an enzyme, hemoglobin, transferrin, streptavidin, a nucleic acid such as for example a molecule consisting of DNA or RNA, a polysaccharide such as chitosan, cellulose, alginates, dextran, a polymer such as polyethylene glycol (PEG), polystyrene, polypropylene, polyethylene, polyacrylamide, a nanoparticle as per examples of quantum dots, carbon nanotubes, metal nanoparticles (Au, Fe3O 4 , Cr 2 O 3 , Al 2 O 3,
• a dendrimer such as PAMAM dendrimers, Cyclotriphosphazene-PMMH.
• R "in this case preferably represents a radical having a fluorophore function, for example cyanines Cy3 and Cy5, Alexa Fluor derivatives, coumarin, fluorescein and rhodamine derivatives such as tetramethylrhodamine (TAMRA), a radiotracer such as for example the DOTA-Gd, DOTA-G a and DOTA- 64 Cu complexes or a molecule containing an atom 18 F or 125 l, an active principle of human therapy (medicament) such as taxol, taxotere, navel bi ne, vinblastine, a molecule capable of interacting with a protein or DNA, for example biotin, tetraacetylfucose, RGD peptides, anthracyclines.
• a radiotracer such as for example the DOTA-Gd, DOTA-G a and DOTA- 64 Cu complexes or a molecule containing an atom 18 F or 125 l,
• the present application also relates to pyrazole compounds of formula I described above, in which R and R 'have the meaning and the preferred values already indicated and R "represents a polypeptide such as, for example, angiotensin II, P, neurokin A, calcitonin, oxytocin, a protein such as an antibody, an enzyme, hemoglobin, transferrin, streptavidin, a nucleic acid such as a molecule consisting of DNA or RNA, a polysaccharide such as chitosan, cellulose, alginates, dextran, a polymer such as polyethylene glycol (PEG), polystyrene, polypropylene, polyethylene, polyacrylamide , a nanoparticle such as quantum dots, carbon nanotubes, metal nanoparticles (Au, Fe3O 4 , Cr 2 O 3 , Al 2 O 3, a dendrimer such as PAMAM dendrimers, cyclotriphosphazene-PMMH.
• R preferably represents a radical having a fluorophore function, for example cyanines C y 3 and C y 5, Alexa Fluor derivatives, coumarin, fluorescein and rhodamine derivatives such as tetramethylrhodamine (TAMRA).
• cyanines C y 3 and C y 5 Alexa Fluor derivatives, coumarin, fluorescein and rhodamine derivatives such as tetramethylrhodamine (TAMRA).
• a radiotracer such as for example the complexes of DOTA-Gd, DOTA-Ga and DOTA- 64 Cu or a molecule comprising an 18 F or 125 I atom, an active principle of human therapy (drug) such as for example taxol, taxotere, navel bine, vinblastine; a molecule capable of interacting with a protein or DNA such as, for example, biotin, tetraacetylfucose, RGD peptides, anthracyclines.
• the present invention is not intended, either with regard to the aforementioned preparation process or with regard to new pyrazole compounds of formula I above, Chunrui Wu 1 - (4-chlorophenyl) -4-pyridyl-2 pyrazole.
• the present application also relates to the use of the novel pyrazole compounds described above as: f) biological tracers for medical imaging or diagnosis (Thazoles containing an 18 F atom and an antibody) for example), / '/') functional polymers for the capture and detection of biomolecules of interest, / '/' / ') molecules for the detection and analysis of DNA, RNA and proteins following the incorporation of fluorescent groups via the process of the invention, (V) nano-objects with therapeutic activity (in the case of dimerimers or polyfunctionalized nanoparticles, via the process of the invention, by an active principle), v) radiopharmaceutical compounds (thazoles comprising an antibody specific for tumor cells and a radioelement for example)
• Example 12 4-heptyl-1-phenyl-1H-pyrazole
• Example 13 The title product of Example 13 was prepared from 3- (4-carboxyphenyl) sydnone and 4-phenyl-1-butyne using procedure C. The product was obtained as a white solid with a yield of 99%.
• Example 14 The title product of Example 14 was prepared from 3- (4-carboxyphenyl) sydnone and 2-methyl-3-butyn-2-ol using procedure A, operating at 37 ° C. product was obtained as a white solid with a yield of 93%. By proceeding under the conditions of procedure A but using as a solvent human blood plasma, the product was obtained in 88% yield.
• Example 19 The title product of Example 19 was prepared from 3- (phenyl) sydnone and 2-ethynylpyridine using procedure C. The product was obtained as a white solid in 95% yield .
• Example 20 The title product of Example 20 was prepared from 3- (phenyl) sydnone and 2-ethynylthiophene using procedure C. The product was obtained as a white solid in 99% yield. %.
• Example 22 The title product of Example 22 was prepared from 3- (phenyl) sydnone and 2- (6- (diethylamino) -3- (diethyliminio) -3H-xanthen-9-yl) -5- ( N- (prop-2-yn-1-yl) sulfamoyl) benzenesulfonate using procedure C and isolation by filtration from the reaction medium. The product was obtained as a violet solid with a yield of 92%.
• the resultant mixture was stirred in a closed flask at 60 ° C. for 16 h.
• the second portion of sodium ascorbate (1.5 mmol), 1.10-phenanthroline (0.15 mmol) was then added to the mixture. and copper sulfate pentahydrate (0.15 mmol) and the new mixture was stirred at 60 ° C. for a further 24 hours.
• Sydnone coupled with bovine serum albumin 1 mg / mL - 0.18 ⁇ , 1 eq.
• N-dansyl-N-propargylamine 1, 8 ⁇ , 10 eq.
• Bathophenanthroline 1, 8 ⁇ , 10 eq.
• the method of the invention can be implemented on starting sydnones carrying biological molecules.
• Example 27 The title product of Example 27 was prepared from 3- (phenyl) sydnone and 5-ethynyl-2'-deoxyuridine using procedure C and isolation by filtration from the reaction medium. The product was obtained as a white solid with a yield of 84%.
• Example 28 Ethyl 1-phenyl-1H-pyrazole-4-carboxylate
• the title product of Example 28 was prepared from 3-phenylsydnone and ethyl propionate using protocol F.
• IR NaCl, cm- 1 : 3124, 3063, 2984, 2901, 1709, 1597, 1560, 1505, 1463, 1413, 1390, 1258, 1150, 1027, 996, 951, 887, 825, 770, 757, 688, 654.
• Example 29 The title product of Example 29 was prepared from 3-phenyl-4-bromosydnone and 4-phenyl-1-butyne using Protocol G. The product was obtained as a yellow solid with a yield of 74% after purification by chromatography (Heptane / Ethyl acetate: 95/5).
• IR NaCl, cm- 1 : 3062, 3027, 2923, 2856, 1598, 1556, 1499, 1455, 1407, 1391, 1241, 1087, 1068, 961, 91, 851, 836, 760, 694;
• Example 30 The title product of Example 30 was prepared from 3- (p-methoxyphenyl) -4-bromosydnone and 4-phenyl-1-butyne using Protocol G. The product was obtained under form of a yellow solid with a yield of 70% after purification by chromatography (Heptane / Ethyl acetate: 95/5).
• the precipitate was then recovered by filtration and recrystallized from methanol to obtain the expected pure product.
• N, N'-Dicyclohexylcarbodiinnide 13 mg, 0.063 mmol was added to a solution of 3- (4-carboxyphenyl) sydnone (13 mg, 0.063 mmol) and N-Hydroxysuccininnide (8.7 mg, 0.076 mmol). in anhydrous dimethylformamide (1 ml) at 0 ° C.
• the resulting solution was stirred at room temperature for 24 h and then filtered.
• the tripeptide H-Gly-Trp-Gly-OH 20 mg, 0.063 mmol was added to the filtrate and the solution was stirred at room temperature for a further 16 hours. The mixture was then concentrated and the residue was concentrated.

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