EP1453840A1 - Phosphonates utiles comme modulateurs de l'activite des lymphocytes t-gamma-9-delta-2 - Google Patents

Phosphonates utiles comme modulateurs de l'activite des lymphocytes t-gamma-9-delta-2

Info

Publication number
EP1453840A1
EP1453840A1 EP02804596A EP02804596A EP1453840A1 EP 1453840 A1 EP1453840 A1 EP 1453840A1 EP 02804596 A EP02804596 A EP 02804596A EP 02804596 A EP02804596 A EP 02804596A EP 1453840 A1 EP1453840 A1 EP 1453840A1
Authority
EP
European Patent Office
Prior art keywords
ppm
nmr
formula
cdc1
yield
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP02804596A
Other languages
German (de)
English (en)
French (fr)
Inventor
Jean-Louis Montero
Ibrahim Rés. Les Hauts de Saint Priest ZGANI
Chantal Menut
Valérie GALLOIS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Innate Pharma SA
Original Assignee
Centre National de la Recherche Scientifique CNRS
Laboratories Mayoly Spindler SAS
Universite de Montpellier
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centre National de la Recherche Scientifique CNRS, Laboratories Mayoly Spindler SAS, Universite de Montpellier filed Critical Centre National de la Recherche Scientifique CNRS
Publication of EP1453840A1 publication Critical patent/EP1453840A1/fr
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • 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
    • A61P31/12—Antivirals
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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
    • 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
    • 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
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3826—Acyclic unsaturated acids
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3895—Pyrophosphonic acids; phosphonic acid anhydrides
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes

Definitions

  • the invention relates to new phosphonate derivatives, to their preparation process, to their use as ligand modulators of ⁇ 9 ⁇ 2 T lymphocytes and to pharmaceutical compositions comprising them.
  • T cells are cells that develop in the thymus. They are responsible for cell-mediated immunity. T lymphocytes are divided into two subgroups corresponding to the receptors with which they are endowed: ⁇ T lymphocytes and ⁇ T lymphocytes.
  • ⁇ T lymphocytes present in peripheral blood represent, in healthy individuals, usually from 1 to 5% of blood lymphocytes and play a role in the immune system.
  • ⁇ 9 ⁇ 2 T lymphocytes (sometimes also called ⁇ 2 ⁇ 2 T lymphocytes) are ⁇ T lymphocytes carrying receptors with variable regions V ⁇ 9 and V ⁇ 2. They represent the majority of ⁇ T lymphocytes in human blood.
  • ⁇ 9 ⁇ 2 T lymphocytes When activated, ⁇ 9 ⁇ 2 T lymphocytes can exert a powerful cytotoxic activity on cells carrying pathogens. In particular, a strong increase in the population of V ⁇ 9 ⁇ 2 cells has been shown in the presence of different pathogens.
  • viruses such as for example the human immunodeficiency virus, or HIV ("Selective increase of a subset of T cell receptor gamma delta T lymphocytes in the peripheral blood of patients with human immunodeficiency type 1 infection ", De Maria A. & al, J. Infect. Dis. 165, 917-919, 1992) or by another virus such as the simian immunodeficiency virus or SIV, the herpes simplex virus or HSV, human herpes virus-6 or HHV-6, vaccinia virus.
  • viruses such as for example the human immunodeficiency virus, or HIV ("Selective increase of a subset of T cell receptor gamma delta T lymphocytes in the peripheral blood of patients with human immunodeficiency type 1 infection ", De Maria A. & al, J. Infect. Dis. 165, 917-919, 1992) or by another virus such as the simian immunodeficiency virus or SIV, the herpes simplex virus or HSV, human herpes
  • Salmonella typhi infectious agent responsible for salmonellosis, Brucella melitensis, responsible for brucellosis, Francisella tularensis, pathogen of tularemia, Plasmodium virax and Plasmodium falciparum which are responsible for malaria, Listeria monocytogenes which is the pathogen of listeriosis in humans.
  • Role of ⁇ T lymphocytes in immune response in human and mice A. Salemo and F. Dieli, Critical Reviews in Immunology, 18: 327-357 (1998)).
  • tumor cell lines are recognized and destroyed by ⁇ 9 ⁇ 2 T lymphocytes, such as for example Daudi cells (P. Fish & al, Science, 250: 1269-1273 (1992)) or the RPMI 8226 line (Seclin, LK & al., Scand. J. munmun. 36: 107-117 (1992)).
  • Daudi cells P. Fish & al, Science, 250: 1269-1273 (1992)
  • RPMI 8226 line Seclin, LK & al., Scand. J. munmun. 36: 107-117 (1992)
  • the ⁇ 9 ⁇ 2 T lymphocytes recognize a wide variety of antigens expressed in pathologies of humans and / or primates. For this reason, it is desired to have molecules which make it possible to stimulate the proliferation of ⁇ 9 ⁇ 2 T lymphocytes, in order to promote the immune response against these pathologies.
  • human ⁇ 9 ⁇ 2 T lymphocytes react, in the case of a mycobacterial infection, with four natural non-peptide molecules of phosphate structure, designated phosphoantigens, which exhibit a stimulating activity for a concentration of the order of 1 to 5 nM (nanomolar) (WO 95/20673 and “Stimulation of human ⁇ T cells by nonpeptidic mycrobacterial ligands” Patricia CONSTANT & al, Science, 264, p. 267-270).
  • phosphate derivatives have shown an interesting activity as stimulants of the proliferation of T lymphocytes ⁇ 9 ⁇ 2, in vitro, we know that the presence of many phosphatases in the human organism or in the primate organism will not allow these molecules to 'reach their target if used in vivo. This is why the Applicant has sought to develop molecules capable of being ligands which modulate ⁇ 9 ⁇ 2 T lymphocytes and which have sufficient stability to retain activity during application to the human or animal organism in primates. especially.
  • Bisphosphonate compounds such as alendronate, ibandronate and pamidronate and were known in the prior art (V. Kunzmann & al, Blood, 15 July 2000, vol. 96, n ° 2, p 384-392). their activity as stimulants of the proliferation of ⁇ 9 ⁇ 2 T lymphocytes. However, it was shown in the aforementioned study that only amino-bisphosphonates had an effect on the proliferation of T lymphocytes, while, according to this study, the other phosphonates tested did not exhibit any activity of this type.
  • A represents a linear, branched or cyclic, saturated or unsaturated C 1 -C 50 alkyl group, this alkyl group (alkenyl, alkynyl) can carry one or more aromatic groups, it can comprise one or more ether bridges, a or several functions chosen from: a carboxylic acid, an ester, an amide, a nitrile, a hydroxyl, an aldehyde, a ketone, a halogen, an amine, a thiol, a thio-ketone, an episulfide, a selenol, a seleno -ketone, a sulphide, a sulphone, a sulphoxide, it can carry one or more heterocycles, n is an integer ranging from 1 to 4, X represents a group chosen from the hydrogen atom and a cationic group pharmaceutically acceptable organic or mineral, B represents a group chosen from:
  • heterocycles capable of being carried by the alkyl chain (alkenyl, alkynyl) of A particular mention is made of the epoxide and aziridine groups.
  • the alkyl chain (alkenyl, alkynyl) of A has an ether bridge, this can be located at any position of the chain, including inside a ring. Preferably, it is located in position ⁇ with respect to the phosphorus atom.
  • X + groups which can be used according to the present invention, mention may be made of: H + , Na + , NH K + , Li + , (CH 3 CH 2 ) 3 NH + or an enzymatic ester function.
  • A represents an alkyl (alkenyl, alkynyl) straight, branched or cyclic Ci - C 50 comprising at least one double bond ⁇ ⁇
  • the compounds according to this variant of the invention and corresponding to formula (I) above are characterized in that A contains from 3 to 25 carbon atoms, even more preferably, A comprises from 5 to 10 carbon atoms. carbon.
  • A represents an alkyl group (alkenyl, alkynyl) linear, branched or cyclic in C1 - C 50 comprising at least one group ⁇ -halohydrin according to formula (II) below, in which Y represents an atom chosen from fluorine, chlorine, iodine and bromine:
  • A represents an alkyl group (alkenyl, alkynyl) linear, branched or cyclic, saturated or unsaturated, in C ⁇ -C 0 comprising at least one epoxy group.
  • A represents an alkyl (alkenyl, alkynyl) straight, branched or cyclic, saturated or unsaturated Ci - C 50 comprising at least one tertiary alcohol group. - ", - ,,
  • A represents an alkyl (alkenyl, alkynyl) straight, branched or cyclic, saturated or unsaturated Ci - C 50 comprising at least one ⁇ -diol moiety.
  • A represents an alkyl (alkenyl, alkynyl) straight, branched or cyclic, saturated or unsaturated Ci - C 50 comprising at least one aldehyde group or an ⁇ -hydroxyaldehyde group.
  • the invention also relates to a process for the preparation of the compounds corresponding to formula (I).
  • R 1 represents a linear, branched or cyclic, saturated or unsaturated C 1 -C 49 alkyl group, this alkyl group (alkenyl, alkynyl) may carry one or more aromatic groups, it may comprise one or more ether bridges, a or several functions chosen from: a carboxylic acid, an ester, an amide, a nitrile, a hydroxyl, an aldehyde, a ketone, a halogen, an amine, a thiol, a thio-ketone, an episulfide, a selenol, a seleno -ketone, a sulfide, a sulfone, a sulfoxide, it can carry one or more heterocycles.
  • the alcohol Ri - OH is treated: (1) with methyl sulfonate chloride in the presence of n-triethylamine in dichloromethane.
  • the methylsulfonate group is then substituted with a bromide by treatment (2) with lithium bromide in dimethylformamide at 50 ° C: O d) II (2)
  • the alkyl bromide Rj-Br is treated with diethyl methylphosphonate in the presence of n-butyl lithium in tetrahydrofuran at -70 ° C.
  • the diethyl phosphonate alkyl R ⁇ CH 2 PO (OC 2 H 5 ) 2 is converted into the corresponding phosphonic acid R ⁇ CH 2 PO (OH) 2 according to the method of
  • Rabinovitz (Rabinovitz, R. J. Org. Chem. 1963, 28, 2975-2978) by treatment with a trimethylsilyl halide to give a bis (trimethylsilyl) phosphonate which hydrolyzes very easily to give the corresponding phosphonic acid.
  • R 2 represents a linear, branched or cyclic, saturated or unsaturated C 1 -C 48 alkyl group, this alkyl group (alkenyl, alkynyl) may carry one or more aromatic groups, it may comprise one or more ether bridges, one or more functions chosen from: a carboxylic acid, an ester, an amide, a nitrile, a hydroxyl, an aldehyde, a ketone, a halogen, an amine, a thiol, a thio-ketone, an episulfide, a selenol, a seleno-ketone, a sulfide, a sulfone, a sulfoxide, it can carry one or more heterocycles.
  • the alcohol R 2 - CH 2 - OH is transformed into the aldehyde R 2 - CHO by one of the treatments conventionally practiced by a person skilled in the art: . Swern oxidation (Mancuso, AJ and Swem, D. Synthesis 1981, 165.185) by treatment with allyl chloride in DMSO.
  • the aldehyde R 2 -CHO is then treated with tetraethyl methylene diphosphonate in the presence of sodium hydride in THF at room temperature to give the corresponding diethyl alkyl phosphonate:
  • R 2 CH CH PO (OC 2 H 5 ) 2
  • the isomer (E) or the isomer (Z) is preferably obtained. But one could also consider obtaining the same product by a completely different process known to those skilled in the art.
  • the diethyl alkyl phosphonate is then converted to the corresponding phosphonic acid by the Rabinowitz method as set out above.
  • the Rabinowitz reaction is carried out in the presence of pyridine in dichloromethane.
  • the hydrolysis of bis phosphonate (triméfhyl silyl) is carried out by treatment with a basic aqueous solution, such as for example, by addition of an aqueous solution of sodium hydroxide 0.1 N.
  • the final product is isolated by purification methods (extractions) well known to those skilled in the art.
  • the method preferentially used for carrying out the phosphorylation of the phosphonic acids obtained in the preceding stages is the Michelson method (Michelson, A.M. Biochem. Biophys. Acta. 1964, 91, 1-13).
  • This method consists in first activating the phosphonic diacids by reaction of the mono-salt of ⁇ -tributylammonium on diphenyl phosphate chloride (generally rapid reaction) to lead to an "activated" phosphonic anhydride. The latter reacts without being isolated in pyridine, with n-tributylammonium orthophosphate, to give the expected pyrophosphonate.
  • This reaction takes place in two stages without purification of the intermediate compound: the first stage is carried out in two hours and the displacement of the diphenyl phosphate group requires eight hours of reaction. Both reactions are total and the yields are satisfactory.
  • the final product is isolated by purification methods well known to those skilled in the art (chromatography on silica gel for example). This reaction gives rise to the formation of secondary products: triphosphonate, symmetrical diphosphonate, symmetrical triphosphonate etc., which are of interest in the present invention and are isolated by chromatography.
  • A carries functional groups liable to be affected by the reactions mentioned above such as bromination reactions, oxidation, addition of a dialkyl methylene phosphonate, deprotection of dialkyl phosphonate, phosphonylation, etc.
  • protective groups of these functional groups are used.
  • Such protective groups are well known to those skilled in the art and are chosen so as to withstand the reaction conditions mentioned above and so that they can be removed under conditions which are sufficiently mild to not affect the entirety of the rest of the molecule.
  • R 3, R t, R 5 independently of one another, a linear, branched or cyclic, saturated or unsaturated C 1 -C 40 alkyl group, this alkyl group (alkenyl, alkynyl) being capable of being a carrier of one or more aromatic groups, of comprising one or more ether bridges, one or more functions chosen from: a carboxylic acid, an ester, an amide, a nitrile, a hydroxyl, an aldehyde, a ketone, a halogen, a amino, a thiol, a thio-ketone, an episulfide, a selenol, a seleno-ketone, a sulfide, a sulfone, a sulfoxide, to be a carrier of one or more heterocycles, x being an integer equal to 0 or 1.
  • the resulting ether is oxidized by the action of a catalytic amount of selenium dioxide in the presence of t-butyl hydroperoxide to regenerate the oxidizing agent in situ from the selenium formed (Umbreit, M. A.; Sharpless, K.B. J. Am.
  • Oxidation with selenium dioxide is a very selective means for obtaining an alcohol or aldehyde function according to the experimental protocol used.
  • This reagent preferentially oxidizes the allylic methyls, forming a stereochemical compound E. Depending on the conditions used, an alcohol is therefore obtained.
  • the coupling is carried out by treatment of the alcohol with sodium hydride at the reflux of THF followed by the addition of alkyl bromide R 3 - Br.
  • A is a derivative of 4- (methyl oxyalkyl) benzophenone type
  • 4- (bromomethyl) benzophenone is previously prepared by treatment of 4-methylbenzophenone with bromine at reflux of carbon tetrachloride.
  • the deprotection of the ether is carried out by the action of a catalytic amount of pyridinium p-toluene sulfonate in methanol, thus giving the compounds with quantitative yields.
  • the alcohol is then oxidized to aldehyde and then transformed into alkyl phosphonate.
  • the Michelson reaction can then be applied to give the pyrophosphonates and the corresponding polyphosphonylated derivatives.
  • R- 6, R representing, independently of one another, a linear, branched or cyclic, saturated or unsaturated C 1 -C 40 alkyl group, this alkyl group (alkenyl, alkynyl) being capable of carrying one or more aromatic groups, to include one or more ether bridges, one or more functions chosen from: a carboxylic acid, an ester, an amide, a nitrile, a hydroxyl, an aldehyde, a ketone, a halogen, an amine, a thiol, a thio-ketone, an episulphide, a selenol, a seleno-ketone, a sulphide, a sulphone, a sulphoxide, to carry one or more heterocycles, the following synthetic scheme can be proposed:
  • the invention also relates to pharmaceutical compositions characterized in that they comprise, in addition to a pharmaceutically acceptable excipient, at least one compound according to formula (I) above. It also relates to the use of a compound corresponding to formula (I) above for the preparation of a drug modulating the proliferation of ⁇ 9 ⁇ 2 T lymphocytes. According to the invention, the compounds corresponding to formula (I) below above show an activity of ligands modulating the proliferation of ⁇ 9 ⁇ 2 T lymphocytes. By modulator is meant either stimulating or inhibiting.
  • the compounds stimulating the proliferation of ⁇ 9 ⁇ 2 T lymphocytes are particularly advantageous for preventing and / or treating infectious diseases such as those caused by viruses, bacteria, protozoan agents which have been listed above. They can also be useful for the prevention and / or treatment of certain tumors.
  • certain chronic inflammatory pathologies can be prevented and / or treated with inhibitors of the proliferation of ⁇ 9 ⁇ 2 T lymphocytes according to the invention.
  • the subject of the invention is the use of a compound corresponding to formula (I) above for the preparation of a composition intended for the prevention or treatment of a pathology inducing activation of ⁇ 9 ⁇ 2 T lymphocytes.
  • the subject of the invention is the use of a compound corresponding to formula (I) for the preparation of a composition intended for the prevention or treatment of an infectious disease, such as those caused by viruses , bacteria, protozoan agents, in particular the human immunodeficiency virus, or HIV, the simian immunodeficiency virus or SIV, the herpes simplex or HSV virus, the human herpes virus-6 or HHV- 6, vaccinia virus, tuberculosis, salmonellosis, brucellosis, tularemia, malaria, listeriosis.
  • infectious disease such as those caused by viruses , bacteria, protozoan agents, in particular the human immunodeficiency virus, or HIV, the simian immunodeficiency virus or SIV, the herpes simplex or HSV virus, the human herpes virus-6 or HHV- 6, vaccinia virus, tuberculosis, salmonellosis, brucellosis, tularemia, malaria, listeriosis.
  • Another subject of the invention is the use of a compound corresponding to formula (I) above for the preparation of a composition intended for the prevention or treatment of certain tumors.
  • the subject of the invention is also the use of a compound corresponding to formula (I) above for the preparation of a composition intended for the prevention or treatment of a chronic inflammatory disease, such as, by for example, systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, Behçet's disease, allogenic transplant rejection, chronic autoimmune hepatitis, polymyositosis, inflammatory colon diseases.
  • the invention extends to therapeutic or diagnostic compositions comprising at least one compound of formula (I). More particularly it relates to a therapeutic composition comprising a compound of formula (I), capable of being administered to a primate, in particular to humans.
  • prevention can be understood to include vaccination.
  • the invention therefore extends to preventive immunostimulatory compositions or to vaccine compositions including at least one compound of formula
  • a composition according to the invention may also advantageously comprise one or more other active principle (s), in particular an active principle acting in synergy with a compound of formula (I).
  • a compound according to the invention can act as a vaccine adjuvant.
  • the vaccinating composition according to the invention is then formed of a known vaccinating composition to which an amount of compound according to the invention is added.
  • composition according to the invention is prepared in a galenical form allowing its administration either by general route, in particular by oral route, by parenteral route, directly in the peripheral blood of the primate or by topical route.
  • one or more suitable excipients are added to the compound of formula (I).
  • the dosage form of a therapeutic or preventive composition according to the invention is produced according to the chosen route of administration, by the traditional dosage formulation techniques.
  • the quantity and concentration of compound (s) according to the invention and the dosage are determined by reference to the known chemotherapeutic treatment of the diseases to be treated or to be prevented, taking into account the bioactivity of the compounds according to the invention vis-à-vis against lymphocytes
  • the compound according to the invention is administered in an amount capable of creating in the peripheral blood of the patient a concentration greater than the IC 50 concentration of the compound.
  • the invention also relates to a process for the preparation of a composition having the property of modulating the proliferation of ⁇ 9 ⁇ 2 T lymphocytes, in which at least one compound according to the invention is used.
  • the invention further relates to a method for preparing a therapeutic or preventive composition. pathologies listed above, in which at least one compound according to the invention is used.
  • the invention relates in particular to a process for the preparation of a composition intended for administration to humans or animals, orally, parenterally, in particular in contact with the peripheral blood of humans or animal or topically, for the preventive or curative treatment of a pathology as stated above, process in which at least one compound according to the invention is used.
  • the subject of the invention is the use of a compound according to formula (I) in an in vitro biological test as a stimulator of the proliferation of ⁇ 9 ⁇ 2 T lymphocytes.
  • the subject of the invention is the use of a compound according to formula (I) in an in vitro biological test as an inhibitor of the proliferation of ⁇ 9 ⁇ 2 T lymphocytes.
  • kits for in vitro diagnosis of a pathology inducing activation of ⁇ 9 ⁇ 2 T lymphocytes characterized in that it comprises at least one compound according to the invention. It further relates to a kit for in vitro diagnosis of a pathology inducing an inhibition of ⁇ 9 ⁇ 2 T lymphocytes, characterized in that it comprises at least one compound according to the invention.
  • a kit for in vitro diagnosis of an infectious disease such as those caused by viruses, bacteria, protozoa agents, of a tumor or of a chronic inflammatory disease, the diagnostic kit operating according to the usual principles known for such devices and based on stimulation or inhibition by the compounds according to the invention.
  • TLC thin layer chromatographies
  • the chromatographies on a silica gel column were carried out with Carlo Erba silica (60 A silica gel, particle size: 35-70 ⁇ m). All the solvents used were distilled and made anhydrous before use according to the procedures described by DD Perrin and WLF Amarego, "Purification of laboratory chemicals", Pergamon Press, 3 rd Edition, London, 1988.
  • the proton NMRs were recorded at temperature ambient on a Bruker AC 250 device (at a frequency of 250 MHz), or Bruker DPX 400 (at a frequency of 400 MHz).
  • the chemical shifts ⁇ are expressed in ppm relative to the tetramethylsilane taken as an external reference.
  • the device is calibrated according to the CHC1 3 signal fixed at 7.24 ppm, acetone fixed at 2.2 ppm or water fixed at 4.79 ppm.
  • the multiplicity of signals is indicated by one or more lowercase letters: s (singlet), d (doublet), t (triplet), q (quadruplet), m (solid or multiplet).
  • the NMR spectra of carbon 13 were recorded at room temperature on a Bruker DPX 400 device (at a frequency of 100 MHz).
  • the chemical shifts ( ⁇ ) are expressed in ppm relative to the tetramethylsilane taken as internal reference.
  • the NMR spectra of phosphorus 31 were recorded at room temperature on a Bruker DPX 200 device (at a frequency of 81.0 MHz). The chemical shifts ( ⁇ ) are expressed in ppm compared to 85% phosphoric acid taken as an external reference.
  • the mass spectra were recorded on a Jeol JMS-DX300 device by the FAB positive or negative ionization method. Two matrices were used: G / T (glycerol-thioglycerol 1/1 v / v) or else NOBA (3-nitrobenzyl alcohol).
  • the phosphonic acid (2 mmol, 1 eq) is dissolved in 20 ml of methanol, there is added n-tributylamine (2 mmol, 1 eq) and the mixture is left under magnetic stirring for 30 minutes at room temperature. The solvent is evaporated. The resulting crude product is co-evaporated with anhydrous pyridine (3 ⁇ 10 ml) to remove traces of water. The phosphonic monosalts of "-tributylammonium obtained are dissolved in 18 ml of anhydrous THF. Diphenyl chlorophosphate (2 mmol, 1 eq) and w-tributylamine (6 mmol, 3 eq) are successively added. The mixture is kept under magnetic stirring at room temperature and under a nitrogen atmosphere for 2 hours.
  • Activated phosphonic anhydride (1.41 ml / hour) is slowly added to the tributylammonium orthophosphate monosalt (6 mmol, 3 eq) dissolved in 20 ml of anhydrous pyridine.
  • the mixture is kept under magnetic stirring, at room temperature and under a nitrogen atmosphere for 15 hours, the solvents are then evaporated and the residual oil obtained chromatographed on silica gel (4: 6, 27% aqueous ammonia: isopropanol).
  • R f 0.35 (4: 6, 27% ammonia: isopropanol).
  • Example 21 General method of deprotection of THP groups: A solution of compound 12 or 13 (5.26 mmol, 1 eq) and of pyridinium toluenesulfonate (0.48 mmol, 0.09 eq) in 40 ml of methanol is maintained under magnetic stirring, at reflux for three hours. The reaction mixture is then concentrated and chromatography on silica gel (1: 1, ethyl ether: petroleum ether) to give colorless oils.
  • Rf 0.5 (1: 1, petroleum ether: ethyl ether)
  • Aldehydes 26 and 27 were prepared according to the oxidation method with pyridinium dichromate described above.
  • the phosphonic acids below were prepared by the action of trimethylsilane bromide on their phosphonic esters as described above.
  • Example 52 ⁇ , ⁇ - (4-Methylpenta-1,3-dienyl) triammonium triphosphonate (44):
  • 3-methylbut-3-enole (10 g, 116 mmol, 1 eq) dissolved in 100 ml of dichloromethane and then triethylamine (23.5 g, 236 mmol) are introduced into a 250 ml flask, under a nitrogen atmosphere. , 2 eq) at -0 ° C.
  • Benzoyl chloride (24.4 g, 174 mmol, 1.5 eq) dissolved in 20 ml of dichloromethane is then added over a period of 10 min.
  • Example 56 4-hydroxy-3-methylbutyl benzoate (48): In a 100 ml flask under a nitrogen atmosphere, the 3-methylbut-3-enyl benzoate (2 g, 10.52 mmol,) is dissolved. 1 eq) in 2 ml of anhydrous THF then the BH 3. Me 2 S (1.8 ml, 3.5 mmol, 2 M solution in THF, 1/3 eq) is added at 0 ° C over a period of 5 minutes; the whole is allowed to return to room temperature. After 2 hours of reaction, the H 2 O 2 (4 ml, 30% aqueous solution, 3 eq) is added dropwise at 0 ° C and the magnetic stirring continued for 30 min.
  • the reaction is stopped by adding 50 ml of water, the phase is extracted organic with dichloromethane (3x100 ml), the organic phases are combined, washed once with water, with a 1N hydrochloric acid solution (3x100 ml), dried over sodium sulfate, concentrated, and the residual oil obtained is chromatographed on silica gel (4: 6, ethyl ether: petroleum ether).
  • the diphenylphosphate chloride (0.34 g, 1.27 mmol, 1 eq) and the ⁇ -trioctylamine (1.34 g, 3.81 mmol, 3 eq) are then added respectively.
  • the mixture is kept under magnetic stirring, at room temperature and under a nitrogen atmosphere for two hours.
  • Activated phosphonic anhydride (1.41 ml / hour) is slowly added to the monosalts of ..- trioctylammonium orthophosphate (1.71 g, 3.81 mmol, 3 eq) dissolved in 40 ml of anhydrous pyridine.
  • the mixture is kept under magnetic stirring, at room temperature and under a nitrogen atmosphere for 15 hours, the solvents are then evaporated and the residual oil chromatographed on silica gel (4: 6, 27% ammonia: isopropanol)
  • Example 69 4-Bromo-2-methylbutene (60): To a solution of lithium bromide (15 g, 182 mmol, 2 eq) in 150 ml of N, N-dimethylformamide brought to reflux, under magnetic stirring and under a nitrogen atmosphere, 4-mesyl-2-methylbutene ( 13.47 g, 91 mmol, 1 eq).
  • Rf 0.5 (ethyl acetate)
  • Rf 0.32 (4: 6, 27% ammonia: isopropanol).
  • Diethyl 4-methyl-2oxa-pent-4-enylphosphonate (96): Diethyl hydroxymethylphosphonate (3 g, 17.8 mmol, 1 eq) is dissolved in 50 ml of THF to which the hydride is added sodium (0.43 g, 17.8 mmol, 1 eq). The addition of 1-chloro-2-methylpropene (1.62 g, 17.8 mmol, 1 eq) is then carried out. After one hour with magnetic stirring, at room temperature and under a nitrogen atmosphere, hydrolysis is carried out with 100 ml of water. Extracted with ether (3x50 ml).
  • EXAMPLE 113 Activation of the proliferation of T lymphocytes in human peripheral blood
  • Human peripheral blood lymphocytes PBMC are isolated from the blood of donors by centrifugation on Ficoll-Hypaque. They are then cultured in 96-well plates at the rate of 2.10 6 cells / ml in 200 ⁇ l of RPMI 1640 medium (Gibco) containing 10% fetal calf serum or human AB serum, 20 mM Glutamine, 10 mM Hepes, ImM sodium pyruvate, 10 ⁇ g / ml penicillin-streptomycin. The molecules to be tested are then added at final concentrations ranging from 0.001 ⁇ M to 500 ⁇ M. Each condition is performed in triplicate.
  • the molecules are diluted in isotonic phosphate buffer (PBS).
  • PBS isotonic phosphate buffer
  • the cells are then incubated at 37 ° C-5% C02 for 4 days.
  • Cell proliferation is then determined by measuring the incorporation of thymidine H (H-TdR). For this, 0.5 ⁇ Ci of 3 H-TdR is added per culture. After 24 hours, the cells are recovered on a Cell Harvester (Packard Instruments) and the radioactivity incorporated in high molecular weight material is counted using a Rack-Beta counter (Packard).
  • IPP isoprenyl pyrophosphate
  • Example 114 Expansion of V ⁇ 9 / V ⁇ 2 Lymphocytes
  • the PBMCs cultured under the conditions described above, were analyzed after 5 days of culture in the presence of different molecules by immunofluorescence in flow cytometry. For this, the cells are recovered, washed in PBS and then incubated in the presence of anti-human CD3 monoclonal antibody conjugated with fluorescein (FITC, FL1) and human anti-V ⁇ 9 coupled to biotin and then revealed with the Streptavidin conjugate. -phycoerythrin (ST-PE, FL2).
  • FITC fluorescein
  • ST-PE -phycoerythrin
  • the labeling is carried out by incubation for 30 minutes with 0.5 ⁇ g of each antibody per million cells.
  • the analysis is carried out after washing on a FACScalibur-SORT cell analyzer-sorting cytofluorimeter (Becton Dickinson, Moutain View, CA).
  • the results are analyzed using Cellquest software. The results are shown in Figures 2 (A to L).
  • FIG. 2A gives the profile (FSC size and SSC granulosity) of the cells studied.
  • Figure 2B shows a fresh PBMC before cultivation.
  • Figure 2C shows a fresh PBMC after 5 days in culture.
  • Figures 2D to 2L show a PBMC after 5 days in culture in the presence of the molecule tested.
  • FIG. 2D phytohemagglutinin A (PHA) l ⁇ g / ml
  • PPI phytohemagglutinin A
  • Figure 2D a large increase in the population of V ⁇ 9 / N ⁇ 2 T cells is observed in cultures stimulated by PPI or by the molecules according to the invention: (E) l-pyrophosphono-4-methylpenta-1,3-diene , (E) l-pyrophosphono-penta-l, 3-diene, (E) l-pyrophosphono-buta-l, 3-diene, 5-pyrophos ⁇ hono-2-methylpent-2-ene, ⁇ , ⁇ -di- [ 4-methylpent-4-enyl] -triphosphonate, 5-pyrophosphono-2-methyl ⁇ entene, 5-triphosphono-2-methylpentene.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Virology (AREA)
  • Biomedical Technology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Biotechnology (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Genetics & Genomics (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • General Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Neurosurgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • AIDS & HIV (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
EP02804596A 2001-12-11 2002-12-05 Phosphonates utiles comme modulateurs de l'activite des lymphocytes t-gamma-9-delta-2 Ceased EP1453840A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0115971 2001-12-11
FR0115971A FR2833266B1 (fr) 2001-12-11 2001-12-11 Nouveaux derives phosphonates, leur procede de preparation, leur utilisation comme modulateurs de l'activite des lymphocytes tgamma9 delta2
PCT/FR2002/004190 WO2003050128A1 (fr) 2001-12-11 2002-12-05 PHOSPHONATES UTILES COMME MODULATEURS DE L'ACTIVITE DES LYMPHOCYTES t-GAMMA-9-DELTA-2

Publications (1)

Publication Number Publication Date
EP1453840A1 true EP1453840A1 (fr) 2004-09-08

Family

ID=8870319

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02804596A Ceased EP1453840A1 (fr) 2001-12-11 2002-12-05 Phosphonates utiles comme modulateurs de l'activite des lymphocytes t-gamma-9-delta-2

Country Status (6)

Country Link
US (2) US20060241087A1 (enExample)
EP (1) EP1453840A1 (enExample)
JP (1) JP2005511748A (enExample)
AU (1) AU2002366577A1 (enExample)
FR (1) FR2833266B1 (enExample)
WO (1) WO2003050128A1 (enExample)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0212666D0 (en) * 2002-05-31 2002-07-10 Secr Defence Immunogenic sequences
US7767842B2 (en) * 2002-12-02 2010-08-03 Innate Pharma Sa Class of γδ T cells activators and use thereof
WO2005077411A2 (en) * 2004-02-10 2005-08-25 Innate Pharma Composition and method for the treatment of carcinoma
US20070218086A1 (en) * 2004-04-26 2007-09-20 Innate Pharma, S.A. Adjuvant Composition and Methods for Its Use
WO2006067635A2 (en) * 2004-12-20 2006-06-29 Innate Pharma S.A. USE OF Ϝδ T LYMPHOCYTE ACTIVATORS AS VACCINE ADJUVANT
BRPI0608926A2 (pt) * 2005-03-22 2010-11-03 Innate Pharma ativador de células t gamadelta, composição farmacêutica, uso de um ativador de células t gamadelta, composição de vacina, método de ativação de uma célula t gamadelta, célula t gamadelta, e, uso de uma célula t gamadelta
GB2443591B (en) * 2005-09-07 2010-04-28 Secr Defence Adjuvanted vaccine
EA200801028A1 (ru) * 2005-10-06 2008-10-30 Иннейт Фарма Соли фосфоантигенов с органическими основаниями и способы их кристаллизации
US8323664B2 (en) * 2006-07-25 2012-12-04 The Secretary Of State For Defence Live vaccine strains of Francisella
EP2083830A1 (en) 2006-11-17 2009-08-05 Innate Pharma Improved methods of using phosphoantigen for the treatment of cancer
GB0906234D0 (en) 2009-04-14 2009-05-20 Secr Defence Vaccine
EP3723867A1 (en) 2017-12-11 2020-10-21 The Procter & Gamble Company Phosphono-phosphate and anionic group containing polymers
US11046798B2 (en) * 2017-12-11 2021-06-29 The Procter & Gamble Company Phosphono-phosphate containing compounds and polymers
CA3083370A1 (en) 2017-12-11 2019-06-20 The Procter & Gamble Company Oral care compositions comprising phosphonate and anionic group containing polymers
US10752646B2 (en) 2017-12-11 2020-08-25 The Procter & Gamble Company Method of making phosphono-phosphate containing compounds
BR112020010126A2 (pt) * 2017-12-11 2020-10-13 The Procter & Gamble Company composições para tratamento bucal que compreendem fosfono-fosfato e polímeros contendo grupo aniônico
CN111372554A (zh) * 2017-12-11 2020-07-03 宝洁公司 包含多价阳离子和含膦酰基-磷酸根聚合物的组合物
JP7065513B2 (ja) * 2018-06-29 2022-05-12 国立研究開発法人産業技術総合研究所 有機リン化合物
WO2020065584A1 (en) 2018-09-27 2020-04-02 Phosphogam, Inc. Methods and compositions for the expansion and use of allogeneic gamma/delta-t cells

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR6914868D0 (pt) * 1969-01-23 1973-03-20 & Co Inc Merck Processos quimicos
ZA774977B (en) * 1976-09-06 1978-06-28 Sab Soc Etudes Applic Biolog Process for the preparation of 1,2-expoxypropyl-phosphonic acid derivatives
US4924024A (en) * 1988-01-11 1990-05-08 E. R. Squibb & Sons, Inc. Phosphorus-containing squalene synthetase inhibitors, new intermediates and method
US5177239A (en) * 1989-07-18 1993-01-05 E. R. Squibb & Sons, Inc. Method for preparing a phosphonic acid ester
US5298655A (en) * 1991-09-27 1994-03-29 Merck & Co., Inc. Farnesyl pyrophosphate analogs
US5827838A (en) * 1992-10-06 1998-10-27 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno & Rijksuniversteit Te Leiden Method for the treatment of diseases related with protein isoprenylation
WO1994019357A1 (en) * 1993-02-23 1994-09-01 Merrell Dow Pharmaceuticals Inc. Farnesyl:protein transferase inhibitors as anticancer agents
US5463181A (en) * 1993-02-23 1995-10-31 Merrell Dow Pharmaceuticals Inc. Farnesyl: protein transferase inhibitors as anticancer agents
US5574025A (en) * 1994-10-26 1996-11-12 Merck & Co., Inc. Inhibitors of prenyl-protein transferases
IT1276162B1 (it) * 1995-11-23 1997-10-27 Baldacci Lab Spa Geranilgeranil-derivati,procedimento per la loro preparazione e relative composizioni farmaceutiche
FR2782722B1 (fr) * 1998-09-01 2001-01-12 Inst Nat Sante Rech Med Nouveaux composes phosphoepoxydes, procede de fabrication et applications
FR2782721B1 (fr) * 1998-09-01 2000-11-03 Inst Nat Sante Rech Med Nouveaux composes phosphohalohydrines, procede de fabrication et applications
DE60024969T2 (de) * 1999-01-21 2006-09-07 Chugai Seiyaku K.K. 2-methyl-3-butenyl-1-pyrophosphorsäuresalze und mittel zur behandlung von lymphozyten
FR2791981B1 (fr) * 1999-04-06 2001-07-20 Inst Nat Sante Rech Med Composes inhibant selectivement les lymphocytes tgamma9delta2, et leurs applications
EP1169996A1 (de) * 2000-07-06 2002-01-09 Ernst Mühlbauer Kg Phosphonsäuren enthaltendes Dentalmaterial
DE10201458A1 (de) 2001-04-11 2002-10-17 Adelbert Bacher Intermediate und Enzyme des Mevalonat-unabhängigen Isoprenoidbiosyntheseweg
DK1408984T3 (da) * 2001-07-20 2009-02-09 Bioagency Ag Organofosforforbindelser til aktivering af gamma/delta T celler

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03050128A1 *

Also Published As

Publication number Publication date
AU2002366577A1 (en) 2003-06-23
FR2833266B1 (fr) 2004-10-22
JP2005511748A (ja) 2005-04-28
US8017596B2 (en) 2011-09-13
US20100204184A1 (en) 2010-08-12
FR2833266A1 (fr) 2003-06-13
US20060241087A1 (en) 2006-10-26
WO2003050128A1 (fr) 2003-06-19

Similar Documents

Publication Publication Date Title
US8017596B2 (en) Phosphonates useful as modulators of T-γ-9-δ-2 activity
BE1004193A3 (fr) Inhibiteurs d'hmg-coa reductase contenant du phosphore, composes intermediaires et leur utilisation.
CA2341574C (fr) Phosphohalohydrines, procede de fabrication et applications
KR20010021682A (ko) 녹내장 치료제로서 부작용이 없는 프로스타글란딘 유도체
JPH05509327A (ja) 抗炎症および抗ウイルス活性を有する蛋白質キナーゼｃモジュレーター
US11826387B2 (en) Use of anti-aging glycoprotein for enhancing survival of neurosensory precursor cells
PL157761B1 (pl) Sposób wytwarzania nowych, zawierajacych fosfor pochodnych kwasu 3-hydroksybutanowego PL PL PL PL PL
HU210560B (en) Process for producing squalene-synthetaze inhibitors containing phosphorous and pharmaceutical compositions containing them
CN109666637A (zh) Vγ9Vδ2 T及其激动剂在治疗肝纤维化、肝硬化和肝癌中的应用
EP1165573B1 (fr) Composes inhibitant selectivement les lymphocytes t gamma 9 delta 2
EP1109818A1 (fr) Phosphoepoxydes, procede de fabrication et applications
EP2417151B1 (fr) Peptides cycliques à activité antiparasitaire
JPH07188028A (ja) 蛋白質のイソプレニル化に関連する疾病の治療方法
JP2003516306A (ja) 膜透過性ホスホイノシチド
JP2709330B2 (ja) ２−テトラヒドロフラン誘導体の鏡像異性体、その中間体およびそれらの製造方法
CH661267A5 (fr) Analogues de prostaglandines, leur preparation et les compositions pharmaceutiques qui les contiennent.
IE53785B1 (en) Cis-bicyclo(3.3.0) octane derivatives, pharmaceutical compositions containing them and processes for the preparation of these compounds and pharmaceutical compositions
FR2733235A1 (fr) Nouveaux dioxazaphosphocanes, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
EP0822936A1 (fr) NOUVELLES TETRAHYDROPYRANO 3,2-d]OXAZOLONES SUBSTITUEES, LEUR PROCEDE DE PREPARATION ET LES COMPOSITIONS PHARMACEUTIQUES QUI LES CONTIENNENT
FR2876104A1 (fr) Composes fluorophosphonocinnamiques, systhese et aplications

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20040618

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO

RIN1 Information on inventor provided before grant (corrected)

Inventor name: GALLOIS, VALERIE

Inventor name: MENUT, CHANTAL

Inventor name: ZGANI, IBRAHIMMONROE PARK TOWERS

Inventor name: MONTERO, JEAN-LOUIS

17Q First examination report despatched

Effective date: 20080508

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: UNIVERSITE MONTPELLIER 2

Owner name: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: INNATE PHARMA

REG Reference to a national code

Ref country code: DE

Ref legal event code: R003

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 20150711