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US20060241087A1 - Phosphonates useful as modulators of t $g(g)9$g(d)2 lymphocyte activity - Google Patents

Phosphonates useful as modulators of t $g(g)9$g(d)2 lymphocyte activity Download PDF

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US20060241087A1
US20060241087A1 US10/498,313 US49831305A US2006241087A1 US 20060241087 A1 US20060241087 A1 US 20060241087A1 US 49831305 A US49831305 A US 49831305A US 2006241087 A1 US2006241087 A1 US 2006241087A1
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Jean-Louis Montero
Ibrahim Zgani
Chantal Menut
Valérie Gallois
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    • C12N5/0636—T lymphocytes

Definitions

  • the invention relates to new phosphonate derivatives, the preparation method and use thereof as ligands modulating ⁇ 9 ⁇ 2 T lymphocytes and pharmaceutical formulations comprising same.
  • T lymphocytes are cells which develop in the thymus. They are responsible for cell mediation immunity. T lymphocytes are divided into two subgroups corresponding to the receptors they comprise: ⁇ T lymphocytes and ⁇ T lymphocytes.
  • ⁇ T lymphocytes of primates present in the peripheral blood represent, in the healthy individual, generally from 1 to 5% of the lymphocytes in the blood and play a role in the immune system.
  • ⁇ 9 ⁇ 2 T lymphocytes (sometimes also referred to as ⁇ 2 ⁇ 2 T lymphocytes) are ⁇ T lymphocytes comprising V ⁇ 9 and V ⁇ 2 variable region receptors. They represent the majority of ⁇ T lymphocytes in human blood.
  • ⁇ 9 ⁇ 2 T lymphocytes When they are activated, ⁇ 9 ⁇ 2 T lymphocytes can exert a powerful cytotoxic activity on cells carrying pathogenic agents. A significant increase in the population of V ⁇ 9 ⁇ 2 cells in the presence of various pathogenic agents has particularly been demonstrated.
  • viruses such as for example 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. et al, J Infect. Dis. 165, 917-919, 1992) or by another virus such as simian immunodeficiency virus or SIV, herpes simplex virus or HSV, human herpes virus-6 or HHV-6, vaccinia.
  • viruses such as for example 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. et al, J Infect. Dis. 165, 917-919, 1992) or by another virus such as simian immunodeficiency virus or SIV, herpes simplex virus or HSV, human herpes virus-6 or HHV-6,
  • They may also consist of cells infected by bacterial infectious agents or protozoa such as, for example Mycobacterium tuberculosis , the infectious agent responsible for tuberculosis in humans (“The primary response of human ⁇ / ⁇ + T cells to Mycobacterium tuberculosis is restricted to V ⁇ 9-bearing cells”, Lucasitz D. et al, J. Exp.
  • Salmonella typhi the infectious agent responsible for salmonellosis, Brucella melitensis , responsible for brucellosis, Francisella tularensis , the pathogenic agent in tularaemia, Plasmodium virax and Plasmodium falciparum which are responsible for malaria, Listeria monocytogenes which is the pathogenic agent in listeriosis in humans. (“Role of ⁇ T lymphocytes in immune response in human and mice”, A. Saplino and F. Dieli, Critical Reviews in immunology, 18: 327-357 (1998)).
  • tumoral cell lines are recognised and destroyed by ⁇ 9 ⁇ 2 T lymphocytes, such as for example Daudi cells (P. Fish et al, Science; 250: 1269-1273 (1992)) or the RPMI 8226 line (Seclin, L. K. et al, Scand. J. Immunol. 36: 107-117 (1992)).
  • ⁇ 9 ⁇ 2 T lymphocytes recognise a wide variety of antigens expressed in human and/or primate conditions. For this reason, molecules are required that make it possible to stimulate the proliferation of ⁇ 9 ⁇ 2 T lymphocytes, so as to favour the immune response against these conditions.
  • human ⁇ 9 ⁇ 2 T lymphocytes react, in the case of mycobacterial infection, with four phosphate structure non-peptide natural molecules, referred to as phosphoantigens, which has 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 mycobacterial ligands” Patricia CONSTANT et al, Science, 264, p. 267-270).
  • these natural antigens are not completely identified and can only be produced in small quantities (WO 95/20673).
  • monoalkylphosphates particularly monoethylphosphate
  • isoprenylpyrophosphate is also recognised as stimulating the proliferation of ⁇ 9 ⁇ 2 T lymphocytes “Non peptide ligands for human ⁇ 6 T-cells”, Tanaka Y. et al, Proc. Natl. Acad. Sci. USA 1994, 91 : 8175-8179)
  • phosphate derivatives have demonstrated a beneficial activity as a stimulant of the proliferation of ⁇ 9 ⁇ 2 T lymphocytes, in vitro, it is known that the presence of a high number of phosphatases in the human body or in the body of primates will not enable these molecules to reach their target if they are used in vivo.
  • biphosphonate compounds such as alendronate, ibandronate and pamidronate and their activity as stimulants of ⁇ 9 ⁇ 2 T lymphocyte proliferation are known.
  • alendronate ibandronate
  • pamidronate pamidronate
  • said compounds being more hydrophobic than the compounds according to the prior art, they have a better bioavailability.
  • the invention relates to new compounds complying with the formula I below, said compounds being characterised in that:
  • A represents a linear, ramified or cyclic alkyl group, saturated or unsaturated at C 1 -C 50
  • said alkyl group (alkenyl, alkynyl) may comprise one or more aromatic groups, it may comprise one or more ether bridges, one or more functions selected 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, it may comprise one or more heterocycles,
  • n is an integer ranging from 1 to 4,
  • X represents a group selected from the hydrogen atom and a pharmaceutical acceptable organic or mineral cationic group
  • B represents a group selected from:
  • the aromatic groups liable to be contained in the alkyl (alkenyl, alkynyl) chain of A particularly include: phenyl, pyridine, benzophenone.
  • heterocycles liable to be contained in the alkyl (alkenyl, alkynyl) chain of A particularly include the epoxide and aziridine groups.
  • the alkyl (alkenyl, alkynyl) chain of A comprises an ether bridge
  • said bridge may be located at any position of the chain, including inside a cycle. Preferentially, it is located in the ⁇ position with respect to the phosphorus atom.
  • the X + groups that can be used according to the present invention include: H + , Na + , NH 4 + , K + , Li + , (CH 3 CH 2 ) 3 NH + or an enzyme-labile ester function.
  • A represents a linear, ramified or cyclic alkyl (alkenyl, alkynyl) group in C 1 -C 50 comprising at least one double bond
  • the compounds according to this alternative embodiment of the invention and complying with formula I above are characterised in that A comprises 3 to 25 carbon atoms, more preferentially, A comprises 5 to 10 carbon atoms.
  • A represents a linear, ramified or cyclic alkyl (alkenyl, alkynyl) group in C 1 -C 50 comprising at least one ⁇ -halohydrine group according to formula II below, wherein Y represents an atom selected from fluorine, chlorine, iodine and bromine:
  • A represents a linear, ramified or cyclic alkyl (alkenyl, alkynyl) group, saturated or unsaturated in C 1 -C 50 comprising at least one epoxide group.
  • A represents a linear, ramified or cyclic alkyl (alkenyl, alkynyl) group, saturated or unsaturated in C 1 -C 50 comprising at least one tertiary alcohol group.
  • A represents a linear, ramified or cyclic alkyl (alkenyl, alkynyl) group, saturated or unsaturated in C 1 -C 50 comprising at least one ⁇ -diol group.
  • A represents a linear, ramified or cyclic alkyl (alkenyl, alkynyl) group in C 1 -C 50 comprising at least one aldehyde group or ⁇ -hydroxyaldehyde group.
  • the invention also relates to a method to prepare the compounds complying with formula I.
  • the compounds, according to the invention may be prepared according to the reaction models given below, according to the various A and B groups.
  • R 1 represents a linear, ramified or cyclic alkyl group, saturated or unsaturated at C 1 -C 49 , said alkyl group (alkenyl, alkynyl) may comprise one or more aromatic groups, it may comprise one or more ether ridges, one or more functions selected 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, it may comprise one or more heterocycles.
  • the alcohol R 1 —OH is treated: (1) with methyl sulphonate chloride in the presence of n-triethylamine in dichloromethane.
  • the methylsulphonate group is then substituted by a bromide by treatment (2) with lithium bromide in dimethylformamide at 50° C.:
  • the alkyl bromide R 1 —Br is treated with diethyl methylphosphonate in the presence of n-butyl lithium in tetrahydrofuran at ⁇ 70° C.
  • the diethyl alkyl phosphonate R 1 CH 2 PO(OC 2 H 5 ) 2 is converted into the corresponding phosphonic acid R 1 CH 2 PO(OH) 2 according to Rabinovitz's method (Rabinovitz, R. J. Org. Chem. 1963, 28, 2975-2978) by treating with a trimethylsilyl halide to give a bis(trimethylsilyl) phosphonate which is hydrolysed very easily to produce the corresponding phosphonic acid.
  • trimethyl silyl bromide is used rather than chloride which requires excessively long reaction times or iodide which generates iodohydric acid which is frequently a problem in multifunctional molecules.
  • R 2 represents a linear, ramified or cyclic alkyl group, saturated or unsaturated at C 1 -C 48 , said alkyl group (alkenyl, alkynyl) may comprise one or more aromatic groups, it may comprise one or more ether bridges, one or more functions selected 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, it may comprise one or more heterocycles.
  • the latter oxidation method is used when R 2 comprises one or more double bonds conjugated with the aldehyde function.
  • the aldehyde R 2 —CHO is then treated with tetraethyl methylene diphosphonate in the presence of sodium hydride in THF at ambient temperature to produce the corresponding diethyl alkyl phosphonate R 2 —CH ⁇ CH—PO(OC 2 H 5 ) 2
  • the isomer E or the isomer Z is preferentially obtained.
  • Diethyl alkyl phosphonate is then converted into the corresponding phosphonic acid using Rabinowitz's method as explained above.
  • the Rabinowitz reaction is carried out in the presence of pyridine in dichloromethane.
  • the bis(trimethyl silyl)phosphonate is hydrolysed by treating in a basic aqueous solution, such as for example, by adding an 0.1 N aqueous soda solution.
  • the method preferentially used to perform the phosphorylation of the phosphonic acids obtained in the previous steps is Michelson's method (Michelson, A. M. Biochem. Biophys. Acta. 1964, 91, 1-13).
  • This method consists of activating the phosphonic diacids initially by reacting the n-tributylammonium mono-salt on diphenyl phosphate chloride (generally rapid reaction) to produce an “activated” phosphonic anhydride.
  • Said anhydride reacts without being isolated in pyridine, with n-tributylammonium orthophosphate, to produce the expected pyrophosphonate.
  • the final product is isolated by means of purification methods well-known to those skilled in the art (silica gel chromatography for example). This reaction gives rise to the formation of secondary products: triphosphonate, symmetric diphosphonate, symmetric triphosphonate, etc., which are of interest in the present invention and are isolated by means of chromatography.
  • A comprises functional groups liable to be affected by the reactions mentioned above such as bromination, oxidation reactions, addition of dialkyl methylene phosphonate, dialkyl phosphonate deprotection, phosphonylation, etc.
  • suitable protective groups of these functional groups are used.
  • Such protective groups are well-known to those skilled in the art and are selected in order to withstand the reaction conditions mentioned above and to be able to be removed under sufficiently safe conditions so as not to affect the integrity of the remainder of the molecule.
  • A comprises an ether bridge, preferentially in ⁇ of an allyl function:
  • R 3 , R 4 , R 5 represent independently from each other, a linear, a ramified or cyclic alkyl group, saturated or unsaturated at C 1 -C 40 , said alkyl group (alkenyl, alkynyl) being liable to comprise one or more aromatic groups, comprise one or more ether bridges, one or more functions selected 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, comprise one or more heterocycles, x being an integer equal to 0 or 1.
  • the resulting ether is oxidised under the effect of a catalytic quantity of selenium dioxide in the presence of t-butyl hydroperoxide to regenerate the oxidising agent in situ from the selenium formed (Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526-5528), (Bhalerao, U. T.; Rapaport, H. J. Am. Chem. Soc. 1971, 93, 4835-4840), (Rabjohn, N. Org. React. 1976, 24, 261-426).
  • Oxidation with selenium dioxide is a very selective means to obtain an alcohol or aldehyde function according to the experimental protocol used.
  • This reagent oxidises preferentially allyl methyls forming an E stereochemistry compound. Depending on the conditions used, this gives
  • Coupling is carried out by treating the alcohol with sodium hydride in a THF reflux followed by the addition of alkyl bromide R 3 —Br.
  • A is a 4-(methyl oxyalkyl)benzophenone type derivative
  • 4-(bromomethyl) benzophenone is prepared beforehand by treating 4-methylbenzophenone with bromine in a carbon tetrachloride reflux.
  • Ether deprotection is carried out under the effect of a catalytic quantity of pyridinium p-toluene sulphonate in methanol thus giving, with quantitative yields, the compounds
  • alcohol is then oxidised into aldehyde and then converted into alkyl phosphonate.
  • the Michelson reaction can then be applied to produce the corresponding pyrophosphonate and polyphosphonylate derivatives.
  • R 6 , R 7 represent independently from each other, a linear, a ramified or cyclic alkyl group, saturated or unsaturated at C 1 -C 40 , said alkyl group (alkenyl, alkynyl) being liable to comprise one or more aromatic groups, comprise one or more ether bridges, one or more functions selected 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, comprise one or more heterocycles, the following synthesis model may be proposed:
  • the alcohol function is protected with a benzoyl group by treating with benzoyl chloride to produce the corresponding benzoyl ether with a quantitative yield.
  • An oxidising hydroboration reaction of this compound makes it possible to obtain the corresponding alcohol:
  • the alcohol obtained above is oxidised under Swern's reaction conditions to produce the corresponding aldehyde.
  • the phosphonic diester function of this compound is converted into phosphonic diacid.
  • the last step (optional) of this synthesis is the phosphorylation of the Michelson phosphonic diacid compound to produce the pyrophosphonic compound:
  • the invention also relates to pharmaceutical formulations characterised 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 complying with formula I above for the preparation of a medicinal product modulating the proliferation of ⁇ 9 ⁇ 2 T lymphocytes. According to the invention, the compounds complying with formula I above show an activity of ligands modulating the proliferation of ⁇ 9 ⁇ 2 T lymphocytes.
  • modulating means either stimulating or inhibiting.
  • Compounds stimulating the proliferation of ⁇ 9 ⁇ 2 T lymphocytes are of particular interest in preventing and/or treating infectious diseases such as those caused by the viruses, bacteria, protozoa agents listed above. They may also be useful for the prevention and/or treatment of certain tumours.
  • Some chronic inflammatory conditions may, according to the invention, be prevented and/or treated by ⁇ 9 ⁇ 2 T lymphocytes proliferation inhibitors according to the invention.
  • the invention relates to the use of a compound complying with formula I above for the preparation of a formulation intended for the prevention or treatment of a condition inducing ⁇ 9 ⁇ 2 T lymphocyte activation.
  • the invention relates to the use of a compound complying with formula I for the preparation of a formulation intended for the prevention or treatment of an infectious disease, such as those caused by viruses, bacteria, protozoa agents, particularly human immunodeficiency virus, or H.I.V., simian immunodeficiency virus or SIV, herpes simplex virus or HSV, human herpes virus-6 or HHV-6, vaccinia, tuberculosis, salmenollosis, brucellosis, tularaemia, malaria, listeriosis.
  • an infectious disease such as those caused by viruses, bacteria, protozoa agents, particularly human immunodeficiency virus, or H.I.V., simian immunodeficiency virus or SIV, herpes simplex virus or HSV, human herpes virus-6 or HHV-6, vaccinia, tuberculosis, salmenollosis, brucellosis, tularaemia, malaria, listeriosis.
  • the invention also relates to the use of a compound complying with the formula I above for the preparation of a formulation intended for the prevention or treatment of certain tumours.
  • the invention also relates to the use of a compound complying with formula I above for the preparation of a formulation intended for the prevention or treatment of a chronic inflammatory disease, such as, for example, systemic lupus erythematosus, multiple sclerosis, rheumatoid polyarthritis, Behcet's disease, allogenic transplant rejection, chronic autoimmune hepatitis, polymyositosis, inflammatory colon diseases.
  • a chronic inflammatory disease such as, for example, systemic lupus erythematosus, multiple sclerosis, rheumatoid polyarthritis, Behcet's disease, allogenic transplant rejection, chronic autoimmune hepatitis, polymyositosis, inflammatory colon diseases.
  • the invention also applies to therapeutic or diagnostic formulations comprising at least one compound according to formula I. More specifically, it relates to a therapeutic formulation comprising a compound according to formula I, capable of being administered to a primate, particularly humans.
  • prevention may be understood to include vaccination. Therefore, the invention also applies to preventive immunostimulant formulations or vaccine formulations including at least one compound according to formula I.
  • a formulation according to the invention may also advantageously comprise one or more other active ingredient(s), particularly an active ingredient acting in synergy with a compound according to formula I.
  • a compound according to the invention may act as a vaccine adjuvant.
  • the vaccination formulation according to the invention is then formed by a known vaccination formulation to which a quantity of compound according to the invention is added.
  • the formulation according to the invention is prepared in a pharmaceutical form enabling the administration thereof either by the systemic route, particularly by the oral route, parenteral route, directly in the peripheral blood of the primate or by the topical route.
  • one or more suitable excipients are added to the compound according to formula I.
  • the pharmaceutical form of a therapeutic or preventive formulation according to the invention is produced according to the selected route of administration, by means of conventional pharmaceutical formulation techniques.
  • the quantity and concentration of compound(s) according to the invention and the dosage are determined with reference to known chemotherapy treatments of the diseases to be treated or prevented, in view of the bio-activity of the compounds according to the invention with respect to ⁇ 9 ⁇ 2 T lymphocytes, the subject to be treated, the disease in question and the desired biological effects.
  • the compound according to the invention is administered in a quantity capable of creating the patient's peripheral blood a concentration greater than the IC 50 concentration of the compound.
  • the invention also relates to a method to prepare a formulation having the property of modulating ⁇ 9 ⁇ 2 T lymphocyte proliferation, wherein at least one compound according to the invention is used.
  • the invention also relates to a method to prepare a therapeutic or preventive formulation with respect to the conditions mentioned above, wherein at least one compound according to the invention is used.
  • the invention particularly relates to a method to prepare a formulation intended to be administered to humans or animals, by the oral route, by the parenteral route, particularly in contact with the peripheral blood of humans or animals or by the topical route, for the preventive or curative treatment of a condition such as that mentioned above, wherein at least one compound according to the invention is used.
  • the invention relates to the use of a compound according to formula I in an in vitro biological test as a ⁇ 9 ⁇ 2 T lymphocyte proliferation stimulant.
  • the invention relates to the use of a compound according to formula I in an in vitro biological test as a ⁇ 9 ⁇ 2 T lymphocyte proliferation inhibitor.
  • an in vitro diagnostic kit for a condition inducing ⁇ 9 ⁇ 2 T lymphocyte activation characterised in that it comprises at least one compound according to the invention.
  • an in vitro diagnostic kit for a condition inducing ⁇ 9 ⁇ 2 T lymphocyte inhibition characterised in that it comprises at least one compound according to the invention.
  • an in vitro diagnostic kit for an infectious disease such as those caused by viruses, bacteria, protozoa agents, a tumour or chronic inflammatory disease, the diagnostic kit functioning according to the usual principles known for such devices and based on stimulation or inhibition by the compounds according to the invention.
  • NMRs were recorded at ambient temperature on a Bruker AC 250 unit (at a frequency of 250 MHz), or Bruker DPX 400 unit (at a frequency of 400 MHz).
  • the chemical displacements ⁇ are expressed in ppm with reference to tetramethylsilane taken as the external reference.
  • the unit is calibrated according to the CHCL 3 signal set at 7.24 ppm, acetone set at 2.2 ppm or water set at 4.79 ppm.
  • the multiplicity of signals is indicated by one or more lower case letters: s (singleton), d (doublet), t (triplet), q (quadruplet), m (mass or multiplet).
  • the NMR spectra of carbon 13 were recorded at ambient temperature with a Bruker DPX 400 unit (at a frequency of 100 MHz).
  • the chemical displacements ( ⁇ ) are expressed in ppm with reference to tetramethylsilane taken as the internal reference.
  • the NMR spectra of phosphorus 31 were recorded at ambient temperature with a Bruker DPX 200 unit (at a frequency of 81.0 MHz).
  • the chemical displacements ( ⁇ ) are expressed in ppm with reference to 85% phosphoric acid taken as the external reference.
  • the mass spectra were recorded on a Jeol JMS-DX300 unit using the positive or negative FAB ionisation method. Two substances were used: G/T (1/1 v/v glycerol-thioglycerol) or NOBA (3-nitrobenzyl alcohol).
  • R f 0.59 (4:6, 27% ammonia:isopropanol).
  • NMR 13 C(CDCl 3 ) (ppm): 15.66-16.43-17.70-18.11 (4C, C-13, C-14, C-15 and C-16); 26.12-27.12 (2C, C-5 and C-9); 40.10-40.54 (2C, C-6 and C-10); 119.53 (d, J 1-p 184.5 Hz, 1C, C-1); 123.71-124.67 (2C, C-7 and C-11); 124.79 (d, J 3-p 24.6 Hz, 1C, C-3); 131.79-136.23 (2C, C-8 and C-12); 144.33 (d, J 2-p 5.9 Hz, 1C, C-2); 149.04 (1C, C-4).
  • Phosphonic acid (2 mmol, 1 eq) is dissolved in 20 ml of methanol, n-tributylamine (2 mmol, 1 eq) is added and the mixture is left under magnetic stirring for 30 minutes at ambient temperature. The solvent is evaporated. The resulting unprocessed product is co-evaporated with anhydrous pyridine (3 ⁇ 10 ml) to eliminate water traces. The phosphonic n-tributylammonium mono-salt obtained is dissolved in 18 ml of anhydrous THF. Diphenyl chlorophosphate (2 mmol, 1 eq) and n-tributylamine (6 mmol, 3 eq) are successively added. The mixture is kept under magnetic stirring at ambient temperature and in a nitrogen atmosphere for 2 hours.
  • orthophosphate n-tributylammonium mono-salt is prepared: orthophosphoric acid (6 mmol, 3 eq) is dissolved in 20 ml of methanol, n-tributylamine (6 mmol, 3 eq) is added. The solvent is evaporated after 20 minutes of magnetic stirring at ambient temperature and the traces of water are then co-evaporated with anhydrous pyridine (3 ⁇ 10 ml).
  • a 70% aqueous tert-butyl hydroperoxide solution (17.13 ml, 177 mmol, 3 eq) is added to selenium dioxide (5.31 mmol, 0.09 eq) in suspension in 20 ml of dichloromethane, at ambient temperature. After 30 min, the compound 6 or 7 (59 mmol, 1 eq) is added drop by drop and magnetic stirring is maintained at 25° C. for 48 hours. The mixture is then taken up with 20 ml of toluene, concentrated and dissolved in 50 ml of ether. The organic phase is washed four times with 10% soda, once with a saturated sodium chloride solution, dried on Na 2 SO 4 and concentrated. The residue obtained undergoes silica gel chromatography (4:6, ethyl ether petroleum ether) to produce:
  • R f 0.5 (1:1, ethyl ether:petroleum ether).
  • R f 0.5 (ethyl acetate).
  • R f 0.56 (4:6, 27% ammonia:isopropanol).
  • R f 0.5 (4:6, 27% ammonia:isopropanol).
  • R f 0.15 (4:6, 27% ammonia:isopropanol).
  • NMR 13 C(D 2 O), ⁇ (ppm): 13.62 (1C, C-10′); 16.76 (1C, C-11′′); 25.91 (1C, C-4′); 39.24 (1C, C-5′); 70.41 (1C, C-1′); 76.46 (1C OCH 2 -benzyl); 120.53 (d, J 9′-P 192.5 Hz, 1C, C-9′); 124.74 (d, J 7′-P 26.3 Hz, 1C, C-7′); 128.08 (2C, C-ar); 128.82 (27C, C-ar); 130.34 (2C, C-ar); 130.74 (2C, C-ar); 129.61 (1C, C-3′); 132.14 (1C, C-4′′); 133.66 (1C, C-2′); 136.32 (1C, C-1′′); 136.99 (1C, C-5′); 140.88 (d, J 8′-P 5.8 Hz, 1C, C-8′); 143.79 (1C, C-4
  • the aldehydes 26 and 27 were prepared according to the oxidation method with pyridinium bichromate described above.
  • R f 0.8 (95:5, petroleum ether:ethyl ether).
  • the phosphonic esters below were prepared according to the Horner-Wadsworth-Emmons method described above.
  • the phosphonic acids below were prepared by means of the action of trimethylsilane bromide on their phosphonic esters as described above.
  • R f 0.4 (4:6, 27% ammonia:isopropanol).
  • R f 0.15 (4:6, 27% ammonia:isopropanol).
  • R f 0.15 (4:6, 27% ammonia:isopropanol).
  • R f 0.10 (4:6, 27% ammonia:isopropanol).
  • R f 0.5 (4:6, 27% ammonia:isopropanol).
  • 3-methylbut-3-enole (10 g, 116 mmol, 1 eq) dissolved in 100 ml of dichloromethane is introduced, followed by triethylamine (23.5 g, 236 mmol, 2 eq) at ⁇ 0° C.
  • Benzoyl chloride (24.4 g, 174 mmol, 1.5 eq) in solution in 20 ml of dichloromethane is then added over a 10 min period.
  • 3-methylbut-3-enyl benzoate (2 g, 10.52 mmol, 1 eq) is solubilised in 2 ml of anhydrous THF and BH 3 .
  • Me 2 S (1.8 ml, 3.5 mmol, 2 M solution in THF, 1 ⁇ 3 eq) is then added at 0° C. over a 5 min period; the whole is allowed to return to ambient temperature.
  • H 2 O 2 (4 ml, 30% aqueous solution, 3 eq) is added drop by drop at 0° C. and magnetic stirring is continued for 30 min.
  • the organic phase is extracted with 3 ⁇ 100 ml ethyl ether, the ethereal phases are collected and washed with water (3 ⁇ 100 ml) and dried on sodium sulphate.
  • oxallyl chloride (0.9 g, 7.1 mmol, 1.1 eq) is placed in solution in 30 ml of dichloromethane.
  • DMSO (1 g, 14.19 mmol, 2.2 eq) in 4 ml of dichloromethane is then added at ⁇ 60° C. and the mixture stirred for 15 min.
  • the reaction is stopped by adding 50 ml of water, the organic phase is extracted with dichloromethane (3 ⁇ 100 ml), the organic phases are collected, washed once with water, with a 1 N hydrochloric acid solution (3 ⁇ 100 ml), dried on sodium sulphate, concentrated, and the residual oil obtained undergoes silica gel chromatography (4:6, ethyl ether:petroleum ether).
  • R f 0.55 (ethyl acetate).
  • R f 0.41 (5:5, 27% ammonia:isopropanol).
  • diphenylphosphate chloride (0.34 g, 1.27 mmol, 1 eq)
  • n-trioctylamine (1.34 g, 3.81 mmol, 3 eq) are then added respectively.
  • the mixture is kept under magnetic stirring, at ambient temperature and in a nitrogen atmosphere for two hours.
  • 3-methylbut-3-enole (11.79 g, 137 mmol, 1 eq) dissolved in 100 ml of dichloromethane is added followed by triethylamine (20.81 g, 205.36 mmol, 1.5 eq) at ⁇ 5° C.
  • Mesyl chloride (17.25 g, 180.67 mmol, 1.1 eq) in solution in 20 ml of dichloromethane is then added over a 5 min period.
  • R f 0.5 (4:6 ethyl ether:petroleum ether).
  • reaction mixture is diluted in 50 ml of ethyl ether, washed three times with a hydrochloric acid solution (1N) and with a saturated sodium chloride solution (2 ⁇ 50 ml), dried on sodium sulphate, concentrated and undergoes silica gel chromatography (eluent ethyl acetate).
  • R f 0.5 (ethyl acetate).
  • R f 0.4 (4:6, 27% ammonia:isopropanol).
  • R f 0.4 (4:6, 27% ammonia:isopropanol).
  • Rf 0.47 (4:6, 27% ammonia:isopropanol).
  • R f 0.5 (4:6, 27% ammonia:isopropanol).
  • R f 0.21 (4:6, 27% ammonia:isopropanol).
  • R f 0.75 (4:6, 27% ammonia:isopropanol).
  • R f 0.15 (5:5, 27% ammonia:isopropanol).
  • R f 0.22 (5:5, 27% ammonia:isopropanol).
  • R f 0.10 (5:5, 27% ammonia:isopropanol).
  • R f 0.15 (5:5, 27% ammonia:isopropanol).
  • R f 0.25 (5:5, 27% ammonia:isopropanol).
  • R f 0.45 (5:5, 27% ammonia:isopropanol).
  • R f 0.46 (5:5, 27% ammonia:isopropanol).

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US20070134273A1 (en) * 2004-02-10 2007-06-14 Francois Romagne 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
US20070249565A1 (en) * 2003-12-02 2007-10-25 Christian Belmant Class of Gamma Delta T Cells Activators and Use Thereof
US20080207568A1 (en) * 2005-03-22 2008-08-28 Innate Pharma S.A. Class of Gamma Delta T Cells Activators and Use Thereof
US20080300222A1 (en) * 2005-10-06 2008-12-04 Innate Pharma Phosphoantigen Salts Of Organic Bases And Methods For Their Crystallization
US20190177490A1 (en) * 2017-12-11 2019-06-13 The Procter & Gamble Company Oral care compositions comprising phosphono-phosphate and anionic group containing polymers
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WO2006067635A2 (fr) * 2004-12-20 2006-06-29 Innate Pharma S.A. Utilisation d'activateurs de lymphocytes g? t comme adjuvants de vaccins
US20090087456A1 (en) * 2005-09-07 2009-04-02 James Edward Eyles Adjuvanted vaccine
WO2008012538A2 (fr) 2006-07-25 2008-01-31 The Secretary Of State For Defence Souche de vaccin vivant
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US7767842B2 (en) 2002-12-02 2010-08-03 Innate Pharma Sa Class of γδ T cells activators and use thereof
US20070249565A1 (en) * 2003-12-02 2007-10-25 Christian Belmant Class of Gamma Delta T Cells Activators and Use Thereof
US20070134273A1 (en) * 2004-02-10 2007-06-14 Francois Romagne 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
US20080207568A1 (en) * 2005-03-22 2008-08-28 Innate Pharma S.A. Class of Gamma Delta T Cells Activators and Use Thereof
US7683045B2 (en) * 2005-03-22 2010-03-23 Innate Pharma S.A. Class of γδ T cells activators and use thereof
US20100222306A1 (en) * 2005-03-22 2010-09-02 Innate Pharma, S.A. Class of Gamma Delta T Cells Activators and Use Thereof
US20080300222A1 (en) * 2005-10-06 2008-12-04 Innate Pharma Phosphoantigen Salts Of Organic Bases And Methods For Their Crystallization
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