US20190330260A1 - Process - Google Patents

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US20190330260A1
US20190330260A1 US16/470,943 US201716470943A US2019330260A1 US 20190330260 A1 US20190330260 A1 US 20190330260A1 US 201716470943 A US201716470943 A US 201716470943A US 2019330260 A1 US2019330260 A1 US 2019330260A1
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reaction mixture
complex alcohol
temperature
minutes
alcohol
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US16/470,943
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Stephen Geytenbeek
Andrew Stirling
Paul David Gavin
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Avecho Biotechnology Ltd
Avecho Biotechnology Ltd
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Avecho Biotechnology Ltd
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    • 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 System
    • 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
    • C07F9/65522—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 condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/095—Compounds containing the structure P(=O)-O-acyl, P(=O)-O-heteroatom, P(=O)-O-CN
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/11—Esters of phosphoric acids with hydroxyalkyl compounds without 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Definitions

  • the invention relates to a phosphorylation process of complex alcohols, and products obtained by that process.
  • Phosphorylation processes and reagents are chosen to avoid significant degradation of the compound being phosphorylated and to produce desired yields.
  • reagents such as 2:2:2-trichloroethyl dichlorophosphate, di-imidazolide chlorophosphate and di-analide chlorophosphate are used under gentle conditions to avoid degradation of the compound being phosphorylated.
  • reagents such as 2:2:2-trichloroethyl dichlorophosphate, di-imidazolide chlorophosphate and di-analide chlorophosphate are used under gentle conditions to avoid degradation of the compound being phosphorylated.
  • such processes have been found to produce limited yields, which would not be economical or suitable for commercial purposes.
  • the reagent phosphorous oxychloride is used, but the reaction typically produces a variety of by-products and hydrogen chloride. Such process may also not be commercially viable given that the reagent phosphorous oxychloride is difficult to handle.
  • the reagent P 4 O 10 which is commonly known as phosphorus pentoxide, but has other names such as phosphorus (V) oxide, phosphoric anhydride and diphosphorus pentoxide, is a white crystalline solid.
  • This reagent has been used for phosphorylation of ethanol and other short chain primary alcohols (i.e. less than 6 carbon atoms) and it has been found to be suitable for phosphorylation of alcohols such as primary fatty alcohols, secondary alcohols and aromatic alcohols.
  • 200043870 describes a process, which involves forming an intimate mixture of one or more of these alcohols and P 4 O 10 , partly hydrated P 4 O 10 or a mixture thereof, at a temperature below 80° C., and allowing the intimate mixture to continue to react for a period of time at this temperature, i.e. below 80° C., until formation of the phosphorylated alcohol is substantially formed. It is clear that the temperature must be kept to a minimum and below 80° C. to avoid degradation.
  • the present inventors have found that complex alcohols can be phosphorylated at a high temperature and that, at such temperatures, desirable yields can be obtained with minimal degradation of the complex alcohols.
  • the invention relates to a process for phosphorylating a complex alcohol, comprising the steps of:
  • the complex alcohol may be a linear or branched alcohol comprising at least 6 carbon atoms (i.e. 6 or more carbon atoms). In some embodiments, the complex alcohol comprises at least 7 carbon atoms. In other embodiments, the complex alcohol comprises at least 8 carbon atoms. In particular embodiments, the complex alcohol comprises at least 10 carbon atoms.
  • the number of carbon atoms mentioned herein refers to the number of carbon atoms that make up the backbone of the linear or branched complex alcohol or the ring system of the cyclic complex alcohol.
  • linear and branched complex alcohols include, but are not limited to, hexanol, hexan-1-ol, heptanol, heptan-1-ol, octanol, octan-1-ol, decanol, decan-1-ol, undecanol, dodecanol, 1-dodecanol, tridecanol, 1-tetradecanol, pentadecanol, cetyl alcohol, stearyl alcohol, 1-methylhexan-1-ol, 2-methylhexan-1-ol, 3-methyl-heptan-1-ol, 4-methylhexan-1-ol, 1-methylhexan-2-ol, 2-methylhexan-2-ol, 3-methyl-hexan-2-ol, 4-methylhexan-2-ol, 1-methylhexan-3-ol, 2-methylhexan-3-ol, 3-methyl-hexan-3-ol, 4-methylhexan-3-ol, 4-
  • the complex alcohol may be a cyclic complex alcohol and may be carbocyclic or heterocyclic. Further, the carbocyclic or heterocyclic complex alcohol may be aromatic or non-aromatic. In some embodiments, the heterocyclic complex alcohol comprises one or more heteroatoms. In one embodiment, the heterocyclic complex alcohol comprises one heteroatom. In another embodiment, the heterocyclic complex alcohol comprises two heteroatoms. The heteroatom may be selected from the group consisting of N, O, S and P.
  • the cyclic complex alcohol may also be monocyclic or polycyclic.
  • the polycyclic complex alcohol may comprise 2 or more rings. In some embodiments, the polycyclic complex alcohol comprises 2 or more rings, wherein at least 2 rings are fused.
  • the complex alcohol is a sterol.
  • the sterol may be a phytosterol.
  • the sterol is cholesterol.
  • the complex alcohol is a chromanol.
  • the chromanol is a tocopherol or tocotrienol.
  • the tocopherol is natural, synthetic, or a combination thereof. Natural tocopherol typically comprises about 96% ⁇ -tocopherol and a small amount of ⁇ -tocopherol. Synthetic tocopherol, on the other hand, typically comprises about 99-98% ⁇ -tocopherol. Furthermore, synthetic tocopherol comprises a mixture of the 8 possible stereoisomers, where only 1 occurs naturally.
  • the tocopherol is ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, tocopherol, or a combination thereof.
  • the tocopherol comprises a-tocopherol.
  • the tocopherol comprises equal to or greater than about 90% ⁇ -tocopherol.
  • the tocopherol is a-tocopherol (i.e. 100% ⁇ -tocopherol).
  • the complex alcohol may also be a pharmaceutical compound, an anaesthetic, or an antioxidant.
  • the pharmaceutical compound is an oncology drug such as a taxane, a nucleoside or a kinase inhibitor, a steroid, an opioid analgesic, a respiratory drug, a central nervous system (CNS) drug, a hypercholesterolemia drug, an antihypertensive drug, an immunosuppressive drug, an antibiotic, a luteinising hormone releasing hormone (LHRH) agonist, a LHRH antagonist, an antiviral drug, an antiretroviral drug, an estrogen receptor modulator, a somatostatin mimic, an anti-inflammatory drug, a vitamin D 2 analogue, a synthetic thyroxine, an antihistamine, an antifungal agent, a nonsteroidal anti-inflammatory drug (NSAID) or an anesthetic.
  • an oncology drug such as a taxane, a nucleoside or a kinase inhibitor, a steroid, an opioid analgesic, a respiratory drug, a central nervous system
  • Suitable oncology drugs include taxanes such as paclitaxel, cabazitaxel and docetaxel, camptothecin and its analogues such as irinotecan and topotecan, other antimicrotubule agents such as vinflunine, nucleosides such as gemcitabine, cladribine, fludarabine capecitabine, decitabine, azacitidine, clofarabine and nelarabine, kinase inhibitors such as sprycel, temisirolimus, dasatinib, AZD6244, AZD1152, PI-103, R-roscovitine, olomoucine and purvalanol A, and epothilone B analogues such as ixabepilone, anthrocyclines such as amrubicin, doxorubicin, epirubicin and valrubicin, super oxide inducers such as trabectecin, proteosome
  • Suitable steroids include anabolic steroids such as testosterone, dihydrotestosterone, estradiol and ethynylestradiol, and corticosteroids such as cortisone, prednisilone, budesonide, triamcinolone, fluticasone, mometasone, amcinonide, flucinolone, fluocinanide, desonide, halcinonide, prednicarbate, fluocortolone, dexamethasone, betamethasone and fluprednidine.
  • anabolic steroids such as testosterone, dihydrotestosterone, estradiol and ethynylestradiol
  • corticosteroids such as cortisone, prednisilone, budesonide, triamcinolone, fluticasone, mometasone, amcinonide, flucinolone, fluocinanide, desonide, halcinonide, prednicarbate, fluocor
  • Suitable opioid analgesics include morphine, oxymorphone, naloxone, codeine, oxycodone, methylnaltrexone, hydromorphone, buprenorphine and etorphine.
  • Suitable respiratory drugs include bronchodilators, inhaled steroids, and decongestants and more particularly salbutamol, ipratropium bromide, montelukast and formoterol.
  • Suitable CNS drugs include antipsychotic such as quetiapine and antidepressants such as venlafaxine.
  • Suitable drugs to control hypercholesterolemia include ezetimibe and statins such as simvastatin, lovastatin, atorvastatin, fluvastatin, pitavastatin, pravastatin and rosuvastatin.
  • Suitable antihypertensive drugs include losartan, olmesartan, medoxomil, metrolol, travoprost and bosentan.
  • Suitable immunosuppressive drugs include glucocorticoids, cytostatics, antibody fragments, anti-immunophilins, interferons, TNF binding proteins and more particularly, cacineurin inhibitors such as tacrolimus, mycophenolic acid and its derivatives such as mycophenolate mofetil, and cyclosporine.
  • Suitable antibacterial agents include antibiotics such as amoxicillin, meropenem and clavulanic acid.
  • Suitable LHRH agonists include goserelin acetate, deslorelin and leuprorelin.
  • Suitable LHRH antagonists include cetrorelix, ganirelix, abarelix and degarelix.
  • Suitable antiviral agents include nucleoside analogs such as lamivudine, zidovudine, abacavir and entecavir and suitable antiretro viral drugs include protease inhibitors such as atazanavir, lapinavir and ritonavir.
  • suitable selective estrogen receptor modulators include raloxifene and fulvestrant.
  • Suitable somastatin mimics include octreotide.
  • Suitable anti-inflammatory drugs include mesalazine and suitable NSAIDs include acetaminophen (paracetamol).
  • Suitable vitamin D 2 analogues include paricalcitol.
  • Suitable synthetic thyroxines include levothyroxine.
  • Suitable anti-histamines include fexofenadine.
  • Suitable antifungal agents include azoles such as viriconazole.
  • Suitable antioxidants include ascorbic acid, hydroxy carotenoids such as retinol, and calciferol.
  • Suitable anesthetics include propofol.
  • the complex alcohol may also be a solvent, such as, for example, tetraglycol and lauryl alcohol.
  • the complex alcohol is sparingly soluble or insoluble in aqueous solution.
  • the complex alcohol may be farnesol.
  • the complex alcohol may be a mixture of two or more complex alcohols.
  • the linear, branched or cyclic complex alcohol is monohydroxy or polyhydroxy.
  • the polyhydroxy complex alcohol comprises 2 hydroxy groups.
  • the polyhydroxy complex alcohol comprises more than 2 hydroxy groups.
  • the polyhydroxy complex alcohol may comprise 3, 4 or 5 hydroxy groups.
  • the complex alcohol is a monohydroxy complex alcohol.
  • the linear, branched or cyclic complex alcohol may be unsubstituted or substituted with one or more substituent groups.
  • substituted or substituteduent refers to a group which may or may not be further substituted with one or more groups selected from C 1-6 alkyl, C 1-6 alkynyl, aryl, aldehyde, halogen, haloC 1-6 alkyl, haloC 1-6 alkenyl, haloC 1-6 alkynyl, haloaryl, hydroxy, C 1-6 alkylhydroxy, C 1-6 alkoxy, —OC 1-6 alkylhydroxy, —OC 1-6 alkylC 1-6 alkoxy, C 1-6 alkenyloxy, aryloxy, benzyloxy, haloC 1-6 alkoxy, haloC 1-6 alkenyloxy, haloaryloxy, nitro, nitroC 1-6 al
  • the complex alcohol is mixed with P 4 O 10 .
  • the P 4 O 10 may be partly hydrated (or a polyphosphoric acid).
  • the molar ratio of hydroxyl group (of the complex alcohol) to phosphorus may be within a range of about 3:1 to about 1:3. In some embodiments, the molar ratio is within the range of about 2:1 to about 1:2. In one embodiment, the molar ratio is about 2:1.
  • the molar ratio is about 1:1, or substantially equimolar.
  • the molar ratio of hydroxyl group (of the complex alcohol) to P 4 O 10 would be about 1:0.25.
  • the process is for phosphorylating a complex alcohol, comprising the steps of:
  • This step involves mixing the complex alcohol and P 4 O 10 until its exothermic reaction temperature is achieved.
  • exothermic reaction is well known in the relevant art. It describes a chemical reaction that releases energy by light or, as in the present invention, heat.
  • exothermic reaction temperature is used herein to refer to the temperature at which the chemical reaction between the complex alcohol and P 4 O 10 commences to release heat.
  • the complex alcohol and P 4 O 10 are mixed until its exothermic reaction temperature is achieved, and may be mixed to form an intimate mixture. Mixing may be achieved by any available means, including stirring (manual or mechanical). In some embodiments, mixing may also involve the use a high-shear mixer.
  • this step may also involve heating the complex alcohol and P 4 O 10 to advance the chemical reaction between the complex alcohol and P 4 O 10 to its exothermic reaction temperature.
  • the complex alcohol and P 4 O 10 may be heated so that its exothermic reaction temperature is achieved in a shorter period of time.
  • the complex alcohol and P 4 O 10 may be heated to advance the chemical reaction between the complex alcohol and P 4 O 10 to its exothermic reaction temperature in about 15 to 30 minutes.
  • no heating is applied so that the chemical reaction between the complex alcohol and P 4 O 10 achieves its exothermic reaction temperature over the time needed to reach this temperature.
  • This step involves allowing the reaction mixture of step (a) to react until the exothermic reaction is complete.
  • heat is generated by the exothermic reaction process and the temperature of the reaction rises without external heating.
  • the exothermic reaction is complete when the temperature of the chemical reaction between the complex alcohol and P 4 O 10 begins to fall.
  • this step does not involve mixing. In alternate embodiments, this step involves mixing. As mentioned above, mixing may be achieved by any available means, including stirring (manual or mechanical), and may also involve the use of a high-shear mixer.
  • This step involves heating or cooling the reaction mixture of step (b) to at least 80° C.
  • the temperature is at least 80° C.
  • the term “at least 80° C.” is used herein to refer to a temperature equal to or greater than 80° C. In some embodiments, the temperature is within the range of at least 80° C. to about 160° C. In other embodiments, the temperature is within the range of about 90° C. to 140° C. In one embodiment, the temperature is about 90° C. In another embodiment, the temperature is about 100° C. In yet another embodiment, the temperature is about 110° C.
  • reaction mixture of step (b) will be cooled to the relevant temperature if the temperature of the reaction mixture of step (b) is higher than this temperature after the exothermic reaction between the complex alcohol and P 4 O 10 is complete.
  • reaction mixture of step (b) will be heated to the relevant temperature if the temperature of the reaction mixture of step (b) is lower than this temperature after the exothermic reaction between the complex alcohol and P 4 O 10 is complete.
  • the heating or cooling of the reaction mixture of step (b) may be allowed to proceed gradually over time.
  • the time may be limited to a specific period of time.
  • the period of time may be limited to about 30 to about 90 minutes, after which external means is used to further heat or to further cool the reaction mixture of step (b).
  • the reaction mixture of step (b) may be maintained at this temperature for about 30 to about 180 minutes. In some embodiments, the reaction mixture of step (b) is maintained at this temperature for about 60 to about 180 minutes. In one embodiment, the reaction mixture of step (b) is maintained at this temperature for about 60 to about 120 minutes. In another embodiment, the reaction mixture of step (b) is maintained at this temperature for about 60 minutes.
  • This step involves hydrolysing the reaction mixture of step (c).
  • Hydrolysis involves the addition of an aqueous solution.
  • the aqueous solution may be water (e.g. deionised water). In some embodiments, an excess amount of water is added during the step of hydrolysis.
  • the reaction mixture of step (c) may be maintained at the hydrolysis temperature of at least 80° C.
  • the term “at least 80° C.” has the meaning mentioned above.
  • the hydrolysis temperature is within the range of at least 80° C. to about 150° C. In some embodiments, the hydrolysis temperature is within the range of about 85° C. to 120° C. In one embodiment, the hydrolysis temperature is within the range of about 90° C. to 110° C. In another embodiment, the hydrolysis temperature is within the range of about 90° C. to 100° C. In yet another embodiment, the hydrolysis temperature is within the range of about 100° C. to 110° C.
  • Hydrolysis may be conducted for about 30 to about 180 minutes. In some embodiments, hydrolysis is conducted for about 30 to about 120 minutes. In one embodiment, hydrolysis is conducted for about 60 to about 120 minutes. In another embodiment, hydrolysis is conducted for about 90 to about 120 minutes. In one embodiment, hydrolysis is conducted for about 60 to about 90 minutes.
  • the process may be conducted in the absence of an additional solvent.
  • additional solvent is used herein to refer to a solvent other than the aqueous solution, such as water, used during the step of hydrolysis.
  • the reaction is conducted without an additional solvent such that the complex alcohol and P 4 O 10 are mixed in neat form.
  • the invention also relates to a product obtained by the process.
  • the product obtained by the process may be a phosphorylated mono-complex alcohol, a phosphorylated di-complex alcohol, or a mixture thereof.
  • the product is a mixture of a phosphorylated mono-complex alcohol and a phosphorylated di-complex alcohol.
  • the molar ratio of the mixture of the phosphorylated mono-complex alcohol and the phosphorylated di-complex alcohol may be at least about 2:1, about 2:1, about 6:4 or about 8:2, or within a range of about 4:1 to about 1:4 or about 6:4 to about 8:2.
  • the product obtained by the process may be a cross-coupled phosphate diester.
  • the product obtained by the process may also comprise residual amounts of unreacted complex alcohol and/or related substances.
  • the process may further involve purification steps.
  • the product obtained by the process may also be further reacted with an amphoteric surfactant.
  • the complex alcohol is a tocopherol
  • the phosphorylated complex alcohol is a tocopheryl phosphate.
  • the tocopheryl phosphate may be a mono-tocopheryl phosphate, a di-tocopheryl phosphate, or a mixture thereof.
  • the amphoteric surfactant is a tertiary amine of the formula NR 1 R 2 R 3 , wherein R 1 is selected from the group consisting of C 6-22 alkyl, and R 2 and R 3 are independently selected from the group consisting of H, (CH 2 ) n COOX, (CH 2 ) n CHOHCH 2 SO 3 X, (CH 2 ) n CHOHCH 2 OPO 3 X, in which X is H or forms a salt with a cation selected from the group consisting of sodium, potassium, lithium, calcium, magnesium, ammonium, alkylammonium and alkanolamine, and n is 1 or 2.
  • C 6-22 alkyl refers to a straight or branched chain or cyclic hydrocarbon group having from 6 to 22 carbon atoms. Examples include, but are not limited to, hexyl, cyclohexyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl and octadecyl.
  • R 1 is a C 12 alkyl (dodecyl), and R 2 and R 3 are independently selected from CH 2 CH 2 COOH and CH 2 CH 2 COONa.
  • the tertiary amine is 3-[2-carboxyethyl(dodecyl)amino] propanoic acid.
  • the tertiary amine is 3,3′-dodecylimino)dipropionic acid monosodium salt (or lauryliminodipropionic acid, sodium lauryliminodipropionate or N-lauryl iminodipropionate).
  • the product obtained by this further process may be lauryliminodipropionic acid tocopheryl phosphates or a salt thereof.
  • the salt is a sodium salt.
  • Synthetic ⁇ -tocopherol and P 4 O 10 were mixed (mass ratio 0.170), and with heating, the exothermic reaction temperature was reached within about 15 minutes. Heating was continued until the reaction mixture a temperature of about 120° C. was achieved and then stopped. The temperature of the reaction mixture continued to rise for a brief period of time. When the exothermic reaction was complete, the reaction mixture was allowed to cool without any external control for about 60 minutes. The reaction was then further cooled to a temperature of about 90° C. before hydrolysis was conducted with deionised water for about 60 minutes.
  • the process produced about 58.52% w/w mono-tocopheryl phosphate and about 30.49% w/w di-tocopheryl phosphate.
  • Synthetic ⁇ -tocopherol and P 4 O 10 were mixed (mass ratio 0.170), and with heating, the exothermic reaction temperature was reached within about 15 minutes. Heating was continued until the reaction mixture a temperature of about 120° C. was achieved and then stopped. The temperature of the reaction mixture continued to rise for a brief period of time.
  • reaction mixture was allowed to cool without any external control for about 60 minutes.
  • the reaction was then further cooled to a temperature of about 90° C. before hydrolysis with deionised water was conducted for about 60 minutes.
  • the process produced about 59.26% w/w mono-tocopheryl phosphate and about 30.91% w/w di-tocopheryl phosphate.
  • Natural ⁇ -tocopherol (0.07% w/w) and P 4 O 10 were mixed (mass ratio 0.170), and with heating, the exothermic reaction temperature was reached within about 15 minutes. Heating was continued until the reaction mixture a temperature of about 120° C. was achieved and then stopped. The temperature of the reaction mixture continued to rise for a brief period of time. When the exothermic reaction was complete, the reaction mixture was allowed to cool without any external control for about 60 minutes. The reaction was then further cooled to a temperature of about 90° C. before hydrolysis with deionised water was conducted for about 60 minutes.
  • the process produced about 55.79% w/w mono-tocopheryl phosphate and about 27.68% w/w di-tocopheryl phosphate.
  • Mass spectrometry analysis of the end product indicated the formation of the desired monophosphate derivative of propofol.
  • Mass spectrometry analysis of the end product indicated the formation of the monophosphate derivatives of propofol and D- ⁇ -tocopherol, as well as the cross-coupled phosphate diester.
  • Mass spectrometry analysis of the end product indicated the formation of the desired monophosphate derivative of lauryl alcohol.
  • ⁇ -Estradiol (0.490 g, 1.80 mmol) and P 4 O 10 (0.140 g, 0.493 mmol) were combined in a Radleys 12 Station Carousel reaction tube and suspended in Triacetin (2 mL). The reaction mixture was heated at 100° C. for 60 minutes and to complete the exothermic reaction. The reaction mixture was then cooled to 90° C. before it was hydrolysed with H 2 O (1.00 g) at that temperature for 60 minutes.

Abstract

An efficient and commercial phosphorylation process of a complex alcohol, such as secondary and tertiary alcohols, with P4O10 at high temperatures, and a product obtained by the process.

Description

    TECHNICAL FIELD
  • The invention relates to a phosphorylation process of complex alcohols, and products obtained by that process.
    • BACKGROUND
  • It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.
  • Phosphorylation processes and reagents are chosen to avoid significant degradation of the compound being phosphorylated and to produce desired yields.
  • In some phosphorylation processes, reagents such as 2:2:2-trichloroethyl dichlorophosphate, di-imidazolide chlorophosphate and di-analide chlorophosphate are used under gentle conditions to avoid degradation of the compound being phosphorylated. However, such processes have been found to produce limited yields, which would not be economical or suitable for commercial purposes.
  • In other phosphorylation processes, the reagent phosphorous oxychloride is used, but the reaction typically produces a variety of by-products and hydrogen chloride. Such process may also not be commercially viable given that the reagent phosphorous oxychloride is difficult to handle.
  • The reagent P4O10, which is commonly known as phosphorus pentoxide, but has other names such as phosphorus (V) oxide, phosphoric anhydride and diphosphorus pentoxide, is a white crystalline solid. This reagent has been used for phosphorylation of ethanol and other short chain primary alcohols (i.e. less than 6 carbon atoms) and it has been found to be suitable for phosphorylation of alcohols such as primary fatty alcohols, secondary alcohols and aromatic alcohols. Australian Patent No. 200043870 describes a process, which involves forming an intimate mixture of one or more of these alcohols and P4O10, partly hydrated P4O10 or a mixture thereof, at a temperature below 80° C., and allowing the intimate mixture to continue to react for a period of time at this temperature, i.e. below 80° C., until formation of the phosphorylated alcohol is substantially formed. It is clear that the temperature must be kept to a minimum and below 80° C. to avoid degradation.
  • The phosphorylation of complex alcohols, such as secondary and tertiary alcohols, with P4O10 at higher temperatures was thought to lead to degradation and/or side reactions such as dehydration and double bond formation. These problems teach away from the use of P4O10 for the efficient and commercial phosphorylation of complex alcohols at high temperatures.
  • The present inventors have found that complex alcohols can be phosphorylated at a high temperature and that, at such temperatures, desirable yields can be obtained with minimal degradation of the complex alcohols.
    • SUMMARY
  • Accordingly, there is provided a process for phosphorylating a complex alcohol, comprising the steps of:
    • (a) mixing the complex alcohol and P4O10 until its exothermic reaction temperature is achieved;
    • (b) allowing the reaction mixture of step (a) to react until the exothermic reaction is complete;
    • (c) heating or cooling the reaction mixture of step (b) to at least 80° C.; and
    • (d) hydrolysing the reaction mixture of step (c).
  • There is also provided a product obtained by the process.
    • DETAILED DESCRIPTION
  • The invention relates to a process for phosphorylating a complex alcohol, comprising the steps of:
    • (a) mixing the complex alcohol and P4O10 until its exothermic reaction temperature is achieved;
    • (b) allowing the reaction mixture of step (a) to react until the exothermic reaction is complete;
    • (c) heating or cooling the reaction mixture of step (b) to at least 80° C.; and
    • (d) hydrolysing the reaction mixture of step (c).
    Complex Alcohol
  • The complex alcohol may be a linear or branched alcohol comprising at least 6 carbon atoms (i.e. 6 or more carbon atoms). In some embodiments, the complex alcohol comprises at least 7 carbon atoms. In other embodiments, the complex alcohol comprises at least 8 carbon atoms. In particular embodiments, the complex alcohol comprises at least 10 carbon atoms. The number of carbon atoms mentioned herein refers to the number of carbon atoms that make up the backbone of the linear or branched complex alcohol or the ring system of the cyclic complex alcohol.
  • Examples of linear and branched complex alcohols include, but are not limited to, hexanol, hexan-1-ol, heptanol, heptan-1-ol, octanol, octan-1-ol, decanol, decan-1-ol, undecanol, dodecanol, 1-dodecanol, tridecanol, 1-tetradecanol, pentadecanol, cetyl alcohol, stearyl alcohol, 1-methylhexan-1-ol, 2-methylhexan-1-ol, 3-methyl-heptan-1-ol, 4-methylhexan-1-ol, 1-methylhexan-2-ol, 2-methylhexan-2-ol, 3-methyl-hexan-2-ol, 4-methylhexan-2-ol, 1-methylhexan-3-ol, 2-methylhexan-3-ol, 3-methyl-hexan-3-ol, 4-methylhexan-3-ol, 1-methylhexan-4-ol, 2-methylhexan-4-ol, 3-methyl-hexan-4-ol, 4-methylhexan-4-ol, 1-methylhexan-5-ol, 2-methylhexan-5-ol, 3-methyl-hexan-5-ol, 4-methylhexan-5-ol, 1-methylhexan-6-ol, 2-methylhexan-6-ol, 3-methyl-hexan-6-ol, 4-methylhexan-6-ol, 1-ethylhexan-1-ol, 2-ethylhexan-1-ol, 3-ethyl-hexan-1-ol, 4-methylhexan-1-ol, 1-ethylhexan-2-ol, 2-ethylhexan-2-ol, 3-ethyl-hexan-2-ol, 4-ethylhexan-2-ol, 1-ethylhexan-3-ol, 2-ethylhexan-3-ol, 3-ethyl-hexan-3-ol, 4-ethylhexan-3-ol, 1-ethylhexan-4-ol, 2-ethylhexan-4-ol, 3-ethyl-hexan-4-ol, 4-ethylhexan-4-ol, 1-ethylhexan-5-ol, 2-ethylhexan-5-ol, 3-ethyl-hexan-5-ol, 4-ethylhexan-5-ol, 1-ethylhexan-6-ol, 2-ethylhexan-6-ol, 3-ethyl-hexan-6-ol, 4-ethylhexan-6-ol, 1-methylheptan-1-ol, 2-methylheptan-1-ol, 3-methyl-heptan-1-ol, 4-methylheptan-1-ol, 1-methylheptan-2-ol, 2-methylheptan-2-ol, 3-methyl-heptan-2-ol, 4-methylheptan-2-ol, 1-methylheptan-3-ol, 2-methylheptan-3-ol, 3-methyl-heptan-3-ol, 4-methylheptan-3-ol, 1-methylheptan-4-ol, 2-methylheptan-4-ol, 3-methyl-heptan-4-ol, 4-methylheptan-4-ol, 1-methylheptan-5-ol, 2-methylheptan-5-ol, 3-methyl-heptan-5-ol, 4-methylheptan-5-ol, 1-methylheptan-6-ol, 2-methylheptan-6-ol, 3-methyl-heptan-6-ol, 4-methylheptan-6-ol, 1-methylheptan-7-ol, 2-methylheptan-7-ol, 3-methyl-heptan-7-ol, 4-methylheptan-7-ol, 1-ethylheptan-1-ol, 2-ethylheptan-1-ol, 3-ethyl-heptan-1-ol, 4-methylheptan-1-ol, 1-ethylheptan-2-ol, 2-ethylheptan-2-ol, 3-ethyl-heptan-2-ol, 4-ethylheptan-2-ol, 1-ethylheptan-3-ol, 2-ethylheptan-3-ol, 3-ethyl-heptan-3-ol, 4-ethylheptan-3-ol, 1-ethylheptan-4-ol, 2-ethylheptan-4-ol, 3-ethyl-heptan-4-ol, 4-ethylheptan-4-ol, 1-ethylheptan-5-ol, 2-ethylheptan-5-ol, 3-ethyl-heptan-5-ol, 4-ethylheptan-5-ol, 1-ethylheptan-6-ol, 2-ethylheptan-6-ol, 3-ethyl-heptan-6-ol, 4-ethylheptan-6-ol, 1-ethylheptan-7-ol, 2-ethylheptan-7-ol, 3-ethyl-heptan-7-ol, 4-ethylheptan-7-ol, 1-methyloctan-1-ol, 2-methyloctan-1-ol, 3-methyl-octan-1-ol, 4-methyloctan-1-ol, 1-methyloctan-2-ol, 2-methyloctan-2-ol, 3-methyl-octan-2-ol, 4-methyloctan-2-ol, 1-methyloctan-3-ol, 2-methyloctan-3-ol, 3-methyl-octan-3-ol, 4-methyloctan-3-ol, 1-methyloctan-4-ol, 2-methyloctan-4-ol, 3-methyl-octan-4-ol, 4-methyloctan-4-ol, 1-methyloctan-5-ol, 2-methyloctan-5-ol, 3-methyl-octan-5-ol, 4-methyloctan-5-ol, 1-methyloctan-6-ol, 2-methyloctan-6-ol, 3-methyl-octan-6-ol, 4-methyloctan-6-ol, 1-methyloctan-7-ol, 2-methyloctan-7-ol, 3-methyl-octan-7-ol, 4-methyloctan-7-ol, 1-methyloctan-8-ol, 2-methyloctan-8-ol, 3-methyl-octan-8-ol, 4-methyloctan-8-ol, 1-ethyloctan-1-ol, 2-ethyloctan-1-ol, 3-ethyl-octan-1-ol, 4-methyloctan-1-ol, 1-ethyloctan-2-ol, 2-ethyloctan-2-ol, 3-ethyl-octan-2-ol, 4-ethyloctan-2-ol, 1-ethyloctan-3-ol, 2-ethyloctan-3-ol, 3-ethyl-octan-3-ol, 4-ethyloctan-3-ol, 1-ethyloctan-4-ol, 2-ethyloctan-4-ol, 3-ethyl-octan-4-ol, 4-ethyloctan-4-ol, 1-ethyloctan-5-ol, 2-ethyloctan-5-ol, 3-ethyl-octan-5-ol, 4-ethyloctan-5-ol, 1-ethyloctan-6-ol, 2-ethyloctan-6-ol, 3-ethyl-octan-6-ol, 4-ethyloctan-6-ol, 1-ethyloctan-7-ol, 2-ethyloctan-7-ol, 3-ethyl-octan-7-ol, 4-ethyloctan-7-ol, 1-ethyloctan-8-ol, 2-ethyloctan-8-ol, 3-ethyl-octan-8-ol, 4-ethyloctan-8-ol, 1-methylnonan-1-ol, 2-methylnonan-1-ol, 3-methyl-nonan-1-ol, 4-methylnonan-1-ol, 1-methylnonan-2-ol, 2-methylnonan-2-ol, 3-methyl-nonan-2-ol, 4-methylnonan-2-ol, 1-methylnonan-3-ol, 2-methylnonan-3-ol, 3-methyl-nonan-3-ol, 4-methylnonan-3-ol, 1-methylnonan-4-ol, 2-methylnonan-4-ol, 3-methyl-nonan-4-ol, 4-methylnonan-4-ol, 1-methylnonan-5-ol, 2-methylnonan-5-ol, 3-methyl-nonan-5-ol, 4-methylnonan-5-ol, 1-methylnonan-6-ol, 2-methylnonan-6-ol, 3-methyl-nonan-6-ol, 4-methylnonan-6-ol, 1-methylnonan-7-ol, 2-methylnonan-7-ol, 3-methyl-nonan-7-ol, 4-methylnonan-7-ol, 1-methylnonan-8-ol, 2-methylnonan-8-ol, 3-methyl-nonan-8-ol, 4-methylnonan-8-ol, 1-methylnonan-9-ol, 2-methylnonan-9-ol, 3-methyl-nonan-9-ol, 4-methylnonan-9-ol, 1-ethylnonan-1-01, 2-ethylnonan-1-ol, 3-ethyl-nonan-1-ol, 4-methylnonan-1-ol, 1-ethylnonan-2-ol, 2-ethylnonan-2-ol, 3-ethyl-nonan-2-ol, 4-ethylnonan-2-ol, 1-ethylnonan-3-ol, 2-ethylnonan-3-ol, 3-ethyl-nonan-3-ol, 4-ethylnonan-3-ol, 1-ethylnonan-4-ol, 2-ethylnonan-4-ol, 3-ethyl-nonan-4-ol, 4-ethylnonan-4-ol, 1-ethylnonan-5-ol, 2-ethylnonan-5-ol, 3-ethyl-nonan-5-ol, 4-ethylnonan-5-ol, 1-ethylnonan-6-ol, 2-ethylnonan-6-ol, 3-ethyl-nonan-6-ol, 4-ethylnonan-6-ol, 1-ethylnonan-7-ol, 2-ethylnonan-7-ol, 3-ethyl-nonan-7-ol, 4-ethylnonan-7-ol, 1-ethylnonan-8-ol, 2-ethylnonan-8-ol, 3-ethyl-nonan-8-ol, 4-ethylnonan-8-ol, 1-ethylnonan-9-ol, 2-ethylnonan-9-ol, 3-ethyl-nonan-9-ol, and 4-ethylnonan-9-ol.
  • The complex alcohol may be a cyclic complex alcohol and may be carbocyclic or heterocyclic. Further, the carbocyclic or heterocyclic complex alcohol may be aromatic or non-aromatic. In some embodiments, the heterocyclic complex alcohol comprises one or more heteroatoms. In one embodiment, the heterocyclic complex alcohol comprises one heteroatom. In another embodiment, the heterocyclic complex alcohol comprises two heteroatoms. The heteroatom may be selected from the group consisting of N, O, S and P.
  • The cyclic complex alcohol may also be monocyclic or polycyclic. The polycyclic complex alcohol may comprise 2 or more rings. In some embodiments, the polycyclic complex alcohol comprises 2 or more rings, wherein at least 2 rings are fused.
  • In particular embodiments, the complex alcohol is a sterol. The sterol may be a phytosterol. In one specific embodiment, the sterol is cholesterol.
  • In other particular embodiments, the complex alcohol is a chromanol. In some embodiments, the chromanol is a tocopherol or tocotrienol.
  • In some embodiments, the tocopherol is natural, synthetic, or a combination thereof. Natural tocopherol typically comprises about 96% α-tocopherol and a small amount of γ-tocopherol. Synthetic tocopherol, on the other hand, typically comprises about 99-98% α-tocopherol. Furthermore, synthetic tocopherol comprises a mixture of the 8 possible stereoisomers, where only 1 occurs naturally.
  • In other embodiments, the tocopherol is α-tocopherol, β-tocopherol, γ-tocopherol, tocopherol, or a combination thereof. In particular embodiments, the tocopherol comprises a-tocopherol. In one embodiment, the tocopherol comprises equal to or greater than about 90% α-tocopherol. In another embodiment, the tocopherol is a-tocopherol (i.e. 100% α-tocopherol).
  • The complex alcohol may also be a pharmaceutical compound, an anaesthetic, or an antioxidant.
  • In some embodiments, the pharmaceutical compound is an oncology drug such as a taxane, a nucleoside or a kinase inhibitor, a steroid, an opioid analgesic, a respiratory drug, a central nervous system (CNS) drug, a hypercholesterolemia drug, an antihypertensive drug, an immunosuppressive drug, an antibiotic, a luteinising hormone releasing hormone (LHRH) agonist, a LHRH antagonist, an antiviral drug, an antiretroviral drug, an estrogen receptor modulator, a somatostatin mimic, an anti-inflammatory drug, a vitamin D2 analogue, a synthetic thyroxine, an antihistamine, an antifungal agent, a nonsteroidal anti-inflammatory drug (NSAID) or an anesthetic.
  • Suitable oncology drugs include taxanes such as paclitaxel, cabazitaxel and docetaxel, camptothecin and its analogues such as irinotecan and topotecan, other antimicrotubule agents such as vinflunine, nucleosides such as gemcitabine, cladribine, fludarabine capecitabine, decitabine, azacitidine, clofarabine and nelarabine, kinase inhibitors such as sprycel, temisirolimus, dasatinib, AZD6244, AZD1152, PI-103, R-roscovitine, olomoucine and purvalanol A, and epothilone B analogues such as ixabepilone, anthrocyclines such as amrubicin, doxorubicin, epirubicin and valrubicin, super oxide inducers such as trabectecin, proteosome inhibitors such as bortezomib and other topoisomerase inhibitors, intercalating agents and alkylating agents.
  • Suitable steroids include anabolic steroids such as testosterone, dihydrotestosterone, estradiol and ethynylestradiol, and corticosteroids such as cortisone, prednisilone, budesonide, triamcinolone, fluticasone, mometasone, amcinonide, flucinolone, fluocinanide, desonide, halcinonide, prednicarbate, fluocortolone, dexamethasone, betamethasone and fluprednidine.
  • Suitable opioid analgesics include morphine, oxymorphone, naloxone, codeine, oxycodone, methylnaltrexone, hydromorphone, buprenorphine and etorphine.
  • Suitable respiratory drugs include bronchodilators, inhaled steroids, and decongestants and more particularly salbutamol, ipratropium bromide, montelukast and formoterol. Suitable CNS drugs include antipsychotic such as quetiapine and antidepressants such as venlafaxine.
  • Suitable drugs to control hypercholesterolemia include ezetimibe and statins such as simvastatin, lovastatin, atorvastatin, fluvastatin, pitavastatin, pravastatin and rosuvastatin.
  • Suitable antihypertensive drugs include losartan, olmesartan, medoxomil, metrolol, travoprost and bosentan.
  • Suitable immunosuppressive drugs include glucocorticoids, cytostatics, antibody fragments, anti-immunophilins, interferons, TNF binding proteins and more particularly, cacineurin inhibitors such as tacrolimus, mycophenolic acid and its derivatives such as mycophenolate mofetil, and cyclosporine.
  • Suitable antibacterial agents include antibiotics such as amoxicillin, meropenem and clavulanic acid.
  • Suitable LHRH agonists include goserelin acetate, deslorelin and leuprorelin.
  • Suitable LHRH antagonists include cetrorelix, ganirelix, abarelix and degarelix.
  • Suitable antiviral agents include nucleoside analogs such as lamivudine, zidovudine, abacavir and entecavir and suitable antiretro viral drugs include protease inhibitors such as atazanavir, lapinavir and ritonavir. Suitable selective estrogen receptor modulators include raloxifene and fulvestrant.
  • Suitable somastatin mimics include octreotide.
  • Suitable anti-inflammatory drugs include mesalazine and suitable NSAIDs include acetaminophen (paracetamol).
  • Suitable vitamin D2 analogues include paricalcitol.
  • Suitable synthetic thyroxines include levothyroxine.
  • Suitable anti-histamines include fexofenadine.
  • Suitable antifungal agents include azoles such as viriconazole.
  • Suitable antioxidants include ascorbic acid, hydroxy carotenoids such as retinol, and calciferol.
  • Suitable anesthetics include propofol.
  • The complex alcohol may also be a solvent, such as, for example, tetraglycol and lauryl alcohol.
  • In some embodiments, the complex alcohol is sparingly soluble or insoluble in aqueous solution. For example, the complex alcohol may be farnesol.
  • In some embodiments, the complex alcohol may be a mixture of two or more complex alcohols.
  • In the above embodiments, the linear, branched or cyclic complex alcohol is monohydroxy or polyhydroxy. In some embodiments, the polyhydroxy complex alcohol comprises 2 hydroxy groups. In other embodiments, the polyhydroxy complex alcohol comprises more than 2 hydroxy groups. For example, the polyhydroxy complex alcohol may comprise 3, 4 or 5 hydroxy groups. In particular embodiments, the complex alcohol is a monohydroxy complex alcohol.
  • In the above embodiments, the linear, branched or cyclic complex alcohol may be unsubstituted or substituted with one or more substituent groups. Unless otherwise defined, the term “substituted” or “substituent” as used herein refers to a group which may or may not be further substituted with one or more groups selected from C1-6alkyl, C1-6alkynyl, aryl, aldehyde, halogen, haloC1-6alkyl, haloC1-6alkenyl, haloC1-6alkynyl, haloaryl, hydroxy, C1-6alkylhydroxy, C1-6alkoxy, —OC1-6alkylhydroxy, —OC1-6alkylC1-6alkoxy, C1-6alkenyloxy, aryloxy, benzyloxy, haloC1-6alkoxy, haloC1-6alkenyloxy, haloaryloxy, nitro, nitroC1-6alkyl, nitroC1-6alkenyl, nitroC1-6alkynyl, nitroaryl, nitroheterocyclyl, amino, C1-6alkylamino, C1-6dialkylamino, C1-6alkenylamino, C1-6alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, acyl, C1-6alkenylacyl, C1-6alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy, mercapto, benzylthio, acylthio, and phosphorus-containing groups.
    • Phosphorylation Reagent
  • The complex alcohol is mixed with P4O10. In some embodiments, the P4O10 may be partly hydrated (or a polyphosphoric acid).
  • The molar ratio of hydroxyl group (of the complex alcohol) to phosphorus may be within a range of about 3:1 to about 1:3. In some embodiments, the molar ratio is within the range of about 2:1 to about 1:2. In one embodiment, the molar ratio is about 2:1.
  • In another embodiment, the molar ratio is about 1:1, or substantially equimolar. In this particular embodiment, the molar ratio of hydroxyl group (of the complex alcohol) to P4O10 would be about 1:0.25.
    • Process
  • The process is for phosphorylating a complex alcohol, comprising the steps of:
    • (a) mixing the complex alcohol and P4O10 until its exothermic reaction temperature is achieved;
    • (b) allowing the reaction mixture of step (a) to react until the exothermic reaction is complete;
    • (c) heating or cooling the reaction mixture of step (b) to at least 80° C.; and
    • (d) hydrolysing the reaction mixture of step (c).
    Step (a)
  • This step involves mixing the complex alcohol and P4O10 until its exothermic reaction temperature is achieved.
  • The meaning of “exothermic reaction” is well known in the relevant art. It describes a chemical reaction that releases energy by light or, as in the present invention, heat. The term “exothermic reaction temperature” is used herein to refer to the temperature at which the chemical reaction between the complex alcohol and P4O10 commences to release heat. The complex alcohol and P4O10 are mixed until its exothermic reaction temperature is achieved, and may be mixed to form an intimate mixture. Mixing may be achieved by any available means, including stirring (manual or mechanical). In some embodiments, mixing may also involve the use a high-shear mixer.
  • In some embodiments, this step may also involve heating the complex alcohol and P4O10 to advance the chemical reaction between the complex alcohol and P4O10to its exothermic reaction temperature. For example, the complex alcohol and P4O10 may be heated so that its exothermic reaction temperature is achieved in a shorter period of time. For example, the complex alcohol and P4O10 may be heated to advance the chemical reaction between the complex alcohol and P4O10to its exothermic reaction temperature in about 15 to 30 minutes.
  • In other embodiments, no heating is applied so that the chemical reaction between the complex alcohol and P4O10 achieves its exothermic reaction temperature over the time needed to reach this temperature.
    • Step (b)
  • This step involves allowing the reaction mixture of step (a) to react until the exothermic reaction is complete. In some embodiments, as the reaction progresses, heat is generated by the exothermic reaction process and the temperature of the reaction rises without external heating.
  • The exothermic reaction is complete when the temperature of the chemical reaction between the complex alcohol and P4O10 begins to fall.
  • In some embodiments, this step does not involve mixing. In alternate embodiments, this step involves mixing. As mentioned above, mixing may be achieved by any available means, including stirring (manual or mechanical), and may also involve the use of a high-shear mixer.
    • Step (c)
  • This step involves heating or cooling the reaction mixture of step (b) to at least 80° C.
  • In this step, the temperature is at least 80° C. The term “at least 80° C.” is used herein to refer to a temperature equal to or greater than 80° C. In some embodiments, the temperature is within the range of at least 80° C. to about 160° C. In other embodiments, the temperature is within the range of about 90° C. to 140° C. In one embodiment, the temperature is about 90° C. In another embodiment, the temperature is about 100° C. In yet another embodiment, the temperature is about 110° C.
  • The reaction mixture of step (b) will be cooled to the relevant temperature if the temperature of the reaction mixture of step (b) is higher than this temperature after the exothermic reaction between the complex alcohol and P4O10 is complete. In the alternative, the reaction mixture of step (b) will be heated to the relevant temperature if the temperature of the reaction mixture of step (b) is lower than this temperature after the exothermic reaction between the complex alcohol and P4O10 is complete.
  • In some embodiments, the heating or cooling of the reaction mixture of step (b) may be allowed to proceed gradually over time. In other embodiments, the time may be limited to a specific period of time. For example, the period of time may be limited to about 30 to about 90 minutes, after which external means is used to further heat or to further cool the reaction mixture of step (b).
  • Once at the heated or cooled temperature, the reaction mixture of step (b) may be maintained at this temperature for about 30 to about 180 minutes. In some embodiments, the reaction mixture of step (b) is maintained at this temperature for about 60 to about 180 minutes. In one embodiment, the reaction mixture of step (b) is maintained at this temperature for about 60 to about 120 minutes. In another embodiment, the reaction mixture of step (b) is maintained at this temperature for about 60 minutes.
    • Step (d)
  • This step involves hydrolysing the reaction mixture of step (c).
  • Hydrolysis involves the addition of an aqueous solution. The aqueous solution may be water (e.g. deionised water). In some embodiments, an excess amount of water is added during the step of hydrolysis. During hydrolysis, the reaction mixture of step (c) may be maintained at the hydrolysis temperature of at least 80° C. The term “at least 80° C.” has the meaning mentioned above. In some embodiments, the hydrolysis temperature is within the range of at least 80° C. to about 150° C. In some embodiments, the hydrolysis temperature is within the range of about 85° C. to 120° C. In one embodiment, the hydrolysis temperature is within the range of about 90° C. to 110° C. In another embodiment, the hydrolysis temperature is within the range of about 90° C. to 100° C. In yet another embodiment, the hydrolysis temperature is within the range of about 100° C. to 110° C.
  • Hydrolysis may be conducted for about 30 to about 180 minutes. In some embodiments, hydrolysis is conducted for about 30 to about 120 minutes. In one embodiment, hydrolysis is conducted for about 60 to about 120 minutes. In another embodiment, hydrolysis is conducted for about 90 to about 120 minutes. In one embodiment, hydrolysis is conducted for about 60 to about 90 minutes.
    • Optional Solvent
  • The process may be conducted in the absence of an additional solvent. The term “additional solvent” is used herein to refer to a solvent other than the aqueous solution, such as water, used during the step of hydrolysis. In some embodiments, the reaction is conducted without an additional solvent such that the complex alcohol and P4O10 are mixed in neat form.
    • Product
  • The invention also relates to a product obtained by the process. The product obtained by the process may be a phosphorylated mono-complex alcohol, a phosphorylated di-complex alcohol, or a mixture thereof. In particular embodiments, the product is a mixture of a phosphorylated mono-complex alcohol and a phosphorylated di-complex alcohol. In these embodiments, the molar ratio of the mixture of the phosphorylated mono-complex alcohol and the phosphorylated di-complex alcohol may be at least about 2:1, about 2:1, about 6:4 or about 8:2, or within a range of about 4:1 to about 1:4 or about 6:4 to about 8:2.
  • In some embodiments, the product obtained by the process may be a cross-coupled phosphate diester.
  • It should be appreciated that the product obtained by the process may also comprise residual amounts of unreacted complex alcohol and/or related substances. In such embodiments, the process may further involve purification steps.
    • Further Process Steps to Obtain Further Products
  • The product obtained by the process may also be further reacted with an amphoteric surfactant.
  • In these embodiments, the complex alcohol is a tocopherol, and the phosphorylated complex alcohol is a tocopheryl phosphate. The tocopheryl phosphate may be a mono-tocopheryl phosphate, a di-tocopheryl phosphate, or a mixture thereof.
  • In one embodiment, the amphoteric surfactant is a tertiary amine of the formula NR1R2R3, wherein R1 is selected from the group consisting of C6-22 alkyl, and R2 and R3 are independently selected from the group consisting of H, (CH2)nCOOX, (CH2)nCHOHCH2SO3X, (CH2)nCHOHCH2OPO3X, in which X is H or forms a salt with a cation selected from the group consisting of sodium, potassium, lithium, calcium, magnesium, ammonium, alkylammonium and alkanolamine, and n is 1 or 2.
  • The term “C6-22 alkyl” refers to a straight or branched chain or cyclic hydrocarbon group having from 6 to 22 carbon atoms. Examples include, but are not limited to, hexyl, cyclohexyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl and octadecyl.
  • In some embodiments, R1 is a C12 alkyl (dodecyl), and R2 and R3 are independently selected from CH2CH2COOH and CH2CH2COONa.
  • In particular embodiments, the tertiary amine is 3-[2-carboxyethyl(dodecyl)amino] propanoic acid. In other embodiments, the tertiary amine is 3,3′-dodecylimino)dipropionic acid monosodium salt (or lauryliminodipropionic acid, sodium lauryliminodipropionate or N-lauryl iminodipropionate).
  • The product obtained by this further process may be lauryliminodipropionic acid tocopheryl phosphates or a salt thereof. In some embodiments, the salt is a sodium salt.
    • EXAMPLES
  • Various embodiments/aspects of the present invention will now be described with reference to the following non-limiting examples.
    • Example 1
  • Synthetic α-tocopherol and P4O10 were mixed (mass ratio 0.170), and with heating, the exothermic reaction temperature was reached within about 15 minutes. Heating was continued until the reaction mixture a temperature of about 120° C. was achieved and then stopped. The temperature of the reaction mixture continued to rise for a brief period of time. When the exothermic reaction was complete, the reaction mixture was allowed to cool without any external control for about 60 minutes. The reaction was then further cooled to a temperature of about 90° C. before hydrolysis was conducted with deionised water for about 60 minutes.
  • The process produced about 58.52% w/w mono-tocopheryl phosphate and about 30.49% w/w di-tocopheryl phosphate.
  • It was also noted that there was about 0.21% w/w unreacted synthetic α-tocopherol.
    • Example 2
  • Synthetic α-tocopherol and P4O10 were mixed (mass ratio 0.170), and with heating, the exothermic reaction temperature was reached within about 15 minutes. Heating was continued until the reaction mixture a temperature of about 120° C. was achieved and then stopped. The temperature of the reaction mixture continued to rise for a brief period of time.
  • When the exothermic reaction was complete, the reaction mixture was allowed to cool without any external control for about 60 minutes. The reaction was then further cooled to a temperature of about 90° C. before hydrolysis with deionised water was conducted for about 60 minutes.
  • The process produced about 59.26% w/w mono-tocopheryl phosphate and about 30.91% w/w di-tocopheryl phosphate.
  • It was also noted that there was about 0.20% w/w unreacted synthetic α-tocopherol.
    • Example 3
  • Natural α-tocopherol (0.07% w/w) and P4O10 were mixed (mass ratio 0.170), and with heating, the exothermic reaction temperature was reached within about 15 minutes. Heating was continued until the reaction mixture a temperature of about 120° C. was achieved and then stopped. The temperature of the reaction mixture continued to rise for a brief period of time. When the exothermic reaction was complete, the reaction mixture was allowed to cool without any external control for about 60 minutes. The reaction was then further cooled to a temperature of about 90° C. before hydrolysis with deionised water was conducted for about 60 minutes.
  • The process produced about 55.79% w/w mono-tocopheryl phosphate and about 27.68% w/w di-tocopheryl phosphate.
  • It was also noted that there was about 0.07% w/w unreacted synthetic α-tocopherol.
    • Example 4
  • Propofol (1.07 g, 6.00 mmol) and P4O10 (0.430 g, 1.51 mmol) were combined in a reaction tube and stirred vigorously. The reaction mixture was heated with a H2O bath (50-90° C.) for over 120 minutes so that the exothermic reaction was complete and then hydrolysed with H2O (0.260 g) at 90° C. for 60 minutes.
  • After cooling to room temperature the reaction mixture was dissolved in EtOH (30 mL), transferred to a 100 mL RBF and concentrated in vacuo (60° C. H2O bath). The residual red oily solid was suspended in hot hexane (90 mL) and filtered hot. The hexane filtrate was concentrated in vacuo (60° C. H2O bath) to ˜25 mL and then cooled on an ice bath for about 120 minutes. The cold suspension was filtered in vacuo and the filter cake was washed with cold hexane (3×15 mL) and dried in a vacuum oven (55° C.) to give a white powder.
  • Mass spectrometry analysis of the end product indicated the formation of the desired monophosphate derivative of propofol.
    • Example 5
  • Propofol (0.565 g, 3.17 mmol), D-α-Tocopherol (1.35 g, 3.13 mmol) and P4O10 (0.462 g, 1.63 mmol) were combined in a Radleys 12 Station Carousel reaction tube. The reaction mixture was heated at 100° C. for 120 minutes to allow the respective exothermic reactions to complete. The reaction mixture was then cooled to 90° C. before hydrolysis with H2O (0.360 g) at that temperature for 60 minutes.
  • After cooling to room temperature, the reaction mixture was diluted with EtOH (30 mL), filtered and concentrated in vacuo (60° C. H2O bath) to give a brown oil substance.
  • Mass spectrometry analysis of the end product indicated the formation of the monophosphate derivatives of propofol and D-α-tocopherol, as well as the cross-coupled phosphate diester.
    • Example 6
  • Lauryl alcohol (0.990 g, 5.31 mmol) and P4O10 (0.530 g, 1.87 mmol) were combined in a Radleys 12 Station Carousel reaction tube and stirred vigorously. The reaction mixture was heated at 100° C. for 60 minutes and the exothermic reaction to complete. The reaction mixture was then cooled to 90° C. before hydrolysis with H2O (0.140 g) at that temperature for 60 minutes.
  • After cooling to room temperature, the reaction mixture was partitioned between Et2O (6 mL) and H2O (6 mL). The Et2O phase was concentrated in vacuo (60° C. H2O bath) to give a yellow liquid.
  • Mass spectrometry analysis of the end product indicated the formation of the desired monophosphate derivative of lauryl alcohol.
    • Example 7
  • β-Estradiol (0.490 g, 1.80 mmol) and P4O10 (0.140 g, 0.493 mmol) were combined in a Radleys 12 Station Carousel reaction tube and suspended in Triacetin (2 mL). The reaction mixture was heated at 100° C. for 60 minutes and to complete the exothermic reaction. The reaction mixture was then cooled to 90° C. before it was hydrolysed with H2O (1.00 g) at that temperature for 60 minutes.
  • After cooling to room temperature, the reaction mixture was washed with hexane (2×25 mL). The resultant suspension was dissolved in THF (30 mL) and concentrated in vacuo (60° C. H2O bath) to give an oily beige solid. Mass spectrometry analysis of the end product indicated the formation of the desired monophosphate derivative.
  • In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word “comprise” or variations such as “comprises” or “comprising” is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

Claims (14)

1-20. (canceled)
21. A process for phosphorylating a complex alcohol, comprising the steps of:
(a) mixing the complex alcohol and P4O10 until its exothermic reaction temperature is achieved;
(b) allowing the reaction mixture of step (a) to react until the exothermic reaction is complete and, if the temperature of the reaction mixture at this point is not at least 90° C., heating the reaction mixture to within a range of 90° C. to 140° C.;
(c) cooling the reaction mixture of step (b) to at least 80° C.; and
(d) hydrolysing the reaction mixture of step (c), wherein hydrolysis is conducted for 30 to 90 minutes.
22. The process of claim 21 wherein the complex alcohol is a linear or branched alcohol comprising at least 6 carbon atoms, or a cyclic complex alcohol.
23. The process of claim 21 wherein the cyclic complex alcohol is carbocyclic, heterocyclic, monocyclic or polycyclic.
24. The process of claim 21 wherein the complex alcohol is a chromanol.
25. The process of claim 24 wherein the chromanol is a tocopherol or tocotrienol.
26. The process of claim 21 wherein step (d) involves the addition of an aqueous solution.
27. The process of claim 21 wherein, in step (b) and/or (c), the temperature of the reaction mixture is maintained for 30 to 180 minutes, 60 to 180 minutes, 60 to 120 minutes, or 60 minutes.
28. The process of claim 21 wherein the temperature of the reaction mixture during the hydrolysis step (d) is at least 80° C., within the range of at least 80° C. to 150° C., within the range of 85° C. to 120° C., within the range of 90° C. to 110° C., within the range of 90° C. to 100° C., or within the range of 100° C. to 110° C.
29. The process of claim 21 wherein hydrolysis is conducted for 60 to 90 minutes.
30. The process of claim 21 wherein the product of the hydrolysis step (d) is a mixture of a phosphorylated mono-complex alcohol and a phosphorylated di-complex alcohol.
31. The process of claim 21 wherein the molar ratio of the mixture of the phosphorylated mono-complex alcohol and the phosphorylated di-complex alcohol is within a range of 6:4 to 8:2, or is 2:1.
32. The process of claim 21 wherein the process further comprises the step of reacting the reaction mixture of step (d) with an amphoteric surfactant, wherein the amphoteric surfactant is a tertiary amine of the formula N1R1R2R3, wherein R1 is selected from the group consisting of C6-22 alkyl, and R2 and R3 are independently selected from the group consisting of H, (CH2)nCOOX, (CH2)nCHOHCH2SO3X, (CH2)nCHOHCH2OPO3X, in which X is H or forms a salt with a cation selected from the group consisting of sodium, potassium, lithium, calcium, magnesium, ammonium, alkylammonium and alkanolamine, and n is 1 or 2.
33. The process of claim 32 wherein the tertiary amine is selected from the group consisting of 3-[2-carboxyethyl(dodecyl)amino] propanoic acid, 3,3′-(dodecylimino)dipropionic acid monosodium salt, lauryliminodipropionic acid, sodium lauryliminodipropionate and N-lauryl iminodipropionate.
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Family Cites Families (301)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2407823A (en) 1946-09-17 Antihemorrhagic esters and methods
US2457932A (en) 1949-01-04 Salts of tocopheryl phosphoric
US2667479A (en) 1951-01-30 1954-01-26 Merck & Co Inc Benzimidazole phosphate
GB778142A (en) 1953-11-20 1957-07-03 Leo Ab High-molecular weight derivatives of hydroxyl group-containing steroids and a method of producing them
US2913477A (en) 1957-03-22 1959-11-17 Merck & Co Inc Antihemorrhagic compounds and processes for preparing the same
US3127434A (en) 1959-10-20 1964-03-31 Hoffmann La Roche Dihydrovitamin k monophosphate compounds and preparation thereof
US3212901A (en) 1961-06-07 1965-10-19 Eastman Kodak Co Stabilized tocopherol concentrates and process for preparing the same
US3331896A (en) 1964-09-15 1967-07-18 Gen Aniline & Film Corp Method of preparing alkali soluble phosphate esters of hydroxylic organic compounds
US3607765A (en) 1968-11-29 1971-09-21 Colgate Polmolive Co Detergent softener compositions
JPS5022535A (en) 1973-06-27 1975-03-11
DE2526938C2 (en) 1975-02-14 1982-04-22 F. Hoffmann-La Roche & Co. AG, 4002 Basel Vitamin preparations
JPS521858A (en) 1975-06-24 1977-01-08 Hitachi Metals Ltd Steel pipe transfer apparatus
JPS5239013A (en) 1975-09-23 1977-03-26 Shintaro Yamada Forced draft diesel engine
JPS6035347B2 (en) 1976-07-26 1985-08-14 エーザイ株式会社 Synthesis method of α-tocopherol
US4141938A (en) * 1976-10-07 1979-02-27 Hoechst Aktiengesellschaft Production of acid orthophosphoric acid ester mixtures
US4444755A (en) 1978-01-23 1984-04-24 Efamol Limited Treatment for skin disorders
US4299906A (en) 1979-06-01 1981-11-10 American Hoechst Corporation Light-sensitive color proofing film with surfactant in a light-sensitive coating
SU925961A1 (en) 1980-08-15 1982-05-07 Московский ордена Трудового Красного Знамени технологический институт пищевой промышленности Process for producing higher fatty acid phosphorilated glycerides
US4369172A (en) 1981-12-18 1983-01-18 Forest Laboratories Inc. Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose
IT1157269B (en) 1982-03-19 1987-02-11 Seuref Ag NEW PHARMACEUTICAL FORMULATIONS CONTAINING COENZYME Q10 SUITABLE FOR TOPICAL ADMINISTRATION
JPS58180410A (en) 1982-04-16 1983-10-21 Shiseido Co Ltd Cosmetic
JPS5944375A (en) 1982-09-06 1984-03-12 Senjiyu Seiyaku Kk Stable aqueous solution of alpha-tocopherol phosphoric ester
JPH0247997B2 (en) 1983-02-25 1990-10-23 Sanyo Chemical Ind Ltd RINSANESUTERUNOSEIZOHO
JPS6048962A (en) 1983-08-26 1985-03-16 Chisso Corp Preparation of sulfamic acid guanidine
JPS6056699A (en) 1983-09-08 1985-04-02 三菱重工業株式会社 Half-warm water catamaran
JPS60197621A (en) 1984-03-19 1985-10-07 Hohnen Oil Co Ltd Hypocholesterolemic
CH661438A5 (en) 1984-04-09 1987-07-31 Seuref Ag Pharmaceutical compositions acting antianossica and metabolic brain.
US4977282A (en) 1984-04-17 1990-12-11 Henkel Corporation Production of d-alpha-tocopherol from natural plant sources
US4603142A (en) 1984-06-01 1986-07-29 Wisconsin Alumni Research Foundation Cholesterol lowering method of use
EP0171009B1 (en) 1984-08-02 1991-05-22 HENKEL CORPORATION (a Delaware corp.) Purification of tocopherols by extraction
JPS6186940A (en) 1984-10-02 1986-05-02 Kao Corp Oil in water type emulsion composition
JPS6191137A (en) 1984-10-11 1986-05-09 Kao Corp External drug composition
JPS61176535A (en) 1985-01-31 1986-08-08 Morishita Jintan Kk Enteric drug preparation
JP2540294B2 (en) 1985-04-09 1996-10-02 花王株式会社 Transdermal formulation
JPS62195393A (en) 1986-02-21 1987-08-28 Yakult Honsha Co Ltd Novel camptothecin derivative and production thereof
JPS6393791A (en) 1986-10-08 1988-04-25 Nippon Shokubai Kagaku Kogyo Co Ltd Phosphoric ester and preparation thereof
JPH0781138B2 (en) 1986-12-02 1995-08-30 株式会社資生堂 Antioxidant
DE3702766A1 (en) * 1987-01-30 1988-08-11 Henkel Kgaa METHOD FOR PRODUCING AND ISOLATING MONOALKYLPHOSPHORIC ACID ESTERS
JP3070744B2 (en) 1987-04-10 2000-07-31 株式会社日立製作所 Vector processing equipment
US4952495A (en) 1987-06-08 1990-08-28 Eastman Kodak Company Hydrolyzable compounds which release electron transfer agents and analytical use of same
PH25859A (en) 1988-01-11 1991-12-02 Takeda Chemical Industries Ltd Composition for treatment of ischemic disorder
US5234957A (en) 1991-02-27 1993-08-10 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5446070A (en) 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
JPH01228920A (en) 1988-03-09 1989-09-12 Kuraray Co Ltd Absorbefacient
DE3813624A1 (en) 1988-04-22 1989-11-02 Basf Ag METHOD FOR PRODUCING D- (ALPHA) -TOCOPHEROL FROM NATURAL PRE-PRODUCTS
JPH01274830A (en) 1988-04-28 1989-11-02 Asahi Denka Kogyo Kk Safe lipid composition having high surface activity
CA2007643A1 (en) 1989-02-01 1990-08-01 Donald S. Karanewsky Combination of an hmg coa reductase inhibitor and a squalene synthetase inhibitor and method for lowering serum cholesterol using such combination
US6028105A (en) 1989-04-06 2000-02-22 Nigra; Thomas P. Topical drug delivery composition and method
JP3040427B2 (en) 1989-05-18 2000-05-15 帝國製薬株式会社 Aspirin-containing ointment composition for treating neuralgia
US5053222A (en) 1989-06-07 1991-10-01 Shiseido Company Ltd. Hair cosmetic composition
US5094848A (en) 1989-06-30 1992-03-10 Neorx Corporation Cleavable diphosphate and amidated diphosphate linkers
DE3927113C2 (en) 1989-08-17 1993-11-25 Dolorgiet Gmbh & Co Kg Agent for the treatment of severe pain conditions and process for their preparation
JPH03120230A (en) 1989-10-04 1991-05-22 Nippon Mining Co Ltd Percutaneous absorbefacient of drug active ingredient and percutaneous absorption type pharmaceutical
JP2854631B2 (en) 1989-11-21 1999-02-03 千寿製薬株式会社 Prevention and treatment of diabetic complications and diseases caused by aging
IT1236843B (en) 1989-11-22 1993-04-21 Simes PROCESS FOR THE PREPARATION OF 4-0-DOPAMINE PHOSPHATES OR ITS DERIVATIVES
JPH03206089A (en) 1990-01-05 1991-09-09 Eisai Co Ltd New vitamin e derivative and production thereof
US5374645A (en) 1990-01-22 1994-12-20 Ciba-Geigy Corporation Transdermal administation of ionic pharmaceutically active agents via aqueous isopropanol
FR2657526B1 (en) 1990-01-31 1994-10-28 Lvmh Rech USE OF AN ALPHA-TOCOPHEROL PHOSPHATE, OR ONE OF ITS DERIVATIVES, FOR THE PREPARATION OF COSMETIC, DERMATOLOGICAL, OR PHARMACEUTICAL COMPOSITIONS; COMPOSITIONS THUS OBTAINED.
US5041434A (en) 1991-08-17 1991-08-20 Virginia Lubkin Drugs for topical application of sex steroids in the treatment of dry eye syndrome, and methods of preparation and application
US5114957A (en) 1990-05-08 1992-05-19 Biodor U.S. Holding Tocopherol-based antiviral agents and method of using same
CA2081982A1 (en) 1990-05-21 1991-11-22 Kenneth John Murray Phenol and pyridinol derivatives as pharmaceuticals
CA2067754C (en) 1990-08-24 2002-06-04 Gregor Cevc Preparation for the application of agents in mini-droplets
WO1992007544A1 (en) 1990-10-26 1992-05-14 Shiseido Co., Ltd. External preparation for skin
SE9003665D0 (en) 1990-11-16 1990-11-16 Kabivitrum Ab MORPHINE PRODRUGS
JP3035742B2 (en) 1990-11-30 2000-04-24 昭和電工株式会社 Cosmetics
JP2983311B2 (en) 1991-02-26 1999-11-29 株式会社資生堂 External preparation for skin
US5646190A (en) 1991-03-01 1997-07-08 Warner-Lambert Company Acne treating-wound healing compositions and methods for preparing and using same
JPH05946A (en) 1991-06-27 1993-01-08 Nichiban Co Ltd Ketotifen-containing percutaneous absorption preparation
US5643597A (en) 1991-08-01 1997-07-01 Lvmh Recherche Use of a tocopherol phosphate or one of its derivatives for the preparation of cosmetic or pharmaceutical compositions and compositions so obtained
FR2679904A1 (en) 1991-08-01 1993-02-05 Lvmh Rech Use of a tocopherol phosphate, or of one of its derivatives, in the preparation of cosmetic or pharmaceutical compositions and compositions thus obtained
EP0535283A1 (en) 1991-10-02 1993-04-07 Merrell Dow Pharmaceuticals Inc. Cardioprotective tocopherol analogs
US5474891A (en) 1991-10-30 1995-12-12 Thomas Jefferson University Plasma-based platelet concentrate preparations with additive
EP0612521B1 (en) 1991-11-11 1999-06-30 Hisamitsu Pharmaceutical Co., Inc. Fomentation containing ketorolac
EP0543417A1 (en) 1991-11-22 1993-05-26 Lipogenics, Incorporated Tocotrienols and tocotrienol-like compounds and methods for their use
US5282312A (en) 1991-12-31 1994-02-01 Tessera, Inc. Multi-layer circuit construction methods with customization features
AU3662093A (en) 1992-02-14 1993-09-03 Robert Lamb Phosphate derivatives of vitamin e to protect cells from effects of aging and injury
JP3207494B2 (en) 1992-04-02 2001-09-10 ロート製薬株式会社 Aqueous suspension formulation
JPH05286848A (en) 1992-04-10 1993-11-02 Senju Pharmaceut Co Ltd Bathing agent
US5731299A (en) 1992-05-29 1998-03-24 The Procter & Gamble Company Phosphonosulfonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism
GB9212450D0 (en) 1992-06-11 1992-07-22 Indena Spa New derivatives of non-steroidal anti-inflammatory,analgesic and/or antipyretic substances,their use and pharmaceutical formulations containing them
US5741518A (en) 1992-08-03 1998-04-21 L'oreal Composition composed of an aqueous dispersion of stabilized vesicles of nonionic amphiphilic lipids
US5773457A (en) 1995-02-15 1998-06-30 Cesar Roberto Dias Nahoum Compositions
WO1994008599A1 (en) 1992-10-14 1994-04-28 The Regents Of The University Of Colorado Ion-pairing of drugs for improved efficacy and delivery
US6384043B1 (en) 1993-02-01 2002-05-07 Gholam A. Peyman Methods of alleviating pain sensations of the denuded eye with opioid analgesics
TW252918B (en) 1993-03-31 1995-08-01 Senju Pharma Co
DE4336557C2 (en) 1993-05-06 1997-07-17 Lohmann Therapie Syst Lts Estradiol-containing transdermal therapeutic system, process for its preparation and its use
JP3179629B2 (en) 1993-06-24 2001-06-25 花王株式会社 Liquid detergent composition
CN1077800C (en) 1993-07-01 2002-01-16 韩美药品工业株式会社 Cyclosporin soft capsule composition
GB9318271D0 (en) 1993-09-03 1993-10-20 Scotia Holdings Plc Tocopherols
CA2129509A1 (en) 1993-09-10 1995-03-11 Kazumi Ogata Pharmaceutical composition for renal disorder and a dialysis solution for extracorporeal hemodialysis
WO1995014457A1 (en) 1993-11-27 1995-06-01 Knoll Ag Compositions comprising iminium ion scavengers and/or nitrite scavengers
JPH07196516A (en) 1993-12-29 1995-08-01 Senju Pharmaceut Co Ltd Therapeutic agent for hemorrhoids
FR2714595B1 (en) 1993-12-30 1996-02-02 Oreal Water in oil emulsion containing retinol, its use and packaging.
JPH07207298A (en) 1994-01-21 1995-08-08 Nippon Oil & Fats Co Ltd Detergent composition
FR2715565B1 (en) 1994-01-31 1996-03-15 Oreal Stabilized cosmetic or dermatological composition containing several precursors of the same active ingredient to maximize its release, its use.
EP0669132A1 (en) 1994-02-23 1995-08-30 van der Kraaij, Antonius Marinus Maria Pharmaceutical composition of vitamin E and acetylsalicylate for treatment and prevention of atherosclerosis
CA2145229A1 (en) 1994-03-29 1995-09-30 Tetsuya Toge Suppressory compositions against hepatic metastases of tumors
US5554781A (en) * 1994-03-30 1996-09-10 Reierson; Robert L. Monoalkyl phosphonic acid ester production process
EP1207135B1 (en) * 1994-03-30 2008-03-05 Rhodia Inc. Phosphation reagent, process and use
JPH07277988A (en) 1994-04-05 1995-10-24 Senju Pharmaceut Co Ltd Locally itch-removing and treating agent
JPH07278587A (en) 1994-04-06 1995-10-24 Kao Corp Detergent composition
TW287103B (en) 1994-04-22 1996-10-01 Senju Pharma Co
JP3362501B2 (en) 1994-04-28 2003-01-07 千寿製薬株式会社 Corneal disorder treatment
JP3396953B2 (en) 1994-05-10 2003-04-14 千寿製薬株式会社 Retinal disease prevention / treatment agent
GB9409778D0 (en) 1994-05-16 1994-07-06 Dumex Ltd As Compositions
JPH07316170A (en) 1994-05-24 1995-12-05 Kao Corp Production of phosphoric monoester
AU2825295A (en) 1994-06-13 1996-01-05 Arcturus Pharmaceutical Corporation Method for the treatment, prevention or minimization of hair loss
US5589504A (en) 1994-07-26 1996-12-31 Cornell Research Foundation, Inc. Treatment of newborn jaundice
CA2152693A1 (en) 1994-08-05 1996-02-06 Kazumi Ogata Therapeutic composition for pancreatitis
IT1274734B (en) 1994-08-25 1997-07-24 Prospa Bv PHARMACEUTICAL COMPOSITIONS CONTAINING POLYUNSATURATED FATTY ACIDS, THEIR ESTERS OR SALTS, WITH VITAMINS OR ANTIOXIDANT PROVITAMINS
JPH0873338A (en) 1994-09-02 1996-03-19 Noevir Co Ltd Skin external preparation
HU215966B (en) 1994-11-21 1999-07-28 BIOGAL Gyógyszergyár Rt. Oral multiple emulsion-preconcentrate containing cyclosporin
KR100261858B1 (en) * 1994-12-09 2000-07-15 고토다쿠야 Process for the preparation of phosphoric monoester
JP3558757B2 (en) * 1994-12-09 2004-08-25 花王株式会社 Method for producing phosphate ester
DE4444238A1 (en) 1994-12-13 1996-06-20 Beiersdorf Ag Cosmetic or dermatological drug combinations of cinnamic acid derivatives and flavone glycosides
SE9404568L (en) 1994-12-30 1996-07-01 Perstorp Ab Use of inositol trisphosphate for drug preparation
AU4515996A (en) 1995-01-09 1996-07-31 Alpha-Therapeutics, Inc. Methods for increasing the bioavailability of biological active agents
JP3526940B2 (en) 1995-01-11 2004-05-17 花王株式会社 Method for producing phosphate ester
FR2730928B1 (en) 1995-02-23 1997-04-04 Oreal COMPOSITION BASED ON LIPIDIC VESICLES WITH ACIDIC PH AND USE THEREOF IN TOPICAL APPLICATION
JPH08231564A (en) 1995-02-28 1996-09-10 Nippon Shokubai Co Ltd Phosphoric acid ester, its production and phosphoric acid ester polymer
GB9505025D0 (en) 1995-03-13 1995-05-03 Medical Res Council Chemical compounds
EP0766960B1 (en) 1995-04-21 2003-09-17 Sekisui Kagaku Kogyo Kabushiki Kaisha External preparations for treating dermatoses
JP3197787B2 (en) 1995-05-17 2001-08-13 花王株式会社 Method for producing branched dimerized alkyl phosphate basic amino acid salt
JPH08311489A (en) 1995-05-19 1996-11-26 Nippon Oil & Fats Co Ltd Detergent composition
US5665389A (en) 1995-05-24 1997-09-09 University Of Maryland At Baltimore Oral dosage composition for intestinal delivery and method of treating diabetes
JP3622267B2 (en) 1995-05-31 2005-02-23 日本油脂株式会社 Cleaning composition
US5607968A (en) 1995-06-07 1997-03-04 Avon Products, Inc. Topical alkyl-2-O-L-ascorbyl-phosphates
JP3609834B2 (en) 1995-07-12 2005-01-12 株式会社 資生堂 Skin preparation
JPH0944375A (en) 1995-07-26 1997-02-14 Hitachi Ltd Automatic test item selection system for test program
JP4115524B2 (en) 1995-10-17 2008-07-09 昭和電工株式会社 High-purity tocopherol phosphates, production method thereof, analysis method thereof and cosmetics
FR2741263B1 (en) 1995-11-22 1997-12-26 Oreal COMPOSITION COMPRISING AN AQUEOUS DISPERSION OF LIPID VESICLES ENCAPSULATING AN ACID-FUNCTIONAL UV FILTER AND USES FOR TOPICAL APPLICATION
CN1229114C (en) 1996-03-27 2005-11-30 印斯拜尔药品股份有限公司 Method of treating ciliary dyskinesia with uridine triphosphates and related compounds
US6077828A (en) 1996-04-25 2000-06-20 Abbott Laboratories Method for the prevention and treatment of cachexia and anorexia
US5885595A (en) 1996-05-13 1999-03-23 Elizabeth Arden Co., Division Of Conopco, Inc. Cosmetic composition with a retinol fatty acid ester
JPH09309813A (en) 1996-05-22 1997-12-02 Nonogawa Shoji Kk Preparation for external use for skin
JPH1045783A (en) 1996-07-29 1998-02-17 Showa Denko Kk Production of hydroxychromanic acid derivative phosphoric ester
CA2209690A1 (en) 1996-07-31 1998-01-31 Sachiko Matsuura Therapeutic drug for acne vulgaris
JPH1067639A (en) 1996-08-26 1998-03-10 Shiseido Co Ltd Vitamin e-vitamin c phosphoric diester/cyclodextrin clathrate and external preparation for skin containing the same
US6022867A (en) 1996-11-27 2000-02-08 Showa Denko Kabushiki Kaisha Method of administering vitamin E to animals and compositions containing tocopheryl phosphates and salts thereof for animals
JPH10155429A (en) 1996-11-27 1998-06-16 Showa Denko Kk Method for supplying vitamin e to animals and tocopherol phosphate for animals or its salts composition
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6727280B2 (en) 1997-01-07 2004-04-27 Sonus Pharmaceuticals, Inc. Method for treating colorectal carcinoma using a taxane/tocopherol formulation
US5804168A (en) 1997-01-29 1998-09-08 Murad; Howard Pharmaceutical compositions and methods for protecting and treating sun damaged skin
US6932975B2 (en) 1997-01-29 2005-08-23 Kao Corporation Cosmetic composition comprising a phosphoric triester and a skin activating component
US6248758B1 (en) 1997-03-13 2001-06-19 Hexal Ag Pharmaceutical antacid
US7179486B1 (en) 1997-04-01 2007-02-20 Nostrum Pharmaceuticals, Inc. Process for preparing sustained release tablets
FR2764891B1 (en) 1997-06-04 2001-04-13 Pacific Corp DERIVED FROM L-ASCORBIC ACID STABLE IN WATER, PROCESS FOR ITS PREPARATION AND COSMETIC COMPOSITION OF BLEACHING THE SKIN CONTAINING IT
US5928631A (en) 1997-06-09 1999-07-27 The Procter & Gamble Company Methods for controlling environmental odors on the body using compositions comprising uncomplexed cyclodextrins
US5906811A (en) 1997-06-27 1999-05-25 Thione International, Inc. Intra-oral antioxidant preparations
JPH1143436A (en) 1997-07-25 1999-02-16 Showa Denko Kk Medicine for preventing/treating periphery blood stream disorder
US5776915A (en) 1997-08-12 1998-07-07 Clarion Pharmaceuticals Inc. Phosphocholines of retinoids
US6096326A (en) 1997-08-15 2000-08-01 Scandinavian-American Import/Export Corporation Skin care compositions and use
IT1294748B1 (en) 1997-09-17 1999-04-12 Permatec Tech Ag FORMULATION FOR A TRANSDERMAL DEVICE
JP3950216B2 (en) 1997-12-26 2007-07-25 日本メナード化粧品株式会社 Topical skin preparation
WO1999033846A2 (en) 1997-12-31 1999-07-08 The University Of Kansas Water soluble prodrugs of secondary and tertiary amine containing drugs and methods of making thereof
JPH11199465A (en) 1998-01-07 1999-07-27 Nonogawa Shoji Kk Skin preparation for external use
AU2113199A (en) 1998-01-12 1999-07-26 Betagene, Inc. Media for neuroendocrine cells
EP1053749A4 (en) 1998-02-03 2003-01-15 Senju Pharma Co Preventives and remedies for neuron digeneration-associated diseaseas
FR2777179A1 (en) 1998-04-09 1999-10-15 Lvmh Rech Cosmetic and dermatological composition with non-greasy feel and useful as carrier
US6461623B2 (en) 1998-04-13 2002-10-08 Kao Corporation Cosmetic composition
US6254853B1 (en) 1998-05-08 2001-07-03 Vyrex Corporation Water soluble pro-drugs of propofol
US6121249A (en) 1998-07-01 2000-09-19 Donald L. Weissman Treatment and prevention of cardiovascular diseases with help of aspirin, antioxidants, niacin, and certain B vitamins
ATE399565T1 (en) 1998-07-07 2008-07-15 Transdermal Technologies Inc COMPOSITIONS FOR THE RAPID AND NON-IRRITATIVE TRANSDERMAL ADMINISTRATION OF PHARMACEUTICALS AND METHODS OF FORMULATION AND ADMINISTRATION THEREOF
US6204257B1 (en) 1998-08-07 2001-03-20 Universtiy Of Kansas Water soluble prodrugs of hindered alcohols
US6703384B2 (en) 1998-09-23 2004-03-09 Research Development Foundation Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof
US6770672B1 (en) 1998-09-23 2004-08-03 Research Development Foundation Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof
IL142082A (en) 1998-09-23 2005-12-18 Res Dev Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof
US6153582A (en) 1998-11-05 2000-11-28 Bausch & Lomb Surgical, Inc. Defined serumfree medical solution for ophthalmology
IT1303787B1 (en) 1998-11-25 2001-02-23 Maria Rosa Gasco "SOLID LIPID NANOSPHERES SUITABLE FOR FAST INTERNALIZATION IN THE CELLS"
US6048891A (en) 1998-12-17 2000-04-11 Loma Linda University Medical Center Use of γ-tocopherol and its oxidative metabolite LLU-α in the treatment of natriuretic disease
AU766255B2 (en) 1999-01-25 2003-10-09 Vital Health Sciences Pty Ltd Improved process for phosphorylation and compounds produced by this process
AUPP829399A0 (en) 1999-01-25 1999-02-18 Swig Pty Ltd Recovery for chroman derivatives
AUPQ037499A0 (en) * 1999-05-14 1999-06-10 Swig Pty Ltd Improved process for phosphorylation and compounds produced by this method
JP2000212082A (en) 1999-01-26 2000-08-02 Showa Denko Kk Preparation for external use for skin
NZ527924A (en) 1999-01-29 2005-01-28 Mars Uk Ltd Antioxidant compositions and methods for companion animals
US6156354A (en) 1999-01-29 2000-12-05 Brandeis University Hyper-absorption of vitamin E dispersed in milks
GB9903547D0 (en) 1999-02-16 1999-04-07 Novartis Ag Organic compounds
DE19912798C1 (en) 1999-03-10 2000-02-17 Andreas Jordan Culturing human cancer cells for molecular biology research comprises culturing fragments of tissue slices
AU3913800A (en) 1999-03-26 2000-10-16 Lipogenics, Inc. Novel antioxidant formulations and methods for using them
US6383471B1 (en) 1999-04-06 2002-05-07 Lipocine, Inc. Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents
CA2372066C (en) * 1999-05-14 2006-01-31 Simon Michael West Process for phosphorylation of primary fatty alcohols,secondary alcohols and aromatic alcohols using p4o10 in the absence of solvent
DE19923551A1 (en) 1999-05-21 2000-11-30 Lohmann Therapie Syst Lts Pharmaceutical preparation with the active ingredient diamorphine and its use in a method for treating opiate addiction
US6184247B1 (en) 1999-05-21 2001-02-06 Amway Corporation Method of increasing cell renewal rate
AU5594700A (en) 1999-06-01 2000-12-18 Ocean Spray Cranberries, Inc. Cranberry seed oil extract and compositions containing components thereof
EP1187618A1 (en) 1999-06-04 2002-03-20 The General Hospital Corporation Pharmaceutical formulations for treating postmenopausal and perimenopausal women, and their use
NZ517833A (en) 1999-08-20 2004-01-30 Ferrosan As Oral delivery of antioxidants vitamin C and vitamin E combinations in slow- and plain-release formulations for treating oxidative stress
US6669951B2 (en) 1999-08-24 2003-12-30 Cellgate, Inc. Compositions and methods for enhancing drug delivery across and into epithelial tissues
US6423742B1 (en) 1999-09-02 2002-07-23 Drake Larson Compositions for reducing vascular plaque formation and methods of using same
GB9921960D0 (en) 1999-09-16 1999-11-17 Pharmacia & Upjohn Spa Formulations for parenteral use of estramustine phosphate and amino acids
KR20020059415A (en) 1999-09-27 2002-07-12 스티븐 씨. 큐웨이 Compositions of tocol-soluble therapeutics
WO2001035998A1 (en) 1999-11-12 2001-05-25 Pharmaderm Laboratories, Ltd. Compositions for transdermal and transmucosal administration of therapeutic agents
AU1780101A (en) 1999-11-19 2001-05-30 Xel Herbaceuticals Transdermal delivery system for alkaloids of aconitum species
JP2001169731A (en) 1999-12-17 2001-06-26 Showa Denko Kk Lipid metabolism improving agent for animal
WO2001046204A1 (en) 1999-12-22 2001-06-28 Merck Frosst Canada & Co. Aromatic phosphonates as protein tyrosine phosphatase 1b (ptp-1b) inhibitors
IT1317736B1 (en) 2000-01-26 2003-07-15 A C R Applied Coating Res S A PATCH FOR LOCAL AND TRANSDERMAL ADMINISTRATION OF PRINCIPIACTIVES EQUIPPED WITH ANIONIC GROUPS AND ELECTRONATTRACTORS.
KR100847678B1 (en) 2000-02-11 2008-07-23 리서치 디벨럽먼트 파운데이션 Tocopherols, tocotrienols, other chroman and side chain derivatives and uses thereof
US6635253B2 (en) 2000-02-29 2003-10-21 Showa Denko Kabushiki Kaisha Composition for enhancing immunological effects
US6346544B2 (en) 2000-03-02 2002-02-12 Oklahoma Medical Research Foundation Desmethyl tocopherols for protecting cardiovascular tissue
JP2001247585A (en) 2000-03-03 2001-09-11 Nof Corp Tocopherol derivative, intermediate for the same, method of producing the same, and application for the same
US6444220B2 (en) 2000-03-16 2002-09-03 Teresa S. Wiley Method and compositions for changing the contour of skin
AU2001247726A1 (en) 2000-03-24 2001-10-08 Baker Norton Pharmaceuticals, Inc. Taxane-based compositions and methods of use
US6361800B1 (en) 2000-04-13 2002-03-26 Cooper Concepts, Inc. Multi-vitamin and mineral supplement
DE10032301A1 (en) 2000-07-04 2002-01-17 Rbs Netkom Gmbh Driving data acquisition, transmission and output system
FR2811546B1 (en) 2000-07-13 2003-09-26 Oreal LONG-LASTING MAKEUP KIT AND METHOD
US6485950B1 (en) 2000-07-14 2002-11-26 Council Of Scientific And Industrial Research Isozyme of autoclavable superoxide dismutase (SOD), a process for the identification and extraction of the SOD in cosmetic, food and pharmaceutical compositions
US6362234B1 (en) 2000-08-15 2002-03-26 Vyrex Corporation Water-soluble prodrugs of propofol for treatment of migrane
KR100365070B1 (en) 2000-08-29 2002-12-16 주식회사 태평양 Tocopherol derivatives and method for preparation thereof
JP4818500B2 (en) 2000-09-05 2011-11-16 株式会社ペンタプラストア Tocotrienol derivative and method for producing the same
WO2002026238A1 (en) 2000-09-26 2002-04-04 Vital Health Sciences Pty Ltd. Phosphate derivative supplements
US6660306B2 (en) 2000-10-12 2003-12-09 Mickey L. Peshoff Wound healing compound
US20030206972A1 (en) 2000-10-13 2003-11-06 Babish John G. Compositions containing carotenoids and tocotrienols and having synergistic antioxidant effect
AU2002220021A1 (en) 2000-11-02 2002-05-15 The Regents Of The University Of California Alpha-tocopherol transfer protein knockout animals
AU2002214820B2 (en) 2000-11-14 2003-08-14 Vital Health Sciences Pty Ltd Formulation containing phosphate derivatives of electron transfer agents
CN1262274C (en) 2000-11-14 2006-07-05 生命健康科学有限公司 Complexes of phosphate derivatives
AUPR549901A0 (en) 2001-06-06 2001-07-12 Vital Health Sciences Pty Ltd Topical formulation containing tocopheryl phosphates
AU2002228648A1 (en) 2000-11-16 2002-05-27 Pharmacia And Upjohn Company Combined therapy against tumors comprising estramustine phosphate and lhrh agonists or antagonists
IN188917B (en) 2000-12-07 2002-11-23 Bharat Surums & Vaccines Ltd
WO2002047680A2 (en) 2000-12-15 2002-06-20 Galileo Laboratories, Inc. Use of tocopherol, metabolites or derivatives thereof or flavonoid metabolites or derivatives thereof in the manufacture of a medicament for the treatment of tissue ischemia
US20020151467A1 (en) 2000-12-21 2002-10-17 Leung Frank K. Methods and compositions for oral insulin delivery
US20020131994A1 (en) 2001-01-10 2002-09-19 Schur Henry B. Non-irritating formulation for the transdermal delivery of substances
US6849271B2 (en) 2001-04-27 2005-02-01 Verion, Inc. Microcapsule matrix microspheres, absorption-enhancing pharmaceutical compositions and methods
TW576859B (en) 2001-05-11 2004-02-21 Shipley Co Llc Antireflective coating compositions
KR100428702B1 (en) 2001-05-26 2004-04-28 주식회사 엘지생명과학 Feed additive compositions for animals comprising polyethoxylated alpha tocopherol ester derivatives
KR100394770B1 (en) 2001-06-05 2003-08-14 주식회사 태평양 Stabilization method of nano-emulsion using tocopheryl derivatives and external application for skin containing the stabilized nano-emulsion
BR0211673A (en) 2001-07-27 2004-07-13 Vital Health Sciences Pty Ltd Dermal therapy using phosphate derivatives of electron transfer agents
AUPR684801A0 (en) 2001-08-06 2001-08-30 Vital Health Sciences Pty Ltd Supplement therapy
RU2302857C2 (en) 2001-09-04 2007-07-20 Тромсдорф ГмбХ унд Ко.КГ Арцнаймиттель Method and plaster for preventing and/or treating the cases of finger-nail dysfunction and/or growth disorders
US20040234602A1 (en) 2001-09-21 2004-11-25 Gina Fischer Polymer release system
WO2003024430A1 (en) 2001-09-21 2003-03-27 Egalet A/S Morphine polymer release system
WO2003026673A1 (en) 2001-09-26 2003-04-03 Vital Health Sciences Pty Ltd. Modulation of vitamin storage
AU2002951045A0 (en) 2002-08-27 2002-09-12 Vital Health Sciences Pty Ltd Method of supplementing nascent endogenous storage forms
JP4370451B2 (en) 2001-09-28 2009-11-25 大塚製薬株式会社 Pharmaceutical composition
JP2003128531A (en) 2001-10-17 2003-05-08 Nonogawa Shoji Kk Dermal external agent
US20030144219A1 (en) 2001-11-15 2003-07-31 Phinney Stephen Dodge Formulations and methods for treatment or amelioration of inflammatory conditions
WO2003049774A1 (en) 2001-12-13 2003-06-19 Vital Health Sciences Pty Ltd Transdermal transport of compounds
IL162614A0 (en) 2001-12-19 2005-11-20 Res Dev Foundation Liposomal delivery of vitamin e based compounds
DE10200578A1 (en) 2002-01-09 2003-07-10 Roehm Gmbh Adhesive and binding agents for dermal or transdermal therapy systems
WO2003063860A1 (en) 2002-01-31 2003-08-07 Kansai Technology Licensing Organization Co., Ltd. Compositions for preventing human cancer and method of preventing human cancer
WO2003068209A1 (en) 2002-02-14 2003-08-21 Sonus Pharmaceuticals, Inc. Metformin salts of lipophilic acids
US7074825B2 (en) 2002-03-07 2006-07-11 Huanbiao Mo Composition and method for treating cancer
CN1652746A (en) 2002-05-09 2005-08-10 昭和电工株式会社 Skin whitening external preparation
EP1507813A4 (en) 2002-05-20 2005-11-23 Ranbaxy Lab Ltd Fat binding using inter-polymer complex of glucosamine and polyacrylic acid
US20040018237A1 (en) 2002-05-31 2004-01-29 Perricone Nicholas V. Topical drug delivery using phosphatidylcholine
CA2494297C (en) 2002-07-29 2011-10-18 Transform Pharmaceuticals, Inc. Aqueous 2,6-diisopropylphenol pharmaceutical compositions
AU2002950713A0 (en) 2002-08-09 2002-09-12 Vital Health Sciences Pty Ltd Carrier
US20040067890A1 (en) 2002-10-04 2004-04-08 Gupta Shyam K. Ascorbic acid salts of organic bases with enhanced bioavailability for synergictic anti-aging and skin protective cosmetic compositions
FR2846651B1 (en) 2002-10-30 2006-06-16 Rhodia Polyamide Intermediates PROCESS FOR PRODUCING CARBOXYLIC ACIDS
US7399784B2 (en) 2002-11-26 2008-07-15 Children's Hospital & Research Center At Oakland Tocopherol and tocotrienol anti-obesity medicaments
US6645514B1 (en) 2002-12-19 2003-11-11 Access Business Group International, Llc Increasing skin cell renewal with water-soluble Vitamin E
EP1578325B1 (en) 2002-12-31 2011-04-27 Transdermal Biotechnology, Inc. Stable topical drug delivery compositions
KR20050086954A (en) 2003-01-17 2005-08-30 바이탈 헬스 사이언시즈 피티와이 리미티드 Compounds having anti-proliferative properties
US7033998B2 (en) 2003-04-11 2006-04-25 All Natural Fmg, Inc. Alcohol-free transdermal insulin composition and processes for manufacture and use thereof
AU2003901812A0 (en) * 2003-04-15 2003-05-01 Vital Health Sciences Pty Ltd Phosphates of secondary alcohols
AU2003901813A0 (en) 2003-04-15 2003-05-01 Vital Health Sciences Pty Ltd Pharmaceutical derivatives
AU2003901815A0 (en) * 2003-04-15 2003-05-01 Vital Health Sciences Pty Ltd Phosphate derivatives
US20050152858A1 (en) 2003-07-11 2005-07-14 Isp Investments Inc. Solubilizing agents for active or functional organic compounds
US8546453B2 (en) 2003-08-14 2013-10-01 Rensheng Zhang Propofol compositions and methods for reducing pain associated with propofol injection
JP2006199589A (en) 2003-09-03 2006-08-03 Ltt Bio-Pharma Co Ltd Nanoparticle containing physiologically active protein or peptide, method for producing the same and external preparation comprising the nanoparticle
CN100536845C (en) 2003-09-23 2009-09-09 中国医学科学院药物研究所 Loratadine paster of penetrating skin
US7207669B2 (en) 2003-12-19 2007-04-24 Arizona Chemical Company Jet printing inks containing polymerized fatty acid-based polyamides
CA3031283A1 (en) 2004-01-22 2005-08-04 University Of Miami Topical co-enzyme q10 formulations and methods of use
NZ549016A (en) 2004-02-13 2012-03-30 Bioavailability Inc A microemulsion preparation of high concentration propofol for anesthetic uses
PT2351555T (en) 2004-02-23 2016-11-29 Euro Celtique Sa Abuse resistance opioid transdermal delivery device
WO2005084678A1 (en) 2004-03-03 2005-09-15 Vital Health Sciences Pty Ltd Alkaloid formulations
DE602005020638D1 (en) 2004-06-29 2010-05-27 Japan Science & Tech Agency SELECTIVE CULTURING METHOD AND SEPARATION METHOD FOR SMALL HEPATOCYTES USING HYALURONIC ACID
KR101238703B1 (en) 2004-08-03 2013-03-04 바이탈 헬스 사이언시즈 피티와이 리미티드 Carrier for enteral administration
JP4523388B2 (en) 2004-11-19 2010-08-11 日本メナード化粧品株式会社 Collagen synthesis promoter and skin external preparation
US20060120979A1 (en) 2004-12-02 2006-06-08 Joel Rubin Skin care composition comprising hydroquinone and a substantially anhydrous base
CA2599424A1 (en) 2005-03-03 2006-09-08 Vital Health Sciences Pty Ltd Compounds having anti-cancer properties
CN101132789A (en) 2005-03-03 2008-02-27 生命健康科学有限公司 Compounds having lipid lowering properties
US20090239827A1 (en) 2005-03-03 2009-09-24 Esra Ogru Compounds having lipid lowering properties
US20060228395A1 (en) 2005-04-11 2006-10-12 Robert Lamb Vitamin E phosphate/phosphatidylcholine liposomes to protect from or ameliorate cell damage
KR20080019228A (en) 2005-06-17 2008-03-03 바이탈 헬스 사이언시즈 피티와이 리미티드 A carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
KR100764679B1 (en) 2005-07-22 2007-10-09 익수제약 주식회사 Patches comprising paroxetine for transdermal application
US20070110739A1 (en) 2005-11-11 2007-05-17 Logsdon Lawrence M Wipe away pain
US7446096B2 (en) 2005-12-19 2008-11-04 Industrial Technology Research Institute Glutathione based delivery system
TW200800223A (en) 2005-12-21 2008-01-01 Shire Pharmaceuticals Inc Transdermal delivery of meptazinol
CA2631653A1 (en) 2005-12-23 2007-06-28 Vital Health Sciences Pty Ltd. Compounds having cytokine modulating properties
DE102006023336A1 (en) 2006-05-18 2007-11-22 Merck Patent Gmbh 1,5-diphenyl-pyrazoles II
WO2008034178A1 (en) 2006-09-21 2008-03-27 Salvatore Iemma Topical depilating composition
RU2373957C2 (en) 2006-10-13 2009-11-27 Александр Метталинович Тишин Therapeutic and diagnostic drug and biologically active substance carrier and application thereof for making drugs and method of regulated controlled drug or biologically active substance delivery with regulated desorption
RU2009125613A (en) 2006-12-05 2011-01-20 Новартис АГ (CH) MICROEMULSION MEDICINAL FORMS OF VALSARTAN AND METHODS FOR PRODUCING THEM
IL181217A0 (en) 2007-02-08 2007-07-04 Haim Levy Pharmaceuticalcompositions based on a microemulsion
FR2921259B1 (en) 2007-09-26 2015-02-13 Lvmh Rech COSMETIC USE OF TOCOPHEROL PHOSPHATE AS AN ANTI-AGING SKIN AGENT
EP2113242A1 (en) 2008-05-02 2009-11-04 Pangaea Laboratories Limited Antioxidant for use in cosmetic, medicated and pharmaceutical preparations
US20090297591A1 (en) 2008-05-30 2009-12-03 Orient Pharma Co., Ltd. Compositions And Methods For The Transdermal Delivery Of Pharmaceutical Compounds
AR072008A1 (en) 2008-06-13 2010-07-28 Merck & Co Inc HETEROBICICLIC COMPOUNDS AS QUINASA P38 INHIBITION AGENTS
US20090319191A1 (en) 2008-06-24 2009-12-24 Rivas Ariel L Method for diagnosis of an infectious disease stage and determination of treatment
CN101524330B (en) 2009-04-20 2013-01-09 重庆莱美药业股份有限公司 Micro emulsion drug carrying system and manufacturing method thereof
US20120202780A1 (en) 2009-12-23 2012-08-09 Paul David Gavin Carrier composition
RU2012133467A (en) 2010-02-05 2014-02-10 Фосфейдженикс Лимитед CARRIER COMPOSITION
AU2011213557B2 (en) 2010-02-05 2015-05-07 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
JP5132700B2 (en) 2010-02-22 2013-01-30 三菱電機株式会社 Hand dryer
CN102821791B (en) 2010-03-30 2015-06-17 磷肌酸有限公司 Transdermal delivery patch
US9987226B2 (en) 2010-12-10 2018-06-05 Ns Technologies Pty Ltd Methods for forming miniemulsions and use thereof for delivering bioactive agents
CN102079756B (en) * 2010-12-27 2012-09-12 锦州惠发天合化学有限公司 Method for synthesizing perfluoroalkyl polyoxyethenyl phosphate fluorosurfactant
EP2685992A4 (en) 2011-03-15 2014-09-10 Phosphagenics Ltd Amino-quinolines as kinase inhibitors
US9328317B2 (en) * 2011-11-04 2016-05-03 The Chemours Company Fc, Llc Fluorophosphate surfactants
CN102911203A (en) * 2012-10-25 2013-02-06 浙江合诚化学有限公司 Preparation method of alkyl phosphate
KR101542541B1 (en) 2014-10-07 2015-08-06 주식회사 대동요업 The tile that prevention of countercurrent is possible
CA3007587C (en) 2015-12-09 2023-12-05 Phosphagenics Limited Pharmaceutical formulation

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