US2913477A - Antihemorrhagic compounds and processes for preparing the same - Google Patents

Antihemorrhagic compounds and processes for preparing the same Download PDF

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US2913477A
US2913477A US647747A US64774757A US2913477A US 2913477 A US2913477 A US 2913477A US 647747 A US647747 A US 647747A US 64774757 A US64774757 A US 64774757A US 2913477 A US2913477 A US 2913477A
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methyl
phytyl
naphthohydroquinone
phosphate
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Ralph F Hirschmann
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Merck and Co Inc
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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 Table
    • 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

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  • This invention relates to Water-soluble derivatives of dihydro vitamin K (2-methyl-3-phytyl-l,4-naphthohydroquinone) having anti-hemorrhagic activity and to the processes for preparing these novel derivatives. More particularly, this invention relates to l-monocarboxylic acid esters of 2-methyl-3-phytyl-1,4-naphthohydroquinone-4-phosphate and to 2-methyl-3-phytyl-1,4-naphthohydraquinone-4-phosphate, and to the intermediates produced in accordance with this invention.
  • vitamin K for example vitamin K emulsion
  • an anti-hemorrhagic compound is available which is capable of effecting a more rapid lowering of the prothrombin time and blood clotting time than that noted with previous preparations.
  • Water-soluble dihydro vitamin K was found to be appreciably more effective than vitamin K emulsion by the intramuscular route. Data obtained in prophylactic and therapeutic studies indicate that water-soluble dihydro vitamin K has a shorter duration of action than vitamin K emulsion. Because of this property, water-soluble dihydro vitamin K should be capable of rapidly reversing excessive hypoprothrombinemia with less liklihood of inducing refractoriness to reinstitution of anticoagulant therapy.
  • novel compounds described in this invention namely l-carboxylic acid esters of 2-methyl-3-phytyl-1,4- naphthohydroquinone-4-phosphate and 2-methyl-3-phytyl- 1,4-naphthohydroquinone-4-phosphate are water-soluble and have been found to provide a prompt lowering of prothrombin time and blood clotting time.
  • a l-monocarboxylic acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinone represented by the following structure 2,913,477 Patented Nov. 17, 1959 wherein R represents a monocarboxylic acid radical, is
  • R is an alkali carboxylic acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinone-4-(dichloro) phosphate having the structure CHr-CH-CHr-G 15H" wherein R is as above.
  • the above compound is treated with alkali to form a monoor di-alkali metal salt of 1- monocarboxylic acid ester of 2-methyl-3-phytyl-l,4- naphthohydroquinone-4-phosphate having the structure wherein R is as above.
  • l-monocarboxylic acid ester of 2-methyl-3-phytyl-1,4-naphth0hydroquinone- 4-phosphate may be reacted with an alcoholic solution in the presence of an acid catalyst such as sulfuric, perchloric, paratoluene sulfonic or suliosalicylic acid and 2- methyl-3-phytyl-1,4-naphthohydroquinone-4-phosphate is recovered.
  • an acid catalyst such as sulfuric, perchloric, paratoluene sulfonic or suliosalicylic acid
  • esters can be prepared by reacting l-monocarboxylic acid ester of Z-methyl-l,4-naphthohydroquinone with phytol in the presence of boron trifluoride to produce the corresponding l-monocarboxylic acid ester of 2-methyl-3-phytyl-l,4-naphthohydroquinone.
  • reaction of a l-monocarboxylic acid ester of 2- methyl-3-phytyl-l,4-naphthohydroquinone with phosphorous oxychloride is conveniently achieved by contacting the reactants in the presence of a suitable reaction medium.
  • Solvents such as pyridine, triethylamine and other tertiary amines are examples of suitable reaction media in which the reaction may be eifected.
  • the desired 1- monocarboxylic acid ester of 2-methyl-3-phytyl-l,4-naphthohydroquinonei-(dichloro)phosphate is recovered by removing the excess phosphorous oxychloride and pyridine by evaporation.
  • the product then may be reacted with dilute aqueous alkali to form l-monocarboxylic acid ester .of 2-methyl-3-phytyl-l,4-naphthohydroquinone4- phosphate in aqueous solution as a mixture of the alkali metal and dialkali metal salt.
  • the solution is extracted with ether and acidified with dilute acid to about pH 1.
  • the l-monocarboxylic acid ester of 2-methyl-3-phytyll,4-naphthohydroquinone-4-phosphate can then be reacted With Claisens alkali to form a mixture of the mono-, diand tri-alkali metal salt of 2-methyl-3-p hytyl- 1,4:naphthohydroquinone-4 phosphate.
  • This latter mixture is..then treateclwith aqueous acid. solution to form 2' methyl 3 phyhyl 1.4 naphthohydroquinone -4- phosphate.
  • the l-monocarboxylic ester of 2-methyl-3-phytyl-l,4-napl1thohydroquinone-4-phosphate can be reacted with methanolic sulfuric acid to form directly the 2-methyl-3-phytyl-l,4- naphthohydroquinone-4-phosphate.
  • the described reaction may be specifically illustrated by the reaction of 2-methyl-3-phytyl-l,4-naphthohydroquinone-l-acetate with phosphorus oxychloride to form 2 methyl 3 phytyl 1,4 naphthohydroquinone lacetate 4 (dichloro)phosphate.
  • 2-methyl-3- phytyl-l,4-naphthohydroquinone-l-propionate is reacted with phosphorus oxychloride to produce 2-methyl-3- phytyl 1,4 naphthohydroquinone l propionate 4- (dichloro)phosphate.
  • any of the l-monocarboxylic acid esters of 2-methyl-3- phytyl 1 1,4 naphthohydroquinone g 4 (dichloro)phosphate obtained above may be reacted with sodium hydroxide solution to form l-monocarboxylic acid esters of 2 methyl 3 phytyl 1,4 naphthohydroquinone 4- phosphate as a mixture of the sodium and disodium salt.
  • the l-monoc'arboxylic acid ester of 2-methyl-3-phytyll,4-naphthohydroquinone-4-phosphate may be reacted with Claisens alkali to form the mono-, diand tri-sodium salt of 2 methyl 3 phytyl 1,4 naphthohydroquinone-4-phosphate.
  • the l-monocarboxylic acid ester of 2- m'ethyl 3 phytyl 1,4 naphthohydroquinone 4 phosphate is dissolved in a suitable solvehtsuch as a low boiling petroleum ether and the resulting solution is extracted with Claisens alkali.
  • a l-rnonocarboxylic acid ester or 2- methyl L 3 phytyl 1,4 naphthohydroquinone 4- phosphate may be reacted with methanolic sulfuric acid to form directly 2-methyl-3-phytyl 1,4 naphth'ohydroqui none-4-phosphate'.
  • the table shows that even after four days the prothrombin time of the control dogs who received no vitaminK -derivatives is between and 37, very much above the normal of 9 to 10 seconds.
  • At 5 hours a significant lowering of prothrombin time was observable but'this efiect was less than with the 2-methyl-3-phytyl-1,4-naphthohydroquinone diphosphate and 2-methyl-3-phytyl-1,4-naphthohydroquinone- 4-phosphate.
  • Themost rapidly acting preparation 2 methyl 3 phytyl-l,4-naphthohydroquinone-4-phosphate, brought about essentially complete reversal of hypothrombinemia within two and one-half hours after doses of 2 or 5 mg./kg. Prothrombin times remained low for the next two and one-half hours but then progressively increased on the following two days, after which they declined toward normal limits. s
  • K compound intravenously a! CHI wherein R" is hydrogen or s NaOH O O--CH.
  • the excess phosphorous oxychloride and pyridine was removed at 40 C. in vacuo and the residue thus obtained was neutralized with dilute aqueous sodium hydroxide to about pH 8 to form 2-methyl-3-phytyl-1,4-naphthohydroquinone-l-acetate-4-phosphate as a mixture of the sodium and disodium salts.
  • the alkaline aqueouslayer was extracted portionwise with 150 rater et er and then acidified with dilute hydrochloric acid to about pH 1.
  • the aqueous solution was then extracted with about 100 ml. of ether, the ether layer separated and concentrated to dryness in vacuo.
  • This reaction mixture contains predominantly disodium 2 methyl 3 phytyl-1,4-naphthohydroquinonel-phosphate, however some mono and trisodium 2 methyl-3-phytyl-1,4-naphthohydroquinone-4- phosphate may be present.
  • the alkaline aqueous layer was extracted with 20 ml. of petroleum ether and then acidified with dilute hydrochloric acid to about pH 1.
  • the 2-methyl-3-phytyl-1,4- naphthohydroquinone-4-phosphate thus formed was then extracted into 100 ml. of ether and the ether solution evaporated to dryness in vacuo. The residual water was removed by co-distillation with benzene.
  • the crude 2- methyl-3-phyty1-1,4 naphthohydroquinone t-phosphate was purified by precipitation from 10 ml. of acetone solution with petroleum ether and benzene.
  • the solution was cooled to about 20 C. and diluted with cc. of ether.
  • the ether solution was washed twice with 100 ml. portions of sodium bicarbonate, water and salt. It was then evaporated to dryness in vacuo and about 54 ml. of petroleum ether was added to the residue. Any solid was removed by filtration, and the filtrate treated with activated charcoal and subsequently extracted with 2% aqueous potassium hydroxide. It was then washed further with sodium chloride solution and the petroleum ether finally removed by concentration in vacuo to about 80 C.
  • the combined ether layers consisting of 240 ml. were washed twice with 50 ml. of saturated sodium chloride solution. The sodium chloride solution picked up some color, leaving behind a slightly brown colored ether layer; The ether layer was evaporated to dryness and further dried by azeotropic distillation with benzene.
  • This reaction mixture contains predominantly disodium 2-methyl-3-phytyl-1,4-naphthohydroquinone-4-phosphate, however some mono and trisodium 2 methyl 3-phytyl-1,4-naphthohydroquinone-4- phosphate may be present.
  • the alkaline aqueous layer was extracted with 20 m1. of petroleum ether and then acidified with dilute hydrochloric acid to about pH 1.
  • the 2-methyl-3-phytyl-1,4- naphthohydroquinone-4-phosphate thus formed was then extracted into 100 ml. of ether and the ether solution evaporated to dryness in vacuo. The residual water was removed by co-distillation with benzene.
  • the crude Z-methyl-S phytyl 1,4 naphthohydroquinone 4-phosphate was purified by precipitation from 10 ml. of acetone Solution with petroleum ether and benzene.
  • a mixture of 3.07 g. of phytol in 8 ml. of dioxane was added slowly to 23.45 g. of 2-methyl-1,4-naphthohydroquinone-l-propionate in 20 ml. of dioxane to which about 0,54 ml. of boron trifluoride etherate had been added.
  • the addition was carried out at about 50 C. in an inert atmosp e an t e act n ll e o ontin f a total of about 1 hour.
  • the solution was coole to about 20 C. and diluted with 100 cc. of ether.
  • the ether solution was washed twice with 100 ml. portions of sodium bicarbonate, water and salt. It was then evaporated to dryness in vacuo and about 54 ml. of petroleum ether was added to the residue. Any solid was removed by filtration, and the filtrate treated with activated charcoal and subsequently extracted with 2% aqueous potassium hydroxide. lit was then washed further with sodium ch10 ride solution and-the petroleum ether-finally removed by concentration in vacuo to about C.
  • the combined ether layers consisting of 240 ml. were washed twice with 50 ml. of saturated sodium chloride solution. The sodium chloride solution picked up some color, leaving behind a slightly brown colored ether layer.. The ether layer was evaporated to dryness and further dried by azeotropic distillation with benzene.
  • R is selected from the group consisting of hydrogen and a lower fatty acid acyl group and R' is selected from the group consisting of halogen and hydroxyl, and compounds wherein the hydrogen atom of at least one of the hydroxyl groups is replaced by an alkali metal.
  • Dialkali metal salt of l-lower fatty acid ester of 2-methy1-3-phytyl-1,4-naphthohydroquinone-4-phosphate 1.
  • Trisodiurn 2 methyl-3-phytyl-1,4-naphthohydroquinone-4-phosphate.
  • Theprocess which comprises reacting 2-methy1-3- phytyl-l,4-naphthohydroquinone-1-propionate with phos phoro'us oxychloride to form 2 methyl 3 phytyl-1,4- naph thohydroquinone 1 propionate-4-(dichloro)phospha te, reacting the latter compound with sodium hydroxide to form a mixture of sodium and disodium Z-methyl- 3 'phytyLl,4-naphthohydroquinone-1-propionate-4-phosphate, reacting the latter compound with hydrochloric acid to form 2-methyl- 3 -phyty1-l,4naphthohydroquinone- 1-propionate-4-phosphate, and reacting the latter compound'with methanolic sulfuric acid to form 2-methyl-3- phytyl-l,4-naphthohydroquinone-4-phosphate.
  • the process which comprises reacting 2-methyl-3- phytyl 1,4 naphthohydroquinone 1 propionate-4-(dichloro)phosphate with sodium hydroxide to'form a mixture of sodium and disodium 2-methyl-3-phytyl-1,4- naphthohydroquinone-1-propionate-4-phosphate.

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Description

United States Patent ANTIHEMORRHAGIC COMPOUNDS AND PROC- I ESSES FOR PREPARING THE SAME Ralph F. Hirschmann, Westfield, N.J., assignor to Merck 8: Co., Inc., Rahway, NJ., a corporation of New Jersey No Drawing. Application March 22, 1957 Serial No. 647,747
20 Claims. (Cl. 260-461) This invention relates to Water-soluble derivatives of dihydro vitamin K (2-methyl-3-phytyl-l,4-naphthohydroquinone) having anti-hemorrhagic activity and to the processes for preparing these novel derivatives. More particularly, this invention relates to l-monocarboxylic acid esters of 2-methyl-3-phytyl-1,4-naphthohydroquinone-4-phosphate and to 2-methyl-3-phytyl-1,4-naphthohydraquinone-4-phosphate, and to the intermediates produced in accordance with this invention.
Due to an overdose of certain anticoagulants or where a proper amount of the anticoagulant is administered but the patient is hypersensitive to such drugs, such anticoagulants may cause serious hemorrhaging in the patient. The immediate concern of the clinician with a patient having a dangerously low prothrombin level due to these anticoagulants is to bring the prothrombin to a safe level as rapidly as possible. Prior to this invention certain types of hemorrhage occurring spontaneously were treated with vitamin K preparations, one of the most active of which being an emulsion of vitamin K (2-methyl-3-phytyl-1,4- naphthoquinone). In instances of hypoprothrombinemia and bleeding due to a variety of anticoagulants, vitamin K for example vitamin K emulsion, has been established as the only efiective preparation available. Nevertheless, in certain critical cases of drug induced hypopro thrombinemia, the action of even vitamin K emulsion was not as rapid as might be desired.
Now an anti-hemorrhagic compound is available which is capable of effecting a more rapid lowering of the prothrombin time and blood clotting time than that noted with previous preparations.
Water-soluble dihydro vitamin K was found to be appreciably more effective than vitamin K emulsion by the intramuscular route. Data obtained in prophylactic and therapeutic studies indicate that water-soluble dihydro vitamin K has a shorter duration of action than vitamin K emulsion. Because of this property, water-soluble dihydro vitamin K should be capable of rapidly reversing excessive hypoprothrombinemia with less liklihood of inducing refractoriness to reinstitution of anticoagulant therapy.
The novel compounds described in this invention, namely l-carboxylic acid esters of 2-methyl-3-phytyl-1,4- naphthohydroquinone-4-phosphate and 2-methyl-3-phytyl- 1,4-naphthohydroquinone-4-phosphate are water-soluble and have been found to provide a prompt lowering of prothrombin time and blood clotting time.
In accordance with this invention a l-monocarboxylic acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinone represented by the following structure 2,913,477 Patented Nov. 17, 1959 wherein R represents a monocarboxylic acid radical, is
' reacted with phosphorus oxychloride to form a l-mono wherein R is an alkali carboxylic acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinone-4-(dichloro) phosphate having the structure CHr-CH-CHr-G 15H" wherein R is as above. The above compound is treated with alkali to form a monoor di-alkali metal salt of 1- monocarboxylic acid ester of 2-methyl-3-phytyl-l,4- naphthohydroquinone-4-phosphate having the structure wherein R is as above.
Reaction of the above compound with a concentrated aqueous alcoholic metal hydroxide such as Claisens alkali, which is a solution of potassium hydroxide in aqueous methanol, results in the formation of the mono-, diand tri-alkali metal salt of 2-methyl-3-phytyl-1,4- naphthohydroquinone-4-phosphate which can be represented by the following formula -CHg wherein R and R" are as above.
The above compound is reacted with an aqueous acid solution and Z-methyI-S-phytyl-1,4-naphthohydroquinone- 4-phosphate having the following structure is recovered.
Instead of employing Claisens alkali, l-monocarboxylic acid ester of 2-methyl-3-phytyl-1,4-naphth0hydroquinone- 4-phosphate may be reacted with an alcoholic solution in the presence of an acid catalyst such as sulfuric, perchloric, paratoluene sulfonic or suliosalicylic acid and 2- methyl-3-phytyl-1,4-naphthohydroquinone-4-phosphate is recovered.
.,In.gen'eral, anysuitable l-inonocarboxylic acid ester of 2-methyl-3-phytyl 1,4-naphthohydroquinone, can .be employed as the starting. material inthis process. -Thus, the acyloxy ,substituent present at the 1-position ofthe naphthohydroquinone nucleus may be an alkyl-acyloxy, arylacyloxy or aralkylacyloxy group derived from a monocarboxylic acid. Ordinarily, however, it is preferred to efiect the reaction using a l-monocarboxylic acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinone in which the acyloxy group contains eight carbons or less. Specific examples of such compounds which can be used in this invention that might be mentioned are 2-methyl-3-phytyll,4-naphthohydroquinone-l-acetate, 2-methyl-3 -phytyl-l, 4-naphthohydroquinone-l-propionate, 2-methyl-3-phytyl- 1,4 naphthohydroquinone l butyrate, 2 methyl 3- phytyl 1,4 naphthohydroquinone l valerate, 2- m ethyl 3 phytyl 1,4 naphthohydroquinone 1 -caproate, 2 methyl 3 phytyl 1,4 naphthohydroquinonel caprylate, 2 methyl 3 phytyl 1,4 naphthohydroquinone 1 phenylacetate, 2 methyl 3 phytyl 1,4- naphthohydroquinone-l-benzoate, and the like. These and similar esters can be prepared by reacting l-monocarboxylic acid ester of Z-methyl-l,4-naphthohydroquinone with phytol in the presence of boron trifluoride to produce the corresponding l-monocarboxylic acid ester of 2-methyl-3-phytyl-l,4-naphthohydroquinone.
The reaction of a l-monocarboxylic acid ester of 2- methyl-3-phytyl-l,4-naphthohydroquinone with phosphorous oxychloride is conveniently achieved by contacting the reactants in the presence of a suitable reaction medium. Solvents such as pyridine, triethylamine and other tertiary amines are examples of suitable reaction media in which the reaction may be eifected.
Following completion of this reaction the desired 1- monocarboxylic acid ester of 2-methyl-3-phytyl-l,4-naphthohydroquinonei-(dichloro)phosphate is recovered by removing the excess phosphorous oxychloride and pyridine by evaporation. The product then may be reacted with dilute aqueous alkali to form l-monocarboxylic acid ester .of 2-methyl-3-phytyl-l,4-naphthohydroquinone4- phosphate in aqueous solution as a mixture of the alkali metal and dialkali metal salt. The solution is extracted with ether and acidified with dilute acid to about pH 1. The mixture is then extracted with ether, the ether layer separated and concentrated to dryness. The last traces of water are then removed by co-distillation with benzene. The residue thus obtained is the l-monocarboxylic acid ester of 2 methyl 3 phytyl 1,4 naphthohydrcquinone-4-phosphate.
The l-monocarboxylic acid ester of 2-methyl-3-phytyll,4-naphthohydroquinone-4-phosphate can then be reacted With Claisens alkali to form a mixture of the mono-, diand tri-alkali metal salt of 2-methyl-3-p hytyl- 1,4:naphthohydroquinone-4 phosphate. This latter mixture;is..then treateclwith aqueous acid. solution to form 2' methyl 3 phyhyl 1.4 naphthohydroquinone -4- phosphate. Instead of employing Claisens alkali the l-monocarboxylic ester of 2-methyl-3-phytyl-l,4-napl1thohydroquinone-4-phosphate can be reacted with methanolic sulfuric acid to form directly the 2-methyl-3-phytyl-l,4- naphthohydroquinone-4-phosphate.
The described reaction may be specifically illustrated by the reaction of 2-methyl-3-phytyl-l,4-naphthohydroquinone-l-acetate with phosphorus oxychloride to form 2 methyl 3 phytyl 1,4 naphthohydroquinone lacetate 4 (dichloro)phosphate. Similarly, 2-methyl-3- phytyl-l,4-naphthohydroquinone-l-propionate is reacted with phosphorus oxychloride to produce 2-methyl-3- phytyl 1,4 naphthohydroquinone l propionate 4- (dichloro)phosphate. In like manner by starting with other appropriate reactants there is obtained 2-methyl3- phytyl 1,4 naphthohydroquinone' l va-lerate 4- (dichloro) phosphate, 2 methyl 3 phytyl 1,4 naphthohydroquinone' 1 :butyrate 4 (dichloro)phosphate, 2 methyl 3 phytyl 1,4 naplithohydroquinone lcaproate 4 (dichloro)phosphate, 2 methyl 3 phytyll,4 naphthohydroquinone l caprylate 4 (dichloro) phosphate, 2 methyl 3 phytyl 1,4 naphthohydroquinone l phenylacetate 4 (dichloro)phosphate, 2- methyl -3 phytyl 1,4 naphthohydroquinone l ben- Zoate 4 (dichloro) phosphate and other similar '1-mono-' carboxylic acid esters of 2-methyl-3-phytyl-l,4-naphth0- hydroqui none-4- (dichloro)phosphate.
Any of the l-monocarboxylic acid esters of 2-methyl-3- phytyl 1 1,4 naphthohydroquinone g 4 (dichloro)phosphate obtained above may be reacted with sodium hydroxide solution to form l-monocarboxylic acid esters of 2 methyl 3 phytyl 1,4 naphthohydroquinone 4- phosphate as a mixture of the sodium and disodium salt.
The mixture of the sodium and disodium l-monocarboxylic acid esters of 2-methyl-3-phytyl 1,4-naphthohydroquinone-4-phosphate when reacted with water or hydrochloric acid forms the l-rnonocarboxylic acid ester of 2 methyl 3 phytyl 1,4 naphthohydroquinone 4- phosphate. 7 k
, The l-monoc'arboxylic acid ester of 2-methyl-3-phytyll,4-naphthohydroquinone-4-phosphate may be reacted with Claisens alkali to form the mono-, diand tri-sodium salt of 2 methyl 3 phytyl 1,4 naphthohydroquinone-4-phosphate. In accordance with the reaction with Claisens alkali, the l-monocarboxylic acid ester of 2- m'ethyl 3 phytyl 1,4 naphthohydroquinone 4 phosphate is dissolved in a suitable solvehtsuch as a low boiling petroleum ether and the resulting solution is extracted with Claisens alkali. In this manner purification and unexpected solvolysis of the acyl group is achieved simultaneously to give an alkaline solution of essentially pure 2 methyl 3 phytyl 1,4 naphthohydroquinone- 4-phosphate as a mixture of the monosodium, disodium and trisodium salt. *The phosphate ester linkage is not cleaved. To isolate the free acid, the alkaline aqueous layer is extracted with petroleum ether and then acidified with dilute hydrochloric acid to about pH 1. The ether is removed by evaporation and the residual Water is removed by codistillation with benzene resulting in 2- methyl-3-phytyl-l,4-naphthohydroquinone-4-phosphate.
I Alternatively, a l-rnonocarboxylic acid ester or 2- methyl L 3 phytyl 1,4 naphthohydroquinone 4- phosphate may be reacted with methanolic sulfuric acid to form directly 2-methyl-3-phytyl 1,4 naphth'ohydroqui none-4-phosphate'. r V
The comparative efficien'ciesof vitamin K wemulsion (2 methyl 3 phytyl} 1,4 naphthoquinone), 2-m'ethyl- 3 phytyl 1,4 naphthohydroquinbne l,4 diph'os'phat'e,
ardized dogs was determined and found to range between nine and ten seconds. Then these dogs were .fed orally 2 mg./kg. of the anti-coagulant 3,3'-methylenebis(4-hydroxycoumarin) on two successive days. Prothrombin tests were made each day andon the second day the prothrombin time had risen to between nineteen and thirty-one seconds. Three dogs were used as controls and did not receive any of the vitamin K compounds. The other seven dogs then received the vitamin K derivatives and prothrornbin determinations were made 2%, 5, 24, 48 and 120 hours after the vitamin K derivative injection. The results of these tests are given in the fol lowing table:
TABLE EXAMPLE 1 Comparative eflicacies of vitamin K compounds in Reversing 3,3-methylenebis(4-hydroxycoumarin) induced hypoprothrombinemia Brothrombin Time, Seconds Vitamin K Compound MgJKg. Days 1 Day 2 Days 2 Days 2 Days 3 Days 4 Days 7 Days 0 Hours 0 Hours 0 Hours 2.5 Hours Hours 24 Hours 48 Hours 120 Hours Controls (No Vitamin K Oomr-nmom Do Emulsion of 2-methyl- 3-phytyl-1, naBhthoquinone o 2 methyl -3 phytyl 1, 4 -naphthohydroqulnone 1, 4 diphos phate Do 2 methyl 3 phytyl 1, 4 naphthohydroquinone 1 propionate-4-phosphate 2 methyl 3 phytyl 1, 4 naph Y thohydroquinone 4 phos phate Do H n- 0 an:
H. H)-' m 00- On cncncn as a .. H 95 M as a... use:
a: as. a: see
t no i- O 3, 3-methylenebis (4-hydroxycoumarin), 2 mg./kg., orally 1 Dose given in terms of vitamin K molar equivalent.
The table shows that even after four days the prothrombin time of the control dogs who received no vitaminK -derivatives is between and 37, very much above the normal of 9 to 10 seconds. Vitamin K emulsion, 2-methyl-3-phytyl-1,4-naphthohydroquinone, at 1 and 2 mg./kg. showed little or no activity within 2 /2 hours. At 5 hours a significant lowering of prothrombin time was observable but'this efiect was less than with the 2-methyl-3-phytyl-1,4-naphthohydroquinone diphosphate and 2-methyl-3-phytyl-1,4-naphthohydroquinone- 4-phosphate. However, at both dose levels, prothrombin levels were essentially normal at the 24 hour interval and remained so thereafter. 2-methyl-3-phytyl-l,4-naphthohydroquinone diphosphate, at l and 2' mg./kg., showed good activity in reversing hypoprothrornbinemia'but reversal was not complete even at 5 hours. One day after treatment, prothrombin times rose again slightly and thereafter returned to normal. 2-methyl-3-phytyl-1,4- naphthohydroquinone-l-propionate-4-phosphate exhibited definite activity. Themost rapidly acting preparation, 2 methyl 3 phytyl-l,4-naphthohydroquinone-4-phosphate, brought about essentially complete reversal of hypothrombinemia within two and one-half hours after doses of 2 or 5 mg./kg. Prothrombin times remained low for the next two and one-half hours but then progressively increased on the following two days, after which they declined toward normal limits. s
The following examples are given to illustrate specific applications of the invention but is should be recognized that the scope of the invention is not to be restricted to the particular embodiments of the invention as disclosed in these examples.
K compound, intravenously a! CHI wherein R" is hydrogen or s NaOH O O--CH.
odium To a solution of 6.5 v of phosphorus oxychloride in 17 ml. of dry pyridine wasadded with vigorous stirring a solution of 4.6 g. of crude 2-methyl-3-phytyl-1,4-naphthohydroquinone-l-acetate"(which can be prepared as described hereinbelow) in 17 ml. dry pyridine, The reaction was allowed to continue in an ice bath for about 30 minutes during which time the temperature rose to about 20-25 C., and 2-methyl-3-phytyl-1,4 naphthohydroquinone-1-acetate-4-(dich1oro) phosphate was formed.
The excess phosphorous oxychloride and pyridine was removed at 40 C. in vacuo and the residue thus obtained was neutralized with dilute aqueous sodium hydroxide to about pH 8 to form 2-methyl-3-phytyl-1,4-naphthohydroquinone-l-acetate-4-phosphate as a mixture of the sodium and disodium salts. The alkaline aqueouslayer was extracted portionwise with 150 rater et er and then acidified with dilute hydrochloric acid to about pH 1. The aqueous solution was then extracted with about 100 ml. of ether, the ether layer separated and concentrated to dryness in vacuo. The last portions of water were removed by co-distillation with "-b'e'ni'eiie. The residue thus obtained was 2-methyl-3phytyl-1,4 naphthohydroquinone-l-acetate -4-phosphate.
2-methyl-3 -phytyl-1 ,4-naphthhydr0quinonewherein R" is hydrogen or sodium- A solution of 1.88 g. of 2-methyl-3-phytyl-l,4-naphthohydroquinone-lacetate-4-phosphate dissolved in 60 ml. of petroleum ether was extracted with 20 ml. of Claisens methanolic alkali(prepared by dissolving 35 g. of potassium hydroxide in 25 ml. of water and diluting to 100 ml. with methanol). This reaction mixture contains predominantly disodium 2 methyl 3 phytyl-1,4-naphthohydroquinonel-phosphate, however some mono and trisodium 2 methyl-3-phytyl-1,4-naphthohydroquinone-4- phosphate may be present.
The alkaline aqueous layer was extracted with 20 ml. of petroleum ether and then acidified with dilute hydrochloric acid to about pH 1. The 2-methyl-3-phytyl-1,4- naphthohydroquinone-4-phosphate thus formed was then extracted into 100 ml. of ether and the ether solution evaporated to dryness in vacuo. The residual water was removed by co-distillation with benzene. The crude 2- methyl-3-phyty1-1,4 naphthohydroquinone t-phosphate was purified by precipitation from 10 ml. of acetone solution with petroleum ether and benzene.
2-methyl-3-phy tyl-1 ,4 -m zph thohydroquinone-l acetate The 2 methyl-3-phytyl-1,4-naphthohydroquinone-l-acetate" utilized as the starting material in this example was prepared as follows: I
p A mixture of 3.07 g. of phytol in 8 ml. of dioxane was added slowly to 23.45 g. of Z-methyl-1,4-naphthohydroquinene-i-acemte in 20 ml. of dioxane to which about 0.54 ml. of boron trifluoride etherate had been added. The addition was carried out at about 50 C. in an inert atmosphere and the reaction allowed to continue for a total of about 1 hour.
At the end of this time,- the solution was cooled to about 20 C. and diluted with cc. of ether. The ether solution was washed twice with 100 ml. portions of sodium bicarbonate, water and salt. It was then evaporated to dryness in vacuo and about 54 ml. of petroleum ether was added to the residue. Any solid was removed by filtration, and the filtrate treated with activated charcoal and subsequently extracted with 2% aqueous potassium hydroxide. It was then washed further with sodium chloride solution and the petroleum ether finally removed by concentration in vacuo to about 80 C.
EXAMPLE 2 2-methyl-3-phytyl-I,4-naphthohydroquinone-4-ph0sphate A To a mixture of 2.68 g. of 2-methyl-3-phytyl-1,4-naphthohydroquinone-l-acetate-4-phosphate, prepared as described in Example 1, in 10 ml. of methanol, was added 0.2 ml. of concentrated sulfuric acid. The solution was allowed to stand at room temperature. The solution was diluted to 40 ml. with methanol and ml. of a saturated solution of sodium chloride was added. This mixture was extracted with three 80 ml. portions of ether. The remaining aqueous layer showed no ultra-violet absorption. The combined ether layers consisting of 240 ml. were washed twice with 50 ml. of saturated sodium chloride solution. The sodium chloride solution picked up some color, leaving behind a slightly brown colored ether layer; The ether layer was evaporated to dryness and further dried by azeotropic distillation with benzene.
The 2 methyl 3 phytyl-l,4-naphthohydroquinone-4- phosphate thus obtained showed the same infra re'd spectrum as described in theabove example;
Treatment of the 2-methy1-3-phytyl-1,4-naphthohydroquinone-4-phosphate thus obtained with one equivalent of base results in the formation of 2-methyl-3-phytyl-1,4- naphthohydroquinone-4-sodium phosphate, while at 4-disodium phosphate is formed.
To a solution of 6.5 ml. of phosphorus oxychloride in 17 ml. of dry pyridinewas added with vigorous stirring a solution of 4.6 g. of crude 2-methyl-3-phytyl-1,4-naphthohydroquinone-l-propionate (which can be prepared as described hereinbelow) in 17 ml. dry pyridine. The reaction was allowed to continue in an ice bath for about 30 minutes during which time the temperature rose to about 20-25 C., and 2-methyl-3-phytyl-1,4-naphthohydroquinone-l-propionate 4 (dichloro)phosphate was formed.
The excess phosphorus oxychloride and pyridine was removed at 40 C. in vacuo and the residue thus obtained was neutralized with dilute aqueous sodium hydroxide to about pH 8 to form 2-methyl-3-phytyl-1,4-naphthohydroquinone-1-propionate-4-phosphate as a mixture of the sodium and disodium salts. The alkaline aqueous layer was extracted portionwise with 150 ml. of ether. and then acidified with dilute hydrochloric acid to about pH 1. The aqueous solution was then extracted with about 100 ml. of ether, the ether layer separated and concentrated to dryness in vacuo. The last portions of water were removed by co-distillation with benzene. The residue thus obtained was 2-methyl-3-phytyl-1,4-naphthohydroquinone-l-propionate-4-phosphate. 1
A sample of 2-methyl-3-phytyl-1,4-naphthohydroquinone-1-propionate-4-phosphate was dried at 100 C. for 90 minutes and showed the following ultra-violet properties in 1% sodium bicarbonate solution: A max. 235 mu E =52,500; 291 m E =5,150.
Z-methyl-3-phytyl-1,4-naphth0hydroquin0ne-4-phosphate A solution of 1.88 g. of 2-methyl-3-phytyl-l,4-naphthohydroquinone-l-propionate-4-phosphate dissolved in 60 ml. of petroleum ether was extracted with 20 ml. of Claisens methanolic alkali (prepared by dissolving 35 g. of potassium hydroxide in 25 ml. of water and diluting to 100 ml. with methanol). This reaction mixture contains predominantly disodium 2-methyl-3-phytyl-1,4-naphthohydroquinone-4-phosphate, however some mono and trisodium 2 methyl 3-phytyl-1,4-naphthohydroquinone-4- phosphate may be present.
The alkaline aqueous layer was extracted with 20 m1. of petroleum ether and then acidified with dilute hydrochloric acid to about pH 1. The 2-methyl-3-phytyl-1,4- naphthohydroquinone-4-phosphate thus formed was then extracted into 100 ml. of ether and the ether solution evaporated to dryness in vacuo. The residual water was removed by co-distillation with benzene. The crude Z-methyl-S phytyl 1,4 naphthohydroquinone 4-phosphate was purified by precipitation from 10 ml. of acetone Solution with petroleum ether and benzene.
Z-meIhyI-S-phytylJ ,4-naphthohydroquinone-1 -propinate The 2-methyl-3-phyty1-1,4-naphthohydroquinone-l-propionate, utilized as the starting material in this example was prepared as follows:
A mixture of 3.07 g. of phytol in 8 ml. of dioxane was added slowly to 23.45 g. of 2-methyl-1,4-naphthohydroquinone-l-propionate in 20 ml. of dioxane to which about 0,54 ml. of boron trifluoride etherate had been added. The addition was carried out at about 50 C. in an inert atmosp e an t e act n ll e o ontin f a total of about 1 hour.
At the end of this time, the solution was coole to about 20 C. and diluted with 100 cc. of ether. The ether solution was washed twice with 100 ml. portions of sodium bicarbonate, water and salt. It was then evaporated to dryness in vacuo and about 54 ml. of petroleum ether was added to the residue. Any solid was removed by filtration, and the filtrate treated with activated charcoal and subsequently extracted with 2% aqueous potassium hydroxide. lit was then washed further with sodium ch10 ride solution and-the petroleum ether-finally removed by concentration in vacuo to about C.
EXAMPLE4 I I 2-methyl-3-phytyl-1 ,4-naphthohydroquinone-4-phosphale' To a mixture of 2.68 g. of 2-methyl- 3 -phytyl-1,4-naph thohydroquinone-l-propionate 4-phosphate, prepared as described in Example 3, in 10 mL; of methanol, was added 0.2 ml. of concentrated sulfuric acid. The solution was allowed to stand at room temperature. The solution was diluted to"40 ml. with methanol and ml. of a saturated solution of sodium chloride was added. This mixture was extracted with three 80 ml. portions of ether. The remaining aqueous layer showed no ultraviolet absorption. The combined ether layers consisting of 240 ml. were washed twice with 50 ml. of saturated sodium chloride solution. The sodium chloride solution picked up some color, leaving behind a slightly brown colored ether layer.. The ether layer was evaporated to dryness and further dried by azeotropic distillation with benzene.
The 2-methyl-3-phytyl 1,4 naphthohydroquinonetphosphate thus obtained showed the same infra-red. spectrum as described in the above example.
Treatment of the 2-methyl-3 -phytyl-1,4-naphthohydroquinone-4-phosphate thus obtained with one equivalent of base results in the formation of 2-methyl-3-phytyl-1,4- naphthohydroquinonel-sodium phosphate, while at higher pH 2-methyl-3-phytyl-1,45naphthohydroquinorie- 4-disodium phosphate'is formed.
Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit of this invention, they are intended to be included within the scope of the appended claims.
I claim:
1. A compound of the formula wherein R is selected from the group consisting of hydrogen and a lower fatty acid acyl group and R' is selected from the group consisting of halogen and hydroxyl, and compounds wherein the hydrogen atom of at least one of the hydroxyl groups is replaced by an alkali metal.
2. Alkali metal salt of l-lower fatty acid ester of 2- methyl-S-phytyl-1,4-naphthohydroquinone-4-phosphate.
3. Sodium 2 methyl 3 phytyl-1,4-naphthohydroquinone-1-acetate-4-phosphate.
4. Dialkali metal salt of l-lower fatty acid ester of 2-methy1-3-phytyl-1,4-naphthohydroquinone-4-phosphate.
5. Disodium 2 methyl-3-phytyl-l,4-naphthohydroquinone-1-propionate-4-phosphate.
6. l-lower fatty acid ester of Z-methyl-S-phytyl-lA- p t yd Qq n ne-4-phosphate.
2; J methyl-3-phyty1*1,4-naphthohydroquinone-l-acetate-4-phosphate.
8. Trialkali metal salt of 2-methyl-3-phytyl-1,4-naphthohydroquinone-4-phosphate.
9. Trisodiurn 2 methyl-3-phytyl-1,4-naphthohydroquinone-4-phosphate.
10. Alkali metal salt of 2-methyl-3-phytyl-1,4-mph thohydroquinone-4-phosphate.
11. 2 methyl 3 phytyl-l,4-naphthohydroquinone-4- phosphate.
12. The process which comprises reacting l-lower fatty acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinone 11 with phosphorus oxychloride toform the l-lower fatty acid ester of 2methyl-3-phytyl4,4-naphthohydroquinone- 4-( dichloro) phosphate, reacting the latter compound with alkali to form a mixture of the monoand di-alkali metal salt of l-lower fatty acid ester of 2-methyl-3-phytyl-l,4- naphthohydroquinone-4-phosphate, 'reacting the latter compound with an inorganic acid tov form 1-lower fatty acid ester of2-methyl-3-phytyl-1,4-naphthohydroquinone 4-phosphate, reacting the latter compound with a concentrated aqueous alcoholic metal hydroxide to form a mixture of the mono-, diand tri-alkali metal salt of 2 methyl 3 phytyl 1,4-naphthohydroquinone-4-phosphate and reacting the latter compound with acid to form 2-methyl-3-phytyl-1,4-naphthohydroquinone-4-phosphate.
13. Theprocess which comprises reacting 2-methy1-3- phytyl-l,4-naphthohydroquinone-1-propionate with phos phoro'us oxychloride to form 2 methyl 3 phytyl-1,4- naph thohydroquinone 1 propionate-4-(dichloro)phospha te, reacting the latter compound with sodium hydroxide to form a mixture of sodium and disodium Z-methyl- 3 'phytyLl,4-naphthohydroquinone-1-propionate-4-phosphate, reacting the latter compound with hydrochloric acid to form 2-methyl- 3 -phyty1-l,4naphthohydroquinone- 1-propionate-4-phosphate, and reacting the latter compound'with methanolic sulfuric acid to form 2-methyl-3- phytyl-l,4-naphthohydroquinone-4-phosphate.
14. The process which comprises reacting Z-methyl-3- phytyl 1,4 naphthohydroquinone 1 acetate 4 (dichlor'o) phosphate with sodium hydroxide to form a mixtureof sodium and disodium 2-methyl-3-phytyl-1,4-naphthohydroquinone-1-acetate-4-phosphate.
15. The process which comprises reacting 2-methyl-3- phytyl 1,4 naphthohydroquinone 1 propionate-4-(dichloro)phosphate with sodium hydroxide to'form a mixture of sodium and disodium 2-methyl-3-phytyl-1,4- naphthohydroquinone-1-propionate-4-phosphate.
16. The process which comprises reacting a mixture of sodium and disodium 2-methyl-3-phyty1-1,4-naphthohydroquinone-l-acetate-4-phosphate with hydrochloric acid to form 2 -methyl-3-phytyl-1,4-naphthohydroquinone-1- acetate-4-phosphate.
17. The process which comprises reacting 2-methyl-3- phytyl 1,4 naphthohydroquinone-l-acetatel-phosphate with a concentrated aqueous alcoholic sodium hydroxide to form a mixture of the diand tri-sodium salt of 2- rnethyl-3 phytyl 1,4-naphthohydro quinone-4-phosphate.
18. The process which comprises reacting l-lower fatty acid ester of 2-methyl-3-phytyl-1,4-naphthohydroquinone- 4-phosphate with an alcoholic solution in the presence of an acid catalyst to form 2-methyl-3-phytyl-1,4-naphthor hydroquinone-4-pl1osphate.
19. The process which comprises reacting Z-methyl-S- phytyl-1,4-naphthohydroquinone 1 propionate-4-phosphate with methanolic sulfuric acid to form 2-methyl-3- phytyl-1 ,4-naphthohydroquinone4-phosphate.
20. Sodium 2 methyl 3 phytyl 1,4 naphthohydroquinonel-phosphate.
References Cited in the file of this patent UNITED STATES PATENTS 2,407,823 Fieser Sept. 17, 1946

Claims (2)

1. A COMPOUND OF THE FORMULA
12. THE PROCESS WHICH COMPRISES REACTING 1-LOWER FATTY ACID ESTER OF 2-METHYL-3-PHYTYL-1,4-NAPHTHOHYDROQUINONE WITH PHOSPHORUS OXYCHLORIDE TO FORM THE 1-LOWER FATTY ACID ESTER OF 2-METHYL-3-PHYTYL-1,4-NAPHTHOHYDROQUINONE4-(DICHLORO)PHOSPHATE, REACTING THE LATTER COMPOUND WITH ALKALI TO FORM A MIXTURE OF THE MONO- AND DI-ALKALI METAL SALT OF 1-LOWER FATTY ACID ESTER OF 2-METHYL-3-PHYTYL-1,4NAPHTHOHYDROQUINONE-4-PHOSPHATE, REACTING THE LATTER COMPOUND WITH AN INORGANIC ACID TO FORM 1-LOWER FATTY ACID ESTER OF 2-METHYL-3-PHYTYL-1,4-NAPHTHOHYDROQUINONE4-PHOSPHATE, REACTING THE LATTER COMPOUND WITH A CONCENTRATED AQUEOUS ALCOHOLIC METAL HYDROXIDE TO FORM A MIXTURE OF THE MONO-, DI- AND TRI-ALKALI METAL SALT OF 2 - METHYL - 3 - PHYTYL-1,4-NAPHTHOHYDROQUINONE-4-PHOSPHATE AND REACTING THE LATTER COMPOUND WITH ACID TO FORM 2-METHYL-3-PHYTYL-1,4-NAPHTHOHYDROQUINONE-4-PHOSPHATE.
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Cited By (19)

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US3051738A (en) * 1957-03-22 1962-08-28 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
US20040052754A1 (en) * 2000-11-14 2004-03-18 West Simon Michael Complexes of phosphate derivatives
US20040096493A1 (en) * 2001-06-06 2004-05-20 West Simon Michael Formulation containing phopshate derivatives of electron transfer agents
US20040241225A1 (en) * 2001-09-26 2004-12-02 West Simon Michael Modulation of vitamin storage
US20040253318A1 (en) * 2001-07-27 2004-12-16 West Simon Michael Dermal therapy using phosphate derivatives of electron transfer agents
US20050089495A1 (en) * 2001-12-13 2005-04-28 West Simon M. Transdermal transport of compounds
US20060241085A1 (en) * 2003-01-17 2006-10-26 West Simon M Compounds having anti-proliferative properties
US20060257459A1 (en) * 2002-08-09 2006-11-16 West Simon M Carrier
US20060281716A1 (en) * 2004-03-03 2006-12-14 West Simon M Alkaloid formulations
US20070135390A1 (en) * 2003-04-15 2007-06-14 West Micheal S Phosphate derivatives
US20090005348A1 (en) * 2005-12-23 2009-01-01 Vital Health Sciences Pty Ltd Compounds Having Cytokine Modulating Properties
US20090036354A1 (en) * 2005-06-17 2009-02-05 Paul Gavin Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
US20090233881A1 (en) * 2005-03-03 2009-09-17 Vital Health Sciences Pty. Ltd Compounds having anti-cancer properties
US8652511B2 (en) 2010-03-30 2014-02-18 Phosphagenics Limited Transdermal delivery patch
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process

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US2407823A (en) * 1946-09-17 Antihemorrhagic esters and methods

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US2407823A (en) * 1946-09-17 Antihemorrhagic esters and methods

Cited By (30)

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Publication number Priority date Publication date Assignee Title
US3051738A (en) * 1957-03-22 1962-08-28 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
US8173145B2 (en) 2000-11-14 2012-05-08 Vital Health Sciences Pty. Ltd. Formulation containing phosphate derivatives of electron transfer agents
US20040052754A1 (en) * 2000-11-14 2004-03-18 West Simon Michael Complexes of phosphate derivatives
US20040097472A1 (en) * 2000-11-14 2004-05-20 West Simon Michael Complexes of phosphate derivatives
US20100222305A1 (en) * 2000-11-14 2010-09-02 Simon Michael West Complexes of phosphate derivatives
US20040096493A1 (en) * 2001-06-06 2004-05-20 West Simon Michael Formulation containing phopshate derivatives of electron transfer agents
US7648710B2 (en) 2001-06-06 2010-01-19 Vital Health Sciences Pty Ltd. Formulation containing phosphate derivatives of electron transfer agents
US20040253318A1 (en) * 2001-07-27 2004-12-16 West Simon Michael Dermal therapy using phosphate derivatives of electron transfer agents
US8008345B2 (en) 2001-07-27 2011-08-30 Vital Health Sciences Pty. Ltd. Dermal therapy using phosphate derivatives of electron transfer agents
US20040241225A1 (en) * 2001-09-26 2004-12-02 West Simon Michael Modulation of vitamin storage
US20050089495A1 (en) * 2001-12-13 2005-04-28 West Simon M. Transdermal transport of compounds
US8841342B2 (en) 2002-08-09 2014-09-23 Vital Health Sciences Pty. Ltd. Carrier
US20060257459A1 (en) * 2002-08-09 2006-11-16 West Simon M Carrier
US20110003774A1 (en) * 2003-01-17 2011-01-06 Vital Health Sciences Pty. Ltd. Compounds having anti-proliferative properties
US20060241085A1 (en) * 2003-01-17 2006-10-26 West Simon M Compounds having anti-proliferative properties
US20070135390A1 (en) * 2003-04-15 2007-06-14 West Micheal S Phosphate derivatives
US8529947B2 (en) 2004-03-03 2013-09-10 Vital Health Sciences Pty. Ltd. Alkaloid formulations
US20060281716A1 (en) * 2004-03-03 2006-12-14 West Simon M Alkaloid formulations
US20090233881A1 (en) * 2005-03-03 2009-09-17 Vital Health Sciences Pty. Ltd Compounds having anti-cancer properties
US20090036354A1 (en) * 2005-06-17 2009-02-05 Paul Gavin Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
US9168216B2 (en) 2005-06-17 2015-10-27 Vital Health Sciences Pty. Ltd. Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
US20090005348A1 (en) * 2005-12-23 2009-01-01 Vital Health Sciences Pty Ltd Compounds Having Cytokine Modulating Properties
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US8652511B2 (en) 2010-03-30 2014-02-18 Phosphagenics Limited Transdermal delivery patch
US9314527B2 (en) 2010-03-30 2016-04-19 Phosphagenics Limited Transdermal delivery patch
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US10188670B2 (en) 2011-03-15 2019-01-29 Phosphagenics Limited Composition
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
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