[go: up one dir, main page]

US3073740A - Method of reducing cholesterol levels with tri- (dialkylaminoalkyl) phosphates - Google Patents

Method of reducing cholesterol levels with tri- (dialkylaminoalkyl) phosphates Download PDF

Info

Publication number
US3073740A
US3073740A US765337A US76533758A US3073740A US 3073740 A US3073740 A US 3073740A US 765337 A US765337 A US 765337A US 76533758 A US76533758 A US 76533758A US 3073740 A US3073740 A US 3073740A
Authority
US
United States
Prior art keywords
tri
dialkylaminoalkyl
phosphate
cholesterol levels
phosphates
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US765337A
Inventor
Samuel M Greenberg
Sr John F Herndon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Smith Kline and French Laboratories Ltd
Original Assignee
Smith Kline and French Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smith Kline and French Laboratories Ltd filed Critical Smith Kline and French Laboratories Ltd
Priority to US765337A priority Critical patent/US3073740A/en
Priority to BE582955A priority patent/BE582955A/en
Priority to FR806330A priority patent/FR1305323A/en
Application granted granted Critical
Publication of US3073740A publication Critical patent/US3073740A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • 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

Definitions

  • organic or inorganic acid in aqueous miscible solvent, such as acetone or ethanol
  • aqueous immiscible solvent such as ethyl ether or chloroform
  • organic salts are those formed with maleic, fumaric, benzoic, ethanedisulfonic, citric, lactic, benzene sulfonic, methane sulfonic, acetic, tartaric, and succinic acids.
  • inorganic salts are those formed with hydrochloric, hydrobromic, sulfuric, nitric phosphoric, and sulfamic acids.
  • hydrochloride salt of the tri-(dialkylaminoalkyl) phosphate is used.
  • novel tri-(dialkylaminoalkyl) phosphates of this invention are prepared by reacting the properly substituted alkanolamines with phosphorous oxychloride according to the following procedure:
  • I lents of the desired alkanolamine in an organic solvent for biological effect Because of the bulk problem or unpleasant taste, they are undesirable forms of medicinal agents for patient consumption.
  • the need for a safe, effective, low dosage medicament for use in this area of hypercholesterolemia has been great.
  • the new tri-(dialkylaminoalkyl) phosphates and the medicinal preparation of this invention are consistently effective in bringing about a rapid drop in plasma cholesterol levels using very much lower dosage regimens than previous agents require. of the effective medicament in a pharmaceutical form both convenient for administration as well as pleasant for patient consumption.
  • the use of these novel tri- (dialkylaminoalkyl) phosphates gives a more dramatic fall in plasma cholesterol levels' than the well known agents for lowering plasma cholesterol such as lipotropic agents and essential fatty acids.
  • the compounds and preparations of this invention have a novel central nervous system stimulant activity which results in utility as an antidepressant agent with low toxicity.
  • the novel tri (diloweralkylaminoloweralkyl) phosphates of this invention are represented by the general formula:
  • This invention also includes nontoxic salts of the above bases formed with nontoxic organic and inorganic acids.
  • Such salts are'easily prepared'by methods known to the art.
  • the base is reacted with either the stoichiometric This allows the administration such as an aromatic solvent, for instance, benzene, xylene or toluene isreacted with phosphorus oxychloride.
  • the reaction temperature is preferably maintained at about 0 to 10 C.
  • the solution is then stirred at a temperature of about 20 to 50 C. and allowed to stand until reaction is complete.
  • the resulting mixture is cooled and water added, separating the upper organic layer and concentrating in vacuo at a maximum temperature of about 50 C.
  • the resultant viscous residue is the tri-(dialkylaminoalkyl) phosphate base.
  • the trihydrochloride salt can be prepared from the base by reacting the base with the calculated amount of dilute isopropanolic hydrogen chlo ride in aqueous miscible solvents, such as acetone or ethanol, with isolation of the salt by cooling.
  • aqueous miscible solvents such as acetone or ethanol
  • the tri-(dialkylaminoalkyl) phosphates of this invention will be administered in a preparation in accordance with this invention comprising a pharmaceutical carrier and a tri-(dialkylarninoalkyl) phosphate of Formula 1 or a non-toxic pharmaceutical salt thereof in an amount to lower plasma cholesterol levels in human beings.
  • the preparation will contain the tri- (dialkylaminoalkyl) phosphate ingredient in an amount of from about 5 mg. to about 300 mg., advantageously from about 15 mg. to about mg.
  • the dosage units will generally be administered from 2 to 5 times daily to provide advantageously a daily dosage regimen of from about '10 mg. to about 1000 mg. preferably about 40 mg. to about 250 mg.
  • the pharmaceutical carrier may be, for example, either a solid or a liquid.
  • solid carriers are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia.
  • liquid carriers are peanut oil, olive oil, sesame oil and water.
  • a wide variety of pharmaceutical forms can be employed.
  • the preparation can be tabletted, placed in a hard gelatin capsule or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 gm.
  • a liquid carrier is used the preparation may be in the form of a soft gelatin capsule, placed in an ampule or in a liquid suspension.
  • the method in accordance with this invention comprises administering internally tri-(dialkylarninoalkyl) phosphate, or a nontoxic salt thereof in an ,amount'to lower plasma cholesterol levels in patients afllicted with hypercholesterolemia.
  • the administration may be parenterally or orally, the preferable route of administration.
  • Advantageously equal doses will be administered three or four times daily. Preferably from about 10 mg. to about 1000 mg. and most advantageously from about 40 mg. to about 250 mg. of the tri-(dialkylaminoalkyl) phosphate will be administered daily.
  • the dose may be individually determined by the physician.
  • the tri-(dialkylaminoalkyl) phosphates are relatively hygroscopic. It is dseirable to include absorbable materials such as silica gel or Micro-Cel in the formulations.
  • the preparations of this invention are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary or variously mixing and dissolving the ingredients as appropriate to the desired end product.
  • Example 1 A solution of 1376 g. of fi-dimethylaminoethanol in 6 liters of dry toluene is stirred and cooled as 396 g. of phosphorous oxychloride is added. The rate of addition is so regulated that the reaction temperature remains at to 10 C. This addition requires about three hours. After the addition is completed, the cooling bath is removed. The solution is stirred at room temperature for about three hours and is allowed to stand overnight. The resulting mixture is cooled to 20 C. and 800 mls. of water is added with stirring. The upper organic layer is separated and concentrated in vacuo at a temperature of 50 C. The resultant base as a viscous liquid is taken up in 3 liters of ethanol and made acidic with 1300 g.
  • ExampleZ Place 515 g. of 5-dimethylaminoisopropanol in 1500 ml. of dry toluene and stir. Cool with an ice bath to 0 to C. and add 122 g. of phosphorous oxychloride. Maintain the temperature at 0 to 10 C. by the rate of addition of the phosphorous oxychloride which requires three hours. When all the phosphorous oxychloride has been added, remove the cooling bath. The solution is stirred at room temperature for about three hours and is allowed to stand overnight. The resulting mixture is cooled to 20 C. and 200 mls. of water added with stirring. The upper organic layer is separated and concentrated in vacuo at a temperature of 50 C.
  • the tri-dimethylaminoisopropyl phosphate and 348 g. of maleic acid are taken up in ethanol, and the crystalline solid is separated on cooling and recrystallized with hot ethanol.
  • the resultant product is the maleate salt of tri-dimethylaminoisopropyl phosphate.
  • Example 3 A solution of 435 g. of B-dimethylaminohexanol in 2 liters of dry toluene is stirred and cooled as 77 g. of phosphorous oxychloride is added. The temperature is kept at 0 to 10 C. and the addition of the phosphorous oxychloride requires about three hours. After the addition was completed the cooling bath was removed. The solution is stirred at room temperature for about three hours and is allowed to stand overnight. The resulting mixture is cooled to 20 C. and 300 mls. of water are added with stirring. The upper organic layer is separated and concentrated in vacuo at a maximum temperature of 50 C. The resultant viscous liquid, which is the base, and 630 g. of citric acid are taken up in 2 liters of ethanol, and the crystalline solid is separated on cooling. The citrate salt of tri-p-dimethylaminohexyl phosphate is then recrystallized from hot ethanol.
  • Example 4 A solution of 1038 g. of p-dibutylaminoethanol in 4 liters of dry toluene is stirred and allowed to cool as 153 g. of phosphorous oxychloride is added.
  • the reaction temperature is 0 to 10 C. and is regulated by the rate of addition of the phosphorous oxychloride. The addition requires about three hours. After the addition is completed, the cooling bath is removed. The solution is stirred at room temperature for three hours and is allowed to stand overnight. The resulting mixture is cooled to 20 C. and 600 ml. of water is added with stirring. The upper layer separated and concentrated in vacuo at a maximum temperature of 50 C.
  • the tri-butylaminoethyl phosphate is taken up in 500 ml. of ethanol and made acidic with 1600 g. of 10% isopropanolic hydrogen bromide.
  • the crystalline tri-butylaminoethyl phosphate trihydrobromide is separated on cooling.
  • Example 5 Tri-(dimethylaminoethyl) phosphate trihydrochloride 25 Micro-Cel (synthetic calcium silicates) 25 Calcium sulfate 225 The above powders are thoroughly mixed and filled into a #2 hard gelatin capsule.
  • the ingredients are mixed and filled into a #2 hard gelatin capsule.
  • Example 7 Mg. Tri-(dimethylaminoethyl) phosphate tricitrate 200 Micro-Cel (synthetic calcium silicates) 150 Calcium sulfate 300 The ingredients are intimately mixed and filled into a. #1 hard gelatin capsule.
  • Example 8 Tri-(dibutylaminohexyl) phosphate trihydrochloride 50 Silica gel (SiO 50 Calcium sulfate, dihydrate Sucrose 25 Starch 15 Talc 5 Stearic acid 3-
  • the sucrose, calcium sulfate, silica gel and tri-(dibutylaminohexyl) phosphate trihydrochloride are thoroughly mixed and granulated with hot 10% gelatin solution.
  • the wetted mass is passed through a #16 US. standard mesh screen directly onto drying trays.
  • the granules are dried at F. and passed through a #20 US. standard mesh screen. These granules are then mixed with the starch, talc and stearic acid, passed through a #60 US. standard mesh screen and then compressed into tablets.
  • Example 9 Gms. Tri-(dimethylaminoisopropyl) phosphate trisulfate 2.50 Sodium chloride .4. 0.35 Water for injection, q.s. to 100.00 ml.
  • the salts are dissolved in 60 ml. of the water and the volume is then brought to 100 ml. The solution is then filtered through a Selas filter, filled into ampuls and autoclaved.
  • Example Tri-(dimethylaminoethyl) phosphate trihydrochloride Ems" Vitamin B gms 0.04 Nicotinamide gms 0.14 Sorbitol gms 25.00 Imitation wild cherry ml 0.10 Water, q.s. to make volume 100.00 ml.
  • Example 11 Tri-diethylaminobutyl) phosphate triacetate gms 4.00 Vitamin B gms 0.04 Nicotinamide gms 0.14 Choline dihydrogen citrate gms 3.00 Betaine gms 4.00 Imitation wild cherry ml 0.10 Sorbitol gms 10.00 Water, q.s. to make volume 100.00 ml.
  • Example 12 Mg. Tri-(dimethylaminoethyl) phosphate trimaleate 75 Peanut oil 225 The ingredients are mixed to a thick slurry and filled into a soft gelatin capsule.
  • a method of lowering plasma cholesterol levels which comprises internally administering in an amount sufficient to lower the plasma cholesterol level compounds of the class consisting of a free base and its nontoxic pharmaceutically acceptable organic and inorganic acid addition salts, the free base having the formula:
  • R and R are alkyl groups containing a maximum of 4 carbon atoms and A represents a divalent saturated alkylene chain containing 2 to 6 carbon atoms separating the nitrogen and oxygen atoms attached thereto by at least 2 carbon atoms.
  • a method of lowering plasma cholesterol levels which comprises internally administering a daily dosage regimen of about 10 mg. to about 1000 mg. of a compound of the class consisting of a free base and its nontoxic pharmaceutically acceptable organic and inorganic acid addition salts, the free base having the formula:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

United States Patent METHOD OF REDUCING CHOLESTEROL LEVELS WITH TRI (DIALKYLAMINOALKYL) PHUS- PHATES Samuel M. Greenberg, Bala-Cynwyd, and John F. Herndon, Sr., Levittown, Pa., assignors to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed Oct. 6, 1958, Ser. No. 765,337 6 Claims. (Cl. 167-55) This invention relates to new tri-(dialkylaminoalkyl) phosphates and to antihypercholesterolemic preparations and a method of reducing cholesterol levels.
Prior to the present invention there has been an intense search for an antihypercholesterolemic agent which is effective in very low quantities, has very low toxicity and is relatively free of untoward side effects. This agent is needed to remove circulating blood cholesterol and to aid in the treatment of atherosclerosis. Previous known antihypercholesterolemic agents, such as the unsaturated fatty acids, achieve their results only by the utilization of inconvenient or unpleasant dosage forms. Extremely large doses of these materials are necessary amount of organic or inorganic acid in aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling, or reacted with an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform with the desired salt separating directly. Exemplary of organic salts are those formed with maleic, fumaric, benzoic, ethanedisulfonic, citric, lactic, benzene sulfonic, methane sulfonic, acetic, tartaric, and succinic acids. Exemplary of inorganic salts are those formed with hydrochloric, hydrobromic, sulfuric, nitric phosphoric, and sulfamic acids. Preferably the hydrochloride salt of the tri-(dialkylaminoalkyl) phosphate is used.
The novel tri-(dialkylaminoalkyl) phosphates of this invention are prepared by reacting the properly substituted alkanolamines with phosphorous oxychloride according to the following procedure:
I lents of the desired alkanolamine in an organic solvent for biological effect. Because of the bulk problem or unpleasant taste, they are undesirable forms of medicinal agents for patient consumption. The need for a safe, effective, low dosage medicament for use in this area of hypercholesterolemia has been great.
The new tri-(dialkylaminoalkyl) phosphates and the medicinal preparation of this invention are consistently effective in bringing about a rapid drop in plasma cholesterol levels using very much lower dosage regimens than previous agents require. of the effective medicament in a pharmaceutical form both convenient for administration as well as pleasant for patient consumption. The use of these novel tri- (dialkylaminoalkyl) phosphates gives a more dramatic fall in plasma cholesterol levels' than the well known agents for lowering plasma cholesterol such as lipotropic agents and essential fatty acids. Furthermore, the compounds and preparations of this invention have a novel central nervous system stimulant activity which results in utility as an antidepressant agent with low toxicity. The novel tri (diloweralkylaminoloweralkyl) phosphates of this invention are represented by the general formula:
FORMULA 1 This invention also includes nontoxic salts of the above bases formed with nontoxic organic and inorganic acids.
Such salts are'easily prepared'by methods known to the art. The base is reacted with either the stoichiometric This allows the administration such as an aromatic solvent, for instance, benzene, xylene or toluene isreacted with phosphorus oxychloride. The reaction temperature is preferably maintained at about 0 to 10 C. The solution is then stirred at a temperature of about 20 to 50 C. and allowed to stand until reaction is complete. The resulting mixture is cooled and water added, separating the upper organic layer and concentrating in vacuo at a maximum temperature of about 50 C. The resultant viscous residue is the tri-(dialkylaminoalkyl) phosphate base. The trihydrochloride salt can be prepared from the base by reacting the base with the calculated amount of dilute isopropanolic hydrogen chlo ride in aqueous miscible solvents, such as acetone or ethanol, with isolation of the salt by cooling.
Advantageously the tri-(dialkylaminoalkyl) phosphates of this invention will be administered in a preparation in accordance with this invention comprising a pharmaceutical carrier and a tri-(dialkylarninoalkyl) phosphate of Formula 1 or a non-toxic pharmaceutical salt thereof in an amount to lower plasma cholesterol levels in human beings. Preferably the preparation will contain the tri- (dialkylaminoalkyl) phosphate ingredient in an amount of from about 5 mg. to about 300 mg., advantageously from about 15 mg. to about mg. The dosage units will generally be administered from 2 to 5 times daily to provide advantageously a daily dosage regimen of from about '10 mg. to about 1000 mg. preferably about 40 mg. to about 250 mg. of the tri-(dialkylaminoalkyl) phosphate. The pharmaceutical carrier may be, for example, either a solid or a liquid. Exemplary of solid carriers are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia. Exemplary of liquid carriers are peanut oil, olive oil, sesame oil and water.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tabletted, placed in a hard gelatin capsule or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 gm. If a liquid carrier is used the preparation may be in the form of a soft gelatin capsule, placed in an ampule or in a liquid suspension. The method in accordance with this invention comprises administering internally tri-(dialkylarninoalkyl) phosphate, or a nontoxic salt thereof in an ,amount'to lower plasma cholesterol levels in patients afllicted with hypercholesterolemia. The administration may be parenterally or orally, the preferable route of administration. Advantageously equal doses will be administered three or four times daily. Preferably from about 10 mg. to about 1000 mg. and most advantageously from about 40 mg. to about 250 mg. of the tri-(dialkylaminoalkyl) phosphate will be administered daily. The dose may be individually determined by the physician.
When preparing the various pharmaceutical forms of this invention care should be taken because the tri-(dialkylaminoalkyl) phosphates are relatively hygroscopic. It is dseirable to include absorbable materials such as silica gel or Micro-Cel in the formulations. The preparations of this invention are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary or variously mixing and dissolving the ingredients as appropriate to the desired end product.
The following examples are not limiting but are illustrative of compounds and pharmaceutical preparations of this invention.
Example 1 A solution of 1376 g. of fi-dimethylaminoethanol in 6 liters of dry toluene is stirred and cooled as 396 g. of phosphorous oxychloride is added. The rate of addition is so regulated that the reaction temperature remains at to 10 C. This addition requires about three hours. After the addition is completed, the cooling bath is removed. The solution is stirred at room temperature for about three hours and is allowed to stand overnight. The resulting mixture is cooled to 20 C. and 800 mls. of water is added with stirring. The upper organic layer is separated and concentrated in vacuo at a temperature of 50 C. The resultant base as a viscous liquid is taken up in 3 liters of ethanol and made acidic with 1300 g. of 10% isopropanolic hydrogen chloride. The crystalline solid separates on cooling and recrystallized from 8.5 liters of hot ethanol. The melting point of the resultant tri-(dimethylaminoethyl) phosphate trihydrochloride is 169- 170 C.
ExampleZ Place 515 g. of 5-dimethylaminoisopropanol in 1500 ml. of dry toluene and stir. Cool with an ice bath to 0 to C. and add 122 g. of phosphorous oxychloride. Maintain the temperature at 0 to 10 C. by the rate of addition of the phosphorous oxychloride which requires three hours. When all the phosphorous oxychloride has been added, remove the cooling bath. The solution is stirred at room temperature for about three hours and is allowed to stand overnight. The resulting mixture is cooled to 20 C. and 200 mls. of water added with stirring. The upper organic layer is separated and concentrated in vacuo at a temperature of 50 C. The tri-dimethylaminoisopropyl phosphate and 348 g. of maleic acid are taken up in ethanol, and the crystalline solid is separated on cooling and recrystallized with hot ethanol. The resultant product is the maleate salt of tri-dimethylaminoisopropyl phosphate.
Example 3 A solution of 435 g. of B-dimethylaminohexanol in 2 liters of dry toluene is stirred and cooled as 77 g. of phosphorous oxychloride is added. The temperature is kept at 0 to 10 C. and the addition of the phosphorous oxychloride requires about three hours. After the addition was completed the cooling bath was removed. The solution is stirred at room temperature for about three hours and is allowed to stand overnight. The resulting mixture is cooled to 20 C. and 300 mls. of water are added with stirring. The upper organic layer is separated and concentrated in vacuo at a maximum temperature of 50 C. The resultant viscous liquid, which is the base, and 630 g. of citric acid are taken up in 2 liters of ethanol, and the crystalline solid is separated on cooling. The citrate salt of tri-p-dimethylaminohexyl phosphate is then recrystallized from hot ethanol.
Example 4 A solution of 1038 g. of p-dibutylaminoethanol in 4 liters of dry toluene is stirred and allowed to cool as 153 g. of phosphorous oxychloride is added. The reaction temperature is 0 to 10 C. and is regulated by the rate of addition of the phosphorous oxychloride. The addition requires about three hours. After the addition is completed, the cooling bath is removed. The solution is stirred at room temperature for three hours and is allowed to stand overnight. The resulting mixture is cooled to 20 C. and 600 ml. of water is added with stirring. The upper layer separated and concentrated in vacuo at a maximum temperature of 50 C. The tri-butylaminoethyl phosphate is taken up in 500 ml. of ethanol and made acidic with 1600 g. of 10% isopropanolic hydrogen bromide. The crystalline tri-butylaminoethyl phosphate trihydrobromide is separated on cooling.
Example 5 Tri-(dimethylaminoethyl) phosphate trihydrochloride 25 Micro-Cel (synthetic calcium silicates) 25 Calcium sulfate 225 The above powders are thoroughly mixed and filled into a #2 hard gelatin capsule.
The ingredients are mixed and filled into a #2 hard gelatin capsule.
Example 7 Mg. Tri-(dimethylaminoethyl) phosphate tricitrate 200 Micro-Cel (synthetic calcium silicates) 150 Calcium sulfate 300 The ingredients are intimately mixed and filled into a. #1 hard gelatin capsule.
Example 8 Tri-(dibutylaminohexyl) phosphate trihydrochloride 50 Silica gel (SiO 50 Calcium sulfate, dihydrate Sucrose 25 Starch 15 Talc 5 Stearic acid 3- The sucrose, calcium sulfate, silica gel and tri-(dibutylaminohexyl) phosphate trihydrochloride are thoroughly mixed and granulated with hot 10% gelatin solution. The wetted mass is passed through a #16 US. standard mesh screen directly onto drying trays. The granules are dried at F. and passed through a #20 US. standard mesh screen. These granules are then mixed with the starch, talc and stearic acid, passed through a #60 US. standard mesh screen and then compressed into tablets.
Example 9 Gms. Tri-(dimethylaminoisopropyl) phosphate trisulfate 2.50 Sodium chloride .4. 0.35 Water for injection, q.s. to 100.00 ml.
The salts are dissolved in 60 ml. of the water and the volume is then brought to 100 ml. The solution is then filtered through a Selas filter, filled into ampuls and autoclaved.
Example Tri-(dimethylaminoethyl) phosphate trihydrochloride Ems" Vitamin B gms 0.04 Nicotinamide gms 0.14 Sorbitol gms 25.00 Imitation wild cherry ml 0.10 Water, q.s. to make volume 100.00 ml.
Example 11 Tri-diethylaminobutyl) phosphate triacetate gms 4.00 Vitamin B gms 0.04 Nicotinamide gms 0.14 Choline dihydrogen citrate gms 3.00 Betaine gms 4.00 Imitation wild cherry ml 0.10 Sorbitol gms 10.00 Water, q.s. to make volume 100.00 ml.
Example 12 Mg. Tri-(dimethylaminoethyl) phosphate trimaleate 75 Peanut oil 225 The ingredients are mixed to a thick slurry and filled into a soft gelatin capsule.
What is claimed is:
1. A method of lowering plasma cholesterol levels which comprises internally administering in an amount sufficient to lower the plasma cholesterol level compounds of the class consisting of a free base and its nontoxic pharmaceutically acceptable organic and inorganic acid addition salts, the free base having the formula:
the free base having the formula:
in which R and R are alkyl groups containing a maximum of 4 carbon atoms and A represents a divalent saturated alkylene chain containing 2 to 6 carbon atoms separating the nitrogen and oxygen atoms attached thereto by at least 2 carbon atoms.
3. A method of lowering plasma cholesterol levels which comprises internally administering a daily dosage regimen of about 10 mg. to about 1000 mg. of a compound of the class consisting of a free base and its nontoxic pharmaceutically acceptable organic and inorganic acid addition salts, the free base having the formula:
6. The method of claim 5 in which the administering is orally.
References Cited in the file of this patent Bull. Soc. Chem. (France), 1957, pages 783-6, as cited in C.A., vol. 51, November 10, 1957, page 1633lb.
Artom: Federation Pro'cs., vol. 15, March 1956, page 213, No. 690.
Artom: J. Biol. Chem., vol. 180, 1949, pages 495-505.
Science, vol. 126, September 27, 1957, pages 610, 611.
Modern Drug Ency., Drug Publications, N.Y., 6th ed., 1955, pages 222, 223.
J.A.C.A., vol. 78, November 23, 1956, pages 5709 to 5730.

Claims (1)

1. A METHOD OF LOWERING PLASMS CHOLESTEROL LEVELS WHICH COMPRISES INTERNALLY ADMINISTERING IN AN AMOUNT SUFFICIENT TO LOWER THE PLASMA CHOLESTEROL LEVEL COMPOUNDS OF THE CLASS CONSISTING OF A FREE BASE AND ITS NONTOXIC PHARMACEUTICALLY ACCEPTABLE ORGANIC AND INORGANIC ACID ADDITION SALTS, THE FREE BASE HAVING THE FORMULA:
US765337A 1958-10-06 1958-10-06 Method of reducing cholesterol levels with tri- (dialkylaminoalkyl) phosphates Expired - Lifetime US3073740A (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US765337A US3073740A (en) 1958-10-06 1958-10-06 Method of reducing cholesterol levels with tri- (dialkylaminoalkyl) phosphates
BE582955A BE582955A (en) 1958-10-06 1959-09-23 Tri- (dialkylaminoalkyl) phosphates and process for their preparation
FR806330A FR1305323A (en) 1958-10-06 1959-09-29 Process for the preparation of sorting phosphates

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US765337A US3073740A (en) 1958-10-06 1958-10-06 Method of reducing cholesterol levels with tri- (dialkylaminoalkyl) phosphates

Publications (1)

Publication Number Publication Date
US3073740A true US3073740A (en) 1963-01-15

Family

ID=25073295

Family Applications (1)

Application Number Title Priority Date Filing Date
US765337A Expired - Lifetime US3073740A (en) 1958-10-06 1958-10-06 Method of reducing cholesterol levels with tri- (dialkylaminoalkyl) phosphates

Country Status (2)

Country Link
US (1) US3073740A (en)
BE (1) BE582955A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3253905A (en) * 1962-06-20 1966-05-31 Smith Kline French Lab Method of treating plants
EP0273444A3 (en) * 1986-12-29 1990-07-11 Otsuka Pharmaceutical Factory, Inc. Use of carboxamide compounds for treating hyperlipidemia and pharmaceutical composition containing them
CN119707657A (en) * 2024-11-20 2025-03-28 江苏嘉福制药有限公司 Refining and purifying process of natural camphor and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3253905A (en) * 1962-06-20 1966-05-31 Smith Kline French Lab Method of treating plants
EP0273444A3 (en) * 1986-12-29 1990-07-11 Otsuka Pharmaceutical Factory, Inc. Use of carboxamide compounds for treating hyperlipidemia and pharmaceutical composition containing them
US5081112A (en) * 1986-12-29 1992-01-14 Otsuka Pharmaceutical Factory Inc. Method for treating hyperlipidemia
CN119707657A (en) * 2024-11-20 2025-03-28 江苏嘉福制药有限公司 Refining and purifying process of natural camphor and application thereof

Also Published As

Publication number Publication date
BE582955A (en) 1960-03-23

Similar Documents

Publication Publication Date Title
US3773939A (en) N-arallyl-n'-aralkyl piperazine pharmaceutical compositions
US3769427A (en) Pharmaceutical compositions and methods of using same
JPS62228016A (en) Remedy for alliviating vomit caused from non-platinum anticancer
US3966962A (en) Triacetin solutions of PGE-type compounds
US2917432A (en) Leukemia treatment
US3073740A (en) Method of reducing cholesterol levels with tri- (dialkylaminoalkyl) phosphates
JPS6117574A (en) Calcium-antagonistic 1-(bis-(4-fluorophenyl)-methyl)-4- (3-phenyl-2-propenyl)-hexahydro-1h-1,4-diazepine, manufacture and medicinal composition
JPH0686455B2 (en) Ginkgolide derivative, method for producing the same, and pharmaceutical composition containing the same
JPS5846089A (en) Heterocyclic compound
ATE90673T1 (en) ANTIFOLATE AGENT.
US3935196A (en) Useful pro-drug forms of theophylline
EP0100815B1 (en) N-(1,3-dithiolan-2-ylidene)anilines and their use as anti-inflammatory and anti-asthmatic agents
US3917833A (en) Amino-substituted benzocycloheptenones for inducing sleep
US4393081A (en) Methyl 3-acetamido-2-(5-methoxy-indol-3-yl) propanoate and hypotensive use thereof
US4189499A (en) Lysine 4-allyloxy-3-chlorophenylacetate and method of its preparation
US3181994A (en) Analgesic biphenyl acetic acid derivatives
US3422191A (en) Compositions and methods for tranquilization employing salts of n-morpholine ethanol
JPS6021147B2 (en) pyrrolidone carboxylic acid creatinine
JPS61126026A (en) Carcinostatic agent containing isoquinolinesulfonamide as active component
JPH02292213A (en) Carcinostatic agent
US3287217A (en) Compositions and methods for stimulat- ing the central nervous system and in- creasing the blood pressure
US3855406A (en) Thiaxanthene derivatives useful for treating peptic ulcers
US3261750A (en) Method of curbing appetite
US4435400A (en) Amino and alkylaminoalkenoate ester derivatives of aminochloronitropyrazine
US3269909A (en) Analgesic methods and compositions of benzoic acid derivatives