US3443014A - 1,3-benzoxazine - 2:4 - dione and pharmacologically acceptable alkali metal salts thereof as analgesics - Google Patents

1,3-benzoxazine - 2:4 - dione and pharmacologically acceptable alkali metal salts thereof as analgesics Download PDF

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US3443014A
US3443014A US125647A US3443014DA US3443014A US 3443014 A US3443014 A US 3443014A US 125647 A US125647 A US 125647A US 3443014D A US3443014D A US 3443014DA US 3443014 A US3443014 A US 3443014A
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benzoxazine
dione
alkali metal
metal salts
pharmacologically acceptable
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Leslie Frederick Wiggins
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Aspro Nicholas Ltd
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof

Definitions

  • the compound 1:3-benzoxazine- 2:4-dione exhibits hypnotic, tranquillising and analgesic activity and is non-gastric irritant, and clinical trials have shown that the compound may be used for the relief of pain in human patients suffering from headache or rheumatic pain.
  • the compound has been found to be .a quick-acting analgesic when given by the oral route.
  • the 1:3-benzoxazine-2z4-dione forms alkali metal salts, such as the sodium salt, which may be employed in place of the dione itself.
  • the toxicity of the compound is such that doses of up to 1000 milligrams may be administered orally say three times a day, whereas its activity is such that doses as low as 10 milligrams each may be employed.
  • the present invention provides a method of treating a person suffering from various types of pain which includes the step of administering to that person at least one dose of from 10* to 1000 milligrams of at least one analgesic compound selected from the class consisting of 1:3- benzoxazine-2r4-dione and pharmacologically acceptable alkali metal salts thereof.
  • a pharmaceutical preparation in dosage unit form comprising 1z3 benzoxazine-2z4-dione or a pharmacologically acceptable alkali metal salt thereof as the active component, together with one or more solid or liquid pharmaceutical diluents or carriers.
  • the dosage unit may contain from 10 to 500, or even 1000, milligrams of the active component. Preferably, the content thereof is from to 200 milligrams or, more advantageously, between 40 and 120 milligrams. -In practice, the dosage may well be 50' or 100 milligrams and it is therefore preferred to provide tablets or other dosage units each containing 50 or 100 milligrams of the 1:3- benzoxazine-Z 4-dione.
  • the dosage unit of the pharmaceutical preparations of the present invention may exist in any of the customary pharmaceutical forms, such as for example tablets, capsules, cachets, packaged powders, pills, ampouled solutions for parenteral administration, suppositories for rectal administration and suspensions for oral administration, although a form adapted for oral administration, especially tablets, is preferred.
  • the percentage of active component in the pharmaceutical preparation may be varied, providing that the preparation, irrespective of the particular form in which the dosage unit may exist, contains suflicient of the active component to have the required pharmacological effect.
  • the preparation should normally contain at least 0.25% by weight of the active component when required for oral administration and at least 0.1% by; weight of the active component when required for administration by injection. If desired, several dosage unit forms may be administered at about the same time.
  • Some examples of the pharmaceuticaldiluents or carriers which may be employed in the pharmaceutical preparations of the invention are sugars such as lactose and sucrose; maize starch; talc; magnesium stearate; calcium phosphate; liquid parafiin; oil of theobrom-a; citric acid;
  • the pharmaceutical preparations may contain, in addition to the active component 1:3-benzoxazine- 2:4-dione, one or more other pharmacologically active substances, for example acetylsalicylic acid, phenacetin, caffeine, codeine, salicylamide, phenazone, iso-propyl phenazone, paracetamol(N-acetyl-p-aminophenol) or amidopyrine. They may, for example, contain phenacetin and also caffeine and/or codeine.
  • one or more other pharmacologically active substances for example acetylsalicylic acid, phenacetin, caffeine, codeine, salicylamide, phenazone, iso-propyl phenazone, paracetamol(N-acetyl-p-aminophenol) or amidopyrine.
  • pharmacologically active substances for example acetylsalicylic acid, phenacetin, caffeine, codeine, salicyl
  • the alkali metal salts of 1:3-benzoxazine-2z4-dione which may be employed in accordance with the present invention are novel compounds.
  • the sodium salt is a white crystalline salt which does not melt up to 310 C. and which is soluble in water to at least 10%, a solution of a concentration of 10% exhibiting a pH of 8.3.
  • This salt may be made by adding to a boiling solution of 25 g. of 4-hydroxycoumarin in 300 ml. of dry ethanol a solution obtained by dissolving 7.0 g. of sodium metal in 100 ml. absolute ethanol, A precipitate forms and on cooling is filtered off and washed with alcohol. After drying, its weight is 23.5 g. Sodium found 12.4%; calculated 12.5%.
  • Example 1 Tablets were prepared from the following:
  • the 1:3-benzoxazine-224-dione, lactose and 89 g. of starch were well mixed and then mixed with a starch paste prepared from the remaining 30 g. of starch and about nine times its weight of hot water.
  • the resulting mass was granulated through a No. 10 mesh B.S.S. sieve and dried at 40 to 50 C.
  • the dried granules were passed through a No. 12 mesh B.S.S. sieve and then well mixed with the magnesium stearate.
  • the resulting granules were then compressed so that each tablet weighed 600 mg. and contained 400 mg. of 1:3-benzoxazine-2:4-dione.
  • the tablet may be scored so that half or quarter of this dosage may be taken.
  • Example 2 may be scored so that half or quarter of this dosage may be taken.
  • Example 3 g. of 1:3-benzoxazine-2z4-dione were mixed with l g. of calcium phosphate and the resulting powdered mixture was filled into hard gelatin capsules such that each contained 100 mg. of the active component.
  • Example 4 100 g. of 1:3-benzoxazine-2z4-dione were milled with 25 g. of liquid paraifin and mg. of the resulting suspension were filled into each soft gelatin capsule which then contained 100 mg. of the active component.
  • Example 5 100 g. of 1:3-benzoxazine-2z4-dione were mixed with l g. of calcium phosphate and the resulting powdered mixture was filled into cachets such that each contained 400 mg. of the active component.
  • Example 6 100 g. of 1:3-benzoxazine-2z4-dione were well mixed with 100 g. of lactose, the resulting powder being packaged so that each individual packaged powder contained 400 mg. of 1:3-benzoxazine-2z4-dione.
  • Example 7 A suspension containing 100 mg. of 1:3-benzoxazine- 2:4dione per 4 ml. teaspoonful was prepared from the following:
  • the orange oil was mixed with the Polyoxyethylene sorbitan monolaurate to form a mixture to which the glycerin was added. The resulting mixture was then added to the abovementioned suspension. Distilled water was thereafter added to volume and the mixture stirred to form a homogeneous suspension.
  • Example 8 Suppositories containing 200 mg. of 1:3-benzoxazine- 2:4-dione in each were prepared as follows:
  • Example 9 Tablets each containing 100 mg. of 1:3-benzoxazine- 2:4-dione and 324 mg. of aspirin were prepared from the following:
  • G. 1 3-benzoxazine-2z4-dione 100 Lactose 20 Maize starch, dried 30 Aspirin 324 Maize starch, dried 64.8 Talc, purified 21.2
  • the granules A and slugs B were well mixed and the talc, passed through a No. 60 mesh B.S.S. sieve, was added to the mixed granules. After again mixing, the granules were compressed into tablets each weighing 560 mg. and containing mg. of 1:3-benzoxazine-2z4-dione and 324 mg. of aspirin.
  • Example 10 Tablets were prepared from the following:
  • each tablet weighed 400 mg. and contained 50 mg. l:3-benzoxazine-2z4-dione, 150 mg. phenacetin and 30 mg. caffeine.
  • Example 11 Tablets were prepared from the following:
  • the 1:3-benzoxazine-2:4-dione, lactose and 11.0 g, of the starch were well mixed and then mixed with a starch paste prepared from the remaining 3.9 g. of starch and water.
  • the resulting mass was granulated through a No. 10 mesh B.S.S. sieve and dried at 40 C. to 50 C.
  • the dried granules were passed through a No, 16 mesh B.S.S. sieve and were then Well mixed with the magnesium stearate.
  • the resulting granules were then compressed so that each tablet weighed 75 mg. and contained 50 mg. of 1:3-benzoxazine-2:4-dione.
  • the tablets may be scored so that half or a quarter of this dosage may be taken.
  • a method of obtaining an analgesic effect which comprises administering an analgesically effective nontoxic quantity of a compound selected from the group consisting of 1:3-benzoxazine-2:44iione and pharmacologically acceptable alkali metal salts thereof,
  • a pharmaceutical preparation in dosage unit form adapted for administration to obtain an analgesic effect comprising, per dosage unit, an analgesically-effective nontoxic amount within the range from about 10 to about 1000 milligrams of at least one compound selected from the group consisting of 1:3-benzoxazine-2z4-dione and pharmacologically acceptable alkali metal salts thereof, and a pharmaceutical diluent.

Description

United States Patent 3,443,014 1,3-BENZOXAZINE 2:4 DIONE AND PHARMA- COLOGICALLY ACCEPTABLE ALKALI METAL SALTS THEREOF AS ANALGESICS Leslie Frederick Wiggins, Wargrave, England, assiguor to Aspro-Nicholas Limited, Slough, England, a British company No Drawing. Filed July 21, 1961, Ser. No. 125,647
Int. Cl. A61k 27/00 U.S. Cl. 424-248 7 Claims This invention relates to new pharmaceutical preparations and their use in medicine.
It has been found that the compound 1:3-benzoxazine- 2:4-dione exhibits hypnotic, tranquillising and analgesic activity and is non-gastric irritant, and clinical trials have shown that the compound may be used for the relief of pain in human patients suffering from headache or rheumatic pain. The compound has been found to be .a quick-acting analgesic when given by the oral route.
The 1:3-benzoxazine-2z4-dione forms alkali metal salts, such as the sodium salt, which may be employed in place of the dione itself.
The toxicity of the compound is such that doses of up to 1000 milligrams may be administered orally say three times a day, whereas its activity is such that doses as low as 10 milligrams each may be employed.
The present invention provides a method of treating a person suffering from various types of pain which includes the step of administering to that person at least one dose of from 10* to 1000 milligrams of at least one analgesic compound selected from the class consisting of 1:3- benzoxazine-2r4-dione and pharmacologically acceptable alkali metal salts thereof.
In accordance with the invention, there is also provided a pharmaceutical preparation in dosage unit form comprising 1z3 benzoxazine-2z4-dione or a pharmacologically acceptable alkali metal salt thereof as the active component, together with one or more solid or liquid pharmaceutical diluents or carriers.
The dosage unit may contain from 10 to 500, or even 1000, milligrams of the active component. Preferably, the content thereof is from to 200 milligrams or, more advantageously, between 40 and 120 milligrams. -In practice, the dosage may well be 50' or 100 milligrams and it is therefore preferred to provide tablets or other dosage units each containing 50 or 100 milligrams of the 1:3- benzoxazine-Z 4-dione.
The dosage unit of the pharmaceutical preparations of the present invention may exist in any of the customary pharmaceutical forms, such as for example tablets, capsules, cachets, packaged powders, pills, ampouled solutions for parenteral administration, suppositories for rectal administration and suspensions for oral administration, although a form adapted for oral administration, especially tablets, is preferred.
The percentage of active component in the pharmaceutical preparation may be varied, providing that the preparation, irrespective of the particular form in which the dosage unit may exist, contains suflicient of the active component to have the required pharmacological effect. In general, the preparation should normally contain at least 0.25% by weight of the active component when required for oral administration and at least 0.1% by; weight of the active component when required for administration by injection. If desired, several dosage unit forms may be administered at about the same time.
Some examples of the pharmaceuticaldiluents or carriers which may be employed in the pharmaceutical preparations of the invention are sugars such as lactose and sucrose; maize starch; talc; magnesium stearate; calcium phosphate; liquid parafiin; oil of theobrom-a; citric acid;
Patented May 6, 1969 syrup B.P.; methyl cellulose; methyl and propyl hydroxybenzoate; and polyoxyethylene sorbitan monolaurate.
If desired, the pharmaceutical preparations may contain, in addition to the active component 1:3-benzoxazine- 2:4-dione, one or more other pharmacologically active substances, for example acetylsalicylic acid, phenacetin, caffeine, codeine, salicylamide, phenazone, iso-propyl phenazone, paracetamol(N-acetyl-p-aminophenol) or amidopyrine. They may, for example, contain phenacetin and also caffeine and/or codeine.
The alkali metal salts of 1:3-benzoxazine-2z4-dione which may be employed in accordance with the present invention are novel compounds. By way of example, the sodium salt is a white crystalline salt which does not melt up to 310 C. and which is soluble in water to at least 10%, a solution of a concentration of 10% exhibiting a pH of 8.3. This salt may be made by adding to a boiling solution of 25 g. of 4-hydroxycoumarin in 300 ml. of dry ethanol a solution obtained by dissolving 7.0 g. of sodium metal in 100 ml. absolute ethanol, A precipitate forms and on cooling is filtered off and washed with alcohol. After drying, its weight is 23.5 g. Sodium found 12.4%; calculated 12.5%.
To illustrate the invention, the following specific examples of pharmaceutical preparations in accordance with the invention will now be given.
Example 1 Tablets were prepared from the following:
G. 1:3-benzoxazine-2:4-dione 400 Lactose Maize starch, dried 119 Magnesium stearate 1 The 1:3-benzoxazine-224-dione, lactose and 89 g. of starch were well mixed and then mixed with a starch paste prepared from the remaining 30 g. of starch and about nine times its weight of hot water. The resulting mass was granulated through a No. 10 mesh B.S.S. sieve and dried at 40 to 50 C. The dried granules were passed through a No. 12 mesh B.S.S. sieve and then well mixed with the magnesium stearate. The resulting granules were then compressed so that each tablet weighed 600 mg. and contained 400 mg. of 1:3-benzoxazine-2:4-dione. The tablet may be scored so that half or quarter of this dosage may be taken.
Example 2 may be scored so that half or quarter of this dosage may be taken.
Example 3 g. of 1:3-benzoxazine-2z4-dione were mixed with l g. of calcium phosphate and the resulting powdered mixture was filled into hard gelatin capsules such that each contained 100 mg. of the active component.
Example 4 100 g. of 1:3-benzoxazine-2z4-dione were milled with 25 g. of liquid paraifin and mg. of the resulting suspension were filled into each soft gelatin capsule which then contained 100 mg. of the active component.
Example 5 100 g. of 1:3-benzoxazine-2z4-dione were mixed with l g. of calcium phosphate and the resulting powdered mixture was filled into cachets such that each contained 400 mg. of the active component.
Example 6 100 g. of 1:3-benzoxazine-2z4-dione were well mixed with 100 g. of lactose, the resulting powder being packaged so that each individual packaged powder contained 400 mg. of 1:3-benzoxazine-2z4-dione.
Example 7 A suspension containing 100 mg. of 1:3-benzoxazine- 2:4dione per 4 ml. teaspoonful was prepared from the following:
1:3-benzoxazine-2z4-dione g 2.5 Methyl cellulose, powdered, 450 1 g 1.0 Syrup B.P. ml 30.0 Methyl hydroxybenzoate g 0.1 Propyl hydroxybenzoate g- 0.02 Orange oil ml 0.5 Citric acid 0.1 Polyoxyethylene sorbitan monolaurate g 3.0 Glycerin ml 5 Distilled water to ml 100 1 This figure represents the viscosity in centipoises of a 2% solution in water at 20 C. as determined in an Ostwald viscometer or a falling sphere viscometer (B.S.S.188 21937) The methyl and propyl hydroxybenzoates were dissolved by boiling in 35 ml. of distilled water and the methyl cellulose was dispersed by stirring in the resulting solution when cooled. The citric acid was dissolved in the resulting mucilage, to which the syrup was then added and mixed therein. The resulting mixture was then triturated with the 1:3-benzoxazine-2z4-dione to form a smooth suspension.
The orange oil was mixed with the Polyoxyethylene sorbitan monolaurate to form a mixture to which the glycerin was added. The resulting mixture was then added to the abovementioned suspension. Distilled water was thereafter added to volume and the mixture stirred to form a homogeneous suspension.
Example 8 Suppositories containing 200 mg. of 1:3-benzoxazine- 2:4-dione in each were prepared as follows:
20 g. of l:3-benzoxazine-2:4-dione were finely powdered and triturated with 80 g. of melted oil of theobroma to form an even suspension. The molten suspension at approximately 45 C. was poured into lubricated suppository moulds of nominal 1 g. capacity to produce suppositories each containing 200 mg. of 1:3-benzoxazine-2z4- dione.
Example 9 Tablets each containing 100 mg. of 1:3-benzoxazine- 2:4-dione and 324 mg. of aspirin were prepared from the following:
A: G. 1:3-benzoxazine-2z4-dione 100 Lactose 20 Maize starch, dried 30 Aspirin 324 Maize starch, dried 64.8 Talc, purified 21.2
broken down and passed through a No. 10 mesh B.S.S.
sieve.
The granules A and slugs B were well mixed and the talc, passed through a No. 60 mesh B.S.S. sieve, was added to the mixed granules. After again mixing, the granules were compressed into tablets each weighing 560 mg. and containing mg. of 1:3-benzoxazine-2z4-dione and 324 mg. of aspirin.
Example 10 Tablets were prepared from the following:
1 3-benzoxazine-2z4-dione 50 Phenacetin Caffeine 30 Lactose 88 Maise starch (dried) 80 Magnesium stearate 2 The 1:3-benzoxazine-2z4-dione, phenacetin, caffeine, lactose and 60 g. of the maize starch were well mixed and then massed together with starch paste prepared from the remaining 20 g. of maize starch and water. The resulting mixture was granulated through a No. 10 mesh B.S.S. sieve and dried at 40 to 50 C. The dried granules were passed through a No. 12 mesh B.S.S. sieve and well mixed with the magnesium stearate which had previously been passed through a No. 60 mesh B.S.S. sieve. The resulting granules were then compressed so that each tablet weighed 400 mg. and contained 50 mg. l:3-benzoxazine-2z4-dione, 150 mg. phenacetin and 30 mg. caffeine.
Example 11 Tablets were prepared from the following:
G. l:3-benzoxazine-2:4-dione 50 Lactose 10 Maize starch (dried) 14.9 Magnesium stearate 0.1
The 1:3-benzoxazine-2:4-dione, lactose and 11.0 g, of the starch were well mixed and then mixed with a starch paste prepared from the remaining 3.9 g. of starch and water. The resulting mass was granulated through a No. 10 mesh B.S.S. sieve and dried at 40 C. to 50 C. The dried granules were passed through a No, 16 mesh B.S.S. sieve and were then Well mixed with the magnesium stearate. The resulting granules were then compressed so that each tablet weighed 75 mg. and contained 50 mg. of 1:3-benzoxazine-2:4-dione. The tablets may be scored so that half or a quarter of this dosage may be taken.
I claim:
1. A method of obtaining an analgesic effect which comprises administering an analgesically effective nontoxic quantity of a compound selected from the group consisting of 1:3-benzoxazine-2:44iione and pharmacologically acceptable alkali metal salts thereof,
2. A method in accordance with claim 1 in which the compound is administered in a dose which comprises from 10 to 1000 milligrams of the compound.
3. A method in accordance with claim 1 in which the compound is administered orally.
4. A pharmaceutical preparation in dosage unit form adapted for administration to obtain an analgesic effect, comprising, per dosage unit, an analgesically-effective nontoxic amount within the range from about 10 to about 1000 milligrams of at least one compound selected from the group consisting of 1:3-benzoxazine-2z4-dione and pharmacologically acceptable alkali metal salts thereof, and a pharmaceutical diluent.
5 6 5. A pharmaceutical preparation in accordance with OTHER REFERENCES claim 4 in a form adapted for oral administration.
6. A pharmaceutical preparation in accordance with Wolfe et Chem Abst" 20570d 1959' claim 5 in the form ofatablet Comanducci, Chem. Abst., vol. 18, p. 1658 1924. 7. A pharmaceutical preparation in accordance with Shapiro 6t 's Val P- 28/1014, 1957 claim 4 comprising phenacetin and at least one compound Wilson, American Drug Index, p, 5-9, 1960.
selected from the group consisting of caffeine and codeine.
ALBERT T. MEYERS, Primary Examiner.
References (med 3. FRIEDMAN, Assistant Examiner. UNITED STATES PATENTS 10 2,943,087 6/1960 Obnacker 260244

Claims (1)

1. A METHOD OF OBTAINING AN ANALGESIC EFFECT WHICH COMPRISES ADMINISTERING AN ANALGESICALLY EFFECTIVE NONTOXIC QUANTITY OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1:3-BENZOXAZINE-2:4-DIONE AND PHARMACOLOGICALLY ACCEPTABLE ALKALI METAL SALTS THEREOF.
US125647A 1961-07-21 1961-07-21 1,3-benzoxazine - 2:4 - dione and pharmacologically acceptable alkali metal salts thereof as analgesics Expired - Lifetime US3443014A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050031688A1 (en) * 2003-08-04 2005-02-10 Ayala William J. Positive wakeup pharmaceutical sleep system with compatible pre-bedtime administration

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2943087A (en) * 1960-06-28 n naoh

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2943087A (en) * 1960-06-28 n naoh

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050031688A1 (en) * 2003-08-04 2005-02-10 Ayala William J. Positive wakeup pharmaceutical sleep system with compatible pre-bedtime administration
US20090041840A1 (en) * 2003-08-04 2009-02-12 Ayala William J Positive wakeup pharmaceutical sleep system with compatible pre-bedtime administration

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