US 3047461 A
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rates This invention relates to a pharmaceutical composition and more particularly is concerned with a novel pharmaceutical composition having a stimulating effect on the central nervous system.
The present invention comprises a pharmaceutical composition containing as the active central nervous system stimulant -phenyl-2-methylimino-4-oxazolidinone which may be represented by the following general formula:
@amao O NH iron; (1)
Due to the mobility of the hydrogen atom it is quite likely that this compound may also exist in several additional tautomeric forms, one of which is shown:
I THCHa rr) It is to be understood that the present invention includes within its scope the above compound in all such tautomeric forms. For ease of description, however, the
compound herein is named as 5-phenyl-2-methylimino-4- oxazolidinone which is descriptive of the tautomeric form in which it is usually named and written.
S-phenyl 2 methylimino-4 oxazolidinone has been found to be a highly useful central nervous system stimulant. It shows a mild stimulant action and excellent anorexic action over a wide range of doses and possesses distinct advantages over other stimulant drugs such as the amphetamines and pipradrol.
Amphetamine and closely related compounds such as methamphetamine have been used as central nervous system stimulants for many years, but numerous undesirable side reactions accompany their administration. For instance, they cause more or less pronounced rise in blood pressure and there is a tendency toward developing tolerance upon continual use. The herein-described compound does not have these serious side-efiects and thus is markedly superior to the amphetamines. The compound of this invention is also, even at high doses, free from the undesirable adrenergic and cardiovascular actions characteristic of the amphetamines. As increasing doses of the amphetamines are given, convulsions are usually observed. The compound of this invention does not cause convulsions as the doses are increased. The compound possesses a low order of toxicity and a desirable spread between eifective and lethal doses; i.e.,
.a safe therapeutic index. The compound has a greater margin of safety than"pipradrol which shows a rather narrow range between effective and toxic doses. Furthermore, the compoundis more active than 5-phenyl-2- imino-4-oxazolidinone described in United States Patent No, 2,892,753. It is approximately 3.3 times as effective in causing a 50% increase in motor activity at a nontoxic .dose. This type of test is well recognized as a useful method for the' determination of stimulant activity and is described by P. B. Dews, British Journal of Pharice macology, vol. 8, page 46 (1953), and by G. Chen et al., Journal of Pharmacology and Experimental Therapeutics, vol. 127, page 241 (1959).
5-phenyl-2-methylimino-4-oxazolidinone is a white, crystalline solid, only slightly soluble in water. basic substance, soluble in aqueous mineral acids at room temperature, and in some cases forms an insoluble acid addition salt. It also dissolves in alkaline solutions.
The active compound may be used in the form of the free base or as a non-toxic acid addition salt such as the hydrochloride, sulfate, phosphate, citrate, etc. The active compound may be administered orally or parenterally and when so administered is a central nervous system stimulant at individual doses ranging from about 1 to 100 milligrams. The dosage regimen can be adjusted to provide the optimum therapeutic response. For example, several doses may be administered daily, or the dose may be proportionately reduced as indicated by the exigencies of the therapeutic situation.
For therapeutic administration this active compound may be incorporated with pharmaceutical excipients and used, for instance, in the form of tablets, dragees, capsules, suppositories, liquids to be administered in drops, emulsions, suspensions, syrups, chocolate, candy, chewing gum, and the like. Such compositions and preparations should contain at least 0.1% of the active ingredient. The percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 2% and about 60% or more of the weight of the unit. The amount of active ingredient in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared in such a manner that a dosage unit form contains between about 1 and 100 milligrams of this compound.
Tablets, pills, dragees, and the like usually contain the following: A binder such as gum tragacanth, acacia, corn starch, or gelatin. A disintegrating agent such as corn starch, potato starch, alginic acid, or the like. A lubricant such as stearic acid, magnesium stearate, talc or the like. A sweetening agent such as sucaryl or saccharin may be added, as well as a flavoring such as peppermint, oil of Wintergreen, or cherry flavoring.
The compound may be prepared by the direct alkylation reaction illustrated by the following equation:
alkylating 0 NH agent J) 1 711 \O/ CHs-Y C [I (about 1 equiv.) N NE N rivatives, separation of the desired product in significant It is a" 3 EXAMPLE 1 -Phenyl-2-M ethylimino-4-0xazolidin0ne To a solution of sodium methoxide prepared by dissolving 12.6 grams of sodium in 500 milliliters of absolute methanol is added 88 grams of 5-pheny1-2-imino-4- oxazolidinone followed by the addition of 51 milliliters of dimethyl sulfate during minutes. The solution is heated at the refluxing temperature about 2 hours and cooled. The mixture is filtered, and some unreacted starting material is collected as the insoluble fraction. The filtrate is concentrated to a thick mass of crystals, and this mixture is dissolved in 500 milliliters of 1 normal sodium hydroxide. It is then extracted with 250 and 100 milliliter portions of methylene chloride, successively. The aqueous layer, containing the desired product, is then acidified with glacial acetic acid, cooled and filtered. The solid obtained is Washed with water and suspended in 550 milliliters of boiling methylene chloride and filtered to remove more unreacted starting material. The methylene chloride solution is dried over sodium sulfate, filtered and concentrated to give crude 5-phenyl-2- methylimino-4-oxazolidinone which is collected by filtration. After two recrystallizations from ethyl acetate, the product melts at 12l-124 C. The crude product may also be purified by partition chromatography on a celite column.
EXAMPLE 2 For 10,000 Tabletsg.
Active ingredient: 5 phenyl 2 methylimlno-inxavnlidinnne Lactose Corn Starch (For mix) Corn Starch (For paste) Magnesium Steal-ate (1%) The active ingredient, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in 800 milliliters of water and heated with stirring to form a paste. This paste is then used to gr-anulate the mixed powders. Additional water is used, if necessary. The wet granules are passed through a #8 hand screen and dried at 120 F. The dry granules are then passed through a #16 screen. The mixture is lubricated with 1% magnesium stearate and compressed into tablets in a suitable tableting machine.
1. A composition having a stimulating effect upon the central nervous system comprising as the essential active ingredient between about 1 and about 100 milligrams per dosage unit of 5-phenyl-2-methylimino-4-oxazolidinone and a pharmaceutical carrier.
2. A process of stimulating the central nervous system a of mammals which comprises administering a composi- This paste is then used to tion to mammals comprising as the essential active ingredient 5-phenyl-2-methylimino-4-oxazolidinone and a pharmaceutical carrier.
3. A process of stimulating the central nervous system of mammals which comprises administering a composition to mammals containing between about 1 and about milligrams of 5-phenyl-2-methylimino-4-oxazolidinone per dosage unit and a pharmaceutical carrier therefor.
Lienert et al: Chem. Abstracts, vol. 51, col. 15805 (1957).