Patent Nov. 4, I924.
-HORACE A. SHONLE, OF INDIA NAPO'LIS, INDIANA, ASSIGNOR TO THE ELI LILLY & COMPANY, OF INDIANAPOLIS, INDIANA, A CORPORATION OF INDIANA.
' ISOL ETHYL BARBITURIC ACID.
T all whom it may concern:
Be it known that I, HORACE A. Sammie, a citizen of the United States, residing at Indianapolis, in the county of Marion and a State of Indiana have invented a new and useful Isoamyl Eth l Barbituric Acid, of which the following is a specification.
\ My invention has for its object the obtaining of a substance which possesses marked hypnotic activity combined with low toxicity, and relates to the production of the hitherto unknown hypnotic substance, isoamyl ethyl barbituric acid or isoamyl ethyl malonyl urea. V
Isoamyl ethyl barbituric acid exhibits pronounced g soporific or hypnotic properties, and at the same time'has such a low toxicity that the ratio of the, toxic dose to the efi'ective hypnotic dose is much greater than in the case of any of the previousl known hypnotics of a similar character, t us afiordm a greater factor of safety. This factor 0 safety is even greater than in the case of isobutyl ethyl barbitunic acid, for which I 2 have filed'an applicatlon for a Patent Serial No. 454,149 of even filing date herewith. This isoamyl ethyl barbituric acid causes no ataxia but produces a. quiet sleep with no disagreeable after effects.-
The new isoamyl ethyl barbituric acid possesses thestructure om-cn, c 0-NH\ cn-c1n0m c o-NH OH:
in which one of the hydrogen atoms attached to a nitrogen atom can be replaced by a monovalent metal, such, for instance, as
i sodium, or by an equivalent of a polyvalent metal, such, for instance, as calcium.
The new is'oamyl ethyl barbituric acid may be produced by various processes. One of these consists in condensing urea with isoamyl ethyl malonic ester in the resence of sodium ethylate, using substantially the following quantities, temperatures, and periods of tlme, although the product may still be obtained in varying yields even if these factors are changed 261 grams (3 moles) of metallic sodium are dissolved in 500 hol, to which are ad ed 100 grams (1 mole) of isoamyl ethyl malonic ester and 37.2 grams (1.6 mole) of urea. This mixture is ams of absolute alco-' llpplicatioi filed March 21, 1921. Serial No. 454,150.
heated in an enameled autoclave for 4 to 6 hours at a temperature of about 105 C. The isoamyl ethyl barbituric acid formed by this condensation is present as its sodium salt. The mixture isthen acidified with hydrocholoric acid and the alcohol removed by distillation. The crude isoamyl ethyl barbituric acid remains as a residue in the distilling flask.
This crude isoamyl ethyl barbituric acid upon re-crystallization from water is obtained in the form of white crystals, which melt at. 153-155 O. The re-crystallized substance is slightly soluble in cold water,
more soluble in hot water, and easily soluble in alcohol and ether, and-has a slightly bitter taste.
Since isoamyl. ethyl barbituric acid possesses one nitrogen-linked hydrogen capable of being replaced with a monovalent metal, such as sodium, or-with an equivalent of a polyvalent metal, it is possible to form metallic salts of this acid. The acid and the metallic salts may be represented by the following formula:
in which X represents either a hydrogen atom and' somewhat less soluble in absolute alco hol. The soluble salts are of value for hypodermic injection.
I claim as my invention: 1. The new substances, which may be represented by the formula:
out-on co-NH CH wherein X represents either a hydrogen atom, an atom of a monovalent metal, or an equivalent of a olyvalent metal.
2. The new su stance, isoamyl ethyl barbituric acid, being a compound displaying a hypnotic action, crystallizing from water in the form of White crystals melting at 153- 155 0., being slightly soluble in cold water, more soluble in hot water, easily soluble in alcohol and ether, having a slightly bitter taste, and forming with the alkali metals salts which are readily soluble in Water.
3. The new substances, which contain the radicle which may be represented by the formula:
4. As a new product isoamyl ethyl barb i turic acid having the formula:
In witness whereof, I have hereunto set v my hand at Indianapolis, Indiana, this 17th day of March, A. D. one thousand nine hun- 20 dred and twenty .one.
HORACE A. SHONLE.