Патент USA US2404319код для вставки
2,404,319 Patented July 16, 1946 UNITED ‘STATES PATENT OFFICE 2,404,319 BUTANOLAMINE SALTS OF THEOPHYLLINE, Robert S. Shelton, Mariemont, Ohio, assignor to The Wm. S. Merrell Company, Reading, Ohio, a corporation of Delaware No Drawing. Application June 28, 1941, Serial No. 400,345 3 Claims. (Cl. 260—253) 1 2 following speci?c example, but it is not limited thereto. This invention relates to new derivatives of theophylline, and more particularly to the the Example-Preparation of the 2-amino-2 ophylline butanolamines, which have important methyl-l-propanol salt of theophylline. Equi advantages for therapeutic use, i. e., the adminis tration of theophylline. They are extremely 5 molecular proportions of theophylline and 2-ami water-soluble, well tolerated and quite free from no-2-methyl-1-propano1 are dissolved in water side reactions when administered. and the water is evaporated until crystallization Theophylline is an important therapeutic is almost complete. The crystals are ?ltered off, agent, largely used for certain heart conditions. and dried. The product has a melting point of Theophylline itself is‘ very slightly soluble in wa- 10 254-256” C‘., softening at 245° C. It has a water ter, and is customarily used in the form of a salt. solubility of about 55%. It may be compounded Aminophyllin, the water-soluble compound of in the form of tablets, for oral administration, or theophylline with ethylene diamine, is very widely may be prepared in solution, for distribution in used, but even this product has relatively limampoules. For the manufacture of solutions for ited water solubility. Furthermore, tablets of 15 packaging in ampoules, it is more convenient to this product discolor very quickly, and solutions of it, distributed in ampoules, frequently precipitate theophylline. Other salts of theophylline, such as the piperizine salts, the ethanolamine simply dissolve the theophylline and the butanol amine in water, without going through the in termediate step of separating the, crystalline salt. Thus, for example, for preparing an ampoule so Salts and the isOprODanolamine salts have been 20 lution containing .48 gram of the salt for each proposed, but have never been as widely used as 2 cc. of water, for packaging in ampoules, it is Aminoplrlyllin~ simply necessary to dissolve 100 grams of the In accordance with the present invention, the ophylline and 46 grams of 2_a,mjnQ-2..methy1_1_ compounds of theophylline with the butanolpropanol in su?icient ampoule water to make 600 ammfes, and particularly z'ammmb‘uta'noluand 25 cc. of solution, ?lter the solution and ?ll it into 2'a'mmo'z‘mebhyl‘ 1 ‘ propanol are Provlded- 2 cc. ampoules. These ampoules may then be These salts are extremely water-soluble, the 2sterilized by heating at 100° C. for 30 minutes a¥¥1n°7 z'methyt'l'propanol salt havmg 3' 50111‘ for three consecutive days, or in other appropri b1l1ty_1n the neighborhood of 55% of Water. In ate ways" They form a Very convenient Way of addition to this property of extreme water solu- 30 administering theophylline Vparentemny The blhty’ the new comPounds are Stable‘. In tabtet solutions are stable, and do not precipitate the form, they do not discolor as does Aminophylhn, ' and solutions for example in ampoules do not ophynme on standmg' precipitate theophylline, even though ’concen- trated beyond any concentration heretofore used - . with the known compounds of theophylline, , _ - a - . . . . nobutanol salt, which is readily prepared 1n the The new compounds are readily prepared, for - The 2'imm"'z'inethyl'l'pmpaml Salt of the 0. example is a part1cularly valuable salt of the . . ophyllme for therapeutic purposes. The 2-am1 00 . - . . ~ . . same way, also exh1b1ts the h1gh water solubihty, example, by dissolving equimolecular proportions t bTt nd fre do from discoloration and of theophylline and the amino-butanol in water S a‘ 111 y’ a‘ f g m h. d . . b1 . and evaporating until crystallization is almost 40 deve opment 0 o ors W 10h are ‘851m B m a’ therapeutic product. Other butanolamine salts, complete. Puri?cation by recrystallization is difficult, because of hydrolysis, but by following such as the salt of theophylline with tris-(hy droxymethyl) -amino-methane and hydroxyeth the procedure described, the new salts are read ily prepared as white crystalline substances of - yl-ethylene-diamine may be prepared in similar ?xed composition, stable at ordinary tempera tures, and which do not decompose, discolor or develop odors. Also, these crystalline materials fashion, and are included within the scope of the invention. I claim: 1. The 'butanolamine salts of theophylline pre are non-hygroscopic, and accordingly, are of pared for use as a therapeutic. further value for distribution in the form of tab 50 2. The 2-aminobutano1 salt of theophylline lets. The new derivatives may be administered orally 7 prepared for use as a therapeutic. 3. The theophylline salt of 2-methyl-2-amino or parenterally. They are comparatively well propanol-l prepared for use as a therapeutic tolerated and quite free from undesirable side e?ects. The invention will be further illustrated by the 55 agent. 1 . ROBERT S. SHELTON.