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Патент USA US2404319

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Patented July 16, 1946
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)
following speci?c example, but it is not limited
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
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,
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
. .
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
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
2. The 2-aminobutano1 salt of theophylline
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
The invention will be further illustrated by the 55
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