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Патент USA US2410469

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' Patented Nov. 5, 1946 -
2,410,469 ‘
umrao STATES PATENT orrica
ALKYL AMINO 'rnnnnor
Gerritt John Van Zoeren, Holland, Micln, assignor
to The Wm. 8. Merrell Company, Cincinnati,
Ohio, a corporation of Delaware .
No Drawing. Application October 12, 1940,
Serial No. 360,962
3 Claims. (oi. zoo-5103i
' 2
cooled in ice water and opened carefull . The
contents are transferred into ‘a distillation ?ask
pounds of the class of aryl-(alkyl-amino)
and heated gradually until the excess of mono-.
alkanes, including both they free amines and the
methylamine is driven off, taking care that no
amine salts. More particularly this invention
relates to. compositions for physiological and Cir boiling over takes place due to the too rapid evo
lutlon of the gas. Subsequently, a large propor
therapeutic use for topical and internal adminis
tion of the solvent methanol is distilled over up
tration and especially to compounds for control
to about 70° C. and the residue is then diluted
ling contractile tissue, especially in the heart and
with about 300 cc. of water. Theresulting aque
blood vessels.
Prior to my invention a considerable number 10 ous alcoholic mixture is‘made distinctly acid to
congo red with an acid such as hydrochloric and
of compounds had been known as vaso constric
extracted with a solvent, such as benzene, to
tors or vaso dilators which have the basic chemi- '
remove any benzene-soluble non-aminated prod
cal structure Ph—C-C-N<.
ucts.‘ The extracted aqueous alcoholic solution is
Considerable study has been devoted to com
then treated, while cooking, with an excess of
pounds of this type and attempts have been made
strong caustic soda and benzene. The mixture
to correlate physiological properties with chemi
is shaken and alowed to stratify. The benzene
cal structure. As reported in the literature these
solution of the amine is washed twice in succes
studies have indicated that in general the prislon with small amounts of water and, after
mary amines are less toxic than the secondary
amines and in general that any increase in mo 20 separation, is distilled directly from a small frac
tioning ?ask. After most of the benzene has I
lecular weight by addition of methyl or alkyl
This invention relates to novel chemical com
been distilled, vacuum is gradually applied and
groups beyond the phenyl propyl primary amines
will result in increased toxicity.
the amine ?nally recovered as a colorless liquid,
boiling at a constant temperature. The free
amine shows vapor pressure-at 75° F. of about
2.2 mm. and a vapor pressure of about 1 mm. is
I have now found that, in certain of these
compounds, the change from primary to second
ary amines results in a decrease in toxicity and
that secondary amines corresponding to! the
attained at. about 65°.
I am giving belowcertain specific examples of ,
my invention and its application in practical use
and I am giving also certainvmodiflcations and
alternatives, but it is understood that these are
not intended to be exhaustive or limiting of the
invention. On the contrary, I am giving these
as illustrations and am giving herewith explana
tions in order fully to acquaint others skilled in
the art with my invention and the principles
amines, beta-phenyl - beta - ethyl-alpha-amino
therapeutic uses and particularly as mild vaso
\ constrictors, or vaso dilators.
Compared with the corresponding primary
amines within this group ‘are very valuable for
ethane, the volatility is not noticeably reduced.
The vase-constrictor activity is very mild, this
factor being substantially greater in the primary
amine, but the toxicity is much less in this methyl
amino compound. Thus in substantially identical
cont-r01 tests on rabbits the minimum lethal dose
(intravenous injection) for thehydrochloride of
the primary amines was shown to be 30 mg. per
' kg. of body weight as compared with 40 mg. per
kg. for the hydrochloride of the secondary amine.
thereof and a suitable manner of its application 40
Example 2
in practical use so that others skilled in the art
may be able to modify the invention to adapt it
‘ Beta-phenyl-beta-ethyl-alpha -(ethyl amino)
and apply it in numerous embodiments each as
may be best suited to the requirements of a par
ticuiar use.
Example 1
ethane, CeH5CH(CzHs)CHzNHCzH5. This com
pound may be made by the same method as indi- V
45 cated in the preceding examples.
The volatility of this compound is somewhat
lower than that of the corresponding primary
amine; and physiological activity in this com
ethane, CsH5CH(C2H5) CHaNI-ICHa. This com
pound has been reversed, the compound going
pound may be prepared, for example: A mixture
of 100 g. betavgphenyl~beta-ethyl-alpha chloro 50 even further in its surprislng- difference from its
corresponding primary amine, ‘and showing ac
ethane and or‘ approximately 50 g. of mono
tivity as a. vaso-dilator, where the corresponding
methylamine dissolved in about 150 cc. methanol
primary amine and the secondary amines of Ex
is charged into a cooled autoclave. The autoclave
amples 1 and 2, have a vase-constrictor effect.
is closed and heated for a number of hours, pref
. erably in an oil bath, at about 130° C‘. It is then 55 The toxicities of the amine and amine salts of
Beta-phenyl-beta-ethyl-alpha- (methyl -amino)
- 4
this example also are less than those of theJcor-l ‘
Alternately, the amine salt may be mixed with
responding primary amines and amine salts:v al
though greater than those of. the methyl amino
suitable diluents such as lactose and starch and
?lled into capsules or compressed into tablets.
- _ compounds ‘of Examples 1 and 2." In correspond
inglycont'rolled tests, the minimum lethal dose
or the hydrochloride (forv intravenous injection
' into rabbits) was
The acid radical may have an important eilect
on volatility and where the volatility is important
those radicals ‘which give the most volatile salts "
shown to be 35 mg. per kg.’ or
will ordinarily be chosen. The acid radical may
likewise airect other properties such as» toxicity,
example, in a nasal inhalent composition as 10 stability, cost of manufacture; etc., and the par
ticular salt to be used in anv case will be chosen
.- '
body weight.
Any of the above compounds may be used, for ,
with these in view, as in the case of‘other'pharm .
- maceuticals already mown to the art.
Benzyl carbinn'l
These compounds may also be combined with
other compounds having physiological action in
The bomeol is dissolved in" the benzyl carbinol
and'to 30 parts oi'the resulting mixture are added
'70 parts of the chosen amine. The relative pro,
15 mixtures or in chemical combinations: e. 2.,
radicals having special physiological action may I
be combined with the amines and administered
as aminesalts. Thus the antipyretlc action of
portions- of benzyl carbinol, borneol and amine’ salicylates may be combined with the action of
may be .varied widely audit desired, the charac 20 amines of my invention on uterine muscle by
ter oi.’ the aromatic mixture may be modi?ed by
administering the amine salicylates. The acetyl
the use 01' other suitable aromatic materials. -
salicylates of the amines may also be used to give
If this is to be used in the common inhalent
combined action in this way. 7
tubes with the composition carried by a suitable
Optically active isomers oi’ the compounds‘
absorbent pad, e. 3., of cotton, within the tube, 25 herein disclosed may be used to advantage instead
themore volatile compounds. especially the beta
phenyl-beta-ethyl-alpha-(methyl-amino) ethane
_ oi‘ the racemic compounds.v
The present application is a continuation-in
part or my prior application, Serial No. 128,789,
will be chosen; and advantageously these will be
used as free amines or as a salt of a weak acid,
iiled March 8, 1937.
e. 8.’, the carbonate. 1! less volatile compounds 80
What I claim is:
are used the composition may still be advanta
l. A compound selected from‘ the class consist
geous for this purpose ii! applied with external _ ing of the tree amine and the corresponding acid
heat or atomization.
‘ addition salts thereof in which the acid free ,
A composition suitable for use as nose drops
possesses the following structural formula
- for application of the vase-constrictor in solution 35
to the nasal mucosa may be'as follows:
Methyl salicylate ________________________ _Oil of pine needles________________________
Corn oil---
97 40
2. A compound selected from the class consist;
ins oi’ the tree amine and the oorres
addition salts thereof in which. the said free
The materials are mixed in the proportions indi
cated and to the resulting mixture is added one
part oi.’ the chosen free amine. The free amine
amino possesses the following structural lormula
may be replaced by its, fatty acid salts and the 45
aromatic character or the composition‘ may be
modi?ed as desired by the use of other well-known
aromatic substances such as menthol, thymol, -
camphor and the like. In place-oi the corn oil,
mineral oil or any other suitable vegetable oil 60
3. A compound selected from the class consist
may be. used. In cases where there are objec
ing or i'ree amines and the corresponding acid
tions to an oil ‘vehicle, the virtues or the com- '
pound may be exhibited in an aqueous base by
the use of'salts such as the hydrochloride; and
For oral administration,~ for example, for con
trol or blood pressure, a composition such as the
_ following is suitable:
Amine salt
addition salts-thereorln which the said tree
amines possess the following structural formula
‘_ '
‘ v
Elixir adluvans _-_-.- ______ __~.j__-_i_ ______ _. 994
in which It is selected from‘ the class consisting
or methyl and ethyl.
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