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Патент USA US2116454

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2,116,454
Patented May 3, 1938
umrso STATES‘ PATENT OFFICE
HIGHLY ACTIVE PREPARATION OF E'RGOT
'
AND PROCESS FOR MAKING SAME
-
"Marvin R. Thompson, Baltimore, Md.
No Drawing. ’ Application August 16, 1934,
Serial No. 740,199
40mins.
(CI. 87-28)
dampened and alkaline drug is then exhaustively
The present invention provides a hitherto un
extracted with ethyl ether, benzol, acetone, chlor
known component of ergot and process for mak
ing the same.
‘ -
This component, henceforth called Ergostetrine,
5 is a substance exhibiting alkaloidal properties,
but differs greatly from all of the hitherto un
known alkaloids of ergot, in that its physiologi
cal, therapeutic or oxytocic activity develops with
remarkable promptness when compared with any
10 of the other hitherto known alkaloids or com‘
ponents of ergot.
,
The known therapeutically significant com
ponents of ergot are “Ergotoxine”, “Ergotamine"
and “Sensibamine”. These components of ergot
or alkaloids are possessed of oxytocic activity, but
this activity manifests itself only in an erratic
and much delayed manner following dosage by
mouth. Even when administered subcutaneously
or intramuscularly the uterine activity of these
20 alkaloids or components of ergot develop very
slowly and feebly compared to Ergostetrine, the
subject of the present invention.
Brie?y stated, the instant invention provides a
hitherto unknown component of ergot, called Er
gostetrine whose physiological, therapeutic or
2
oxytocic activity develops with a marked degree
of quickness when compared with-other known
alkaloids, and consists of the “residual alkaloid”
as a‘ single chemical entity which remains after
30 the chemical removal of all of the other hitherto
known alkaloidal substances.
Ergostetrine differs from all other hitherto
known alkaloids or components of ergot in that
ethylenes, the chlor-methanes, or any one of the
common organic solvents. The solution of the
total alkaloidal bases in the organic solvent is
concentrated in vacuo with or without the aid of
a slight amount of heat. The amount of con
centration necessary depends of course upon the
particular organic solvent used, and the acid em
ployed to convert the free bases to their corre
sponding salts. An acid is then added, such as
10'
sulphuric, hydrochloric, or phosphoric acid, to 7
convert the alkaloidal bases to their correspond
ing salts. This causes a substantially complete
precipitation of all alkaloids except Ergostetrine,
the latter alkaloidal salts remaining in solution
because of its greater solubility in all organic
solvents.
After removal of the other alkaloids by ?ltra
tion, Ergostetrine is obtained in amorphous, im 20
pure form from the clear ?ltrate by evaporating
to dryness in vacuo. By leaching the residue with
small portions of water and ?ltering, until ap
proximately 100 CC ot' the aqueous solution of
Ergostetrine sulphate is obtained, the Ergostetrine 25
can then be obtained as the dry amorphous base
by (a) precipitating the base from the aqueous
solution by partial saturation with sodium bi
carbonate, collecting the Ergostetrine base on a
filter and drying to constant weight in vacuo 30
over a suitable dehydrating agent; or (b) by
slightly alkalinizing the aqueous solution of Er
gostetrine sulphate and shaking out with several
it is considerably more soluble in water as the‘ small portions of ether or other immiscible or
free
base or its salts than the hitherto known ganic solvent. The Ergostetrine base passes into 35
35
alkaloids or their salts. Its most readily apparent the layer of immiscible solvent, and can be ob
and therapeutically all important diiierence lies
in the fact that its oxytocic action develops with
a marked degree of rapidity and intensity fol
40 lowing either oral, or parenteral administration,
as compared by actual test with any of the other
hitherto known alkaloids or puri?ed preparations
of ergot.
.
tained as the dry substance by removal of the
volatile solvent in vacuo, or (c) by obtaining the
total alkaloids in ethereal solution by direct alka
line extraction of ergot or its aqueous extract, 40
removing the ether in vacuo and drying. and re
dissolving the total alkaloids in the smallest nec
essary amount of acetone, adding water to the
,The new component, Ergostetrine as such can , acetone which causes all other alkaloids to pre
45
45 be obtained as a dry powder, either from crude cipitate. After discarding the precipitate the
ergot or from crude ergot extracts in various ways, ‘amorphous Ergostetrine base is obtained by re
moval of the solvent.
'
and for-illustrative purposes I hereinafter de
scribe several preferred methods of making the
same.
50
From crude ergot ,
In accordance with one procedure I mix 1 kilo
gram of ?nely powdered ergot, preferably de
iatted with benzine, with a su?icient quantity of
55 anv aqueous solution or mixture of any alkali,
such as hydroxides, carbonates or bicarbonates
of sodium, potassium, ammonium, lithium, stron
tium, calcium, magnesium, etc. to render it evenly
and distinctly damp, and to impart a slightly but
60 de?nitely alkaline reaction to the mixture. The
From crude ergot extracts
Crude aqueous or hydro-alcoholic extracts 50
(liquid, semi-solid or, solid) prepared by simple
procedures such as described by the U. S. Phar
macopoeia, the British Pharmacopoeia or the
National Formulary can serve as a convenient
starting point for the preparation of Ergostet 55
rine.
An amount of such extracts representing 1 kilo
gram of original ergot, is preferably de-alcohol
ized in the conventional manner, alkalinized to
litmus by the addition ‘of any one of the alkalies
2
8,1 16,154
above mentioned. and exhaustively shaken out
with immiscible solvent such as ether, bensol
chloroform etc. The total alkaloids pass into the
layer of the immiscible solvent. From this point
the lt'rgostetrlne can be obtained as the base or its
corresponding salts as above indicated.
It is understood that the Ergostetrine so ob
tained may be further puri?ed as desired by con
ventional alkaloldal puri?cation procedures, such
as repeating the steps above mentioned.
What is claimed is:
1. A process for obtaininga hitherto unknown
component of ergot, consisting of mixing a pre
determined quantity of powdered ergot with
aqueous solution oi! alkali, extracting the damp
ened and alkaline drug with an organic solvent,
and then concentrating and reducing the volume
of the solution of the total alkaloidal bases in the
organic solvent, adding an acid of the group con
20
sisting of sulphuric, hydrochloric and phosphoric
acids, causing the conversion of the total alka
loids to theirv corrmponding sulphates, hydro
. chlorides or phosphates and resulting in a sub
25
stantially complete precipitation or all the alka
loids except the desired component.
2. A process for obtaining a hitherto unknown
component of ergot, consisting oi’ mixing a pre
determined quantity oi.’ powdered ergot‘with an
aqueous solution of alkali, exhaustively extract
30 ing the dampened and alkaline drug with an or
ganic solvent, concentrating the solution oi.’ the
total alkaloidal bases in vacuo and reducing the
volume, adding an acid of the group consisting of
sulphuric, hydrochloric and phosphoric acids,
35 causing the conversion 01' the total alkaloids to
determined quantity of de-iatted powdered ergot
with an aqueous solution of alkali, exhaustively
extracting the dampened and alkaline drug with
an organic ‘solvent, then concentrating the solu
tion of the total alkaloidal bases in vacuo and
reducing the volume, adding an acid oi’ the group
consisting oi’ sulphuric, hydrochloric and phos
phoric acids, causing the conversion or the total
alkaloids to their corresponding sulphates. hy
drochlorides or phosphates and resulting in a
substantially complete precipitation oi’ all the
alkaloids except the desired component, remov
ing said alkaloids by ?ltration, then evaporating
the ?ltrate to dryness in vacuo and leaching the
residue with small portions of water to obtain an
aqueous solution oi’ the component salt, precipi
tating the base of the component from the aque.
ous sulphate solution by alkalinizing to litmus
with alkaline substances, collecting the base oi’
the component on a ?lter, and drying to con
stant weight in vacuo over a dehydrating agent.
4. A process for obtaining a hitherto unknown
component of ergot, consisting of mixing a pre
determined quantity oi de-tatted powdered ergot
with an aqueous solution oi alkali, exhaustively 26
extracting the dampened and alkaline drug with
an organic solvent, then concentrating the solu
tion of the total alkaloidal bases in vacuo, and
reducing the volume, adding an acid of the group
consisting of sulphuric, hydrochloric and phos
phoric acids, causing the conversion of the total
alkaloids to their corresponding sulphates, hy
drochlorides or phosphates and resulting in a
substantially complete precipitation of all the
alkaloids except the desired component, remov~ 35
their corresponding sulphates, hydrochlorides or
phosphates and resulting in a substantially com
ingsaid alkaloids by ?ltration, then evaporating
plete precipitation of all the alkaloids except the
desired component, removing said alkaloids by
residue with small portions of water to obtain an 1
40 ?ltration, and then obtaining an aqueous solution _
of the component salt from the clear ?ltrate by
evaporating to dryness in vacuo, and leaching the
residue with small portions 01' water.
'
3. A process for obtaining a hitherto unknown
45 component of ergot, consisting of mixing a pre
the ?ltrate to dryness in vacuo and leaching the
aqueous solution of the component salt, then ob
taining the component as a dry amorphous base 40
by slightly alkalinixing the component salt solu
tion and shaking out with several small portions
of immiscible organic solvents, and ?nal removal
of the volatile solvent in vacuo.
_
MARVIN R. THOMPSON.
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