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Патент USA US3092653

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3,92,643
Patented June 4, 1963
1
2
3,092,643
After complete extraction of the plant with one of
PREPARATION 0F ALLOPREGNANE - 20 - HY
these solvents or a mixture thereof, the extracts are
DROXY-3-0NE AND OF ALLGPREGNANE
3-20-DIONE
Jean Louis Paul Mainil, Boitsfort, Belgium, assignor to
stirred with a solution of acetic, hydrochloric, oxalic
or other ‘acid sufficiently strong to displace the principles
combined with the rubber and with the chlorophyll. It
Societe Anonyme Oletta, Luxembnrg
is generally desirable to use concentrations of at least
No Drawing. Original application Sept. 26, 1958, Ser.
25%, ‘depending upon the acids.
No. 763,431. Divided and this application June 12,
The solvent and the acid .are separated, if necessary
1962, Ser. No. 201,791
with ?ltration. The aqueous part is added to any solid
Claims priority, application Belgium Sept. 27, 1957
10 part remaining on the ?lter.
3 Claims. (Cl. 260-3973)
The principles in acid solution are made alkaline with
The present invention relates to ‘the preparation of
ammonia or by :a sodium carbon-ate solution so as to
allopregnane-20-hydroxy-3-one and of allopregnane-S
dissociate the principles A and C from the other prin
ZO-dione.
ciples. The alkaloid is then extracted by means of a
The invention is characterized in that respectively 15 solvent or a mixture of solvents immiscible with Water,
amino-3a-allopregnane-20-ol (Funtumidine: C21H37ON)
and amino - 3oz - 'al-lopregnane - 20 _ one
(Funtumine:
such as ether ‘or chloroform, or miscible with Water, such
as ethyl or methyl alcohol. On distillation, ‘a residue is
obtained and is dried, the residue consisting of the alka
C21H35ON) are caused to react with hypochlorous acid,
the chloramine obtained is treated by means of sodium 20 loids or bases mixed with other substances and resins
heretofore regarded as impurities.
ethylate so as to obtain the corresponding ketamine and
These substances A and C are taken up individually
‘the latter is hydrolized.
in methanol and, if desired, recrystallized several times.
The present invention is based on alkaloids and prin
The substance having a melting point of 260° C. can
ciples isolated from plants of the genus Funtumia (Apoc
also be obtained by distilling or otherwise treating the
yn-aceae) and more particularly from the species F. 25 extraction solvents ‘after elimination of the basic prin
substance
ciples and ?rom,
of the‘for
chlorophyll
example, methanol
and by recrystallizin-g
or ethyl acetate.
This application is a divisional based on my earlier
Latifolia.
application, Serial No. 763,431, ?led September 26, ~l958.
Investigations have shown that crystallizable alkaloids
Experience shows ‘that the product obtained is a sapo
genin which ‘is positive to Liebermann’s reaction. Its
‘and principles, combined with the latex of this plant, can 30 infra-red spectrum shows an OH band at about 3 Ill/.0 and
be isolated in an advantageous and economic yield from
a C—-O band at about 6 my. This substance contains
no nitrogen.
this species of the genus Funtumi-a and from any part
of the plant.
The crude residual mixture of alkaloids and bases can
These ‘alkaloids and bases are useful in veterinary ther 35 also be obtained by extraction with acid water or neutral
or acid alcohol by concentrating and extracting the resi
apy and as an intermediary product (raw product) for
due by means of a solvent immiscible in the alkaline
synthesis of other steroids. More particularly, the al
phase.
kaloids are useful in controlling respiratory action and
The residual mixture can be directly treated by ‘suc
the nervous systems of animals. They are two in num
cessive recrystallizatious until pure principles are obtained.
ber, and are hereinafter called alkaloids A and C, re 40
The chemical characteristics of bases A and C are as
spectively.
The physiological properties of alkaloids A and C have
been the subject of experiments and more detailed par
ticulars will hereinafter be ‘given.
For the isolation of these products, use is made of
of alkalids from the plants, account being taken ‘of
one of the methods generally employed for the isolation
the fact that each fraction is combined with the latex
and/or the chlorophyll ‘of the plant.
The plants or parts thereof, such as the leaves, trunk
bark or roots, depending on the season ‘at which the crop
is taken, are crushed and then Washed in petroleum ether.
‘follows.
Alkaloid (principle) A:
Empirical formula: C21H37ON.
Developed formula: 3-a-amino-allopregnane-ZO-ol.
Infra-red spectrum: OH, NH bands at about 3”; no
(‘:0 bands; its chloro'hydrate has a 2080 cm.-1
'a band NHs‘l".
Melting point:
182° C.
(0013:: 0 in methanol.
Gives a hydrochloride of MP. 290° C.
Alkalcid (principle) C:
The cells are burst by a current of steam or by other
Empirical formula: C21H35ON.
Developed formula: B-a-aminO-alIOpregnane-ZO-one.
chemical or physical means. The plants are then made 55
‘Melting point: 123 ° C.
alkaline with ‘a solution either of 20% ammonia or of
10% or 5% sodium carbonate, or with milk of lime or
It gives a hydrochloride of M1’. 280° C. having a
of magnesia, or they are moistened with water.
rotatory
power of +60 in methanol and the infra-red spec~
After contact for several hours with the ‘alkaline me
trum of which exhibits NH bands in the region of 3/1, a
dium, the plant is extracted in a Soxhlet apparatus, a 60
NH3+ band at 4.9”, a 0:0 hand at ‘about 5.9/1. and
mixer, a percolator or a rotative extractor, with petroleum
another band at about 6.2,u, which may correspond Ito
ether, ether, benzene, chloroform, ethyl acetate or other
a C=C vibration.
solvents polar or non-polar chlorinated or non-chlori
These reactions and identi?cations show that it is a
nated, alone or in admixture.
‘ketonic alkaloid.
aooaeas
Toxicity DL5U
Action on the central
nervous system.
5 times more anaes-
thetic than cocaine
sulphate so as to avoid the presence of Water.
5 times more anaes‘
thetic than cocaine
on the cornea of the
on the cornea of the
rabbit; Temperature
ture reducer and
reducer and anti~
Gardiotonlc _________ _- On the isolated auri-
cle; On the rabbit’s
heart in situ.
Respiratory analeptic. On the normal rabbit
pyretic.
0n the rabbit’s heart
in situ.
phinized rabbit.
phinized rabbit.
tension.
10 is boiled under re?ux for 40 minutes with a solution of
On the normal rabbit
and on the mor
Diuretic _____________ -_
by the method of Wohl and Goldschmidt, Ber. 46; 2731
(1913). After agitation for one hour, the ethereal solu
tion is ?ltered to separate the sodium sulphate, and is
evaporated to dryness in vacuo. The crystalline residue
On the isolated auricle:
and on the mor-
Cardiovascular ...... _. Vasodllatation hypo-
The ethereal hypochlorous acid solution is prepared
5
rabbit; Tempera-
antipyretic.
Kidney _____________ -.
of alkaloid C (Furltumine) in solution in ethereal solu
tion cooled to 10° C., with agitation. The entire opera
tion is carried out in the presence of anhydrous ‘sodium
Alkaloid A, 28 mgJkg. Alkaloid C, 30 rug/kg.
sodium ethylate in 50 ml. of absolute ethanol. The solu
rtion is thereafter poured into 300 ml. of water slightly
acidi?ed with sulphuric acid. The mixture is allowed
Vasodilatation hypo
tension.
to stand for 24 hours and the precipitate formed is suc
No action.
Anabolic ____________ __ Slightly per os nil by
tion filtered and dissolved in chloroform. The chloro
No oestrogenic action; No oestrogenic action; 15 formic solution is Washed with water, dried and evapo
injection.
Hormonal and metabolic action.
No androgenic action; No folliculinostimulant action.
Suprarenal __________ ._ Weight unchanged after 40 days as com-
No folllculino-stim
ulant action.
rated to dryness in vacuo.
mg. is obtained.
Weight unchanged af
pared with controls.
Ascorbic acid and _
Ascorbic acid and
cholesterol content
cholesterol content
unchanged as com-
unchanged as com- 1
pared with controls.
pared with controls.
Liver ________________ _. Slight increase in dry
Prevents glycogen de-V
weight; Prevents
glycogen depletion
After recrystallization from hexane and alcohol, allo
prognane-3,20-dione, M.P. ZOO-202° C. and (a)D-|-128
(CHCls), is obtained.
By the same method, alkaloid A or its ZO-position cp'i
ter 40 days as com
pared with controls;
mer can be converted into the two sterolic alcohols 20
pletion of the liver
liydroxy-allopregnanc-3-one.
(like cortisone).
.
Alkaloid A is advantageously oxidized to give alkaloid
C in ketonic form by the use of chromic acid in acetic
' of the liver (like
_
A residue weighing 1:800
cortisone).
Trauquilizing Action- 25 mg./kg. per day reduces the motility of rats
by changing the number of movements
recorded in 6 hours from 16,500 to 2,500.
‘acid solution or by any other method.
Injectable solutions containing 5 rug/cc. of the hydro
chloride of alkaloid A or C can be prepared by dis 30
solving it in propylene glycol (30 parts) diluted with dis
tilled water (70 parts). Other injectable solvents such
as methyl acetamide, etc., may be employed. Concen
trations of 1 mg./cc. of hydrochloride can be obtained 35
in distilled water alone.
It is also possible to prepare tablets for therapeutic
use by using, vfor example, the following recipe:
[Hydrochloride of alkaloid A or O 10 mg. or 25 mg.]
40
Lactose.-.__
Rice starch
Magneisum stearate _____________________________________ _.
Talc
71
80
56
80
2
2
37
37
The invention also concerns the production of deriva
tives of alkaloid C (Funtumine) preserving the amino
function in the 3-p-osition, as follows.
,
(1) Reduction of the ketone function of alkaloid C
For example, the alkaloid and the lactose are granu 45 into an alcohol function (Funtumidine) :
_
3-u-rzmino-ZO-o-hydraxy-all0pregnane: Fzmtum‘ia‘ina
lated. After drying, the other ingredients are added to
Funtumidine is advantageously obtained by reduction of
enable ready dis-solution in the stomach and lubricants
Funtumine by means of sodium in ‘alcohol.
to enable ready compression of the tablets.
7 200 mg. of Funtuniine are dissolved in 20 cc. ‘of abso
Principals A and C may be converted into mineral
salts, such as vsulphates, hydrochlorides, nitrates or hy 50 lute alcohol. To this solution, maintained at boiling
point, are added in small fractions, over the course of 1
drobromides, or into organic salts, such as tartrates, ci
‘hour, 3 times the calculated quantity of sodium. The
trates, gluconates, camphorates, camphosulfonates and
alcohol is driven oil by distillation in vacuo and the
acetates.
residue is taken up in Water ‘and extracted with methylene
For the production of hydrochlorides ‘of bases A and C,
the puri?ed base in suspension in very hot water may be 55 chloride. The organic solution is dried ’over "anhydrous.
sodium sulphate, ?ltered “and distilled to dryness. The
employed as starting material. The pH value is adjusted
residue (200 mg.) is crystallized from ethyl acetate and
to 4 with a mixture of methanol and hydrochloric acid
gives the 'dihydrogenated derivative of Funtumine, which
and the white hydrochloride is allowed to cool. They are
is identical with Funtumidine: M.P. 178° (MD-H0
very sparingly soluble in the cold.
'
The alkaloids A and C, hereinafter called Funtumidine 60 (CHCl3).
'
'
3~u-amino-ZO-B-hya’roxy-all0pregnane: ZO-epi-Funtum‘i
and Funtumine respectively, may be used as starting ma
dine.—T-he epimer of 'Funtumidine is obtained by: the
reduction of Funturnine by means of potassium b‘orohy
drid'e in solution in methyl alcohol.
terials for the production of other steriods, particularly
for obtaining dihydro-progesteronc in an advantageous
yield (allopregnane-3-20-dione) .
It is particularly advantageous to obtain these sub 65
stances by preparing the chloramine by action of hypo
chlorous acid in ethereal solution. This chloramine is
200 mg. of Funtumine are dissolved in 10 cc. of
methanol. To
solution ‘are added 200 mg. of potas
sium borohydride. The mixture is constantly stirred for
dechlorinated by means of sodium ethylate and [the ket
5 hours at room temperature. The excess of horohydride
amine obtained is hydrolized in sulphuric acid solution
is them entirely ‘consumed. The solution is poured into
7 to give allopregnanc-S-ZO-dione in a good yield.
.
Example
The calculated quantity of hypochlorous acid in
ethereal solution, cooled. to —20° C. (the quantityis
‘calculated mol. per mol.) is added dropwise to 1 ‘gram
70 100 cc. of water and the precipitate is extracted with an
organic solvent such as other or methylene chloride. The
organic solution is dried and evaporated to dryness. The
crystalline residue is recrystallized from ethyl acetate.
180 mg. of 20~epi-Funtumidine: M.P. 167° C.,' are ob
tained.
3,092,643
5
6.
(2) Production of 3-amino derivatives of androstane
from Funtumine:
3-a-amino-androstane-17-B-ol.—-The 17 ?-hydroxy com
pound of 3-a-amino-androstane can be ‘obtained by the
action of peracids with the retention of the con?guration
in the 17-position. In this reaction, using peracetic ‘acid,
What is claimed is:
[1. A process for the preparation of allopregnane-ZO
hydroxy-3-one and of allopregnane-3-20-dione, said proc
ess comprising reacting 'amino-3wallopregnane-20-‘ol and
iamino-3wal1opregnane-20-one with ‘hypochlorous acid,
treating the chloramine thus obtained with sodium ‘eth
ylate ‘to ‘obtain the corresponding 'ketamine, and hydro
17?aacetoxy-3-a-arninoaandrostane is obtained, ‘together
with 21-acetoXy-Funtumine. The latter product consti
lyzing the latter.
rtutes a -by-product of the reaction. These ‘operations are
summarized as follows:
OH;
/
2. The process according to claim 1 wherein the reac
10 rtion with hypochlomus acid takes place in ethereal solu
rtion.
3. The process according to claim 1 wherein the hy
OHIOAC
:aa
drolysis takes place in sulfuric solution.
15
No references cited.
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