close

Вход

Забыли?

вход по аккаунту

?

Патент USA US3052685

код для вставки
United States Patent O??ce
7
3,052,675
Patented, Sept. _4, 1,962
1
2
3,052,675
'It is another object of the invention to provide proc
esses ‘for the preparation of the novelbis-(hydroxy-meth
yl)‘-5a-pregnanes of Formula I.
‘It is a further object of the invention to obtain novel
intermediates for the preparation of the 20-bis-(hydroxy
BIS-(HYDROXY-METHYL)-5u-PREGNANES AND
DERIVATIVES THEREOF
Daniel Bertin, Montrouge, Antoine Locatelli, Aubervil
liers, Jean Mathieu, Montfermeil, Georges Muller,
Nogent-sur-Marne, and Hubert Fritel, Paris, France,
methyl) -5a-pregnanes of Formula I.
assignors, by mesne assignments, to Roussel-UCLAF,
S.A., Paris, France, a corporation of France
'
It is an additional object of the invention to prepare
‘
No Drawing. Filed Feb. 10, 1961, Ser. No. 88,282
Claims priority, application France Mar. 8, 1960
20 Claims. (Cl. 260-—239.55)
The present invention relates to novel bis(hydroxy
methyD-Sa-pregnanes and derivatives thereof and the
process for the‘ preparation of said compounds. The in
vention particularly relates to compounds having the 15
formula
pharmaceutical compositions comprising ZO-bis-(hydroxy
methyl) -5u-pregnanes of Formula I for the treatment of
heart conditions.
These and other objects and advantages of the inven
tion will become obvious from the following detailed’
description.
The compounds of the invention of ‘Formula. I are pro
duced from the novel intermediate having the formula
CH3 CHzOAG
CH3 01120
I/
0
\ornoae
(II)
25
wherein R1 is selected from the group consisting of :0
wherein R2 and R3, are selected from the group consist
and
ing of hydrogen, phenyl, phenyl substituted lower alkyl
and lower alkyl. R2 and R3 are preferably methyl groups.
The novel intermediate is reacted in a number of Ways
depending upon the desired ?nal product.
The novel intermediates of Formula II are prepared
by the Grignard reaction of 318-acyloxy-5a-pregnane-20
one With a lower alkoxymethyl magnesium halide to form
and Ac is selected from the group consisting of hydrogen,
an acyl radical of an organic carboxylic acid having 1
to 18 carbon atoms and an anion of a mineral acid.
The products of the invention are distinguished by their
cardiotropic activity coupled with a dilation action of 35 3?-acyloXy-20-lower alkoxymethyl-5u-pregnane-20-ol, de
hydration of the latter to form 3?-acyloXy-20-formyl-5m
coronaries. They are useful each time that a speci?c ac
pregnane, condensing said compound with formaldehyde
and saponifying simultaneously to form 20dbis-(hydroxy
methyl)~5a-pregnane-3dol and reacting the latter with
tion on the heart muscle is necessary, this action ‘being
in addition accompanied with a bene?cial augmentation
of sanguinine irrigation of the said heart muscle.
It is an object of the invention to obtain novel bis-hy 40 a ketone or aldehyde to form compounds of Formula H.
The reaction scheme is illustrated in Table I.
TABLE I
drQXY-methyD-Su-pregnanes of Formula I.
CH3
OH;
I OHgO
i R‘
5/! J: W on
H
_
l/
(IJH;
i
CH/gCHnOH
O
3%)
NWH
I
_
CH
.._.,
n
no
~
I
H
I!
CH3 OHgQ
RI .
HO
H
(II)
onion
3,052,675
3
wherein R is an acyl group of an organic canboxylic acid
having 1 to 18 carbon atoms and R2 and R3 are selected
from the group consisting of hydrogen, phenyl, phenyl
substituted ‘lower alkyl ‘and :“lower alkyl and R4 represents
a lower alkyl radical.
A preferred process for the preparation of the com
pounds vof Formula ‘11 comprises reacting 3ls-acyloxy-5u
pregnane-ZO-one with methoxy methyl magnesium bromide
in an inert organic solvent such Ias tetrahydrofuran at low
temperatures of the order of 0° to 10° C. in the presence 10
of amercuric halide catalyst such as mercuric chloride to
R0
form 3/8-acyloXy-20-methoxy methylene-.Sa-pregnane-ZO
o1, reacting the latter with phosphorus oxychloride to
form 3,8-acYloxyQO-formyl-Sa-pregnane, condensing said
product with formaldehyde according to Tollens’ reaction 15
in the presence of methanolic potassium hydroxide to
form 2o-bis-(hydroxyemethyl)-5a-pregnane-3?-ol and re
.0113 0132011
/\
acting the latter with an aldehyde Or ketone such as ace
tone at room temperature in the presence of perchloric
(5/
’
\omon
acid to form compounds of Formula II.
The ketone or aldehyde may be aliphatic or aromatic.
Examples of suitable ketones are acetone, methyl ethyl
R0
ketone, ethyl propyl ketone and acetophenone. Exam
ples of suitable aldehydes are formaldehyde, acetalde
hyde, butyraldehyde, benzaldehyde and phenylacetalde
hyde.
,
I
H
25
The process for the preparation of compounds of For
mula I wherein R1 is
CH3 CHQOAC
‘ \omoac
30
(0 Ac
‘H
/
comprises acylating the alkylidene or arylalkylidene of
Formula II to form the alkylidene or arylalkylidene of
36-acyloxy-20-bis-(hydroxy-methyl)-5u-pregnane and re 35
acting the latter under acidic conditions to form 3?-acyl
A00;
,
H
(I)
oxy-ZO-bis-(hydroxy-methyl)-5a-pregnane. The ZO-‘bis-hy
droxy-methylene ‘groups of ‘this latter compound may be
esteri?ed with an organic carboxylic ‘acid having 1 to 18
wherein R, Ac, R2 and R3 have the above de?nitions.
The method for the preparation of compounds of
carbon atoms or a mineral acid and, if desired, then hy 40 ‘Formula I which possess a 3-one group (R1==O)
drolyzing the esteri?ed product to form ZO-bis-(acyloxy
comprises OXidiZing the alkylidene or arylalkylidene of
methyl) ~5a-pregnane-3B-ol.
20-bis-(hydroxy-methyl)~5a-pregnane-3B-ol to form the
’A preferred process for preparing compounds of For
mula I wherein R1 is
alkylidene or arylalkylidene of 20i-bis-(hydroxy-methyl)
45 5oc-pregnane-3-0ne, reacting the latter under acidic con
ditions to form 20-bis-(hydroXy-methyl)-5a-pregnane-3
one and reacting said compound with an esterifying agent
to form ZO-bis-(acyloxy-methyl)-5a-pregnane-3-one.
A preferred process for preparing 3-one compounds of
comprises preparing the acetonide of 20-bis-(hydroxy
methyD-Su-PregnaneG?-OI as discussed previously, acylat 50 ‘Formula I comprises oxidizing the aceto-nide of 20-bis
ing said acetonide with acetic acid anhydride in pyridine
(hydroxy-methyl)-5a-pregnane-3B-ol with chrornic acid
to ‘form the acetonide of 3/8-acetoxy-2G~bis-(hydroxy
in pyridine at temperature between 0 and 15° C. to form
methyD-Sa-pregnane and reacting said product with aque
the acetonide of ZO-bis-(hydroxy-methyl)'-5u~pregnane-3
ous acetic acid or a mineral acid in an aqueous alcoholic
one, reacting the latter with aqueous acetic acid to form
medium to form 3,8-acetoxy-20-bis-(hydroxy-methy1)*-5u 55 ZO-bis-(hydroXy-methyl)-5a-pregnane-3-one. This com
pregnane. This compound may esteri?ed in the 20-bis
pound may be esteri?ed by reacting, with fuming nitric
(.hydroxyemethyl) groups by reacting with fuming nitric
acid at temperatures about —5° to —-15 ° C. to form 20
acid at temperatures about —5° to —15° C. to form 3,8
acetoxy-20-bis-(nitrato methyD-Sa-Pregnane which can
bis-(nitrato-methyl)-5ot-pregnane-3-one.
then 'be saponi?ed to form 20-bis-(nitrato methyl)v-5a
pregnane-BB-ol. This preparation is illustrated in Table II.
60
The reaction
scheme is outlined in Table III.
TABLE III
TABLE II
CH3 01120
CH3 C1120
R2
R!
t/ X
I \omo R3
65
HO
HO
(II)
(II)
75
3,052,675
6
5
in 160cc. of water containing a small amount'of sodium
chloride was introduced into the solution, and the organic
phases were separated from the aqueous phase.
The aqueous phase was extracted with tetrahydrofuran
and the combined tetrahydrofuranic phases were washed
successively with a saturated solution of sodium chloride,
twice by a saturated solution of sodium chloride and
sodium bicarbonate and ?nally by a saturated solution
of sodium chloride until the reaction mixture was neutral.
0_
10 The wash waters were reextracted by tetrahydrofuran.
The washed tetrahydrofuranic phases were combined,
H
dried over magnesium sulfate, ?ltered and evaporated to
dryness in a water bath.
The raw product was dissolved in 400 cc. of pyridine
15 and 200 cc. of acetic anhydride were added. The mix
ture was allowed to remain for a period of eighteen hours
and then was poured into 6 liters of a mixture of ice and
water. After agitating for a period of one hour, the
CH3 CHgOH
|/
C\OHQOH
crystalline precipitate was vacuum ?ltered, washed with
20 water and dried at 80° C.
O__
Puri?cation was effected by
repeated trituration with methanol under agitation and at
re?ux. 83 gm. of 20-methoxymethyl-3p-acetoxy-Sa
pregnane-ZO-ol were obtained, having a melting point of
I
l
H
25
CH3 OHZOAC
l/
185-187.5° C.
The product was soluble in tetrahydrofuran and di
methylformamide, slightly soluble in ethanol, acetone,
benzene, chloroform and ether, insoluble in water.
I O\ CHZOAG
Analysis.—C25H42O4: Molecular Weight=406.59. Cal
culated: C, 73.85%; H, 10.41%. Found: C, 74%; H,
30 10.4%.
The compound is not described in the literature.
o—
The starting compound, 3?-acetoxy-20-ketoallopreg
l
H
nanc, was prepared after the method described by D. H.
R. Barton and J. D. Cox, J. Chem. Soc., 1948, 783—93.
(I)
Step B—Preparati0n 0f ZO-bis-(hydroxy-melhyl)-5oc
35
wherein R2, R3 and Ac have the above de?nitions.
pregnane-3?-0l.—29 gm. of 3B-acetoxy-20~methoxy
The term “Ac” and “acyl” used in the above tables and
methyl-Sa-pregnane-ZO-ol were subjected to the action of
description may represent the acyl radical of an organic
carboxylic acid having 1 to 18 carbon atoms or the anion
of a mineral acid. Suitable organic carboxylic acids are
alkanoic and alkenoic acids such as acetic acid, trimethyl
acetic acid, propionic acid, 4,4-dimethyl pentanoic acid,
IO-undecenoic acid; cycloalkylalkanoic acids such as ,8
cyclopentyl propionic acid; arylalkanoic acids such as
phenyl propionic acid; cycloalkanoic acids such as hexa
hydrobenzoic acid and hexahydroterephthalic acid; and
phenyl carboxylic acids such ‘as benzoic acid and 3,5-di
87 cc. of phosphorus oxychloride. The mixture was agi
tated for a period of three hours, then poured into a
mixture of water and ice and the agitation continued for
a further period of thirty minutes. The reaction mixture
was neutralized with sodium bicarbonate and agitated for
a period of thirty minutes. The residue was vacuum
?ltered, washed with bicarbonated water, then with water
45 until the wash waters were neutral. 26.5 gm. of 3?-ace
toxy-20-formyl-5u-pregnane were obtained, being a yield
of 99%. This compound has a melting point of 120
nitro benzoic acid. Examples of suitable mineral acids
125° C.
are nitric acid and sulfuric acid.
26.5 gm. of 3,B-acetoxy-ZO-formyl-Sa-pregnane were in
In the following examples there are described several
preferred embodiments to illustrate the invention. How 50 troduced under an atmosphere of nitrogen into 265 cc.
of methanol and 26.5 cc. of 30% formol. 14 cc. of con
ever, it should be understood that the invention is not in
centrated potassium hydroxide solution were added. The
tended to be limited to the speci?c embodiments.
reaction mixture was then agitated for a period of about
Example I
forty-seven hours and the residue was vacuum ?ltered,
PREPARATION OF THE ACETONIDE 0F ZO-BIS
55 triturated successively with methanol and with water and
(HYDROXY-METHYL)-5a~PREGNANE—3?-OL
dried.
Step A—Preparati0n of 20-meth0xymethyl-3Bracetoxy
The raw product was puri?ed by solution in the hot in
5 a-pregnane-20-0l.--19.9 gm. of magnesium turnings and
dimethylformamide, decolorization with animal charcoal,
1.54 gm. of mercuric chloride were introduced into 241
crystallization in the cold and recrystallization a second
cc. of tetrahydrofuran. The mixture was agitated at room
60 time from dimethylformarnide. _5.9 gm. of 20-bis-(hy
temperature for a period of three hours, then cooled to
0° C. and there was added thereto, in a period of about
droxy-methyl)5a-pregnane-3B-ol were obtained, having a
thirty minutes, while maintaining the temperature be
The product was easily soluble in dimethylformamide,
dioxane and tetrahydrofuran, very slightly soluble in
melting point of 260.5“ C.
tween 0 and +5 ° C., the solution:
Cc.
Methoxymethyl bromide _____________________ __ 63.7
Tetrahydrofuran
241
65
'
ethanol, ether, acetone, benzene and chloroform, insoluble
in Water.
Analysis.—C23I-I40O3: Molecular weight=364.55. Ca1
culated: C, 75.77%; H, 11.06%. Found: C, 75.7%; H,
The agitation was containued for a period of thirty
11.2%.
r
minutes at the same temperature. Then a solution of
96.5 gm. of 3?-acetoxy-20-keto allopregnane in 350 cc. 70 This compound is not described in the literature.
of tetrahydrofuran was introduced over a period of about
thirty minutes at a temperature between about ‘0 and +5 °
C. and the agitation was continued for a period of two
Step C-—Preparati0n of the acetonide of ZO-bis-(hy
droxy-methyl)-5a-pregnane-3,B-0l.-4.036 .gm. of 20-bis
(hydroxy-methyl)-5a-pregnane-3,8-ol were placed in sus
pension in 404 cc. of acetone. The mixture was agitated
hours while maintaining the same temperature.
Next a solution of 140 cc. of 22° Bé. hydrochloric acid 75 and 0.6 cc. of 65% perchloric acid added. After com;
3,052,675
plete solution of the pregnane compound, the agitation
over magnesium sulfate, ?ltered and evaporated to dry
was continued at room temperature and under nitrogen
ness under vacuum on a water bath.
for a period of threefhours. 2 gm. of sodium bicarbonate
were added, the agitation ‘continued for a further thirty
aliquots of ethanol, dissolution in re?uxing ethanol, ?l
minute period and then the acetone was removed under
tration in the hot and recrystallization by cooling to 0°
vacuum on a water bath.
to +5° C. for a period of one hour.
Puri?cation was effected by agitation in two separate
0.697 gm. of 3?-acetoxy-20-bis-(nitratomethyl)-5a
The crystalline residue obtained was taken up in 250
cc. of water, triturated, vacuum ?ltered, washed with
pregnane were obtained, being a yield of 80.4%. This
product had a melting point of 150° C. and a speci?c
water until the wash water was neutral, and dried at 80°
C. 4.335 gm. of the acetonide of ZO-bis-(hydroxy 10 rotation [a]D2°=—8° (c.=0.5% in dimethylformamide).
The product was soluble in ether, benzene and chloro
methyl)—5u—pregnane-3?-ol were obtained, being a yield
form, slightly soluble in ethanol and acetone, insoluble
of 96.7% and having a melting point of 150° C. and
in water.
170° ‘C.
Analysis.-~C25HM,O8N2: Molecular weight=496.59.
The product can be recrystallized from acetone or
from methanol.
15 Calculated: C, 60.46%; H, 8.12%; N, 5.64%. Found:
C, 60.2%; H, 8%; N, 5.8%.
This compound is not described in the literature.
This compound is not described in the literature.
Example ll
Step C-Preparation of 20-bis-(nitratomethyD-Sa
pregnane-3?-Ol.—0.271 gm. of 3B-acetoxy-2‘0-bis-(nitrato
‘PREPARATION OF ZO-BIS-(NITRATOMETHYL){m
PREGNANE-EiB-‘OL
Step A—Preparati0n of 3-[3-acet0xy-20-bis(hydroxy
20 methyD-Sa-pregnane were introduced into 11 cc. of the
following solution:
methyl)-5a-pre_gnane.--l.5 gm. of the acetonide of 20
bis-(hydroxy-methyl)-5u-pregnane-3,8-ol were dissolved
in 7.5 cc. of pyridine and 3 cc. of acetic anhydride and
Cc.
10 N sodium hydroxide solution ___________ _'____. 0.75
the solution was allowed to remain at rest for a period 25
of about three hours.
The solution was then poured under agitation into a
mixture of water and ice. The agitation was continued
Demineralized water ________________________ __
3.7
Ethanol __________________________________ __
50
and the reaction mixture was agitated under nitrogen.
After eight hours of reaction, crystallization was started
for a period of about two hours and the solution
by the addition of a small quantity of water. Then the
was vacuum ?ltered. The precipitate was washed several 30 total solution was poured into 110 cc. of a mixture of
times with water and dried at 60° C. 1.61 gm. of the
water and ice. The crystalline precipitate was vacuum
acetonide of 3?-acetoxy-20-bis-(hydroxy-methyD-Su
?ltered, washed with water until the wash water was
pregnane were obtained, being a yield of 97.6%. This
neutral and dried at 60° C.
product had a'melting point of 120° and 136° C.
Puri?cation of the raw product was effected by dis
1.6 gm. of the raw product were introduced into 16 35 solution in ethanol at re?ux and recrystallization in the
cc. of 60% acetic acid. The reaction mixture was
cold, then by triturationv with ethanol.
heated for a period of one hour at 80° ‘C. and then
0.147 gm. of 20-bis~(nitratomethyl)-5a—pregnane-3?
cooled for a period of two hours at a temperature be
01 were obtained, being a yield of 70%. This product
tween ‘0° and +5° C. The precipitate was vacuum ?l
had a melting point of 90° and 143° C. and a speci?c
tered, triturated several times with water and dried at 40 rotation [a]D2°=—6°:3 (c.=0.5% in dimethylform
80° C. 1.045 gm. of SB-acetoxy-ZO-bis-(hydroxy
amide).
methyD-Sa-pregnane were obtained, being a yield of
The product was soluble in ethanol, ether, acetone,
96.5%.
benzene and chloroform, insoluble in water.
Puri?cation was effected with a yield of 67% by dis
Analysis.—‘C23H38OqN2: Molecular weight=454.55.
solution at re?ux in ethyl acetate, cooling for a period 45 ‘Calculated: C, 60.77%; H, 8.43%; N, 6.16%. Found:
of one hour between 0 and +5 ° C., vacuum ?ltering,
C, 60.7%; H, 8.4%; N, 5.8%.
trituratiug ‘the precipitate with iced ethyl acetate and dry
This compound is not described in the literature.
ing the crystals at 80° C. The product obtained had a
melting point of 225° C. and a speci?c rotation
[-aJD2°=—7.7°:3 (c.=0.5% in dimethylformamide).
The recrystallization can be effected in acetone.
The product was soluble in ethanol, acetone, ethyl
acetate and chloroform, slightly soluble in benzene and
ether, insoluble in water.
Example 111
50
PREPARATION OF ZO-BIS-'(NITRATOMETHYL)-5a
PREGNANE-3-ONE
Step A—Preparati0n of the acetonide of ZO-bis-(hy
droxymethyl)-5a-pregnane-3-one.--2.860 gm. of chromic
Analysis.—C25H42O4: Molecular weight=406.59. Cal 55 acid were introduced in small amounts into 28.6 cc. of
culated: C, 73.85%; H, 10.41%. Found: C, 73.7%;
pyridine, cooled to a temperature between about +5 and
H, 10.2%.
,+10° C. by an ‘ice bath and the temperature of the mix
This compound is not described in the literature.
Step B—-Preparati0n of d’?-acetoxy-ZO-bi?nitrate
methyl)¢5u-pregnane.—4.55 cc. of 48° Bé. nitric acid
are ‘introduced ‘slowly into 7.1 cc. of acetic anhydride
cooled to —10° C. Then a solution of 0.710 gm. of
ture was allowed to rise.
Then a solution of 2.860 gm.
of the acetonide of 20~bis- (hydroXy-methyl)Jot-pregnanc
35-01 in 28.6 cc. of pyridine was added. The reaction mix
ture remained under agitation for a period of eighteen
hours. Then 17.2 cc. of methanol were added in order
to destroy the excess of the oxidant and the agitation was
cc. of chloroform was added slowly under agitation and
continued for a period of another two ‘hours. The residue
under nitrogen at a temperature between about —5° -65 was vacuum ?ltered, triturated with pyridine and the mix
and —10° C. The solution was maintained for a period
ture poured into 750 cc. of a mixture of water and ice.
of ‘twenty minutes ‘at —-5° ‘to —10° C. The reaction
After one hour of rest, the mixture was vacuum ?ltered
mixture was poured into '140 cc. of a mixture of water
and the residue was triturated with water. The product
obtained contained salts of chromium. This residue was
and ice.
taken up‘ by 85 .cc. of methylene chloride. The solution
The aqueous phase was extracted With chloroform.
The organic phase was washed successively with water,
obtained was ?ltered, dried over magnesium sulfate and
a small quantity of alumina was added. The mixture was
with bicarbonated ‘water and again with water until the
agitated for a period of ?fteen minutes and ?ltered on an
wash liquors were neutralized. The wash liquors were
alumina bed. The magnesium sulfate and alumina were
reextracted with chloroform which was in its turn, re
washed. The chloroform solutions were combined, dried 75 then rinsed and triturated with methylene chloride.
3B-‘acetoxy-2i0-bis-(hydroxy-methyl)-5a~pregnane in 8.5
3,052,675‘
10
The granules obtained were placed on a perforated bed
on a dish and put in a ventilated dryer at a temperature of
The methylene chloride solutions were combined, evap
orated to dryness under normal pressure, then under vacu
50° C. The dry granules were ground and passed through
um. 2.540 gm. of the acetonide of ZO-bis-(hydroxy-meth
a metal screen of appropriate dimension, then mixed with
yl) -5ot-pregnane-3-one were obtained, being a yield of
88-89% , having a melting point of 175° C.
5 talc and magnesium stearate for lubrication. The granu
lated powder was transformed into tablets of adequate
This product can be puri?ed by solution in ethanol at
weight by mechanical pressure in a press. The tolerance
re?ux and recrystallization.
of mean weight of a lot of 10 tablets was —'_-5 per 100
This product is not described in the literature.
Step B-Preparation of ZO-bis-(hydroxy-methyl) -5a
of the theoretical weight. For ingestable commodities,
pregnane-3-one.—0.830 gm. of the acetonide of 20-bis
it was found preferable that the weight of the tablets be
(hydroxy-methyl) -5a-pregnane-3-one were introduced into
not more than 750 mg. nor less than 80 mg.
26 cc. of 80% acetic acid. The mixture was heated to 80°
C. and agitated for a period of one hour. The reaction
mixture was cooled to a temperature below 20° C., neu
the tablets was found preferably to be between 0.6 and 6
From this fact, the percentage of active principle in
per 1,000.
tralized with ammonia, diluted with water and allowed to 15
rest for one‘ hour. The crystalline residue was vacuum
?ltered and washed with water and submitted to saponi
?cation. The crystalline residue was then triturated at
room temperature with 8.3 cc. of methanol and 0.5 cc.
PHARMACOLOGICAL STUDY
Action on the Coronary Blood Flow
Study of the action of the said compounds on the coro
nary blood ?ow was effected on the isolated heart of the
of concentrated potassium hydroxide solution, agitated for 20 rabbit,
utilizing a technique inspired from Langendorft'
a period of two and one-half hours and ?nally poured into
(Arch.
Gesam.
Physiol., 1895, 61, 291).
80 cc. of a mixture of water and ice.
In this method, the heart was suspended by the aorta to
0.722 gm. of 20-bis-(hydroxy-methyl)~5m-pregnane-3
a tube and the coronary system was perfused by means
of this tube under a constant pressure of 5 cm. of mercury
one were obtained, being a yield of 96.7%.
The raw product was puri?ed by dissolution at re?ux,
recrystallization from ‘dioxane, vacuum ?lten'ng and tri
by a Locke serum having a pH of 7.2 to 7.3, heated to
37° C. The compound being studied was placed in solu
tion in ethanol and this solution was diluted by means of
turation with the same solvent, giving a product having a
melting point of 270° C. and a speci?c rotation
the Locke serum to the desired concentration.
By a
proper apparatus, the coronary blood ?ow was registered
and parallelly the ventriculary contractions. The table
below furnishes the results obtained by these compounds,
(c.=0.5% in dimethylformamide).
as well as the results from 20-bis-(hydroxy-methyl)-5;3
The raw product may also be puri?ed by recrystalliza
pregnane-3ot-ol-1l-one trinitrine and papaverine, under
tion from dichlorethane or methylene chloride, or by solu
the same experimental conditions.
tion in pyridine and reprecipitation with water.
The product was soluble in chloroform, tetrahydro
'furan, dioxane and dimethylformamide, slightly soluble
in ethanol, acetone and benzene, insoluble in water.
Increase
of
Effect on the Ven
tricular Con
Threshold Coronary Duration
Analysis.-—C23H38O3: Molecular weight=362.54. Cal
culated: C, 76.2%; H, 10.56%. Found: C, 75.6%; H,
Substance
Active
Ooncentra-
tion in 'y/CC.
10.5%.
This compound is not described in the literature.
Blood
Flow
tractions
in
minutes
in
Ampli-
Percent
Frev
tude in quency in
Percent
Percent
Step C—Preparation of ZO-bis-(nitratomethyl) ~50;
pregntzne-3-one.—l2 mg. of 20~bis-(hydroxymethyl)~50:
pregnane-3-one were dissolved in 0.4 cc. of a mixture of 3
cc. of acetic anhydride and 1 cc. of 48° Bé. nitric acid
cooled to —-10° C. The reaction mixture was allowed to
remain for quarter of an hour at —10° to —5° C. and
?ve minutes at +5 ° C. It was poured into 5 cc. of a
mixture of water and ice. The residue was vacuum 50
?ltered, washed with water and triturated with 1 cc. of
ethanol. 9 mg. of 20-bis-nitratomethyl)-5a-pregnane-3
one were obtained. The raw product could also be recrys
0.1
0. 5
0. 2
1. 0
10.0
30
80
20
10
20
>25
20
>45
2-20
15
0
0
~0
0
0
0
0
0
—5
0
I—20—bis-(nitratomethyl)~5a-pregnane-3B-ol.
II—20-bis-(nitratomethyl)-5a-preg'nane-3-one.
III-20-bis-(hydroxy-methyl)-5?-pregnane-3a-ol-1l-one.
IV-Trinitrine.
V—Papaverin'e.
Acute Toxicity
tallized from acetone, and had a melting point of 172° C.
Toxicity tests were made on mice of the Ro‘cklan'd strain
and 176° C. It was soluble in dioxane, slightly soluble 55 weighing
between 18 and 22 gm. The compounds were
in ethanol, insoluble in water.
used
in
suspension
containing 10 mg. per co. in a dispersing
This compound is not described in the literature.
solution. They were injected in this form by subcutaneous
The 20-bis~(hydroxy-methyl)-5a-pregnanes of the in
method in groups of 10 mice in doses of 50 and 100 mg./
vention can be used orally in the form of tablets or par
kg. respectively. The animals were held under observation
enterally by intramuscular injection in the form of aque 60 for one week. No symptoms of intoxication and mortal
ous or oily suspensions, or even by venous methods in the
form of a solution in an adequate excipient and also by
rectal method. They can be made in the form of injectable
solutions, injectable suspensions, put up in ampules or in
?asks, in tablets and in suppositories.
EXAMPLES OF PHARMACEUTICAL COMPOSITIONS
Tablets Containing 0.5 Mg.
In an appropriate mixer, there was introduced succes
ity, were noted in the course of this period.
204bis(nitratomethyl) - 50c — pregnane - 3t? — 01
was
non
toxic in a dosage of 50 mg./ kg. while 20-bis(nitrato
methyl)~5a-pregnai1e-3-one was non-toxic at a dosage of
65 100 mg./kg.
While the compounds of the invention are useful in the
treatment of angina of the chest and of the coronaritis,
they also possess a-peripheral vasodilatory action and anti_
spasmodic activity and are therefore useful in treating
70 asthma, bronchial spasms and arterial spasms.
Various modi?cations of the process and the products
of the invention may be made Without departing from
poured an aqueous solution of gelatine in a quantity nec
the scope or spirit thereof, and it is to be understood that
essary and suf?cient to obtain a mixture capable of being
the invention be limited only asde?ned in the appended
granulated through a perforated metal die.
75 claims.
sively the active compound, white sugar, potato starch
and lactose. On the homogenized mixture, there was
3,052,675
.
12
11
pregnane-3 13-01, reacting the said product with a compound
We claim:
selected from the group consisting of
-1. A compound having the formula
o
CH3 OHgOAc
‘Hg-1R2
(\U‘BQM...
.3
and
0:0
1O
wherein R1 is selected from the group consisting of =0
and
\Ra
to form the corresponding alkylidene of 20-bis-(hydroxy
methyl)-15a-pregnane-3B-ol and recovering the latter.
13. The process of claim 12 wherein the lower alkoxy
methyl magnesium halide is methoxy methyl magnesium
15 bromide.
14. The process of claim 12 wherein the simultaneous
condensation and saponi?cation is eiTected with formalde
and Ac is selected from the group consisting of hydrogen,
hyde in the presence of methanolic potassium hydroxide.
an acyl radical of an organic carboxylic acid having 1 to
1-8 carbon atoms and an anion of a mineral acid.
'15. The process of claim 12 wherein 20-bis~r(hydroxy
methyl)-5a-pregnane-3/3-ol is reacted with acetone in the
presence of perchloric acid to form the acetonide of 20
bis- (hydIoXy-methyl ) -5 et-pregnene-B ?-ol.
,
16. A process for the preparation of a compound hav
. 20-lbis-(nitratomethyl)-5o¢-pregnane-3?-ol.
3,8-acetoxy - 20 - bis-(nitratomethyl)-5a-pregnane.
. 3,8-acetoxy - 20 - bis-.(hydroXy-methyl)-5a-pregnane.
ing the formula
. 20-bis-(hydroxy-methyD-Sa-pregnane-35-ol.
. 20-bis-(hydroXy-methyl)-5a-pregnane-3-one.
25
. .20Jbis~,(nitratomethy1) -5a~pregnane-3-one.
. A compound having the formula
CH3 01120
R:
30
wherein Ac is selected from the group consisting of hy
35 drogen, an acyl radical of an organic carboxylic acid hav
ing 1 to 18 carbon atoms and an anion of a mineral acid
H
which comprises oxidizing a compound having the
formula
wherein R1 is selected from the group consisting of
CH; CHzO
40
B2
\C/
and :0 and Ac is selected from the groups consisting of
hydrogen, an acyl radical of an organic carboxylic acid
having 1 to 18 carbon atoms and an anion of a mineral 45
acid and R2 and R3 are selected from the group consisting
of hydrogen, phenyl, phenyl substituted lower alkyl and
lower alkyl.
9. The acetonide of ZO-bis-(hydroxy-methyl)-5oc-preg
nane-3?-ol.
HO
i
H
wherein R2 and R3 are selected from the group consisting
50 of hydrogen, phenyl, phenyl substituted lower alkyl and
lower alkyl to form a compound having the formula
10. The acetonide of 3?-acetoxy - 20 - bis-(hydroxy
methyl) -5a-prcgnane.
11. The acetonide of 204bis4(hydroxy—methyl)dot-preg
nane-3-one.
12. A process for the preparation of a compound hav
(EH/301120
55
I
R2
01520 \Ra
ing the formula
.0
l
60
H
wherein R2 and R3 have the above de?nitions, hydrolyzing
the latter under acidic conditions .to form ZO-bis-(hydroxy
methyl)-5o¢-pregnane-3-one and recovering the desired
HO
compound.
65
17. A process for the preparation of a compound
having the formula
wherein R2 and R3 are selected from the group consisting
of hydrogen, phenyl, phenyl substituted lower alkyl and
lower alkyl which comprises reacting 3 ?-acyloxy-S a-preg
nane-20-one with a lower alkoxy methyl magnesium halide 70
to form 3B-acyloxy-20-lower alkoxy-methyl-Six-pregnane
CH3 ,OHgOAc
/\
1 J3
20-01, dehydrating the latter with phosphorous oxychloride
to form 3?-acyloxy - 2O - formyl-Sa-pregnane, simultane
ou'sly condensing the said compound with formaldehyde
and saponifying to form ZO-bis-(hydroxy-methyl) -5a 75
A00
m_ _
('1 /
3,052,675
13
wherein Ac is selected from the group consisting of hy
drogen, an acyl radical of an organic carboxylic acid hav
ing 1 to 18 carbon atoms and an anion of a mineral acid
which comprises reacting a compound having the formula
CH3 CHZO
R2
14
wherein R is an acyl radical of an organic carboxylic
acid having 1 to 18 carbon atoms and R2 and R3 have the
above de?nitions, hydrolyzing the latter to form 3?-acyl
oxy-ZO-bis-(hydroxy-methyl)-5a-pregnane and recovering
the desired compound.
r18. The process of claim 17 wherein the ?rst acylating
agent is acetic acid anhydride.
19. A process for the preparation of 20-bis-(nitrato
methyD-Sa-Pregnane-I’a?-OI which comprises reacting the
acetonide of ZO-bis-(hydroxy-methyl)-5a—pregnane-3?-ol
10 with acetic acid anhydride to form the acetonide of 3p
HO
acetoxy-ZO-bis-(hydroXy-methyl)-5a-pregnane, hydrolyz
ing the latter with aqueous acetic acid to form 3B-acetoxy
i
H
ZO-bis-(hydroxy-methyl)-5a-pregnane, reacting the said
wherein R2 and R3 are selected from the group consisting 15 product with fuming nitric acid to form 3/3-acetoxy-20
bis-(nitratomethyl)-5a-pregnane, saponifying the said
of hydrogen, phenyl, phenyl substituted lower alkyl and
lower alkyl with an acylating agent of an organic car
boxylic acid having 1 to 18 carbon atoms to form a com
pound having the ‘formula
product to form ZO-bis-(nitratomethyl)~5a-pregnane-3/3
01 and recovering the latter.
20. A process for the preparation of ZO-bis-(nitrato
methYD-Sa-pregnane-B-One which comprises oxidizing the
CH3 CHZO
R:
acetonide of 20-bis-(hydroXy-methyl)-5a-pregnane-3f3-ol
with chromic acid to form the acetonide of 20-bis-(hy
droXy-methyl)-5a-pregnane-3-one, hydrolyzing the latter
with aqueous acetic acid to form 20—bis-(hydroXy-methy1)
Sa-pregnane-S-Dne, reacting said product with fuming
25 nitric acid to form ZO-bis-(nitratomethyl)-5a-pregnane-3
H
one and recovering the latter.
No references cited.
Документ
Категория
Без категории
Просмотров
0
Размер файла
831 Кб
Теги
1/--страниц
Пожаловаться на содержимое документа