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Патент USA US3079391

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Uite dtates Patent O?ice
Patented Feb. 2%, 1963
i
3,67%331
éd?-AMENG ANDRGSTANES
Albert Bowers, Mexico City, Mexico, nsstgnor, by mesne
gssl?nments,
to Syntax {Ionic-ration, a corporation of
a
a
on
h
No Drawing. Filed Nov. It), 1969, Ser. No. 63,373
29 Claims. (Q3. 256-4395)
The present invention relates to novel cyclopentano
phenanthrene compounds and to a process for the prep
10
aration thereof.
More particularly the present invention relates to C-6,
A00
l9-arnine derivatives of the androstane series and more
speci?cally to C-6,l9-amine derivatives of and-rostane-ZB,
l7?-diol and of 176t-lO‘W61‘ alkyl-androstane-3?d7,8-diol
and to esters thereof with hydrocarbon carboxylic acids
of less than 12 carbon atoms.
The novel compounds of the present invention which
exhibit high anabolic activity with low androgenicity and
which are hypotensive agents in additions to having fungi
static properties and lowering the cholesterol level are
i i e
lllH
N-Cl
5H:
15
l
He
on’
/\
CH2-——I
2D
on
L__R
/\
N
represented by the following formula:
I “R
I "R
CHzCyl
><CH3
l /
a_____
I
25 'R O
_
i\/
A
00
_
i I
VII
BITE
CH3
CH;
VIII: R=hydroge
30
In the above formula R represents hydrogen or a lower
alkyl group and R’ represents hydrogen or the acyl group
of a hydrocarbon carboxylic acid of less than 12 carbon
‘atoms which may be saturated, unsaturated, of straight,
branched, cyclic or cyclic-aliphatic chain, aromatic and
VIIIa: R=iower alkyl
In the above equation R and R’ have the same meaning
as previously set forth; Ac represents the acetyl radical
but other acyl radicals of hydrocarbon carboxylic acids of
_ less than 12 carbon atoms of the type previously men~
a tioned may be employed.
may be substituted by functional groups such as hydroxyl,
alkoxy of up to 5 carbon atoms, acyloxy of up to 8 carbon
in practicing the process outlined above, the starting
compound, androstane-E?,l7?-di0l-6-one diacetate (i) or
atoms, aniino, nitro or halogen.
the Not-lower alkyl derivative thereof is prepared by re
Typical ester groups are
the acetate, propionate, bu tyrate, enanthate, benzoate,
trimethylacetate, t-butylacetate, phenoxyacetate, cyclo
pentylpropionate, aniinoacetate and ,B-chloropropionate.
The novel compounds of the present invention may be
repared by a process illustrated by the following
equation:
(‘3A0
Ione
to
Nil
40 acting o5-androstene-3t3,i7?-diol diacetate or Not-lower
alltyl-M-androstene-3,8,l'i?-diol diacetate in dioxane solu
tion containing a catalytic amount of perchloric acid with
N-brornoacetamide to form 5<x~bronio-androstane-35,65,
i7/3-triol-3,l7-diacctate or. the 17CL-lOVlSI' alkyl derivative
thereof, which upon oxidation With chromatic acid in
acetone solution is converted into the corresponding 6
keto derivative. Reductivc debrornination of the latter
derivative as by treatment with zinc and acetic acid affords
the diacetate of androstane-3B,17/3-diol-6-one or of 17a
lower alkyl-androstane-3?,l7?-diol-6-one (I).
Upon re?uxing the latter ketone with hydroxylarnine in
pyridine solution, there is formed the C-6 oxime (H)
MO. ’\5
/I
a AC0
which upon hydrogenation in the presence of a platinum
oxide catalyst is converted into the 6-amino derivative
55 (III). The latter is then reacted with ethyl formate un
der anhydrous conditions to altord the (3-6 formarnide
:\) II
(Ii
~ IHIOH
(IV) Which upon reduction with lithium aluminum hy
([DAo
l
I so
/
$.00;
' not
€_ AGO—
:
IV
BITE
5H0
l
I()Ac
!
:
III
NH:
dride affords the free C-6-N-methylainino-3B-ol corn
pound. Preferential esteri?cation or" the 3~hydroxy group‘
so is effected With acetic anhydride in pyridine and there is
thus formed the 3?-acetoxy-C-G-N-methylarnino com
pound (V) which upon subsequent treatment with N
chlorosuccinirnide is converted into the (l-o-N-ch‘loro-N
methylamine (VI). Upon subjecting a sulfuric acid solu
tion of the latter compound to ultra-violet light, there is
formed the l9-chloro~6-N~1nethylarnino compound (Vii)
which is treated with dilute methanolic potassium hy
droxide solution ‘for a period of time in the order of 60
hours to form the novel C-6,19-aniino-androstane-3?,17,6‘
7 (3 diol (VH1: R'=hydrogen) or the l7a-alky1 derivative
(Villa: R'=hydrogen). Upon conventional esteri?ca
tion with a hydrocarbon carboxylic acid anhydride of less
3,079,381
4
3
with water to neutral, thus yielding 6.5 g. of Git-amino
than 12 ‘carbon atoms, there is formed the 3/3-monoesters
3B,17t3-diacetoxy-androstane.
of VIII and Villa and also the 3,B,l7[3-diesters of VIII.
Esteri?cation of a tertiary hydroxyl group at C-17I8 is
Example V
effected by reaction with a hydrocarbon carboxylic acid
5.7
g.
of
6-amino-3p‘,17lB-diacetoxy-androstane
was re
anhydride in benzene solution in the presence of p-toluene UK
?uxed under anhydrous conditions with 120 cc. of anhy
sulfonic acid.
drous ethyl formate, evaporated to dryness under vacuum
The following examples serve to illustrate but are not
and the residue crystallized from acetone-hexane to a?ord
intended to limit the scope of the invention:
35,175 - diacetoxy - androstane-6?-N-formylamine;
Example I
10
A suspension of 10 g. of the diacetate of As-androstene
M.P.
235-238" C.;Eoz]D -62(CHCl3).
Example VI
35,17?-diol in 100 cc. of dioxane was treated with 12 cc.
A solution of 4 g. of the above compound in 120 cc. of
of 0.46 N perchloric acid and then with 4 g. of N-brorno
anhydrous tetrahydrofuran was added dropwise to a sus
acetamide; the N-bromoacetamide was added little by
little, with stirring, in the course of one hour, in the dark 15 pension of 4 g. of lithium aluminum hydride in 200 cc.
of anhydrous tetrahydrofuran and the mixture was re
and maintaining the temperature around 15°. The mix
?uxed for 1 hour with stirring. Acetone was added cau
ture was stirred for 1 hour further in the dark at room
tiously to decompose the excessof hydride, then saturated
temperature; it was then decolorized by the addition of
aqueous sodium sulfate solution and ?nally solid anhy
10% aqueous sodium bisul?te solution, 1 liter of water
was added and the product was extracted with methylene 20 drous sodium sulfate were added. The solid was ?ltered
and washed well with hot ethyl acetate, and the ?ltrate
chloride; the extract was washed with water, dried over
and washings were evaporated to dryness under reduced
anhydrous sodium sulfate and the solvent was evaporated
pressure. The residue was dissolved in 15 cc. of pyridinev
under reduced pressure at room temperature. The resi
and 1.1 equivalents (1 cc.) of acetic anhydride, kept at
due was crystallized from acetone-hexane to afford 3,17_
diacetate, of 5a-bromo-androstaneé???,l7g3-triol; M.P. 25 10” for 16 hours, poured into water, heated for an addi
tional half an hour, and the formed precipitate collected
172-174“; [s15 —44‘’; yield 77%.
by ?ltration. Crystallization from acetone-hexane gave
There was prepared 100 cc. of an 8 N solution of
the 646 - N-methylamino-androstane-3B,17B-diol-3-acetate
chrornic acid from 26.7 g. of chromium trioxide, 23 cc.
compound.
of concentrated sulfuric acid and distilled water. A solu
Example VII
tion of 10 g. of the 3,17-diacetate of SOC-bI'OHlO-Zllldl'O 30
A stir-red solution of 1 g. of the above methylamino
stane-3?,6e,l7?-triol in 100 cc. of acetone was cooled to
0° C. and treated with the 8 N solution of chromic acid
compound in 500 cc. of methylene chloride was treated
until the characteristic color of chromium trioxide per
with 1 g. of N-chlorosuccinimide and the mixture was
sisted in the mixture. The 8 N solution of chromic acid
stirred for 15 minutes further. The solution was then
was. added in a slow stream, under an atmosphere of nitro 35 washed with water, dried and evaporated to dryness at low
gen, with stirring and at 0° C. The mixture was then
temperature. Recrystallization from acetone gave 6?-N
stirred at 0° C. under an atmosphere of nitrogen for 2
chloro - N-methylamino-androstane-il?,17,8-diol-3-acetate
minutes further, poured into ice water and the precipitate
was collected by ?ltration, washed with water and dried
under vacuum, thus affording the diacetate of Soc-bl‘OmO
androstane - 3133,1713 - diol-6-one.
A sample crystallized
from acetone-hexane had M.P. 188—l91°; [ed]; »~l68°.
A mixture of the above compound, 10 g. of zinc dust
and 250 cc. of glacial acetic acid was refluxed for 2 hours,
plus recovered starting material.
Example VIII
A solution of 1 g. of the chloromethylamino compound
(Example VII) in 15 cc. of 90% sulfuric acid was irra
diated for 24 hours with a sun lamp; water was added and
the resulting precipitate ?ltered to afford 6,8-N-methyl
at the end of which it was ?ltered through celite under an 45 amino-l9-chloro-methyl-androstatue-313,1713-diol 3-acetatc.
atmosphere of nitrogen and the ?ltrate was concentrated
to a smallvolume under reduced pressure; after cooling
it was diluted with ice water and the precipitate ‘of the
diacetate of androstane-3?,17B-diol-6-one was collected by
?ltration, washed with water and dried.
Example II
By substituting in the procedure of Example I the di
acet-ate of A5-androstene-3/3J7/8-diol by the diacetate of
17u-ethyl-A5-androsterm-3,8,17,8-diol, there was produced
the diacetate of 17<x—ethyl-androstane-3?,17?-diol-6-one.
Example III
A solution of 15 g. of an-drostane-3;3,1718-diol;6-one di
acetate in 45 cc. of anhydrous pyridine was treated with
15 g. of hydroxylamine hydrochloride previously dis
solved in 90 cc. of water.
The mixture was re?uxed for
18 hours; it was then poured into ice water, the formed
precipitate was collected by ?ltration, washed with water
and dried. Recrystallization from methanol afforded the
oxime of 3,8,17l3-diacetoxy-androstan-6-one; M.P. 253
255° C. (9.2 g.) and a second crop, M.P. 245—248° C.
Example IX
500 mg. of the ?nal product produced in Example VIII
were dissolved in 10 cc. of 1% methanolic potassium hy
droxide and the mixture was kept :at room temperature for
60 hours. After dilution with water and ?ltration of the
product, there were obtained 380 mg. of 6,l9—N-methyl
' amino-androstane-3B,17,6-diol.
Example X
:By applying the procedure described in Examples III
through 1X to the diacetate of 17a-ethyl-androstane
35,17/3-diol-6-0ne prepared in Example 11, there were
produced all of the compounds described in such ex
amples having an ethyl group at C-17a.
Example XI
A mixture of 500 mg. of 6,19-N-methylamino-andro
stane-3;8,17B-diol, 5 cc. of pyridine and 5 cc. of acetic
anhydride was kept at room temperature overnight,
poured into ice water and the solid collected by ?ltration,
washed with water and dried. There was thus obtained
6, 19~N-methylamino-androstane-3B, l7l3-diol diacetate.
Example XII
A solution of 13.3 g. of the above oxime in 200 cc. of 70
By
following
the
method
of the preceding example, but
acetic acid was hydrogenated under pressure (50 pounds)
using propionic, caproic and cyclopentylpropionic an
overnight using 1.9 g. of platinum oxide as a catalyst.
(2.9 g.).
Example IV
After ?ltration of the catalyst, the solvent was evaporated
to dryness under vacuum and the residue triturated with
saturated sodium bicarbonate solution, ?ltered and washed
hydride as esterifying agents, there were obtained the
dipropionate, dicaproate and dicyclopentylpropionate o?
6, l9-N-methylamino-androstane-3)8,175-diol.
3,079,381
5
6
Example XIII
than 12 carbon atoms of 65,19-N-methylamino-andro
stane-3,8,l7;8-diol.
Examples XI and XII were repeated, but using 170:
5. 613,19~N-methylamino-androstane-3,B,17?-dio1 diace~
ethyl-6,19 - N-methylamino-androstane - 35,175-diol as
starting material, there were thus produced 17u-ethyl
tate.
6,1Q-N-methylamino-androstane-3?,17/3-dio1 3-acetate and
the corresponding 3-propionate, B-caproate and 3-cyclo
propionate.
6. 618,19-N-methylamino - androstane - 35,17p-dio1 di
pentylpropionate.
-
7. The G3 hydrocarbon carboxylic acid esters of less
than 12 carbon atoms of 6,8,19-N-methylamino-17a-1ower
Example XIV
A solution of 200 mg. of 17a-ethyl-6,19-N-methyl
amino-androstan-I'a?l7,9-diol 3-acetate in 12 cc. of ben
10
zene was treated with 0.5 cc. of propionic anhydride and
alkyl androstane-3B,1713-diol.
8. The hydrocarbon carboxylic acid diesters of less
than 12 carbon atoms of 6/3,19-N-methylamino-l7a-lower
alkyl-androstane-3,8,1718-dio1.
100 mg. of p-toluenesulfonic acid; the mixture was kept
at room temperature for 48 hours, washed well with
water; sodium carbonate solution and water to neutral,
dried over anhydrous sulfate and evaporated to dryness.
Crystallization from acetone-hexane gave the 3-acetate,
‘9. 17a-ethyl-6?,19 - N-methylamino - androstane - 3B,
17,8-diol 3-acetate.
'
10. 17a-ethyl-6?,19 - N~rnethylamino-androstane ~ 3/3,
17?-diol-3-caproate.
.111. 17u-ethyl-6/3,19-N-methylamino - androstane - 3B,
17-propionate of 17a-ethyl-6,19-N-methylarnino-andro
17,6-diol-3-acetate-17-propionate.
start-35,17B-diol.
12. 17m-ethyl-6?,1Q-N-methylamino - androstane - 318,
Example XV
20 l7/8-diol-diacetate.
By applying the method of the preceding example, but
13. 17u-ethyl-6?,19-N-methylamino - androstane - 3,8,
17B-diol-3-caproate-17-acetate.
using acetic anhydride instead of propionic anhydride,
17a~ethyl-6,19-N ~ methylamino-androstane - 313,17?-diol
14. The hydrocarbon carboxylic acid esters of less
B-acetate and the corresponding 3-caproate were con
than 12 carbon atoms of 6B-N~formylamino-androstane
verted respectively into 17u-ethyl-6,l9-N-methylamino
3;8,17?-di0l.
androstan - 3,8,17,8-dio1- diacetate and 17a-ethyl-6,19-N
methylamino _ androstane-Bp,17?-diol-3-caproate 17~ace~
15. o?-N-formylamino - androstane-3,B,l7;9-diol diace
tate.
tate.
I claim:
16. The C-3 hydrocarbon carboxylic acid esters of less
than 12 carbon atoms of 6;.3-N-methylamino-androstane
1. A compound of the following formula:
3/3,17/3-dio1.
17. 6/3-N~methylamino-androstane - 3?,17?-diol 3-a-ce
OR’
pogo
tate.
~
‘
. 18. The G3 hydrocarbon carboxylic acid esters of less
35
than 12 carbon atoms of 6B-N-chloro-N-methylamino
androstane-3?,17}8-diol.
19. 6/3-N-ch1oro - N-methylamino-androstane - 3,8,17,8
diol 3-acetate.
20. In the process of producing a 6/3,19-N~methyl
40
amino-androstane-3?,17p3-diol the steps comprising react
ing a 6-amino androstane-3,8,17B- diacylate with ethyl
formate, reducing the thus formed C-6 ?ormamide with
lithium aluminum hydride to form 6-N-methylamino
wherein R is selected from the group consisting of hydro
gen and lower alkyl and R’ is selected from the group
androstane-3/3,17?-dio1, esterifying the latter compound
consisting o? hydrogen and a hydrocarbon carboxylic
and thereafter treating with a chlorinating agent N-chlo
acyl group of less than 12 carbon atoms.
45
rosuccinimide and then irradiating the thus formed 6/3
2. 6B,l9-N-methylamino-androstane-343,1713-diol.
3. 613,19-N-methylamino-17a-ethyl- androstane-3?,l7?
diol.
4. The hydrocarbon carboxylic acid diesters of less
N - chloro - N - methylamino - androstane derivative with
ultra-violet light.
No references cited.
UNITED STATES PATENT OFFICE
CERTIFICATE OF CORRECTION
Patent No. 3,079,381
February 26v 1963
Albert Bowers
It is hereby certified that error appears in the above numbered pat
ent requiring correction and that the said Letters Patent should read as
corrected below.
Column 1, lines 23 to 31, the formula should appear as
shown below instead of as in the patent:
column 2, lines 16 to 301 the left-hand side formula should
appear as shown below instead of as in the patent:
OR’
VIII : Ithydrogen
Villa: R:lower alkyl
Signed and sealed this 22nd day of October 1963°
“(Si-EAL)
Ajtieiti
:iRhEbT W~ SWIDER
Attesting Officer
EDWIN LI REYNOLDS
Ac'tiz'zg Commissioner of
Patents
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