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Патент USA US3087952

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United States Patent 0 " 1C6
3,087,942
Patented Apr. 30, 1963
1
2
3,087,942
The novel compounds of this invention conform to
the following structural generic formula:
PREPARATION OF ANABOLIC AGENTS
Klaus Briickner, Klaus Irmscher, and Josef Gillissen,
Darmstarlt, Germany, assignors to E. Merck Aktienge
sellschaft, Darmstadt, Germany
No Drawing. Filed Oct. 25, 1961, Ser. No. 147,469
Claims priority, application Germany Oct. 29, 1960
4 Claims. (Cl. 260—397.4)
This invention relates to the preparation of novel
steroid compounds having a high anabolic activity and 10
a low androgenic activity.
_
An anabolic agent, sometimes called a myotrephic
wherein R is selected from the group consisting of:
CH3—CO-S— and hydrogen, and wherein at least one
R represents -CH3—CO--S—; and wherein X is selected
agent, promotes storage of protein and generally stimu
lates tissues.
These agents are useful for the treatment
of persons debilitated by various metabolic and endocrine 15 from the ‘group consisting of: 1H,H and methylene.
disorders. Unfortunately, though, anabolicagents usu
As typical examples of the novel steroids of this inven
ally also exhibit a signi?cant androgenic effect, and, there
tion, there are included:
fore, debilitated females cannot be treated with these
7 u-acetylthiod 7 a-methyl-testosterone
anabolic agents without the danger of imparting mascu
20 la-acetylthio-l7a-methyl-testosterone
line characteristics to the females.
'1a,7u-di-acetylthio- li7a-methyl-testosterone
A classical example of an anabolic agent having an
7a-acetylthio-l6-methylene~l7a-methyl-testosterone
excessive androgenic activity is the compound testos
-l a- acetylthio- l~6 -methylene~l 7a-methyl-testo sterone
terone.
1a,7a-di-acetylthio-lo-methylene-17a-methyl-testosterone
A great deal of effort has been expended to upgrade
25
the anabolic-androgenic activity of testosterone, but usu
To demonstrate the improved anabolic-androgenic
ally with no outstanding success. For example, in a
ratios of the compound of this invention, reference is
paper by R. M. Dodson and Robert C. Tweit, in the
made to the following table, wherein the anabolic-andro
Journal of the American Chemical Society, volume ‘81,
genic ratios of the 7a- and lloc-acetylthio substitution prod
pages 12-24 (1959‘), there is reported a modi?cation of
nets are compared to the same compound devoid of the
30
testosterone by the introduction of a 7- as well as a 1
acetylthio groups:
acetylthio group into both testosterone, the li7-ester there
of, and 4-androstene-3,l7-dione. These 7- and l-acetyl
'
thio derivatives were tested and the results indicated a
Oompound
Ratio of ana
bolic/andro
genie activity
decrease in both the androgenic and anabolic activities
of these. steroids.
In contrast to these results, it is to
be appreciated that modi?ed testosterones are sought
which exhibit a decreased androgenic activity, but simul
methyl-testosterone _______________________________ __
1
7a-acetylthio:lhmethyl-testosterone _________________ .c
3. 71
1a,7a-di-acety1thio-17a-methyl-test0sterone ___________ _.
4. 55
taneously either maintaining or increasing the anabolic
la-acetylthi0;16-methylene-lM-methyl-testosterone_____
4. 14
la-acetylthioLl7a-methyl-testosterone _______________ __
1. 86
activity.
The object of this invention, therefore, is to provide
new steroid compounds having a high anabolic activity
and a low androgenic activity.
40
The anabolic-androgenic ratios thus obtained are com
pared to the well known anabolic compound methyl
testosterone, the ratio of which is l.
The trials were
Upon further study of the speci?cation and appended
conducted according to the commonly used method of
claims, other advantages and objects of the present in 45 Hershberger et al. described in proceedings of the Society
vention will become apparent.
for Experimental Biology and Medicine, vol. 83, page
To attain the objects of this invention, it has been un
expectedly discovered that by the incorporation of an
v1-75 (1953), the dose being 1 or ill) mg. per animal.
The novel compounds of this invention are particularly
e?‘icacious anabolic agents which can be administered
acetylthio group in the 70:. or lot positions, or both, in
17a-methyl-testosterones, there are obtained steroids which 50 perorally, preferably in 5 mg. doses. These drugs may
exhibit a high anabolic effect and a low androgenic effect.
be manufactured in the form of tablets, pills, dragees,
These novel derivatives, capable of oral administration,
solutions or emulsions with the aid of the usual phar
exhibit an increased anabolic effect and a substantially
maceutical auxiliary agents and excipients. The preferred
reduced androgenic effect, as compared to the unsub
concentration of the solutions is 1 mg./cc.
stituted 17a-methyl-testosterone.
55
The novel compounds of this invention can be pro
These excellent physiological properties of the new
derivatives are quite surprising in view of the aforemen
tioned Dodson and Tweit paper which teaches that the
duced by conventional methods from 17a-methyl-testos
terone derivatives which are unsaturated in the .1,2.
and/ or the 6,7-positions. These aforesaid raw materials
are reacted with thioacetic acid under conventional con
introduction of a 7- and l-acetylthio group into testoster
one and the l7-esters thereof, result in a decrease in the 60 ditions.
anabolic effect of the parent compound. This inven
tion, on the other hand, teaches that there is an in
crease in the anabolic effect when the 7:1- and lot-acetyl
thio groups are introduced into the 17a-methyl-testoster
ones.
Furthermore, it was discovered that upon the intro
duction of the 70c- and lot-acetylthio groups to the 16
methylene derivatives of l7-u~methyl-testosterones an even
further reduction in the androgenic effect is obtained,
while the anabolic effect is maintained constant, as com
Preferably it is advantageous to conduct the
reaction in contact with ultra-violet radiation, and in the
presence of an inert solvent, such as benzene, dioxane,
toluene, carbon tetrachloride, etc.
It is to be appreciated that the foregoing brief descrip
65 tion of the method of producing the novel steroids of
this invention is adequate to teach a steroid chemist
skilled in the art how to produce the novel compounds
of this invention.
The following examples, therefore, are merely preferred
70 speci?c embodiments of this invention, and are not in
pared to the corresponding substitution product which
tended to be limitative of the speci?cation and appended
does not have a 16-methylene group.
claims.
8,087,942
3
4
Example 1
further recrystallization at 157—160° C.; (ocD+30° C.
(dioxane); Amax240 ma,
El'?’m, 450
Example 5
According to Example 1, the 7a-acetylthio-16-methyl
ene-l7a-methyl-testosterone is produced from 6-dehydro
7 g. 6-dehydro-»17a-methyl-testosterone are heated in
20 ml. thioacetic acid on a steam bath for 1.5 hours. The
thioacetic acid is thereafter extracted by vacuum and
the residue is crystallized from methanol. The 7 a-acetyl
thio --17a - methyl - testosterone melts at 162-163 ° C.;
Amax'238 ml‘,
16-methylene-17a-methyl-testosterone.
Eli’... 500; (a)n—-69.3° C.
Example 2
Melting point
147—149° C.; Amax 238 mp,
10
El'?'m 500; (a)n—149.3° (dioxane)
Example 6
4 g. 17a-methyl-1,4,6-androstatriene-ll7?-ol-3-one are
According to Example 2, the 1a,7a-di-acetylthio-l6
boiled in 12 ml. thioacetic acid under re?ux for 11/:
methylene-17a-methyl-testosterone is produced from tl6~
hours. This reaction mixture is thereafter concentrated 15 methylene-17a-methyl-1,4,6-androstatriene-3-one-175 - ol.
in vacuum to dryness and the 1a,7a-di-acetylthio-17a
Melting point 1‘94-196° C.; Amax238 ma,
Elli... 421
methyl-testosterone is crystallized from the residue after
treatment with methanol; melting point 202-204" C.;
(u)D—74.6° C. (dioxane); 7\max237.5 ma,
Ell’... 449
From the foregoing description, one skilled in the art
20 can readily appreciate the essential characteristics of this
invention, and without departing from the spirit and scope
of these essential characteristics, one can modify and
adapt this invention into varying usages and conditions.
Example 3
Consequently, such modi?cations and adaptations should,
2.9 g. l-dehydro-l7a-methyl-testosterone are dissolved
in 10 ml. thioacetic acid and are boiled under re?ux 25 and are intended to be, within the full range of equivalents
of the following claims.
for 1.5 hours. The reaction composition is thereafter
concentrated in vacuum and the residue is crystallized
What we claim is:
1. la,~7a-di-acetylthio-17a-methyl-testosterone.
from ether. The obtained 1a-acetylthioa17a-methyl
2.
7a-acetylthio-1=6-methylene-l7a-methyl-testosterone.
testosterone melts at 160a161° C.; (a)D+98° (Chlf.); 30
3. la-acetylthio-l6-methylene-17a-methyl-testosterone.
Amax240 ml",
4. 1a,7a-di-acetylthio-16-methylene-1‘7a~methyl-testos
Ell’... 426
terone.
References Cited in the ?le of this patent
Example 4
13.25 g. 1-dehydro-16-methy1ene-17a - methyl-testoster
35
one are boiled in 15 ml. thioacetic acid under reflux for
1%, hours. The solution is thereafter concentrated in
vacuum, the residue is crystallized from ether/petroleum
ether, and the l-acetylthio-16-methylene-17a-methyl-tes 40
tosterone is puri?ed by recrystallization from ether. The
melting point is 154~155° C. The product melts after
UNITED STATES PATENTS
2,859,222
Dodson et al ___________ __ Nov. 4, 1958
2,875,215
2,929,763
Dodson et a1 __________ .._ Feb. 24, 1959
Wettstein et a1 _________ __ Mar. 22, 1960
OTHER REFERENCES
Iriarte et al.: 81 J.A.C.S. 436-438 (1959).
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