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Патент USA US3100214

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3,100,209
,
United States Patent 0 ' 1C6
Patented Aug. 6, 1963
2
1
ble thus making them particularly valuable as drugs via
both the oral and parenteral routes.
Of the novel compounds encompassed Iby the general
3,100,209
3-AlVIIN 0-1,3,5(10)-ESTRATRIENE-DERIVATIVES
AND PROCESS FOR THEIR MANUFACTURE
Erwin Schwenk, Shrews'nury, Mass, and Allen M. Gold,
New York, N.Y., assignors to The Worcester Founda
tion for Experimental Biology, Shrewsbury, Mass, a
corporation of Massachusetts
No Drawing. Filed Apr. 27, 1960, Ser. No. 24,915
19 Claims. (Cl. 260-3973)
formula, the preferred group are those wherein at least
one of R1 and R2 are acetyl. The novel 3-arninoestra
trienes while being therapeutically active are also use
ful as intermediates in preparing the preferred 3-(N-acyl
amino)- and 3-(N,N—diacylarnino)-estratrienes.
Our novel S-amin-oestratrienes may be prepared either
10 through the rearrangement of an oxime of a 3-keto-A4
19-nor steroid such as l9-nortestosterone or through the
reaction of a IO-quinol acetate such as lOE-acetoxy-IA
This invention relates to novel, therapeutically active
amino steroids and derivatives thereof and to methods
estradiene-3,17-dione with benzylamine. In the former
for their preparation. More speci?cally, our invention
process, 194nortestosterone, for example, is converted to
relates to aminoestratrienes and, in particular, to 3-amino
l,3,5(10)-estratrienes which possess an oxygen function 15 19-nortestosterone oxime according to known procedures
utilizing hydoxylamine hydrochloride. The 19-nortes
at C-17, and to the derivatives thereof.
tosterone oxime intermediate is then converted to a 3
amino-ar-omatic A-ring steroid of our invention by re
The novel aminoestratrienes of our invention are repre
sented by ‘the following formula; and include their salts
with acids:
action at elevated temperatures (usually at re?ux) with
20 a lower alkanoic acid anhydride such as acetic anhydride
to give S-(N-acetylamino) -1,3,5 ( 10) -estratriene-17B-ol
CH3
17-acetate, a novel compound of our invention. By sub
jecting the 3-(N-acetylamino)-estratriene thus obtained
to strong acid hydrolysis such as that utilizing sulfuric
25 acid followed [by neutralization of the amine acid salt
thereby formed, there is obtained 3-amino-l,3,5(10)-estra
triene-17B-ol.
When other lower alkanoic acid anhydrides such as
propionic or butyric anhydrides are substituted for acetic
111-1?R:
anhydride in the aforementioned procedure, 19-nortes
tosterone oxime is converted to the corresponding 3-(N
(I)
acylamino) - estratriene, i.e. 3 - (N - propionylamino)
wherein X is a member of the group consisting of O, 35
(H, 1802), (or-methyl, ?OZ), and (a-ethinyl, BOZ)
wherein Z is a menrber of the ‘group consisting of H
and acyl; and R1 and R2 may be the same or di?erent
and are members of the group consisting of H, lower
1,3,5(10) - estratriene - 17/8 - 01 17 - propionate and 3
(N -. butyrylamino) - 1,3,5(l0) - estratriene - 17B - 01 17
butyrate, respectively.
According to our process, the 3-oxime of any 3-keto
A4-19-nor steroid may similarly be boiled with a lower
alkanoic acid anhydride and there will be obtained the
corresponding 3 - (N-acylamino) - 1,3,5(10) - tridehydro
alkyl, benzyl or acyl.
40 steroid. For example, l9-norethisterone (l7u-ethinyl
By the term acyl is contemplated acid radicals of hy
l9~nor-4-androstene-l7?-ol-3-one) when reacted with hy
drocarbon carboxylic acids preferably having up to eight
droxylamine hydrochloride gives 19-norethisterone oxime
carbon atoms. Included in this group are aromatic acids
which upon reaction with acetic .anhydride according to
exempli?ed by benzoic acid or alkyl substituted benzoic
our process yields a novel compound of our invention, 3
acids and, preferably, lower alkanoic acids such as formic, 45 (N-acetylamino) -17a-ethiny1-1,3,5( l0)-estratriene - 17B
acetic, phenylacetic, propionic, t-butylacetic, valeric, ca
ol 17-acetate. Similarly, 17a—etl1yl-l9-nortestosterone is
proie and the like.
converted to l7a-ethy1-19~nortestosterone oxime which is
The term alkyl includes hydrocarbon radicals contain
boiled with acetic anhydride to give the novel 3-(N
ing up to six carbon atoms and, preferably, up to four
aoetylamino)-l7a-ethyl-l,3,5 ( 10)-estratriene-17B - 01 17 carbons including methyl, ethyl, n-propyl, isopropyl, n 50 acetate. Strong acid hydrolysis of each of the aforemen
butyl, sec.-butyl and t-b-utyl.
tioned tertiary alcohols followed by neutralization with a
The aminoestratrienes of the general formula possess
estrogenic activity as well as anti-gonadotropic and anti
androgenic properties. They are thus useful as a pitui
tary gonadotrophin inhibitor in relieving menopausal
symptoms as well as treating conditions such as arterio
weak base such as sodium carbonate yields the corre
sponding free amine, i.e. 3-amino-l7a-ethinyl-l,3,5(l0)
55 estratrn'ene-17/8-ol and 3 - amino - 17cc - ethyl - 1,3,5(10)
estratriene-l7?-ol.
Alternatively, according to our process indicated below
wherein are prepared the novel 3-aminoestratiienes of
this invention, an amino group is introduced at the 3-car
sess analgesic properties. Our novel aminoestratrienes
can be administered orally to the animal organism in 60 bon of a steroidal 3-keto-qui-nol acetate such as 105
sclerosis. In addition, acyl compounds such as 3-(N
acetylamino)-l,3,5(10)-estratriene-175-01 17-acetate pos
conventional dosage forms such as pills, capsules, ta'blets,
syrups or elixirs; or by injection in liquid forms adapta
{ble ‘for steroid administration. The salts of the com
pounds of our invention advantageously are water solu
acetoxy-l,4-estradiene-3,l7-dione (II) by condensation
with a
amine, preferably benzylamine. An in
termediary Sohi? base (III) is formed which rearranges
with the loss of acetic acid yielding a second intermediary
3,100,209
4
Schiff base (IIV), which, upon acid hydrolysis followed by
neutralization of the amine acid salt thereby formed,
from the consideration of solubility, the solvating medi
um preferably boils in the range of 100° C. to 200° C.
yields a 3-aminoestratriene of our invention, 3-amino
Benzylamine is both the amine and solvent of choice in
preparing the novel 3-arnino steroids not only because of
1,3,5(10)-estratriene-l7-one (I’).
its high boiling point (187° C.), its high basicity, and
o H3
I
0:0
relatively unhindered nature, but also because of the acti
vation by the phenyl group of the hydrogen atoms alpha
‘1)
to the nitrogen. Other solvents which may be used are
xylene or durene.
The starting compound, ,, log-acetoxy-l,4-estradiene
3,17-dione mentioned above was used for illustrative pur
O-AQ \J CaHsCHzNH:
poses. Other lOg-acetoxy steroidal quinols may be used
as starting compounds such as IOg-acetoxy-lA-estradi
——>
ene-l7,8-ol-3—one, lOg-acetoxy-I7a-methy1-L4-estradiene
(H)
17?~ol-3-one, 10£-acetoxy-17u-ethinyl-1,4-estradiene-l7;8
‘i Hi
0:0
02
0
‘
pounds are prepared from. their corresponding 3-hydroxy
1,3,5i( 10)-estratrienes by oxidation with lead tetra-acetate
(\i
/
i
N
ol-3~one and the 17-esters thereof. These starting com
i’
—-—>
(III)
80, 5683 (1958). Thus, estrone (1,3,5(10)-estratriene
3-01-‘17-one) when oxidized with lead tetra-acetate in
———>
N
OHaCeHs
as described by Gold and Schwenk in J. Am. Chem. Soc.
20
acetic acid yields IOE-acetoxy-l,4-estradiene-3,l7-dione
(compound II). In like manner, estradiol ( 1,3,5 (10)
(IV)
estratriene-3,17?~diol), 17cc - methyl - 1,3,5 ( 10) - estratri
CHCQH;
cue-3,17,8-diol, and the like, when reacted with lead
tetra-acetate and acetic acid are converted to ldg-acetoxy
O
l,4~estradiene-l7?-ol-3—one and l0g-acetoxy-l7a-methyl
1,4~estradiene-17?-ol-3-one, respectively.
Although the IOtE-acetoxy-1,4-diene-3-one steroids de
scribed above are the starting compounds of choice, the
corresponding IOE-hydroxy steroid or other 10-lower
alkanoic acid esters thereof may also be used as inter
, mediates for our novel process.
N_
I
Ha
'
(I’)
In actual practice, the intermediary bases (III) and
(IV) are not necessarily isolated. The quinol acetate II
35
roids, for example,
The lILE-hydroxy ste
lOg-hydroxy-d,4-estradiene-3,l7
dione, are obtained from the corresponding IDs-acetates
by means of an alkali metal alcoholate such as sodium
methoxide in methanol as described by Gold and
Schwenk supra. Other lower alkanoyl ester intermediates
and an excess of primary amine are re?uxed together for
a period of from one to ?our hours (when benzylarmine 40 such as 1[lg-propionyloxy-1,4-estradiene-3,17-dione are
prepared by the oxidation of a starting material such as
is used, preferably about 21/2 hours). The intermediary
3-hydroXy-1,3,5(10)-estratriene-17-one in the same man
Schi? base thus obtained need not be isolated but is hy
ner as are the l0g-acetoxy compounds by replacing lead
drolyzed by heating the reaction mixture in the presence
tetra-acetate by the corresponding lead salt of propionic
of an acid such as sulfuric acid. The amine salts there
acid or by the use of pnopionic acid together with lead
by for-med are conveniently neutralized by making the re
oxide. Other alkan'oic acids such as caproic or valcric
action mixture basic with sodium bicarbonate, for ex
can he used in the place of proprionic acid.
ample, and extracting the novel amine product (I') with
Although the 17a-methyl-17?-hydroxy andlh-ethinyb
an organic solvent such as methylene chloride.
l7?~hydroxyestratrienes of our invention may be pre
Although benzylamine is preferred in carrying out our
inventive process, other primary amines may he used 50 pared from the corresponding 17-substituted-10g-acetoxy
1,4—estradiene intermediates or from the. oximes of 17¢
such as those of the general formula
R
RI
wherein R and R’ may lbe alike or dissimilar and at least
methyl-l9-nortestosterone and l7a-ethinyl-l9-nortestos
terone according to the heretofore described processes,
it is preferred to introduce these groups following the
55 introduction of the 3-amino group into the molecule.
Thus, the 17¢x-methyl-l7l3-hydroxy-3-aminoestratrienes of
' the general formula are prepared from 3-amino-1,3,
one of the substituents R and R’ is phenyl, p-chloro
5(10)-estratriene-l7-one (or ‘an N-substituted derivative
phenyl, or other similar aromatic residues. When R and
thereof) in conventional manner with, for example, an
R’ are not alike the disimilar substituent may be hydrogen
alkyl lithium reagent such as methyl lithium in ether at
or an alkyl residue such as methyl, ethyl and the like. 60 low temperatures or with a Grignard reagent such as
Other amines which maybe used in our‘ process are those
methyl magnesium iodide in ether.
containing a carbonyl group on the carbon alpha to the
The 17-keto-3-aminoestratrienes are also convertible
amine group, for example, aminoacetone
(NHZOHZCOOHS)
and aminoacetamide (NH2CH2CONH2). The amines of
choice for our reaction are those possessing at least one
hydrogen alpha to the nitrogen activated by a benzene
ring, because the ease with which the intermediate (III)
to the l7a-ethinyl-17?-hydroxy derivatives. In particu
65 lar, the 17-keto group is transformable into the 17d
ethinyl~17/8-hydroxy function by reaction with sodium
acetylide in liquid ammonia.
Our 17-hydroxy-aminoestratrienes are also convertible
to the l7oz-ethinyl-l7i8-hydroxy ‘and 17a-methyl-l75
hydroxy
analogs by ?rst oxidizing the 17?-hydrc-xy group
70
will lose acetic acid is determined partly upon the ease
to 17-keto in a conventional manner and then proceeding
with which an whydrogen atom can be extracted from
the Schilf base (HI).
Our novel process whereby steroidal quinol acetates
are converted to amino analogs of estrone and estradiol
may-be carried out in the presence of a solvent. Aside
as above.
The N-substituted derivatives of our invention are pre
pared from the corresponding S-aminoestratrienes by
using conventional reactions.
Thus, treatment of
3-amino-1,'3,5('10)~estratriene-l7?-ol with methyl iodide,
3,100,209
6
EXAMPLE 1
in an inert solvent, for example, yields either 3-(N-meth
ylamino) -l,3,5 (10) -estratriene—17/8-ol or 3-(N,N-dimeth
3-Amin0-1,3,5 (10) -Estratriene-l 7-One
y1amino)-1,3,5(l0)-estratriene-17B-ol depending on the
A solution of 0.5 g. of 105-acetoxy-1,4-estradiene-3,17
dione in 5 ml. of benzylamine is re?uxed for 21/2 hours.
Most of the benzylamine is removed from the reaction
mixture by warming in a stream of nitrogen and the
residue is then re?uxed with 50 ml. of 2 N sulfuric acid
amount of methyl iodide used and the length of the re
'action time.
In a similar fashion, the N-benzyl derivatives of our
invention, such as 3-(N-benzylamino)-1,3,5(10)-estra
triene~17?-ol is obtained by reacting the free amino com
for two hours. The reaction mixture is then cooled, ex
pound, e.g. 3-amino-l,3,5(l0)-estratriene~l7,B-ol, with a
with ether, made alkaline with solid sodium car~
benzylhalogenide in conventional manner, or by reduc 10 tracted
bonate and then extracted with methylene chloride. The
tion of the Schi? base IV as obtained by heating 10g
latter organic extracts are combined, dried over sodium
acetoxy-l,4-estratriene-17?4ol-3-one with benzylamine as
sulfate and evaporated to a residue. Ten ml. of cyclo
heretofore described, omitting the subsequent treatment
hexane is added to the residue and left at room tempera
with acid.
ture for a short time. The crystalline precipitate separates
The N-acyl derivatives are conveniently prepared from 15 and- is ?ltered and sublimed at 140° C. (0.01 mm). The
the corresponding B-aminoestratrienes by reaction with
resulting white powder is recrystallized several times from
an acid anhydride or chloride in the presence of pyridine.
benzene-cyclohexane to yield 3-amino-l,3,5(l0)-estra
For example, 3-amino-1,3,5(l0)-estratriene-17-one when
triene-l7-one, M.P. 192-192.6° C.
>
reacted with acetic anhydride and pyridine yields 3-(N
acetylamino)-1,3,5(10)-estratriene-l74one. Any free hy 20 New 238 my (9,100), 292 mp. (1,900), [04],,25 +60°
max.
droxyl groups which may be present are also esteri?ed
(chloroform)
1,3,5 ( 10) -estratriene-17,8-ol 17-acetate.
_
.
Analysis.-Calcd. for C1aH22ON3: N, 5.20‘. Found:
under these reaction conditions. Thus, 3-amino-1,3,
5 ( l0)-estratriene—l7,8~ol when reacted with acetic anhy
dride and pyridine is converted to 3-(N-acetylamino)
N, 5.62.
‘
EXAMPLE 2
25
3-(N-Acetylamino)-1,3,5(10)-Estratriene-1 7-0ne
Acetic anhydride may be replaced by anhydrides of
other acids in the above procedures and the correspond
ing N-acyl derivatives are obtained. Thus, pyridine in
To a solution of 80 mg. of 3-amino-1,3,5(10)-estra
triene-17-one (the compound of Example 1) is in 1 ml.
conjunction with an acid anhydride such as butyric an~
hydride or benzoyl chloride when reacted with a 3-amino 30 of pyridine, there is added 0.2 ml. of acetic anhydride and
the mixture is allowed to stand at room temperature for
estratriene of ,Formula I will form the corresponding
one hour. Water (10 drops) is added and after one hour
3-(N-acylamino)-estratriene, i.e. a 3-(N-butyrylamino)
10 ml. of 2 N sulfuric acid is added. A precipitate is
and 3-(N~benzoylamin0) eestratriene, respectively.
formed which is ?ltered, washed with water and recrystal~
By changing the amounts of reactants in the above
described procedures and modifying reaction conditions 35 lized from aqueous methanol to give a product which is
sublimed at 195° C. (0.02 mm.) and is recrystallized
such as temperature and length of reaction time, one can
twice from aqueous methanol to give 3-(N-acetylamino)
obtain either a mono- or di-N-acyl or N-alkyl derivative,
1,3,5 ( 10)-estratriene-17—one, M.P. 255—256° C.
whichever is desired.
Convenient methods of obtaining an estratriene of our 40
Am?“ 247 my. (15,500), 289 my. (1,100), [041923 +l61°
invention possessing a 3-N-acyl and a 17-hydroxy group
( dimethylformamide )
are by treating the free 3-amine with an acid, formic
acid, thus forming a 3-(N-formylamino)~17-hydroxy
Analysis.-—Calcd. for CZOH25OZN: C, 77.13; H, 8.09‘; N,
4.50. ‘Found: C, 77.43, 77.61; H, 8.12, 8.24; N, 4.59.
estratriene for example, or by shaking an aqueous sus
pension of the 3-amino derivative with an acid anhydride 45
such as acetic anhydride to obtain a 3-(N-acetylamino)
17-hydroxyestratriene. For example, 3-amino-l7m-eth
inyl-l,3,5(lO)-estratriene-17?-ol reacted with aqueous
acetic anhydride yields 3-(N-acetylamino)-17a-ethinyl
1,3,5 ( 10) -estratriene—l7B-ol.
Novel 3-aminoestratrienes of our invention wherein
the hydrogens of the amino group are replaced by dis
similar groups neither of which is hydrogen, such as in
In a similar manner, by substituting other lower
alkanoic acid anhydrides such as caproic anhydride and
propionic anhydride for acetic anhydride in the above
procedure the corresponding 3-(N-acylamino)-estratrienes
are obtained, i.e. 3-(N-caproylamino)-l,3,5(10)-estra
50
triene-17-one and 3-(N-propionylamino) -1,3,5( 10) -estra
triene-17-one, respectively.
EXAMPLE 3
3 - (N-benzyl-N-acetylamino)-1,3,S(l0)-estratriene-17;3
3-Amin0-l,3,5‘(10)~Estratriene-1 718-01
o1 17-acetate are obtained by adding the appropriate re 55
agent to a monosubstituted derivative. For example, by
A. The sulfuric acid salt of 3-amino-1,3,.5(10)-estra
reacting an N-monosubstituted aminoestratriene such as
triene-17B-0l.—A solution of 0.30 g. of l0g-acetoxy-17B
3-(N-benzylamino)-l,3,5(10)-estrat1iene-17?-ol with ace
tic anhydride in pyridine there is obtained 3-(N-benzyl-N
hydroxy-1,4-estradiene-3-one in 3 ml. of benzlyamine is
re?uxed for two hours. From the reaction mixture the
acetylamino)-estratriene-l7B-ol l7-acetate.
60 benzylamine is evaporated in a stream of nitrogen. To
Acid addition salts of the 3-aminoestratrienes of the
the resultant residue is added 5 m1. of 2 N sulfuric acid
general formula such as the phosphoric acid salt, the sul
.and 25 ml. of water ‘and the mixture distilled to half the
furic acid salt or the hydrochloroic acid salt of 3-amino
original volume. The residue from this distillation is
re?uxed for 1% hours, then cooled. A precipitate sepa
from the corresponding free amine according to known 65 rates which is isolated by ?ltration, washed with water
techniques. For example, an equimolar quantity of an
and dry ether, dried ‘and recrystallized three times from
hydrous hydrogen chloride in methanol added to a
methanol to give the sulfuric acid salt of 3-amino~1,3,5
methanolic solution of 3-amino-1,3,5(10)-estratriene-17p
(10)-estratriene-17/3-ol which decomposes at 320° C.
1,3,5 (10)-estratriene-17[3-01, are conveniently prepared
01 yields the novel 3-amino-1,3,5(l0)-estratriene-l7?-ol
Analysis.-—Calcd. for ‘c13H25ON.u/2.H2‘SO41 N, 4.37; S,
70 4.99. Found: N, 4.32; S, 5.10. '
hydrochloric acid salt.
The following examples are illustrative of methods by
B. 3-amino-1,3,5 (l0)-estratriene-17?-Ql. -— The sulfate
salt in Example 3A is shaken with benzene and aqueous
which the novel compounds of our invention may be
made and are not to be construed as limiting the scope of
the invention, the scope of our invention being de?ned
.by the appended claims.
sodium carbonate solution until dissolved. The aqueous
layer is separated and the benzene solution dried over
75 sodium sulfate and evaporated to a residue which is
3, 100,209
.
crystallized from benzene-cyclohexane to give 3-amino
1,3,5(10)-estratriene-17?-ol, M.P. 143° C.
’
.
‘
( chloroform)
5
’
s
3-(N-C'aproylamino) -1,3,5(10) ~Estratriene-l7B-Ol
H223 237 mu (7,900), 292 my (1,500) [a1]?! +71°
EXAMPLE 4
.
EXAMPLE 6
17-Caproate
'
3-amino-1,3,5(10)-estratriene-17?-ol (the compound of
Example 3) is reacted with caproic acid 'anhydride and
Hydrochloric Acid Salt 0)‘ 3-A mino~1,3,5 (10) -Estratriene
pyridine in a manner similar to that described in Example
175-01
5C. The resultant product is isolated in the described
manner and crystallized from aqueous methanol to give
To 3-amino~l,3,5(10)-estratriene-17?-ol (the com
3-(N-caproylamino) 4,3,5 ( 10) -estratriene-17,8-ol 1’7-cap
pound of Example 2) in methanol is added an equimolar 10 roate.
quantity of anhydrous hydrogen chloride in methanol.
Water is added and a precipitate results which is crystal
EXAMPLE 7
lized from methanol~water three times and ?nally with
anhydrous methanol to give the hydrochloric acid salt of
3-Amino-17a-Ethinyl-1,3,5 (10)-Estratriene-l7?-O1
3-amino-1,3,5(10)-estratriene-17?-ol, M.P. 274° C.
Analysis.—-Calcd. for C18H25ON.HCl: C, 70.22; H,
8.51; N, 4.55; CI, 11.53. Found: C, 70.32; H, 8.58; N,
4.00; Cl, 11.61.
EXAMPLE 5
300 mg. of potassium is dissolved with stirring in 100
ml. of liquid ammonia in a dry atmosphere. A stream of
acetylene is passed into he stirred cold solution until ab
sorption is complete and the color has changed completely.
While continuing a slow stream of acetylene, a solution of
20 500 mg. of 3-amino-l,3,5(10)-estrat1iene-17-one (the
compound of Example 1) in 10 ml. of dry tetrahydrofuran
is added dropwise. After the addition is complete, the
mixture is stirred for two hours after which, 1 ml. of
water is carefully added dropwise to decompose any ex
3- (N-A cetylamino-l,3,5 (10) -Estratriene-17B-0l
-
15
17-Acetate
A. 19-n0rtest0sterone oxz'me.—-To a solution of 2.42 g.
of 19-nortestosterone in 30 ml. of methanol is added a 25 cess reagent. The solution is then allowed to evaporate
solution of 1.86 g. of hydroxylamine hydrochloride and
.J’ g. of sodium acetate hydrate in 10 ml. of water. The
mixture is re?uxed on the steam bath for three hours and
the methanol evaporated until the reaction mixture is a
saturated solution. The solution is seeded and slowly
cooled. The resulting precipitate is ?ltered and dried in
vacuo to give 19-nortestosterone oxime which is used
without further puri?cation in the following procedure.
B. 3-(N-acetylamino) -I,3,5(10) -estratriene-1 75-01 17
acetate.—The crude oxime as prepared in Example 5A is
re?uxed for three hours with 25 ml. of acetic anhydride
and then is poured into 250 ml. of cold water. ' The mix
ture is allowed to stand for one hourwith occasional stir
by warming to room temperature followed by evaporation
in vacuo. The vresulting residue is crystallized from eth
anol to give 3-amino-l7a-ethinyl-1,3,5( l0) -estratriene‘
17?-0l.
EXAMPLE 8
3-Amino~17a-Methyl-1,3,5(10) -Estratriene-17?-Ol
'Ilo a solution of 500 mg. of 3-arnino~l,3,51( 10)-estra
triene-17-J-on'e (the compound of Example 1) in 5 ml. of
dry anisol under an atmosphere of nitrogen, there is added
with stirring a solution of 1.1 g. of methyl magnesium
iodide in 5 ml. of ether. The addition is maintained drop~
wise at such a rate that the heat generated maintains the
ring and then is extracted with chloroform. The organic
reaction mixture at re?ux temperature. After the addition
extracts are combined, washed with water and potassium 40 is complete, the mixture is re?uxed with stirring for two
bicarbonate solution, dried over sodium sulfate and evap
hours. The mixture is then cooled and a saturated solu
orated to a residue which is chromatographed on 80 g. of
ti‘on of aqueous ammonium chloride added. The aqueous
neutral alumina. ‘The material is introduced onto the
layer is separated and the organic solution is washed with
column in a benzene solution and eluted with 500 ml.
water to neutrality, dried over magnesium sulfate, ?ltered
each of benzene, 10% chloroform-benzene and 30% 45 and evaporated in vacuo to a residue which is crystallized
chloroform-benzene. The eluate is collected in 250 ml.
fractions which are distilled to dryness in vacuo.
The
crystalline fractions are combined, dissolved in 30 ml. of
hot benzene and 30 ml. of cyclohexane added. The solu
tion is heated to boiling, then cooled, A precipitate re
sults which is ?ltered, dried and recrystallized from anhy
drous methanol to give 3-(N-acetylamine)-l,3,5~(10)-es
tratriene-17?-ol-l7-acetate, M.P. 207.5‘-209.8° C.
A122“ 249 mu (15,000) in?ection at 273 my); [041324 +15°
( chloroform)
'
'
Analysis.-—Calcd. for C22H29O3N: C, 74.33; H, 8.22;
N, 3.94. Found: C, 74.27; H, 8.29; N, 3.92’.
Alternatively, the compound of this example is pre
from acetone-hexane to give 3-amino-17u-methyl-1,3,5
(‘10) -es-trat~riene- 1 75-01.
EXAMPLE 9‘
3- (N—Dimetkylamz'no) -1 ,3,5 (10)-Estratriene-17?-Ol
To a solution of 500 mg. of 3-amino-1,3,5(-l0)-estra—
triene-l7?aol (the compound of Example 3) in 4 ml. of
dry tetralhydrofuran and 2 ml. of methanol is added 1 g.
55 of sodium carbonate. Three m1. of methyl iodide is added
in three portions and the mixture is re?uxed for two hours
with stirring then concentrated in vacuo. Water is added
to the resultant residue. A precipitate forms which is
?ltered and crystallized from methanol to give 3-l(N-di
pared by the following procedure.
C. 3-(N-acetylamino)-1,3,5 (10) —estratriene-17?-o! 17
methylamino) -l,3,5 (‘10) -estratriene- 1713-01.
acetate.—To 10 mg. of 3~amino-l,3,5(10)-estratriene
3-1 (N-Benzylamino) -] ,3,5*(] 0) -Estratriene-1 716-0l
To a solution of 3-amino-1,3,5‘(l10)-estratriene-l7?-ol
'(the compound of Example 3) in 5 ml. of dry tetra-hydro
17?-ol (the compound of Example 3) is added 0.5 ml. of
pyridine and 0.1 ml. of acetic anhydride. The reaction
EXAMPLE 10
mixture is allowed to stand at room temperature for two 65
furan is added 4.5 ml. of benzyl bromide. The mixture
hours. Water is added and after one hour-10 ml. of 2 N
is stirred and re?uxed for one hour and evaporated in
sulfuric acid is added. A precipitate forms which is ?l
vacuo to a residue which is triturated with aqueous so
tered, washed with water, recrystallized from aqueous
dium bicarbonate solution. The resultant solid is collected
methanol, then sublimed at 195° C. (0.02 mm.) to yield
a solid product which is recrystallized from methanol and 70 by ?ltration land crystallized from aqueous acetone to give
dried at 100° C. in vacuo to give 3-(N-acetylamino)-l,3,
3-(N~benzylamino)-l,3,5i(10)-estratriene-17?~ol.
5 (10)-estratriene-17/3-ol 17-acetate, M.P. 210-214” C.
EXAMPLE 1!
(There is no depression in the melting point taken of a
mixture of the produce produced ‘by procedure C with that
3-(N-Methylamino) -1,3,5 (10 ) ~Estratriene-17B-O‘l
of procedures A and B.)
‘
To a solution of 500 mg. of 3-amino-1,3,5(10)-estra
3,100,209
10
EXAMPLE 17
triene-l‘TB-ol (the compound of Example 3) in 50 ml. of
dry tetrahydrorfuran is added 4 m1. of methyl iodide. The
3- (N-Methyl-N-Benzy lamina) -] ,3,5 (10) -Estratriene
mixture is stirred and re?uxed dior one hour and then
evaporated in vacuo to a residue which is tritunated with
1 7-One
A. 3- (N-methylamino) -] ,3,5 (10) -estratriene-17-one.—
aqueous sodium bicarbonate solution. The resultant solid 5
In a manner similar to that described in Example 11,
is collected by ?ltration and crystallized from methanol
3-amino-l,3,5 (10-estratriene-17-one (the compound of
to give 3-(N-methylamino)-1,3,5>(10)-estratriene-l7B-ol.
Example 1) is reacted with methyl iodide in tetrahydro
EXAMPLE 12
furan to give 3 - (N - methylamino)-l,3,5(l0)-estratriene
3-' (N-A cetylamino) -] 7a-Methyl-1,3,5 (1 0) -Estratriene
17?-Ol 17-Acetate
l7-one.
10
l7-one.--In a manner similar to that described in Ex
In a manner similar to that described in Example 5C,
3 - amino - 17a - methyl-1,3,5(10)-estratriene-l7?-ol
ample 10, 3-(N-methylamino)-l,3,5(10)-estratriene-l7
(the
one in tetrahydrofuran is reacted with benzyl iodide. The
compound of Example 8) is reacted with acetic anhydride
and pyridine and the resultant product isolated and puri
?ed to give 3-(N-acetylamino)-l7a-methyl-1,3,5'(10)-es
tratriene-l7f3-ol l7-acetate.
resultant product is isolated and puri?ed as described to
give 3-(N-methyl-N-benzylamino)-l,3,5(10) - estratriene
17-one.
EXAMPLE 13
3-(N-Diacetylamin0) 4,3,5 (10 ) -Estr4atriene-17~One
To a solution of‘ 800 mg. of 3-amino-l,3,5 (10)-estra
l 7?-Ol 1 7-A cetate
triene-17-one (the compound of Example 1) in 2 ml. of
pyridine, there is added 1 ml. of acetyl chloride and the
In a manner similar to that described in Example 5C,
mixture is allowed to stand overnight at room tempera
ture. Water is added and after one hour, 10 ml. of 2 N
3 - (N -1benzylamino) - l,3,5'(10) - estratriene-l7?-ol (the
compound of Example 10) is reacted with acetic an
hydride and pyridine to give 3-(N-benzyl-N-acetylamino)- '
sulfuric acid is added. A precipitate forms which is ?l
tered, washed with water and recrystallized from aqueous
1,15,5(1-0)-estratriene-l7,8-o1 17-tacetate.
methanol to give 3-(N-diacetylamino)-1,3,5 ( 10)-estratri
EXAMPLE l4
J 7?-Ol 1 7-A cetate
In a manner similar to that described in Example 5C,
-
EXAMPLE 18
3-(N-Benzyl-N-Acetylamino) -1,3,5t(10) -Estratriene
3- (N-Methyl-N-A cetylamz'no) -] ,3,5'(10) -Estratriene
'
B. 3- (N-methyl-N-benzylamino) -] ,3,5 (10 ) -estratriene
ene-l7-one.
3O
We claim:
.
1'. A compound selected from the group consisting of
aminoestratrienes of the following structural formulae:
3 -(N -rnethylamin0) -:l,3,5=(10)-estratriene-l7B-ol (the
CH3
compound of Example 11) is reacted with acetic an
hydride and pyridine to give 3-(N-met-hyl-N-acetylamino)
X
35
l
1,3,5( 10) -estratriene-l7B-ol l7-Acetate.
EXAMPLE ‘l5
3- (N-A cetylamiino) -] 7a-Ethinyl-1,3,5\(10) -Estratriene
.
17,8-0l 17-Acemte
40
A. 17a-ethinyl-l9-n0rtestoster0ne 0xime.—Ir1 the man
ner described in Example 5A, 17u-ethinyl-l9-nortestos
terone is reacted with hydroxylarm'ne hydrochloride and
and
sodium acetate. The resultant product is isolated in the 45
described manner to ‘give 17a-ethinyl-l9-nortestosterone
voxime.
R1—-N
‘
Z
CH3
Y
|
B. 3 - (N-acetylamino) - 17a-ethinyl-1,3,5(10)-estratri
ene-17B-0l 17-acetate.-—-I\n the manner described in Exam
ple 5B, l7a-ethinyl-l‘9-nortestoster0ne toxime is reacted .50
with acetic anhydride. The resultant product is isolated
and puri?ed as described to give 3-l(N-acetylamino)-l7u
ethinyl- 1,3,5 (|1§0)-estratriene-l7;8-ol l7aacetate.
HaN
Alternatively, the compound of this example is pre
pared as follows:
wherein R1 and R2 are members selected from the group
consisting of lower. alkyl, benzyl, and an acid radical of
a hydrocarbon carboxylic acid having up to eight carbon
To 10 mg. of 3-amino-17u-ethinyl-1,3,5(l0)-estratri- '
ene-l7B-ol (the compoundof Example 7) is added 0.5
m1. of pyridine and 0.1 ml. of acetic anhydride. The reac
atoms; X is a member selected from the group consisting
tion mixture is left overnight at room temperature. Water
is added and after one hour 10 ml. of 2 N sulfuric acid 60 of ‘O, (H, 502), (Qt-methyl, p02) and (a-ethinyl, 1802)
wherein Z is a member selected from the group consisting
is added. A precipitate forms which is ?ltered, washed
of H and an acid radical of a hydrocarbon carboxylic
with water and recrystallized from aqueous methanol to
acid having up to eight carbon atoms; and Y is a member
give 3 - N -\acetylamino-lh-ethinyl-l,3,5t(10)-estratriene
selected from the group consisting of (oz-methyl, ISOZ)
175-01 l7-acetate.
EXAMPLE 16
and (a-ethinyl, BOZ), wherein Z is as heretofore de?ned.
65
2. A compound of the formula
3 -(N-Benzoylamino) -] 7a-Methyl-1 ,3 ,5 (10) -Estratriene
1 75-01
10 mg. of 3-amino-l7a-methyl-1,3,5(10)-estratriene
176-01 (the compound of Example 8) is reacted with 0.1 70
ml. of benzoyl chloride and 0.5 ml. of pyridine in a man
ner similar to that described in Example 50. The result
ant product is isolated in the described manner to give
3-(N-benzoylamino) - 17oz - methyl-l,3,5(10)-estratriene
175-01.
75
3,100,209
11
v
i
wherein X is a member of the group consisting of keto,
(H, 1801-1) and (H, ?-lo'wer alkanoyloxy) and.R is lower
alkanoyl.
,
a
.
a primary amine having the following general formula
>
R\
3. 3-(N-acylamino) - 1,3,‘5(l0) - estratriene - 17 - one
/.CHNH:
wherein acyl is' an acid radical of a hydrocarbon car
boxylic acid having up to eight carbon atoms.
_
12
eight carbon atoms; the steps which comprise condensing
R!
4. 3 - (N - acylarnino) - 1,3,5(10) - estratriene-l7B-ol
wherein R is a member selected from the group consist
wherein acyl is an acid radical of a hydrocarbon car
mg of an aryl radical and a radical containing a carbonyl
boxylic acid having up to eight carbon atoms.
5. 3 - (N - acylamino).-1,3,5_(10)-estratriene-17/3-ol 17
acylate wherein acyl is an acid radical of a hydrocarbon
carboxylic acid having up to eight carbon atoms.
group, said carbonyl group being bonded to the carbon
10'.
alpha to the amino group; and R’ is a member selected
from the group consisting of H, aryl, and alkyl with a
steroidal p-quinol of the following formula:
*6. 3-(N-acylamino)-17a-methyl-1,3,5(l0) - estratriene
1713-01 wherein acyl is an acid radical of a hydrocarbon
carboxylic acid having up to eight carbon atoms.
15
'
7. 3-(N-acylamino)-l7a-methyl-1,3,5(10) - estratriene
175-01 17-acylate wherein acyl is an acid radical of a
hydrocarbon carboxylic acid having up to eight carbon
atoms.
-
8. 3-(N-acylamino)-17a-ethinyl-1,3,5(10) - estratriene
20
v1718-01 wherein acyl is an acid radical of a hydrocarbon
carboxylic acid having up to eight carbon atoms.
wherein ‘X is as above de?ned, and T is a member of the
group consisting of H and lower alkanoyl, to form an in
9. 3-(N-acylamin0)-17a-ethinyl~1,3,5(10) - estratriene
17f3-o1 17-acylate wherein acyl is an acid radical of a hy
drocarbon carboxylic acid having up to eight carbon 25 termediary Schi? base; hydrolyzing by means of an in
atoms.
organic acid said Schi? base to form an acid salt of a
-
3-aminoestratriene having the following general formula:
10. 3-amino-l7a-ethinyl-1,3,S ( I0) -estratriene~17?-ol.
11. 3-amino~17a-ethinyl-1,3,5(10)-estratriene - 175 - 01
17 -loWer alkanoate.
12. 3-amino-7u-methyl-1,3,5 ( 10 ) -estratriene-17?-ol.
Al)‘:
30
13. 3-amino-l7a-methy1-l,3,5(10)-estratriene - 17B - o1
I
17-lower alkanoate.
14. 3-(N-acetylamino)-1,3,5 ( 10) -estratriene-17-one.
l5. 3-(N-acetylamino)-1,3,5(10)-estratriene - 17B - ol
17-acetate.
35
HaN
_
16. In the process of preparing compounds of the group
consisting of estratriene derivatives of the following for
wherein X is as above de?ned, and neutralizing said
mula and the pharmaceutically acceptable acid addition
S-aminoestratriene acid salt by means of an inorganic base
salts thereof:
to
form the corresponding free amine.
40
17. The process according to claim 16 wherein the pri
mary amine is benzylamine.
18. The process according to claim 16 wherein benzyl
amine is condensed with 1?g-acetoxy-1,4-estradiene-3,l7
4-5 dione and there is obtained 3-arnino-l,3,5(10)-estratriene
i‘
(\I/?In
Home
I
1
, 19. The process according to claim 16 wherein benzyl
it.
wherein X is a member of the group consisting of O, 50
(H, {302), (oz-methyl, B02) and (u-ethdnyl, 502) wherein
Z is a member of the group consisting of H and an acid
radical of a hydrocarbon carboxylic acid having up to
eight carbon atoms; and R1 and R2 are members of the 55
group consisting of H, lower alkyl, benzyl and an acid
radical of a hydrocarbon carboxylic acid having up to
amine is condensed with l0i-acetoxy-l,4-estradiene-1‘7-ol
.3-one ‘and there is obtained 3-amino-1,3,5(10)>estratriene
17,8-01.
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,225,419
2,418,603
Logemann et a1 ________ __ Dec. 17, 1940
'Schwenk et al __________ -_ Apr. 8, 1947
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