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Патент USA US3074990

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'
‘
"
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assists
,
I,
Patented Jan. 22, 19%?
2
1
bis-oxygenated-1,4-pregnadiene-17a ~ 01 - 20 - one (Com
pound 7). The reactions indicated hereinabove may be
3,674,979
chemically represented as follows:
d-MQNQ-?XiME DERIVATIVES @F (1-4
‘
UNSATURATED STERQHDS
ornoR
George 1. Fees, Arnbier, 1%., and Lewis H. Sarett, Prince
ton, NL, assiguors to Merck & Co, Hue, Rahway,
NJ, a corporation of New Eersey
No Drawing. Filed May 8, H61, Ser. No. 108,243
24 Claims. (Cl. 260-39145)
This invention is concerned generally with novel steroid 10
compounds and with processes of preparing them. More
particularly, it relates to novel 3-(mono-oximino substi
0:
tuted) - C-4 - unsaturated - 20-keto-l7-hydroXy-11,21-bis
oxygenated-steroids of the pregnane series, and with proc
esses of preparing these new compounds by reacting the 15
win“
'3
Compound 5
Compound 3
GHBO P.
corresponding A4 - 3,20 - diketo-17-hydroxy-l1,2l-bis-oxy
genated-steroid with a hydroxylamine compound. These
0:0
/\ I "OH
3 - (mono-oximino substituted)-C-4-unsaturated-20-keto
17-hydroxy-11,2l-bis-oXygenated-steroids as for example,
Z
4-pregnene-l7m,21-diol-3,11,20 - trione 3 - monoxirne and 20
1,4-pregnadiene-17<x,2l-diol-3,11,20 - trione 3 - monoxime
/\ I /
‘Mimi/l3
have been found to possess cortisone activity, whereas the
corresponding ZO-mono-oximes and 3,20-dioximes of 4
pregnene-17a,2l-diol-3,l1,20-trione possess no cortisone
activity whatsoever.
Moreover, the 115,21-bis-oxy 25
Compound 6
genated-l,él-pregnadiene-17u-ol-3,20-dione 3 - monoximes
(and their O-alkyl and O-alkanoyl derivatives), in addi
(EH20 R
tion to possessing cortisone-activity, do not possess any
appreciable sodium or Water retention action and are
therefore substantially free .of undesired side e?ects.
These novel 3-(mono-oximino substituted)-C-4-unsatu
z—‘/\l
rated-ZO-keto-l7-hydroxy-1l,21-bis-oxygenated-steroids of
the pregnane series, subject of the present invention, may
be chemically represented as follows:
+ HzN-OQ ---—-->
0:
CHzOR
=0
or
t=°
~--orr
Compound 5
Compound 4
({JHaOR
40
0:0
/\ [MOE
no /
QO-N- 2-!I
Compound 1
CIJHQOR
C=O
Compound 7
Z05“
MQQ
wherein Q is hydrogen or alkyl and R and Z have the
signi?cance above-de?ned.
’ The C - 4 - unsaturated 3-alkanoyloximino-ZO-keto-17
hydroxyd1,21-bis-oxygenated steroids of the pregnane
series are prepared by reacting the corresponding 3-mon
oxime with an alkanoylating agent e.g., an alkanoic anhy
dride such as acetic anhydride, propionic anhydride, an
alkanoyl halide, such as tertiary butyl-acetyl chloride, and
Compound 2
the like.
The -C-4 unsaturated 3,20-diketo-17-hydroxy-11,21-bis
wherein R is hydrogen or acyl, Y is hydrogen, alkyl or
alkanoyl, and Z is a keto or hydroxy radical.
60
These novel 3-(mono-oximino substituted)-C~4-unsatu
oxygenated-steroids of the pregnane series utilized as
the pregnane series and their O-alkyl derivatives, may be
4-pregnene-115,17u,21-trio1-3,20-dione, 4-pregnene - 11B,
starting materials in the presently invent-ed process include
rated-ZO-keto-17-hydroxy-1l,21-bis-oxygenated-steroids of
17u,21—triol-3,20-dione 2l-(lower alkanoate), 4-pregnene
prepared by reacting the corresponding C-4 unsaturated
3,20-diketo-17-hydroxy-11,2l-bis-oxygenated-steroid such
65 11B,l7a,21-triol-3,20-dione ill-acetate, 4 - pregnene - 11,8,
low) with approximately one molecular equivalent of a
1’7a,2l-triol-3,20-dione 2l-(tertiary butyl-acetate), 4
V
2l-(lower alkanoate), 4-pregnene4
diol—3,1l,20-trione
17e,21-diol-3,11,20-trione Zl-acetate, 4-pregnene-17a,21
the corresponding 3-(rnono-oxirnino substituted)-11,21—
3,20-dione 2l-(l0wer alkanoate), 1,4-pregnadiene-11B,
as 11,21 - bis - oxygenated _ 4-pregnene-l7u-ol-3,20-dione
(Compound 3 hereinbelow) and 11,21-bis-oxygenated-1,4
pregnadiene-17a-ol-3,20-dione (Compound 4 hereinbe
pregnene-l7a,2l-diol-3,l1,20-trione, 4 - pregnene-17a,21
'
hydroxylamine compound (Compound 5) such as hydrox 70 diol-3,11,20 - trione 2l-propionate, 1,4-pregnadiene-11B,
17 a,21-triol-3,20-dione, 1,4-pregnadiene-113,l7m,21-triol
ylamin-e, an O-alkyl-hydroxylamine, etc., thereby forming
3,074,979
3
4
17a,21-triol-3,20-dione 21-acetate, 1,4-pregnadiene-11B,
17m,2l-trio1-3,20-dione ZI-(tertiary butyl-acetate), 1,4
2‘1-trio1-3,20-dione S-monoxime 21- (lower alkanoate),
pregnadiene-l7u,21-diol-3,11,20-trione, 1,4 - pregnadiene
2l-acetate, 1,4-pregnadiene-11B,17a,2l-tri0l-3,20-dione 3-4
monoxime 21-(tertiary butyl-acetate), 1,4-pregnadiene-
1,4-pregnadiene-11/3,17u,21-triol-3,20-dione 3 - monoxime
17¢,2l-di0l-3,l'lg20jtrione 21-(lower alkanoate), 1,4-preg
nadiene-17e,2;1-diol-3-,11,20-trione H21-acetate, 1,4#preg
l1B,17a,21-triol-3,20-dione 3-(O-alkyl-0Xime), 1,4-preg
nadiene-17a,21-diol-3,11,20-trione 21-propionate, and the
like.
nadiene-"l1B,17a,21-triol-3,20-dione 3-(O-alkyl-oxime) 21_
(lower alkanoate), 1,4-pregnadiene-11B,l7a,2l-triol—3,20
'
The hydroxylamine compounds'used in the reaction in
clude hydroxylamine, O-alkyl-hydroxylamines such as
dione 3-(O-m-ethyl-oxime) 2l-acetate, 1,4-pregnadiene
O - methyl - hydroxylamine, O - ethyl-hydroxylamine, 10
onate, and the like.
O-propyl-hydroxylamine, and the like.
The reaction between the hydroxylamine compound
and the C-4 unsaturated 3,20-diketo-17-11,21-bis-oxy
genated-steroid of the pregnane series is conducted by
20-keto-17-hyd'roxy-l1,21-bis-oxygenated-steroids of the
pregnane series~as, for example, the O-alkanoyl derivative
bringing approximately equimolecular equivalents of
15 by reacting said 3'-mo'noximes with an alkanoic anhydride
these reactants together in a substantially anhydrous
organic solvent as, for example, a lower alkanol, such as
ethanoL'methanol, or isopropanol, a tertiary amine such
such as acetic anhydride, propionic anhydride, an alkanoyl
halide such as tertiary butyl-acetyl chloride and the like,
l1t3,l7a,21-triol-3,20-dione 3-(o-ethyl-oxirne) 2l-propi
Other 3 - (mono-oximino-substituted)-C-4éunsaturated
of the' foregoing ,3-monoximes are conveniently prepared
in'the'presence' of a tertiary amine such as pyridine, colli
as-pyr-idine, and the like. The hydroxylamine compound
dine, and, the like, thereby forming 3'~(alkanoyl-oximino)
is conveniently incorporated into the reaction mixture in 20 4-pregnene-11?,17a,21-triol-20-one 21-alkanoate,. 3-ace
the form of a salt e.g., hydroxylamine hydrochloride,
toximino-4-pregnene- 115,17a,2‘1-triol¥20-one 2 l-acetate, 3
O-met'hyl-hydroxylamine hydrochloride, along with a
(alkanoyl - oximino) - 4-pregnene~17a,21-diol-11,20-dione
molecular excess' of a base such as an alkali metal ace
21‘ - alkanoate, 3 - acetoxiruinoé4>pregnene-17a,21-diol-1l,
tate, e.g., sodium acetate, a tertiary amine, e.g., pyridine,
ZO-dione 21l-acetate, 3-(~alkanoyl-oximino)-1,4-pregnadi
and the like. The mixture of hydroxylamine compound 25 ene-17a,2l'-diol~11~,20-dione 2’1-alkanoate, 3-acetoximino
(free base), 04 unsaturated-3,20-diketo-17-hydroxy-l1,
1,4.pregna'diene-17a,21-diol-11,20 - dione 21 - acetate, 3
2l-bis-oxygenated-steroid, and organic solvent is allowed
to stand at room temperature for about 12-60 hours,
(alkanoylloximino)-1,4-pregnadiene-ll?,170:,2l-triol - 20
material is recrystallized-from an organic solvent such as
ethanol is warmed to eifect solution and the solution is
one 2'l-alkanoate, 3-acetoximino—1,4-pregnadiene-11,3,17a,
thereby forming the‘ corresponding ' 3-(mono~oximino
21¢t'riol-2Q-one 21-acetate, and the like.
substituted) ~ C-4 unsaturated-ZO-keto- 17 -hydroxy-1 1,21 30 _'The following examples illustrate methods of carrying
bis-oxygenated-steroid. This 3-(mono-oximino-substi
out ‘the present invention, but it isto be understood that
tut’ed) steroid compound is conveniently recovered by
these examples are given for purposes of illustration and
diluting the reaction mixture with ice water, and extract
not of limitation.
ing the resulting aqueous mixture with ya halogenated
Example 1‘
hydrocarbon solvent such as chloroform; this halogenated
35
Asuspension
of
201
mg. of 4-pregnene--17a,21-dioI-3,
hydrocarbon extract is washed free of- acidic ‘and basic
11,20-trio'ne‘
21-acetate
in
2 ml. of pyridine and 2 ml. of
impurities, dried, evaporated to dryness, and the‘ residual
ethyl acetate, ethyl‘ acetateaether, ‘ethyl acetatejacetone,
cooled to room temperature.
53 mg. of hydroxylamine
example, 4-pregnene-11?,l7a,2l-triol-3,20-dione S-mon
water, and the crystalline product which precipitates is
etc. to give, in substantially pure form, the 3-(mono 40 hydrochloride is then added to the solution and the re
sulting mixture is allowed to stand at room temperature
oximino-substituted) -C-4 unsaturated-ZO-keto-17-hydroxy
overnight. The reaction solution is diluted with ice
11,21-biséoxygenated-steroid of the pregnane series as, for
recovered by ?ltration, washed with water, dried and re
oxime, 4 - pregnene - 11;9,17u,21 - triol-3,20-dione 3-mon—
oxime 2l-(lower alkanoate), 4-pregnene-11?,17a,2l-triol
3,20~dione 3-monoxime 21-acetate, 4-pregnene-11?,17a,
21..-triol-‘3,20-dione 3-m0n0xime ZI-(tertiazry butyl-ace
tate), 4-pregnen-e-1113,17a,21-triol-3,20-dione 3-(O-alkyl.
crystallized from ethanol to give substantially pure 4
45 pregnene-17a,21-diol-3,l1,20-tri0ne 3-monoxime 2l-ace
tate; M.P. 263—266° C. (160.
Example 2
oxime), 4 - pregnene -. 1l,8,17a,21 - triol - 3,20-dione 3
(O-alkyl-oxime) 21-(lower alkanoate), 4-pregnene-1l?,
17a,21-t1‘i0l-3,20-dl011$ 3-(O-methyl-oxime) 21-acetate,
4-pregnene-11p,17a,21-triol-3,20-dione 3-(O-ethyl-oxime)
21-propionate, 4-pregnene-1-7a,21-diol-3,11,20-trione 3
omooo'oHiowiIm
50
'00
H0
mondx'iine,‘ 4-pregnenell7a,21-diol-3,11,20-trione 3-mon—
oxime 21-(1ower alkanoate), 4-pregnene-17a,21-diol-3,11,
2D5trio'n'e 3-monoxim'e ZI-acetate, 4-p'reg‘nene-17a,21-diol-.
55
3,ll,20-trione 3finonoxime 21-propionate, 4-pregnen‘ea
17d,214,diol-3,11,20-trione 3-monoxime 21-‘(tertiary butyl
ace‘tate) ,' 4~pregnene-l7ot,21-di0l-3,1l,20-t1'ione 3(Op-a1kyl
oxime), 4-pregnene-l7u',2 l-diol-3,l1,20-trione 3-(O-alkyl
oxime) 2l-'(lower alkanoate), 4-pregnene-17a,21-_diolV-3,
11,20-trione 3-(O-methyl-oxime) 21-acetate, 4-pregnene
~l7d,21-diol-3,11,20-trione 3-(O-ethyl-oxime) 2l-butyrate,
N5“
Compound 8
60
CHQO CYO CHIC (CHO:
to, .
1,4-pregnadiene-17a,21-diol-3,11,20atrione 3 - monoxime
H0
1,4-pregnadiene-17a,21-dio1-3,l1,20 -‘ trione 3 - monoxime 65
2l-(loitver alkanoate), 1,4-pregnadiene-17u,21-dio1-3,11,
2'0-trione'3-monoxime 21-acetate, 1,4-pregnadiene-17u,21
diol-3,1l,20'-trione 3-monoxime .21-Vpr0pionate, 1,4-preg
‘(U
nadiene-17a,21-diol-3,11,20-trione. 3-monoxime 2l-(ter
, tiai'y rb'u‘tykacetate), ‘1',4-pregnadiene—17a,21-diol-3,11,20
trione 3-(Op-alkyl-bxime) 2l-(lower alkanoate), 1,4-preg
nadiene417a,21-diol-3,1l,20?trione 3 -' (O - methyl-oxime)
Zlra'cetate, 1,4-pregnadiene-17a,21-diol-3,11,20-trione 3
70
V
"
7
,
Compound 9
v To a solution ‘of 258 mg. of 4-pregnene-11B,'17u,21
triol-3,20-dione 21-(tertiary 'butyl-acetate) ‘i'n' 25ml. of
(O-ethylf-oxime) .21-butyrate, 1,4-pregnadiene-1l?,17a,
pyridine and 2.5 m1. of ethanol is added 53 mg. of hydrox
21@tri'o1‘-3,20"-dione 3=monoxime, 1,4-pregnadiene-‘11p,17ot, ‘75 ylamme vhydrochloride, and the‘ resulting solution is at
3,074,979.
5
M.P. 210-215° C.
and recrystallized from ethanol, benzene and ethyl acetate
to give substantially pure 4-pregnene-11,B,17m,21-triol-3,
Example 8
To a solution of 305 mg. of 1,4-pregnadiene-17u,21
ZO-dione 3-monoxime ZI-(tertiary butyl-acetate); Ml’.
237-239” C.
6.
acetone-ether to give substantially pure 1,4-pregnadiene
17 a,21-diol-3,1 1,20-trione 3-(O-rnethy1-oidme) 21-acetate;
lowed to stand at room temperature for 23 hours. The
reaction mixture is diluted with ice water, and the crys-.
tals which separate are collected, washed with water, dried,
diol-3,11,20-trione 3-monoxime 21-acetate in 1.5 ml. of
pyridine is added 1.0 ml. of acetic anhydride, and the re
sulting mixture is heated at 100° C. for 15 minutes. The
Example 3
A mixture of 500 mg. or 4-pregnene-l1/8,17a,2l-triol 10 reaction mixture is cooled and the cooled mixture is
quenched with ice water. The crystalline material which
3,20-dione 21-acetate, 5 ml. of pyridine and 115 mg. of
separates
is recovered by ?ltration, washed, dried, and re
hydroxylamine hydrochloride is maintained at room tem
crystallized from ethyl acetate and acetone to give sub
perature for 65 hours. Ice and water is added to the re
stantially pure 3-acetoximino-1,4-pregnadiene-17oc,2l-diol
action mixture and the resulting aqueous mixture is ex
tracted with chloroform. The chloroform extract is dried 15 11,20-dione 2l-acetate; MP. 242-247" C.
Various changes and modi?cations may be made in car
and evaporated to dryness under vacuum. The residual
rying out the present invention without departing from the
material is crystallized from ethylacetate-ether, and the
crystalline product thus obtained is recrystallized from
ethylacetate-ethanol to give substantially pure 4-pregnene
spirit and scope thereof. Insofar as these changes and
modi?cations are within the purview of the annexed
claims, they are to be considered as part of our invention.
We claim:
11p,17a,21-triol-3,20-dione 3-monoxime 21-acetate; M.P‘.
227-2290 C. dec.
1. 3-(mono-oximinosubstituted) ~ C - 4 - unsaturated
Example 4
20-keto-17-hydroxy-11,21-bis-oxygenated steroids of the
pregnane series, having unsaturation in the A-ring se
402 mg. of 4-pregnene-17ot,21-diol-3,11,20-trione 21
acetate (1 mmo-le) and 95 mg. O-methyl hydroxylamine 25 lected from the group consisting of C-4 unsaturation and
01:04 unsaturation.
hydrochloride (1.14 mmoles) are dissolved in 2 m1. of
2. S-(mono - oxim-ino - substituted)-4-pregnene-17a,21
pyridine, and the resulting solution is maintained at room
temperature for a period of approximately 22.5 hours.
diol-11,20-dione.
3. 4-pregnene-17a,21-diol-3,11,20etrione S-monoxime.
The reaction mixture, containing precipitated pyridine hy
4. 4-pregnene-l7ot,2l-diol - 3,11,20 — trione S-(O-alkyl
drochloride, is diluted with ice water, and the crystalline
pro-duct which separates is recovered by ?ltration, washed
with water, dried, and recrystallized from ethyl acetate to
oxime) 21-(lower alkanoate).
give substantially pure 4-pregnene-17a,21-diol-3,11,20-tri
l7oc,2l-triol-20-one.
5. 3-(mono-oximino-substituted) - 4 - pregnene- 11,8,
one B-(O-methyl-oxime) Zl-acetate; MP. 205-209" C.
Example 5
35
6. 4-pregnene-l1B,17a,2l-triol-3,20-dione 3-monoxime.
7. 4-pregnene-11B,17a,2l-triol-3,20-dione 3-monoxime
2l-(lower alkanoate).
To a solution of 411 mg. of 4-pregnene-17u,2l-diol-3,
8. 4-pregnene-l1,6,l7<>t,2l-triol-3,20-dione 3-monoxirne
11,20-trione B-monoxime 21-acetate in 5 ml. of pyridine
is added 2.5 ml. of acetic anhydride and the resulting solu
21-(tertiary butyl-acetate) .
9. 4-pregnene-11B,17a,21-triol - 3,20 - dione 3-(O-a1kyl
tion is heated at about 100° C. for approximately 20 min 40 oxime) 21-(lower alkanoate).
10. 3-(alkanoyl-oximino) - 4 - pregnene - 1111170521
utes. The reaction mixture is cooled, diluted with ice
triol-ZO-one 21- (lower alkanoate) .
water, and the aqueous mixture thus obtained is extracted
11. B-(mono ~ oximino - substituted)-1,4-pregnadiene
three times with chloroform. The chloroform extract is
washed with dilute aqueous sodium bicarbonate solution,
17 a,21-diol-11,20-dione.
12. 1,4—pregnadierre-17a,2l-diol-3,11,20-trione 3 -mon
with dilute aqueous hydrochloric acid, and with water,
and is then dried and evaporated to dryness in vacuo.
oxime.
13. 1,4-pregnadiene-17a,2l-diol-3,l1,20-trione B-(O-al
The residual material is crystallized from ethyl acetate
ether and is then recrystallized from acetone-ether-petro
kyl-oxirne) 21-(lower alkanoate) .
leum ether to give substantially pure 3-acetoximino-4
l4. 3-(mono-oximino-substituted) - 1,4 - pregnadiene
11,13,17a,21-triol-20-one.
15. 1,4-pregnadiene-11B,17oc,21~triol»3,20-dione 3-mon
pregnene-17ot,21»diol-11,20-dione ZI-acetate; M.P. 178
185" C. dec.
Example 6
oxirne.
16. 1,4-pregnadiene-l1p,17a,21-triol-3,20‘-dione 3-mon
oxime 21-(lower alkanoate).
17u,21-diol-3,11,20-trione Zl-acetate in 1.8 ml. of pyri
17. 1,4-pregnadiene-11,6,17a,21-triol-3,20-dione 3-mon
dine is added 80 mg. (1.15 mmoles) or hydroxylamine hy 55
To a solution of 400 mg. (1 mmole) of 1,4-pregnadiene
drochloride. After 27 hours at room temperature, the re
oxime ZI-(tertiary buty'l-acetate).
action mixture is diluted with ice Water, and the crystalline
material which precipitates is recovered by ?ltration,
washed, dried, and recrystallized from ethyl acetate to
3-(O-alkyl-oxirne) 21-(lower alkanoate) .
give substantially pure 1,4-pregnadiene-17a,21-diol-3,11,
ZO-trione 3-monoxime ZI-acetate; MP. 235-238° C.
Example 7
18. 1,4 - pregnadiene - 11,8,l7a,21 - triol - 3,20 - dione
19. 3-(alkanoyl-oximino) - 1,4 - pregnadiene-11B,17u,
60
21-triol-20-one 21-(lower alkanoate).
20. The process which comprises reacting a C-4 unsat
urated - 3,20 - diketo-17-hydroxy-l1,21-bis-oxygenated ste
roid of the pregnane series with approximately one molec
ular equivalent of a hydroxylarnine compound thereby
11,20-trione Zl-acetate (1 mrnole), 95 mg. of O-methyl 65 forming the corresponding 3-(mono-oximino-substituted)~
A mixture of 400 mg. of l,4—pregnadiene-l7a,2l-diol—3,
hydroxylamine hydrochloride (1.14 mmoles) and 3 ml.
C-4-unsaturated - 20 - keto-17-hydroxy-11,21-bis-oxygen
of pyridine is maintained at room temperature for approx
ated-steroid.
imately 23 hours. The reaction mixture is diluted with
ice water, and the resulting aqueous mixture is extracted
with chloroform. The chloroform extract is washed with
dilute aqueous sodium bicarbonate solution, with dilute
aqueous hydrochloric acid, and with Water, and dried.
The chloroform is evaporated from the resulting washed
and dried extract, and the residual material is crystallized
21. The process which comprises reacting 4-pregnene
17a,21-diol-3,11,20-trione ZI-alkanoate with approxi
mately one molecular equivalent of hydroxylamine
to produce 4-pregnene-17a,21-diol-3,11,20-trione 3-mon
oxime Zl-alkanoate.
22. The process which comprises reacting 1,4-pregna
diene-17ot,21-diol-3,11,20-trione 21-alkanoate with ap
from ethyl acetate-ether followed by recrystallization from 75 proximately one molecular equivalent of hydroxylamine
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