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Патент USA US3076809

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United States Patent
"
/
3,076,802
‘ Patented Feb. 5, 1963'
2
1
droxide and dioxane. This chloroamide is allowed to re
3,076,802
20-[w-(TERTIARY-AMINO)LOWER ALKANOYLAMI
D0] PREGN-S-EN-Zi?-OLS, ESTERS CORRESPOND
act with dimethylamine in butanone to produce ZO?-(di
methylaminoacetamido)pregn-S-en-S?-ol.
The instant 3/3-hydroxy compounds can, alternatively,
be obtained by hydrolysis of the corresponding 3-esters.
ING, AND INTERMEDIATES THERETO
Raymond E. Counsel], Skokie, Ill., assignor to G. D.
Typically, 20oz-(dimethylaminoacetamido)pregn-S-en-Ii?
Searle & Co., Chi. ago, Ill., a corporation of Delaware
No Drawing. Filed Dec. 1, 1961, Ser. No. 156,475
11 Claims. (Cl. 260—239.5)
ol B-acetate is allowed to react with aqueous potassium
amino-amides of the pregnane series and, more particu
ols, suitably by reaction with a lower alkanoic acid an
hydride in pyridine. 20cc - (dimethylaminoacetamido)
hydroxide in dioxane to yield the free 313-01.
The 3/8-(lower alkanoates) of this invention can be
The present invention is concerned with novel steroidal 10 manufactured also by acylation of the corresponding 3,6’
larly, with 20-[w-(tertiary-amino)lower alkanoylamido]
pregn-S-en-‘s‘?-ol, for example, is treated with propionic
anhydride and pyridine to afford the corresponding 3
pregn-5-en-3B-ols and esters thereof, which are repre
sented by the structural formula
propionate.
CH3
CH3
The compounds of this invention display valuable phar
macological properties. They are, for example, hypo
CHM/v NHCOAlk-Z
chlolesterolemic agents as is evidenced by their ability
CH3
to inhibit the hepatic synthesis of cholesterol. They are
20 also antibiotic agents in view of their ability to inhibit
' the growth of Chlorella vulgaris. In addition, these com
pounds are intermediates in the manufacture of the N
substituted 20-aminopregn~5~en-3?-ols and corresponding
esters of my copending application Serial No. 81,254,
2.5 ?led January 9, 1961, now Patent No. 3,013,008, of which
wherein R is hydrogen or a lower alkanoyl radical, Alk
is a lower alkylene radical, Z is the residue of a secondary
amine selected from the group consisting of di-(lower
the present application is a continuation-in-part.
The invention is disclosed in further detail by the fol
lowing examples which represent speci?c embodiments
of this invention, without, however, limiting it either in
alky1)amines, cycloalkylamines, morpholine, and N-alkyl 3.0 spirit or in scope. Amounts of materials are given in‘
piperazines, and the wavy line indicates the alternative
or or p con?guration of the substituent at carbon atom
20
parts by weight and temperatures are given in degrees
centrigrade (° 0.).
Example 1
The lower alkanoyl radicals encompassed by the R term
are exempli?ed by formyl, acetyl, propionyl, butyryl, 35 To a solution of 18 parts of 20ot-aminopregn-5-en-3?
valeryl, caproyl, and the branched-chain isomers thereof,
ol 3-acetate in 240 parts of benzene containing 7.3 parts
and the lower alkylene radicals represented by Alk are
exempli?ed by methylene, ethylene, trimethylene, tetra
of triethylamine is added dropwise a solution of 7.5 parts
of chloroacetyl chloride in 20 parts of benzene, and
methylene, pentamethylene, and the branched-chain radi
this mixture is stirred and heated at re?ux for about one
40 hour, then cooled and ?ltered. The ?lter cake is washed
cals isomeric therewith.
Equivalent to the organic bases of this invention are the
with benzene, and the ?ltrate is washed successively with
corresponding non-toxic salts, which are exempli?ed by
dilute hydrochloric acid, aqueous sodium bicarbonate,
the citrate, tartrate, maleate, ascorbate, gluconate, lactate,
and water, dried over anhydrous sodium sulfate contain
_ succinate, phosphate, sulfate, hydrobromide, and hydro
ing decolorizing carbon, and stripped of solvent at re
45
chloride.
duced pressure. The residue is crystallized from ethanol
Starting materials suitable for the manufacture of the
to yield 20w(chloroacetamido)pregn-5-en-3B-ol S-acetate,
instant compounds are the 20-aminopregn-S-en-B‘?-ols and
Ml’. about 196-199"; [a]D=--44°. This compound is
corresponding B-esters.
The ZO-aminopregn-S-en-SB-ol
3-esters are allowed to react with a chloroalkanoyl chlo
represented by the structural formula
ride to afford the corresponding chloroalkanoylamido 50
compounds. Treatment of these novel intermediates with
n-o-mnoocmol
the appropriate secondary amine results in the tertiary
amino) alkanoylamido 3-esters of this invention. These
CHI me i
processes are speci?cally illustrated by the acylationof
ZOa-arninOpregn-S-en-3;3-ol B-acetate with chloroacetyl, 55
chloride to yield the novel 20a-chloroacetamidopregn-S
en-3B-ol 3-acetate, which is treated with dimethylamine to
produce 20a-(dimethylaminoacetamido)pregn-5-en-3B-ol
3-acetate.
When the 20 - aminopregn-S-en-3B-ols are
utilized as starting materials, two molecular equivalents 60
of the chloroalkanoyl chloride are required, resulting in
acylation of the B-hydroxy group also. Treatment of
these ester-amides with aqueous potassium hydroxide in
dioxane results in preferential hydrolysis of the ester group
to yield the chloroalkanoylamido substances, which are
treated with a secondary amine, resutling in the instant
(tertiary-amino)alkanoylamido-S-ols. The reaction of
20?-aminopregn-5-en-3[3-01, for example, with 2 molecular
equivalents of chloroacetyl chloride affords the novel in
CHsCO0-
Example 2
The substitution of 15.9 parts of ZOB-arninopregn-S-en
35-01 and 16.9 parts of ?-chloropropionyl chloride in the
process of Example 1 results in ZOB-(B-chloropropionyl
i-amido) -pregn-5-en-3/3-o1 3- ( ?-chloropropionate) .
Example 3
The reaction of 15.9 parts of ZOB-aminopregn-S-en-B?
termediate, 20,8-(chloroacetamido)-pregn-5-en-3/3-ol 3 70
01 and 15.0 parts of chloroacetyl chloride by the process
chloroacetate, which yields ZOB-(chloroacetamido)pregn
of Example 1 results in 20B-(chloroacetamide)pregn-5
S-en-BB-ol upon hydrolysis with aqueous potassium hy
3,076,802
3
4
en-B?-ol 3-chloroacetate, which is presented by the struc
with ether. The organic mixture is washed with water,
dried over anhydrous potassium carbonate containing de
colorizing carbon, and evaporated to dryness in vacuo.
The resulting crystalline residue is recrystallized from
aqueous ethanol to yield pure 20a-(pyrrolidinoacetami
do)pregn-5-en-3;8-ol 3-acetate, M.P. about 157-160",
which is represented by the structural formula
tural formula
I
CHa-—(5—NHC 0 011101
CH3 H30 I
i
OH:
/
10
' CH]
ClCHaCOO
Example 4
To a solution of 49.8 parts of ZOB-(?-chloropropion
15
amido)pregn-5-en-3/8-ol 3-(?-chloropropionate) in 250
CHaCOO
parts of dioxane is added 6 parts of potassium hydroxide
in 2 parts of water, and the mixture is stored at room
Example 8
temperature for about 16 hoursythen is extracted with 20
ether. The organic layer is washed with water, dried over
By substituting 2.08 parts of morpholine and otherwise
anhydrous sodium sulfate, and stripped of solvent at re
proceeding. according to the processes of Example 7, 20a
duced. pressure. The residue is crystallized fromwethyl
(morpholinoacetamido)pregn-S-en-Zi?aol 3-acetate, M.P.
acetate to produce 20p-(p-chloropropionamido)pregn-S
about 173—176°, is obtained. This compound is repre
en-3/3-ol.
25 sented by the structural formula
Example 5
l
/
\
To a solution of 8.72‘ parts of 20a-(chloroacetamidoj
n-o-NnooornN
0
pregn-5éen-3?-ol 3-acetate in 87 parts of toluene contain-}
on, E30
’ h“
ing 20 parts of butanone is added-a solution of 9 parts of 30
dimethylamine in 26 parts of toluene, and this mixture is
heated at 50-55° in a. suitable sealed container for about
40 hours. The reaction mixture is cooled, washed with
water, dried. over anhydrous potassium carbonate contain
ing. decolorizing carbon, and evaporated to dryness at 35
reduced pressure. The resulting residueis crystallized
from heptane to produce 20a-(dimethylaminoacetami
do)pregn-5-en-3?-ol. 3-acetate, M.P. about 159-161.5°;
[a]D=—52.5°. This substance is represented ‘ by the
structural formula
Example 9
The substitution of 2.39 parts of N-methylpiperazine
in the procedure of Example 7 results in 20a[(N-methyl
piperazino)acetamido]pregn-5-en-3B-ol ,B-acetate, M.P.
9e
I_H—C—NHOOCH:N(CH:)':
about 145-147°. It is represented by the structural for
mula
on, H“?
45
N-CH)
CH3
50
Example 6
The substitution of 43.2 parts of ZOa-(dimethylamino
acetamido)pregn-5-en-3?~ol 3-acetate in the procedure of 55
Example 10
Example 4 results in 20a-(dimethylaminoacetamido)
The substitution of 2.04 parts of piperidine in'the'pro
pregn-5-en-3l3-ol, M.P. about 188-189°, which is repre
ced'ure of Example 7 produces a'material, which is re
sented by the structural formula
crystallized from ‘methanol to a?ord 20a-(piperidino
acetamido)pregn-5-en-3?-ol 3-acetate, M.P. about 171.5
on,
60 172.5‘’. It is represented by the structural formula
CH3
'
/
65
Example 7
A solution of 4.4 parts of 20w(chloroacetamido)preg -
5fen-3B-ol S-acetate and 1.7 parts ;of p-yrrolidinein 44
parts of benzene is heated at re?ux for about 20. hours,
Example 11
_' A solution of 9 parts of i20a-(chloroa'cetamido)-pregn
then‘ is allowed to cool to room temperature‘ and is diluted 75 5;en-3B¢ol 3-acetate and 4.4 parts of'diethylamine inl54
3,076,802
5
6
parts of benzene is heated at 50—55° in a suitable sealed
container for about 48 hours. The cooled mixture is
?ltered, and the ?ltrate is evaporated to dryness in vacuo.
Crystallization of the solid residue from aqueous meth
onate is obtained. This compound is represented by the
structural formula
anol a?ords 20a-(diethylaminoacetamido)pregn-S-en-BB
ol S-acetate, M.P. about 147—149°, which is represented
by the structural formula
CH3
/
CBS 1130
CHsCHrCOQ
15
/
What is claimed is:
1. A compound of the structural formula
CH3
CH3
GHaCOO
Example 12
20
The reaction of 8.1 parts of 20?-(,B~chloropropion
amido)pregn-5-en-3,6-ol with 14.6 parts of diethylamine
according to the procedure of Example 5 results in 20/?
(B-diethylaminopropionamido)pregn-S-en??-ol, which is 25
represented by the structural formula
H
30
CH3
/
30
wherein R is selected from the group consisting of hydro
gen and lower alkanoyl radicals, Alk is a lower alkylene
radical, and Z is selected from the group consisting of di
(lower alkyl)arnino radicals and radicals of the structural
formula
l
N
(XL,
\_/
35 wherein X is selected from the group consisting of meth
ylene, epoxy, and methylimino radicals, and n is selected
from the group consisting of 0 and l.
2. A compound of the structural formula
HO
Example 13
CH3
CH3
40
CH ~w NHC O Alli-Z
A mixture of one part of 2018-(?-diethylarninopropion
CH3
amido)pregn-5-en-3B—ol, 13 parts of propionic anhydride,
and 20 parts of pyridine is kept at room temperature for
about 16 hours, then is diluted with ice and water. The 45
resulting aqueous mixture is made alkaline to pH 9 by
the addition of sodium carbonate, then is extracted with
benzene. This organic solution is washed with water,
/
HO
, N dried over anhydrous sodium sulfate, and concentrated to
ryness to produce 201%(,B-diethylaminopropionamido) 50
wherein Alk is a lower alkylene radical and Z is a di
pregn-S-en-SSB-ol 3-propionate. This compound is repre
(lower alkyl) amino radical.
sented by the structural formula
3. 200a - pyrrolidinoacetamidopregn - 5-en-313-0l 3-ace
tate.
H
4. 200a - morpholinoacetamidopregn - 5 - en - 3p - ol 3
acetate.
5. 20oz - [(N-methylpiperazino) acetamidoJpregn - 5 -en
fl
35-01 S-acetate.
6. 20a - piperidinoacetamidopregn - 5 - en - 318 - ol 3
acetate.
/
7. 20oz - diethylarninoacetamidopregn - 5 - en - 31B - ol
S-acetate.
CHaCHaCOO-
8. 20a-dimethylaminoacetamidopregn-5-en-3?-ol.
\
9. 20a - dimethylaminoacetamidopregn - 5 - en-3,B-ol 3
Example 14
By substituting one part of ZOa-(dimethyIaminoaceta
mido)pregn-5-en~3p-ol in the procedure of Example 13,‘
20w(dimethylaminoacetamido)pregn-S-en-B‘?-ol 3-propi
65
acetate.
10. 20a-chloroacetamidopregn-5-en-3B-ol 3-acetate.
11. 20,8-chloroacetamidopregn-S-en-BB-o1 3-chloroace
tate.
No references cited.
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