Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
1995-03-13
2002-08-20
Badio, Barbara P. (Department: 1666)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C552S611000, C540S108000, C540S112000
Reexamination Certificate
active
06437157
ABSTRACT:
OBJECTS OF THE INVENTION
It is an object of the invention to provide the novel steroids of formula I and their non-toxic, pharmaceutically acceptable acid addition salts and a novel process and novel intermediates for their preparation.
It is another object of the invention to provide novel compositions and a method for controlling fertility in male warm-blooded animals.
These and other objects and advantages of the invention will become obvious from the following detailed description.
THE INVENTION
The novel 20-substituted steroids of the invention are selected from the group consisting of a compound of the formula
wherein R
1
and R
2
are individually selected from the group consisting of alkyl of 1 to 12 carbon atoms and aralkyl of 7 to 15 carbon atoms or taken together form a saturated heterocycle of 5 to 6 ring members optionally having a second ring heteroatom selected from the group consisting of sulfur, oxygen and nitrogen. R
3
is an &agr;-alkyl of 1 to 8 carbon atoms, n is an integer from 2 to 15, R
4
is alkyl of 1 to 12 carbon atoms, R
5
is selected from the group consisting of hydrogen, alkyl of 1 to 12 carbon atoms and acyl of an organic carboxylic acid of up to 12 carbon atoms and the wavy lines indicate that the 17- and 20-asymmetrical centers are independent of the absolute R and S configurations and their non-toxic, pharmaceutically acceptable acid addition salts.
Examples of R
1
, R
2
, R
4
and R
5
as alkyl of 1 to 12 carbon atoms are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl-butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethyl-pentyl, 3-ethyl-pentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl, nonyl, 2,4-dimethylheptyl and n-decyl, preferably methyl, ethyl or isopropyl. When R
1
and R
2
is aralkyl of 7 to 15 carbon atoms, it is preferably benzyl or phenethyl.
Examples of R
1
and R
2
forming with the nitrogen to which they are linked a saturated heterocycle with 5 or 6 ring members optionally containing another hetero ring atom chosen from oxygen, nitrogen and sulfur are piperidino, morpholino, thiomorpholino, piperazino and pyrrolidino.
Examples of R
3
as alkyl of 1 to 8 carbon atoms are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methyl-phenyl, 2,3-dimethyl-butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethyl-pentyl and 3-ethylpentyl, preferably methyl.
Examples of acyl of an organic carboxylic acid of up to 12 carbon atoms are acetyl, propionyl, butyryl, benzoyl, valeryl, hexanoyl, acryloyl and crotonoyl as well as formyl.
Examples of acids for the formation of non-toxic, pharmaceutically acid addition salts are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, alkane sulfonic acids such as methane or ethane sulfonic acid, arylsulfonic acids such as benzene or p-toluene sulfonic acid and arylcarboxylic acids. The addition salts of hydrochloric acid are preferred.
Among the preferred compounds are those of formula I wherein n is 2 and those of the formula
wherein R
1
and R
2
are defined above and their non-toxic, pharmaceutically acceptable acid addition salts.
Specific preferred compounds of formula I are (20R) (8&agr;,9&bgr;,13&agr;,14&bgr;,17&agr;) 20-[((dimethylamino)-ethyl)-amino]-19-nor-&Dgr;
1,3,5(10)
-pregnatrien-3-ol, (20S)(8&agr;,9&bgr;,13&agr;,14&bgr;,17&agr;) 20-[((dimethylamino)-ethyl)-amino]-19-nor-&Dgr;
1,3,5(10)
-pregnatrien-3-ol, (20R)(8&agr;,9&bgr;,13&agr;,14&bgr;,17&bgr;) 20-[((dimethylamino)-ethyl)-amino]-19-nor-&Dgr;
1,3,5(10)
-pregnatrien-3-ol, (20S) (8&agr;,9&bgr;,13&agr;,14&bgr;,17&bgr;) 20-[((dimethylamino)-ethyl)-amino]-19-nor-&Dgr;
1,3,5(10)
-pregnatrien-3-ol, as well as their acid addition salts. Most preferred is (20S) (8&agr;,9&bgr;,13&agr;,14&bgr;,17&agr;) 20-[((dimethylamino)-ethyl)-amino]-19-nor-&Dgr;
1,3,5(10)
-pregnatrien-3-ol and its acid addition salts.
The novel process of the invention for the preparation of the compounds of formula I comprises subjecting a compound of the formula
wherein R
3
is defined as above to an acylation agent or alkylation agent to obtain a compound of the formula
wherein R
3
is defined as above and R′
5
is alkyl of 1 to 12 carbon atoms or acyl of an organic carboxylic acid of up to 12 carbon atoms, reacting a compound of formula II or IIA with a cyanidation agent to form a compound of the formula
in which R
3
and R
5
have the same meanings as above and in which the wavy line indicates that the product is presented in the form of pure stereoisomers (17&agr;-OH, 17&bgr;-CN) or (17&agr;-CN, 17&bgr;-OH) or in the form of a mixture thereof, subjecting the latter to a dehydration reaction to obtain a compound of the formula
in which R
3
and R
5
have the above meanings, reducing the 16-17 double bond to obtain a compound of the formula
wherein the wavy line indicates that the —CN is in position 17&agr; or 17&bgr;, or in the form of a 17&agr; and 17&bgr; mixture, and R
3
and R
5
have the above meanings, reacting the latter with an organometal reagent of R
4
as defined above, then to the action of an acid hydrolysis agent to obtain a compound of the formula
wherein R
3
, R
4
and R
5
have the above meanings and in which the wavy line indicates that the —COR
4
is in position 17&agr; or 17&bgr;, or in the form of a 17&agr; and 17&bgr; mixture, reacting the latter with a hydroxyl-amine salt to obtain a compound of the formula
wherein R
3
, R
4
and R
5
have the above meanings and in which the wavy line indicates that —C(R
4
)═N—OH is in 17&agr; or 17&bgr; position or in the form of a 17&agr; and 17&bgr; mixture, and the oxime is in the syn or anti position, or in the form of a syn and anti mixture, reducing the oxime to obtain a compound of the formula
wherein the wavy line indicates that —NH
2
is in 20R or 20S position or in the form of a 20R and 20S mixture, and R
3
, R
4
and R
5
have the above meanings, reacting the latter with an acyl halide of the formula
X—CO—(CH
2
)
n
′—NR
1
R
2
wherein X is halogen, R
1
and R
2
are as defined above, n′ is equal to n−1, n being defined as above, then, optionally to a selective hydrolysis in the 3-position of the diacylated compound formed to obtain a compound of the formula
wherein the wavy lines, R
1
, R
2
, R
3
, R
4
, R
5
and n′ have the above meanings, reducing the keto group of the said amide, and optionally to one or more of the following reactions in any order:
acylation in position 3,
alkylation in position 3,
saponification of acyloxy in position 3,
separation of the different stereoisomers,
salification with an organic or mineral acid to obtain the compound of formula I.
The acylation agent is preferably a carboxylic acid derivative, for example acid chloride or an anhydride in the presence of a base such as pyridine. The optional alkylation is carried out by the usual methods with an alkylation agent such as preferably an alkyl halide like alkyl iodide or alkyl sulfate.
The cyanidation agent is preferably sodium or potassium cyanide and the cyanidation reaction is preferably carried out in a lower alcohol such as methanol in the presence of acetic acid. The dehydration reaction can be carried out using a dehydration agent such as phosphorus oxychloride in pyridine.
The reduction of the 16-17 double bond can be carried out either by catalytic hydrogenation with the hydrogenation agent being hydrogen in the presence of catalysts such as palladium on charcoal, or a rhodium reagent such as Wilkinson reagent, or by the action of sodium borohydride in ethanol, or by the action of magnesium in methanol. This reduction is either stereospecific and allows the
CH-substituent to be obtained in position 17&agr; or in position 17&bgr;, or it is non-stereospecific in which a mixture of
Bonfils Armelle
Philibert Daniel
Badio Barbara P.
Bierman, Muserlian and Lucas
Hoechst Marion Roussel
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