19-nor-pregnene derivatives and pharmaceuticals containing...

Details 19-nor-pregnene derivatives and pharmaceuticals containing... 19-nor-pregnene derivatives and pharmaceuticals containing...

1998-11-05

2001-01-30

Qazi, Sabiha N. (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

Acyclic carbon bonded directly to three benzene rings or to...

C552S515000, C552S516000, C552S519000, C552S520000, C552S557000, C552S586000, C552S592000, C552S597000, C552S511000, C514S171000, C514S177000, C514S170000

Reexamination Certificate

active

06180803

ABSTRACT:

The invention relates to substituted 19-nor-pregnene derivatives, methods of making these compounds and pharmaceutical compositions containing them.
The compounds according to this invention have specific and powerful progestational properties, and are devoid of residual androgenic activity.
19-nor-pregnene derivatives substituted in position 1,2- have been described in the literature. For example, FR-A-1 525 916 relates to a method of preparing compounds of the formula:
in which R is hydrogen or an acyl residue such as acetyl or hexanoyl.
In addition, 19-nor-pregnene derivatives substituted in position 6- are described in the following documents:
* FR-A-1 524 013 which relates to 3-enol ether pregnane derivatives obtained from the 4-pregnene-3,20-diones of the formula:
among which 6&agr;-methyl-17&agr;-hydroxy-4-pregnene-3,20-dione may be cited;
* DE-A-2 148 261 which describes a method of preparing 6&agr;-methyl-19-nor-pregnenes of the formula:
in which R
1
is hydrogen or methyl and R
2
is a (C
1
-C
9
)alkyl; or
* BE 757 285 which relates to pharmaceuticals containing 3,20-dioxo-6&agr;-methyl-17&agr;-acetoxy-19-nor-&Dgr;
4
-pregnene.
19-nor-pregnene derivatives such as those described above usually exhibit however androgenic side effects.
On the other hand, the conversion of 17&agr;, 20-isopropylidenedioxy-4,5-seco-3-pregnyn-5-one to 6,6-dimethyl-17&agr;-hydroxyprogesterone is disclosed in U.S. Pat. No. 3,891,677.
The Applicant has now found that 19-nor-pregnene derivatives which possess at least two substituents in position 1-, 2-, 1,2- and/or 6-, display a potent progestational activity while being devoid of residual androgenic activity.
A first aspect of this invention thus encompasses compounds having the structure represented by the following general formula (I):
wherein:
R
1
, R
2
, R
3
, R
4
and R
6
each independently represent hydrogen or a (C
1
-C
6
)alkyl,
R
5
is hydrogen, a (C
1
-C
6
)alkyl or a —COR
7
group where R
7
is a (C
1
-C
6
)alkyl,
n is zero or one, and
X is oxygen or a hydroxyimino group,
provided that when n=0, at least two of R
1
, R
2
, R
3
and R
4
are different from hydrogen and that when n=1, R
3
and R
4
are not simultaneously hydrogen.
As used herein, the term “alkyl” means a branched or linear saturated hydrocarbon radical, such as for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
As used herein the group —COR
7
wherein R
7
is a (C
1
-C
6
)alkyl includes, for example, acetyl, propionyl, butyryl, isobutyryl, t-butyryl, valeryl and hexanoyl, acetyl being preferred.
Preferred compounds of formula (I) are those wherein R
1
, R
2
and R
6
are hydrogen, R
3
and R
4
are a (C
1
-C
6
)alkyl, R
5
is a group —COR
7
and n is zero, those where X is oxygen being especially preferred. Also preferred are the compounds of formula (I) wherein R
1
, R
2
, R
4
and R
6
are hydrogen, R
3
is a (C
1
-C
6
)alkyl, R
5
is a group —COR
7
and n is one. Further preferred are the compounds of formula (I) wherein R
4
and R
6
are hydrogen, R
3
is a (C
1
-C
6
)alkyl, R
5
is a group —COR
7
and n is zero. Among the latter, those where R
1
is hydrogen and R
2
is a (C
1
-C
6
)alkyl and those where R
1
is a (C
1
-C
6
)alkyl and R
2
is hydrogen are also preferred, those where X is oxygen being especially preferred.
According to another aspect, the invention relates to a method of preparing the compounds of formula (I): they can be made following the reaction scheme below in which R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, n and X have the same meaning as set forth above.
Compounds 5 where R
3
and R
4
are a (C
1
-C
6
)alkyl can be prepared as follows: Compounds 1 are prepared using a process similar to that described in DE-A-2 148 261. In the case where R
5
=—COR
7
, they are saponified by sodium hydroxide in a mixture of ethanol and tetrahydrofuran. Products 1 (R
5
=H) are separated by precipitation in water followed by crystallization in an alcohol, preferably methanol or ethanol. Then, they are dissolved in toluene to which is added 1 to 10 molar equivalents of ethylene glycol, preferably 5 molar equivalents, triethylorthoformate and a catalytic amount of p-toluenesulfonic acid. The reaction mixture is stirred at a temperature of about 20° C. to 80° C., preferably 40° C. for about 2 to 8 hours. The reaction mixture is cooled and poured into iced water and extracted with a suitable organic solvent. The residue obtained after evaporation of the solvent can be purified by crystallization or by flash-chromatography to yield the compounds 2.
Treatment of compounds 2 with 3-chloroperoxybenzoic acid (MCPBA) in methylene chloride gives a mixture of 5,6-oxiranes 3 which are separated by crystallization or by flash-chromatography. Addition of an excess of R
4
-magnesium-halide to the compounds 3 in tetrahydrofuran at a temperature of about 20° C. to 60° C. for about 8 hours, and treatment of the reaction mixture with a solution of ammonium chloride and extraction with toluene and evaporation of the solvent gives the compounds 4.
Deprotection followed by dehydration of the tertiary hydroxy group gives the compounds 5 which can be optionally esterified by known processes used for esterification in steroid chemistry or alkylated by an alkyl halide according to conventional methods of Williamson ether synthesis such as that described by B. G. Zupancic and M. Sopcic,
Synthesis,
1979, 123 or by D. R. Benedict et al.,
Synthesis,
1979,428-9.
Compounds 6 where R
3
is (C
1
-C
6
)alkyl and R
4
is hydrogen can be prepared as follows:
Compounds 6 with the 5&bgr;-H configuration are obtained by hydrogenation of compounds 1 or 5 in tetrahydrofuran, acetic acid or an alcohol such as methanol, ethanol or propanol, with palladium or a palladium or platinium derivative.
Compounds 6 with the 5&agr;-H configuration can be obtained by chemical reduction of compounds 1 or 5 with sodium dithionite using a procedure described by F. Camps et al.,
Tetrahedron Lett.,
1986, 42, n.16, 4603-4609 or R. S. Dhillon et al.,
Tetrahedron Lett.,
1995, 36, n.7, 1107-8.
The compounds of formula (I) can be obtained as follows:
Bromination followed by dehydrobromination of the compounds 6 according to well-known techniques (Y. J. Abul-Haij,
J. Org. Chem.,
1986, 51, 3059-61; C. Djerassi and C. R. Scholz,
J. Am. Soc.,
1948, 417; R. Joly et al,
Bull. Soc. Chim. Fr.,
1957, 366) gives the compounds 7 (R
1
=R
2
=H).
Compounds 5 (R
5
=H) can be transformed to their 20,20-ethanedioxy derivatives then converted to their 2-hydroxymethylene sodium salt and alkylated using an alkyl iodide such as methyl iodide, ethyl iodide or propyl iodide following the method described by N. W. Atwater et al. in
J. Org. Chem.,
1961, 23, 3077-83 to obtain compounds 10 (R
1
=H, R
2
=alkyl, n=0).
Optionally, chemical reduction by hydrogenation of the 4,5-double bond of compounds 10 (R
1
=H, R
2
=alkyl, n=0), followed by bromination/dehydrobromination gives compounds 7 (R
1
=H, R
2
=alkyl).
Addition of a lithium dialkylcuprate LiCu(R
1
)
2
or of the corresponding alkylmagnesium halide under copper catalysis (for example CuI, CuCI or CuCN) to compounds 7 (R
1
=R
2
=H) gives compounds 12 (R
1
=alkyl) which can be converted to compounds 10 (R
1
=alkyl, R
2
=H, n=0) using well-known techniques for the introduction of a 4,5-double bond in steroid chemistry, or transformed to compounds 7 (R
1
=alkyl, R
2
=H) by dehydrogenation or by bromination/dehydrobromination. Compounds 12 can also be alkylated in position 2- by a similar process to obtain compounds 10 (R
2
=alkyl, n=0) which are then converted to compounds 7 (R
1
=R
2
=alkyl) as described above.
Compounds 9 (R
1
=H or alkyl, R
2
=H or alkyl, n=1) are prepared by reaction of compounds 7 (R
1
=H or alkyl, R
2
=H or alkyl) with a dimethylsulfoxonium methylide produced by the reaction of trimethylsulfoxonium io

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