C-11 substituted steroids for treating menopausal complaints

Details C-11 substituted steroids for treating menopausal complaints C-11 substituted steroids for treating menopausal complaints

1999-10-25

2001-07-10

Cook, Rebecca (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

Reexamination Certificate

active

06258803

ABSTRACT:

The invention relates to the use of steroids for the manufacture of a medicament for treating or preventing menopausal complaints, especially for treating or preventing osteoporosis.
Many of the steroids according to this invention, which are used for the treatment of menopausal complaints, are known per se.
For instance, 11&bgr;-alkyl steroid are known from U.S. Pat. No. 3,983,144. These steroids are described to have interesting anti-fertility activity. Other 11&bgr;-alkyl steroids having anabolic, androgenic, and progestational activity are disclosed in U.S. Pat. No. 3,325,520. Related progestational compounds for menstrual and ovulation control are further known from Australian patent application AL 6614974, European patent application 0,145,493, and U.S. Pat. No. 3,465,010. Steroids having unsaturated hydrocarbon groups at position 11 of the steroid skeleton are known from U.S. Pat. No. 4,292,251, which patent discloses uterotropic and ovulation inhibiting activity, and from above-mentioned EP 0,145,493.
It has now been found that compounds having the general formula:
wherein
R
1
represents O, (H,OH), or two hydrogens atoms;
R
2
is hydroxy, optionally etherified or esterified;
R
3
is (2-6 C) alkynyl, optionally substituted with hydroxy;
R
4
is CN or one of the hydrocarbon groups selected from (1-6 C) alkyl, (1-6 C) alkoxy, (2-6 C) alkenyl, (2-6 C) alkynyl, and (2-6 C) alkylidene, each of said hydrocarbon groups may optionally be substituted with halogen, hydroxy or (1-6 C) alkoxy; and
R
5
is hydrogen or (1-6 C) alkyl, can be used for treating or preventing postmenopausal complaints, and especially osteoporosis.
One of the most serious menopausal complaints is bone loss (osteoporosis), which characteristically affects women. The aim of this invention is to provide a medicament which is able to prevent bone loss, and possibly to increase bone mass, and further to treat climacteric complaints. Preferably the active ingredients of these medicaments have strong estrogen and weak or non-existing androgenic activity. Preferred medicaments further have favourable bleeding properties, do not induce endometrium proliferation, and have a favourable HDL/LDL (high/low density lipid) ratio.
In a preferred embodiment the compounds have the general formula I wherein R
1
represents O or two hydrogens atoms; R
2
is hydroxy; R
3
is ethynyl; R
4
is selected from the group consisting of methyl, (2-6 C) alkynyl, (2-6 C) alkylidene, and one of (2-6 C) alkyl, (2-7 C) alkoxy-alkyl, (1-6 C) alkoxy, or (2-6 C) alkenyl, which may optionally be substituted with halogen; and R
5
is hydrogen or (1-6 C) alkyl.
More preferred is the use of steroids having the general formula I wherein: R
1
is O; R
2
is hydroxy; R
3
is ethynyl; R
4
is ethyl, 2-fluoroethyl, ethynyl, (2-6 C) alkenyl optionally substituted with fluorine, or (2-6 C) alkylidene optionally substituted with fluorine; and R
5
is hydrogen or methyl. In the preferred embodiment R
5
is hydrogen.
Even more preferred is the use of steroids having the general formula I wherein: R
1
is O; R
2
is hydroxy; R
3
is ethynyl; R
4
is ethyl or ethynyl; and R
5
is hydrogen.
The invention further relates to new steroids having the general formula I wherein:
R
1
represents O;
R
2
is hydroxy, optionally etherified or esterified;
R
3
is (2-6 C) alkynyl, optionally substituted with hydroxy;
R
4
is CN, (2-6 C) alkyl optionally substituted with halogen, or (2-6 C) alkenyl substituted with halogen; and
R
5
is hydrogen or (1-6 C) alkyl;
or wherein
R
1
represents two hydrogens atoms;
R
2
is hydroxy, optionally etherified or esterified;
R
3
is (2-6 C) alkynyl, optionally substituted with hydroxy;
R
4
is CN or one of the hydrocarbon groups selected from (2-6 C) alkyl, (1-6 C) alkoxy, (2-6 C) alkenyl, (2-6 C) alkynyl, and (2-6 C) alkylidene, each of said hydrocarbon groups may optionally be substituted with halogen, hydroxy or (1-6 C) alkoxy; and
R
5
is (1-6 C) alkyl.
The steroids of general formula I wherein R
1
is O; R
2
is hydroxy; R
3
is ethynyl; R
4
is 2-fluoroethyl or 2-fluoroethenyl; and R
5
is hydrogen are preferred steroids.
Other preferred steroids are steroids of general formula I wherein R
1
represents two hydrogens atoms; R
2
is hydroxy; R
3
is ethynyl; R
4
is (2-6 C) alkyl, (2-6 C) alkylidene or (2-6 C) alkenyl, each of which groups may be substituted with fluorine; and R
5
is methyl.
In the definition of R
2
the OH group may be etherified or esterified. The term etherified means that the hydroxy group is etherified with a lower alkyl group, preferably having 1-6 carbon atoms, such as methyl, ethyl, propyl, sec-butyl and the like. The term esterified means that the hydroxy group is esterified with a lower alkanoyl group, preferably having 2-6 carbon atoms, like acetyl, propionyl, and the like. In principle any ester suffices as long as the ester group cleaves when the compound is administered in vivo.
The (1-6 C) alkyl group in the definition of formula I is a branched or unbranched alkyl group having 1-6 carbon atoms, such as methyl, ethyl, propyl, butyl, tert-butyl, pentyl and hexyl. Preferably the alkyl group is methyl (especially for R
5
) and ethyl (especially for R
4
). The term (2-6 C) alkyl has the same meaning with the exception of methyl.
The (2-6 C) alkenyl group is a branched or unbranched alkenyl group having 2-6 carbon atoms, like vinyl, 2-propenyl, and 1,3-butadienyl.
The (2-6 C) alkynyl group is a branched or unbranched alkynyl group having 2-6 carbon atoms, like ethynyl, propynyl, butynyl, and the like.
The (2-6 C) alkylidene group is a branched or unbranched alkylidene group having 2-6 carbon atoms, like ethylidene, propylidene, 2-methylpropylidene, and the like.
The term halogen used in the definition of formula I means fluorine, chlorine, bromine or iodine. Fluorine is the preferred halogen.
The term (1-6 C) alkoxy means an alkoxy group, the alkyl moiety of which is a (1-6 C) alkyl group as previously defined.
The term (2-7 C) alkoxyalkyl means a (1-6 C) alkyl group as previously defined substituted by a (1-6 C) alkoxy group as previously defined, the total number of carbon atoms being between 2 and 7.
The new compounds of this invention can be prepared by condensation of 11-keto steroids of the general formula:
wherein
R
1
represents O;
R
2
is hydroxy, optionally etherified or esterified;
R
3
is (2-6 C) alkynyl, optionally substituted with hydroxy; and
R
5
is hydrogen or (1-6 C) alkyl;
or wherein
R
1
represents two hydrogens atoms;
R
2
is hydroxy, optionally etherified or esterified;
R
3
is (2-6 C) alkynyl, optionally substituted with hydroxy; and
R
5
is (1-6 C) alkyl;
the active groups of which are optionally protected, is condensed with a Wittig(-like) compound of the formula R
4
′R
4
″CH—W, wherein R
4
′R
4
″C forms the group R
4
which is the optionally halogen, hydroxy, or (1-6 C) alkoxy substituted (2-6 C) alkylidene group as previously defined, or R
4
′″Li, wherein R
4
′″ is (2-6 C) alkyl or (2-6 C) alkenyl optionally substituted with halogen, hydroxy, or (1-6 C) alkoxy, in which reactive groups can be protected by protective groups which are known in the art (see for example T. W. Green: Protective Groups in Organic Synthesis, Wiley, N.Y., 1981), and W is a Wittig, Wittig-Horner or Peterson-like moiety, optionally followed by halogenation and dehydration or by hydration, after which the compound obtained is converted into a nitrile or condensed with a Wittig(-like) compound of the formula R
6
W, wherein W has the previously given meaning and R
6
is independently hydrogen, halogen or (1-6 C) alkyl, followed by hydroboration, optionally followed by alkylation, halogenation, or halogenation and dehydrohalogenation, or (partial) hydrogenation, after which optionally present protective groups are removed.
Suitable reagents are triphenylphosphoranes such as R
4
′R
4
″CH—P(Hal)Ph
3
and the like, and suitable Peterson reagents are, for example, trimethylsilane reagents like R
4
′R
4
″C(MgHal)Si(CH
3
)
3
, wherein Ha

Affiliated with

Also associated with

Rating

C-11 substituted steroids for treating menopausal complaints does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with C-11 substituted steroids for treating menopausal complaints, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and C-11 substituted steroids for treating menopausal complaints will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2521228