Drug – bio-affecting and body treating compositions – Contraceptive
Reexamination Certificate
2000-03-30
2001-11-06
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Contraceptive
C514S169000, C514S178000, C514S179000, C514S182000, C552S514000
Reexamination Certificate
active
06313180
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a new class of steroid compounds, and in particular to a steroid compound having the formula (I)
wherein:
R
3
is ═O; —OH; ═NOR; —OR or —OOCR, in which R is an alkyl group having 1 to 6 carbon atoms;
R
6
is H; ═CH
2
or —(CH
2
)
m
H with m is 1 or 2 wherein the steroid compound optionally may have one or more double bonds chosen from the group of &Dgr;9(10); &Dgr;5(10); &Dgr;4(5); &Dgr;11(12); &Dgr;14(15); or any of the rings A or B may be aromatic; The presence or absence of hydrogen atoms that have not been depicted, depends on whether a given ring is saturated, unsaturated, or aromatic, and is immediately evident to the normally skilled person.
R
7
is H; C
1-4
-alkyl; C
2-5
alkenyl or C
2-5
-alkynyl, wherein the alkyl, alkenyl or alkynyl group may be substituted with 1 to 3 halogen atoms independently selected from the group of fluorine and chlorine atoms;
R
11
is H; C
1-4
-alkyl; C
2-4
-alkenyl; C
2-4
-alkynyl or C
1-4
-alkylidene, wherein the alkyl, alkenyl; alkynyl or alkylidene group may be substituted with 1 to 3 halogen atoms independently selected from the group of fluorine and chlorine atoms;
E represents, including carbon atoms 16 and 17 of ring D, a four to seven-membered ring, said ring being a with respect to the D-ring, substituted with R
E
and optionally comprising one or two endocyclic double bonds; The &agr;-position of ring E vis-à-vis ring D is essential, as the corresponding steroids having a ring E in the &bgr;-position do not possess the required biological activity. It should be noted that, for reasons of nomenclature, some compounds according to the invention have a name which includes a reference to 16&bgr; and/or 17&bgr; substituents. However, irrespective thereof, in all compounds of the invention, the E-ring as a whole is &agr;.
R
E
is H; C
1-6
-alkyl; C
2-6
-alkenyl; C
2-6
-alkynyl; C
1-6
-alkylidene; C
2-6
-spiro-annulated cycloalkyl; —OR; —SR; —OOCR; —NHR; —NRR; —NHCOR, wherein R (and in the case of R
E
being —NRR each R independently of the other) is an alkyl with 1 to 6 carbon atoms; —NCO; —(CH
2
)
n
—N
3
or —(CH
2
)
n
—CN, with n is 0 to 5, wherein the alkyl, alkenyl, alkynyl, alkylidene or cycloalkyl group may be substituted with 1 to 3 substituents independently selected from the group consisting of —OR; —SR; —OOCR; —NHR; —NRR; and —NHCOR, with R being defined as above, fluorine atoms and chlorine atoms;
R
17
is —OH; —OCH
2
OR; —OR or —OOCR wherein R is an alkyl with 1 to 6 carbon atoms;
Any alkyl alkenyl, alkynyl and alkylidene groups in the steroid compound having the formula (I) may be branched or unbranched. If R
3
, R
6
or R
11
is connected to the steroid skeleton through a single bond, the substituted carbon atom of the steroid skeleton either comprises a hydrogen atom or is involved in a double carbon-carbon bond. R
E
is connected to the E-ring through a single bond, the substituted carbon atom of the E-ring also comprises a hydrogen atom.
It was surprisingly found that the steroid compounds of the present invention have excellent and interesting estrogenic and/or progestagenic properties. Due to these specific characteristics, the steroid compounds of the present invention are very suitable for use in the prevention or treatment of peri-menopausal or post-menopausal complaints, including climacteric symptoms such as hot flushes and mood disturbances, urogenital complaints such as incontinence, skin (and vagina epithelium) atrophy, and other symptoms associated with estrogen-deficiency or estrogen withdrawal, such as osteoporosis, atherosclerosis, and Alzheimer's disease. The steroid compounds according to the invention are very suitable for the prevention or treatment of osteoporosis resulting from estrogen-deficiency.
Furthermore, the steroid compounds of the present invention can be used for contraceptive purposes.
BACKGROUND OF THE INVENTION
Steroid compounds having a 16, 17-ring substitution have been described. Chemical Abstracts 89: 215660p (Kamernitskii A V. et al.) describes a steroid compound comprising a 16,17 anellated 5- or 6-membered ring and an acetyl group at position 17. The compounds disclosed in this publication however differ from the steroid compounds according to the present invention in that the carbon atom at position 11 carries a hydrogen atom.
Chemical Abstracts 123: 285604t (Wang, J. et al.) discloses steroid compounds having a 10-membered E-ring with two triple bonds, a hydroxyl group at position 17, and a hydrogen atom at position 11.
EP 411.733 (Schering AG) discloses a steroid compound having a 6-membered E-ring, the carbon atom at position 17 being involved in a CO-bond. The compounds disclosed in EP 411733 however differ from the steroid compounds according to the present invention in that the carbon atom at position 11 carries a (substituted) aryl group. These compounds are disclosed to be competitive antagonists for progesterone.
SUMMARY OF THE INVENTION
Thus, none of this prior art references disclose the steroid compounds according to the present invention. The steroid compounds according to the present invention differ from those disclosed in the state of the art by the substitution at position 11, 16, and 17. More in particular, the steroid compounds according to the invention comprise a ring E, sharing carbon atoms at position 16 and 17 with the five-membered ring D and being &agr; with respect to said D-ring. In addition, the carbon atom at position 17 is substituted with an oxygen atom-comprising group through a CO bond. The carbon atom at position 11 does not carry an aryl group.
Furthermore, none of the above publications suggests the interesting pharmaceutical properties of the steroid compound according to the present invention. Hence, the steroid compounds according to the present invention form a novel class of steroid compounds, as defined by their in vitro and in vivo activity.
Specifically for obtaining selective estrogen activities, in the steroid compounds according to the invention, the E-ring suitably is a five-membered ring. It is preferred that the E-ring is a six-membered ring, in view of the compounds' favourable estrogen/progestogen profiles, which include both potent, selective estrogens, and potent mixed estrogen/progestagen compounds. According to a preferred embodiment, the A-ring is aromatic and the remaining rings are saturated, wherein it is further preferred that R
7
is &agr;-propyl. The most preferred compound, coded Org 38515, is further characterized in that R
3
and R
17
are OH, and R
6
, R
11
, and R
E
are H.
The present invention also relates to a pharmaceutical composition comprising the steroid compound according to the invention mixed with a pharmaceutically acceptable auxiliary, such as described in the standard reference, Gennaro et al., Remmington's Pharmaceutical Sciences, (18th ed., Mack publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture.). The mixture of the steroid compounds according to the invention and the pharmaceutically acceptable auxiliary may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liquids the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g. nasal spray. For making dosage units, e.g. tablets, the use of conventional additives such as fillers, colorants. polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used. The steroid compounds of the invention may also be included in an implant, a vaginal ring, a patch, a gel, and any other preparation for sustained release.
Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof used in suitable amounts.
Furthermore, the invention relates to the use of the steroi
Akzo Nobel N.V.
Badio Barbara P.
Sullivan Michael G.
LandOfFree
Steroid compounds having contraceptive and anti-osteoporosis... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Steroid compounds having contraceptive and anti-osteoporosis..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Steroid compounds having contraceptive and anti-osteoporosis... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2585244