Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
2000-12-20
2002-05-14
Qazi, Sabiha (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C514S182000, C514S172000, C514S173000, C514S174000, C552S508000, C552S610000, C552S523000, C552S623000
Reexamination Certificate
active
06388109
ABSTRACT:
DESCRIPTION
The invention relates to new 14,15-cyclopropano steroids of the 19-norandrostane series, their production and pharmaceutical preparations that contain these compounds.
14,15-Cyclopropano steroids of the 19-norandrostane series of general formula I
as described.
In general formula I, R
1
is a hydrogen atom or an alkyl radical with 1-9 carbon atoms,
R
2
stands for a hydrogen atom or a methyl group,
R
3
and R
4
, independently of one another, stand for a hydrogen atom, for a hydroxy group, for an acyloxy group —O—CO—R
5
with R
5
standing for 1-10 carbon atoms, for a carbamoyloxy group O—CO—NHR
6
, with R
6
standing for a hydrogen atom, an alkyl or aryl radical with 1-5 carbon atoms in each case, for a sulfamoyloxy group —O—SO
2
—NR
7
R
8
with R
7
and R
8
, independently of one another, in each case standing for a hydrogen atom, an alkyl group with 1 to 5 carbon atoms or together with the nitrogen atom for a pyrrolidino, piperidino or morpholino group, for a grouping —CH
2
R
9
with R
9
standing for a hydroxy group, an alkyloxy group with 1-5 carbon atoms, a chlorine or bromine atom, an azido, nitrilo or thiocyano group or for a grouping —SR
10
with R
10
standing for an alkyl group with 1-5 carbon atoms,
or R
3
and R
4
together stand for an oxo group,
or R
3
and R
4
, with the inclusion of C-17, form a spirooxirane or a 2,2-dimethyl-1,3-dioxolane,
and the 14,15-cyclopropane ring is arranged either in &agr;- or &bgr;-position, whereby R
2
is an &agr;-position, if the cyclopropane ring is in &bgr;-position and vice versa.
The compounds according to the invention, the new 14,15-cyclopropano steroids of the 19-norandrostane series, have not yet been described. Their biological action is still unknown.
The object of this invention is to make available 14,15-cyclopropano steroids of the 19-norandrostane series of general formula
and their pharmaceutically acceptable salts as well as a process for their production.
Another object is to make available pharmaceutical preparations that contain at least one compound of general formula I or their pharmaceutically acceptable salts.
In general formula I
R
1
is a hydrogen atom or an alkyl radical with 1-9 carbon atoms,
R
2
stands for a hydrogen atom or a methyl group,
R
3
and R
4
, independently of one another, stand for a hydrogen atom, for a hydroxy group, for an acyloxy group —O—CO—R
5
with R
5
standing for 1-10 carbon atoms, for a carbamoyloxy group —O—CO—NHR
6
, with R
6
standing for a hydrogen atom, an alkyl or aryl radical with 1-5 carbon atoms in each case, for a sulfamoyloxy group —O—SO
2
—NR
7
R
8
with R
7
and R
8
, independently of one another, in each case standing for a hydrogen atom, an alkyl group with 1 to 5 carbon atoms or together with the nitrogen atom for a pyrrolidino, piperidino or morpholino group, for a grouping —CH
2
R
9
with R
9
standing for a hydroxy group, an alkyloxy group with 1-5C atoms, a chlorine or bromine atom, an azido, nitrilo or thiocyano group or for a grouping —SR
10
with R
10
standing for an alkyl group with 1-5 carbon atoms,
or R
3
and R
4
together stand for an oxo group,
or R
3
and R
4
, with the inclusion of C-17, form a spirooxirane or a 2,2-dimethyl-1,3-dioxolane,
and the 14,15-cyclopropane ring is arranged either in &agr;- or &bgr;-position, whereby R
2
is in &agr;-position, if the cyclopropane ring is in &bgr;-position and vice versa.
Most preferred are
17&bgr;-Hydroxy-14&agr;,15&agr;-methylenestr-4-en-3-one (J 1129),
17&agr;-hydroxy-14&agr;,15&agr;-methylenestr-4-en-3-one,
17&bgr;-hydroxy-15&bgr;-methyl-14&agr;,15&agr;-methylenestr-4-en-3-one,
17&bgr;-hydroxy-15&agr;-methyl-14&bgr;,15&bgr;-methylenestr-4-en-3-one,
17&bgr;-hydroxy-17&agr;-hydroxymethyl-14&agr;,15&agr;-methylenestr-4-en-3-one,
17&agr;-methoxy-17&bgr;-methyloxymethyl-14&agr;,15&agr;-methylenestr-4-en-3-one,
17&bgr;-hydroxy-7&agr;-methyl-14&agr;,15&agr;-methylenestr-4-en-3-one,
17,20-isopropylidenedioxy-14&agr;,15&agr;-methylene-19,21-bis-nor-17&agr;-pregn-4-en-3-one,
3-oxo-14&agr;,15&agr;-methylenestr-4-en-17&bgr;-yl-sulfamate,
3-oxo-14&agr;,15&agr;-methylenestr-4-en-17&bgr;-yl-n-butanoate,
17&bgr;-hydroxy-17&agr;-methyloxymethyl-14&bgr;,15&bgr;-methylenestr-4-en-3-one (J 1222),
17&agr;-ethylthiomethyl-17&bgr;-hydroxy-14&bgr;,15&bgr;-methylenestr-4-en-3-one (J 1411),
17&agr;-chloromethyl-17&bgr;-hydroxy-14&bgr;,15&bgr;-methylenestr-4-en-3-one (J 1364),
17&agr;-azidomethyl-17&bgr;-hydroxy-14&bgr;,15&bgr;-methylenestr-4-en-3-one (J 1370),
17&agr;-bromomethyl-17&bgr;-hydroxy-14&bgr;,15&bgr;-ethylenestr-4-en-3-one (J 1424),
17&bgr;-hydroxy-17&agr;-rhodanomethyl-14&bgr;,15&bgr;-methylenestr-4-en-3-one (J 1470),
17&agr;-cyanomethyl-17&bgr;-hydroxy-14&bgr;,15&bgr;-methylenestr-4-en-3-one (J 1517).
The invention also relates to a process for the production of the compounds according to general formula I and their pharmaceutically acceptable salts, which is characterized in that a compound of general formula II
in which R
1
, R
2
, R
3
and R
5
have the above-indicated meaning, is produced by enol ether cleavage in a way that is known in the art.
The enol ether cleavage is performed by the action of strong acids, such as sulfuric acid, hydrochloric acid or organic sulfonic acids, on the compounds of general formula I that are dissolved in a suitable organic solvent.
Subjects of this invention are pharmaceutical substances for oral, rectal, subcutaneous, intravenous or intramuscular use, which together with the commonly used vehicles and diluents can contain at least one compound of general formula I or its acid addition salts as an active ingredient.
Pharmaceutical preparations of the invention are produced with the commonly used solid or liquid vehicles and/or diluents and the generally commonly used adjuvants corresponding to the desired type of administration in a suitable dosage and in a way that is known in the art. In the case of a preferred oral form for dispensing, preferably tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspensions are also prepared as a depot form.
In addition, parenteral dosage forms such as injection solutions or else suppositories are also considered.
Dosage forms as tablets can be obtained by, for example, mixing the active ingredient with known adjuvants, such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, explosives such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents that can achieve a depot effect, such as carboxylpolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.
Coated tablets can be prepared analogously by coating cores that are produced analogously to the tablets with agents that are commonly used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. In this case, the coated tablet shell can also consist of several layers, whereby for example, the above-mentioned adjuvants are used.
To improve the taste, the solutions or suspensions with the active ingredient according to the invention can be mixed with substances such as saccharin, cyclamate or sugar and/or with flavoring substances, such as vanillin or orange extract. In addition, they can be mixed with suspension adjuvants, such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoic acid.
The preparation of capsules can be carried out by mixing a pharmaceutical substance with vehicles such as lactose or sorbitol, which then are introduced into the capsules.
The production of suppositories is preferably carried out by mixing the active ingredient with suitable vehicles, such as neutral fats or polyethylene glycols or derivatives thereof.
In addition, the pharmaceutical preparation forms can be percutaneous preparation forms, e.g., transdermal therapeutic systems (TS) or gels, sprays or ointments or intranasal preparation forms such as nose spray or nose drops.
The 14,15-cyclopropano steroids of the 19-norandrostane seri
Elger Walter
Kaufmann Günter
Ring Sven
Schneider Birgitt
Schubert Gerd
Jenapharm GmbH & Co. KG
Millen White Zelano & Branigan P.C.
Qazi Sabiha
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