Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-05-29
2003-06-17
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S178000, C514S182000, C514S169000, C552S515000, C552S516000, C552S519000, C552S526000, C552S530000, C552S533000
Reexamination Certificate
active
06579864
ABSTRACT:
This application is the 35 U.S.C. §371 filing of PCT/EP00/11787, filed Nov. 23, 2000.
FIELD OF THE INVENTION
The invention relates to new 3-methylene steroid derivatives with therapeutic effects and to the preparation of pharmaceutical preparations comprising a 3-alkylidene steroid.
BACKGROUND OF THE INVENTION
Steroids with methylene substituents at the 3 position of the steroid skeleton and 1-2 or 4-5 double bonds are known and claimed to be useful for therapeutic use (BE 696,235 and BE 654,772, respectively). The presumed medical indication is due to anabolic, estrogenic and progestogenic actions. None of these compounds has lived up to the expectations for such use and there was no expectation for utility as medicines in other areas, although many diseases still remain unsatisfactorily treated with presently available drugs. Notably, diseases of the immune system, such as rheumatoid arthritis and autoimmune diseases are in need for better drugs. Corticosteroidal agents are of some use for the treatment of these diseases, but improvements, both with respect to efficacy and number or severity of side effects, are needed.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides for 3-methylene steroid derivatives and prodrugs thereof, which steroid derivatives have the general formula 1
wherein
R
1
is H or together with R
3
forms a &bgr;-epoxide or R
1
is absent if there is a 5-10 or 4-5 double bond;
R
2
is (C
1
-C
5
)alkyl or CF
3
;
R
3
is &bgr;H, &bgr;CH
3
or together with R
1
forms a &bgr;-epoxide or R
3
is absent if there is a 5-10 double bond;
R
4
is H, lower alkyl;
Y is [H, H] [OH, H], ═O, [OH, lower alkyl], [OH, (C
2
-C
5
)alkenyl], [OH, (C
2
-C
5
)alkynyl] or (C
1
-C
6
)alkylidene, whereby said alkyl, alkenyl, alkynyl and alkylidene is optionally halogenated; or ═NOR
5
, whereby R
5
is H, lower alkyl.
Dotted lines represent an optional double bond.
Preferred compounds according to the invention are those wherein R
4
is H and Y is [OH, H], ═O, [OH, lower alkyl], [OH, (C
2
-C
5
)alkenyl], [OH, (C
2
-C
5
)alkynyl] or (C
1
-C
6
)alkylidene, whereby said alkyl, alkenyl, alkynyl and alkylidene optionally might be halogenated.
In this description terms have the following meaning:
A lower alkyl is a branched or unbranched alkyl group having preferably 1-6 carbon atoms, like hexyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl, and methyl. Most preferred are alkyl groups having 1-3 carbon atoms.
(C
1
-C
5
)alkyl is a branched or unbranched alkyl group having 1-5 carbon atoms, for example methyl, ethyl, isopropyl, butyl, sec-butyl, tert-butyl etc.; Preferred are alkyl groups having 1-3 carbon atoms.
(C
2
-C
5
)alkenyl is a branched or unbranched alkenyl group having 2 to 5 carbon atoms, such as ethenyl, 2-butenyl, etc. Preferred are alkenyl groups having 2-3 carbon atoms.
(C
2
-C
5
)alkynyl is a branched or unbranched alkynyl group having 2-5 carbon atoms, such as ethynyl and propynyl etc. Preferred are alkynyl groups having 2-3 carbon atoms.
(C
1
-C
5
)alkylidene is a branched or unbranched alkylidene group having 1-5 carbon atoms, such as methenyl, butylidene etc. Preferred are alkylidene groups having 2-3 carbon atoms.
Halogen is fluorine, chlorine, bromine, and iodine.
Prodrugs are compounds which are designed to form a compound of the invention in the body of a recipient for treatment. In general such prodrugs can be esters or ethers of the 17-hydroxyl function.
A preferred embodiment of this invention is a compound as described above having a 5-10 double bond. Most preferred is the compound (7&agr;,17&agr;)-7-methyl-3-methylene-19-norpregn-5(10)-en-20-yn-17-ol. Excluded from the invention are the compounds (7&agr;,17&bgr;)-7&agr;-methyl-3-methylene-4-estren-17-ol, (7&agr;,17&agr;)-7-methyl-3-methylene-19-norpregn-4-ene-17-ol, (7&agr;,17&agr;)-7-methyl-3-methylene-19,21-dinorpregn-4-ene-17-ol, (7&agr;)-17-keto-7-methyl-3-methylene-4-estrene, (7&agr;,17&agr;)-7-methyl-3-methylene-19-norpregn-4-en-20-yn-17-ol, 17&bgr;-hydroxy-7&agr;-methyl-3-methylene-17&agr;-propen-2-yl-4-estrene, and 17&bgr;-hydroxy-7&agr;-methyl-3-methylene-17&agr;-buten-2-yl-4-estrene. The disclaimer relates to the disclosures in BE 696,235.
The epoxide compounds (R
1
and R
3
together form &bgr;-O-) of this invention can be prepared by oxidation of a compound having the formula 2 in which the symbols have the meaning as defined above, with metachloroperoxybenzoic acid
The 3-methylene group in a compound of the invention can be obtained by performing a Wittig reaction using methyltriphenylphosphonium bromide and potassium t-butoxide with corresponding 3-keto precursor steroids, which are characterized by formula 3, wherein Y
2
is as Y, as defined above, except that it is not ═O and the other symbols have the meaning as defined before.
The 17-alkylidene compounds of the invention can be prepared by a Wittig reaction of a 3-ketal derivative of the 17-keto derivative according to formula 4, wherein the symbols have the meaning as defined before, with an alkyltriphenylphosphonium bromide followed by the hydrolysis of the 3-ketal function. The compounds having Y═H, H at the 17-position (formula 2) of the invention can be prepared by Wolff-Kishner reduction of the 17-keto moiety of the 3-ketal compound of formula 4, wherein the symbols have the meaning as defined before. The 17-oxime derivatives of the invention can be prepared by condensation of the 17-ketofunction (formula 4) with hydroxylamine derivatives. The 16-alkyl compound of the invention can be prepared by alkylation of the 16-position of the 17-keto compound (Y═O, formula 4).
The above indicated reagents for transformation of the starting compounds and their ways of reacting with compounds are known in the art, but not yet applied for the group of compounds to be prepared to obtain the compounds of the invention. Starting materials can be obtained by methods described in the literature. A specifically relevant reference is Van Vliet et al. Recl.Trav.Chim.Pays-Bas; EN; 105; 4; 1986; 111-115, which text is incorporated into this description by way of reference. Notably, it is described therein that 17-alkyl-3-keto-derivatives according to formula 3, wherein Y
2
is [OH, lower alkyl] and the other symbols have the meaning as defined before, can be obtained by catalytic hydrogenation, for example with PtO
2
/H
2
, of a compound according to formula 3, wherein Y
2
is [OH, alkenyl] or [OH, alkynyl] and the other symbols have the meaning as defined before. Derivatives according to formula 5 can be obtained by purification from a mixture of compounds formed after the Birch reduction of the 4-en-3-one derivative according to formula 6, whereby both in formula 5 and in formula 6 the symbols have the meanings as defined before.
A 4-en-3-one derivative according to formula 6, wherein R
3
is H and the other symbols have the meanings as defined before, can be obtained from a compound according to formula 7 by double bond isomerisation (according to methods described in van Vliet et. al. 1986).
A 4-en-3-one derivative according to formula 6, wherein R
3
is methyl and the other symbols have the meanings as defined before, can be obtained according to the methods described in Grunwell et. al., Steroids Vol. 27, pages 759-771, 1976, which publication is incorporated herein by reference.
Further methods to obtain compounds according to formula 7 as starting material can be prepared as described by van Vliet et al. 1986.
The use of compounds as defined by formula 1 is for immunomodulation in mammals. A compound of this invention can in particular be used in the treatment of arthritic diseases such as rheumatoid arthritis (RA) and autoimmune diseases (AIDs) such as Sjögren's syndrome and systemic lupus erythematosus (SLE). It can also be used prophylactically for such diseases. Furthermore, a compound according to this invention can be used for the preparation of medicines comprising a
Bagchus Wilhelmina Maria
Plate Ralf
Akzo Nobel NV
Milstead Mark W.
Qazi Sabiha
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