Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-06-22
2004-07-27
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S169000, C514S177000, C552S623000, C552S625000, C552S505000
Reexamination Certificate
active
06767903
ABSTRACT:
This invention relates to new 7&agr;, 17&agr;, 17&bgr;-substituted testosterone derivatives of general formula I and their use as pure antiandrogens for long-term therapy for androgen-dependent diseases, especially for long-term antiandrogen therapy for prostate cancer.
Current therapies of androgen-dependent diseases are based on the reduction or as complete as possible elimination of androgen-induced effects. This can be done by blocking the domains of androgen receptor (AR), to which the androgens bind as ligands, or by reduction of the available amount of androgens themselves (ligand depletion). In prostate cancer treatment, “ligand depletions mean” a reduction of the serum testosterone level of testicular origin, which is to be achieved either with use of orchidectomy (removal of a testicle) or by hormone treatment with LRRH analogs or estrogens in high doses. This therapy for inhibiting androgen synthesis and/or reducing androgen concentration is effective only to a limited extent, however, since it has been noted in the meantime that even in the case of total absence of an androgen, non-blocked androgen receptors can be biologically active (ligand-independent AR activation).
As an alternative or as an amendment to “ligand depletion,” the antiandrogen therapy is used, which is based on the antagonistic blocking of the androgen receptor by so-called “antiandrogens” (nonsteroidal or steroidal compounds). Known antiandrogens, which are already used in clinical practice for prostate cancer treatment, are CPA (Schering AG), flutamide (Schering Plough), Casodex (Zeneca) and Anandron
(R)
(Roussel).
Although 80% of patients first respond to the above-mentioned therapies, almost all of these patients suffer a relapse as early as after an average treatment period of 12-18 months. It has been shown that even the AR blocking by the currently available antiandrogens is inadequate, since the latter either have insufficient active strength and/or can even activate the androgen receptor, i.e. can act like androgens (partial agonism).
Compounds that can act as inhibitors of androgen synthesis and for as blockers of the androgen receptor are also described in WO91/00732. In this case, these are substituted steroids, which have at least one long side chain in one of positions 6&agr;, 7&agr;, 14&agr;, 15&agr;, 16&agr;, 17&agr; and 17&bgr;. Described as preferred compounds are EM 101, a testosterone that is substituted in 17&bgr;-position with hydroxy and in 7&agr;-position with a long-chain alkylamide, and EM 150, a testosterone that is substituted in 17&bgr;-position with hydroxy and in 17&agr;-position with a long-chain iodoalkine. These compounds also have the above-described drawbacks.
In summary, it has been determined that there is currently no satisfactory therapy for androgen-dependent diseases, such as, e.g., for prostate cancer, and in particular no long-term therapy is possible. The known antiandrogen compounds do not have the necessary active strength to ensure complete blocking of the androgen receptor activity or to have a partially agonistic action.
The object of this invention was therefore to provide potent antiandrogenic compounds that make possible a long-term therapy for androgen-dependent diseases. In particular, prostate cancer can be treated effectively with these compounds.
The object of this invention is achieved by new 7&agr;-, 17&agr;-, 17&bgr;-substituted testosterone derivatives of general formula I
in which
R
6
represents a hydrogen atom, a hydroxy group, a C
1
-C
10
alkoxy group, a C
1
-C
10
alkanoyloxy group or a halogen atom,
R
15
and R
16
each are a hydrogen atom or together form a bond,
R
17a
represents a C
1
-C
4
alkyl group, a C
2
-C
4
alkinyl group, or a radical of Formula C
n
F
m
H
o
, whereby n=1, 2, 3 or 4, m>1 and m+o=2n+1,
R
17b
is a hydroxy group, a C
1
-C
10
alkoxy group or a C
1
-C
10
alkanoyloxy group,
A is an unbranched C
1
-C
13
alkylene group,
B represents an oxygen n atom, a grouping —S(O)
p
—, whereby p=0, 1 or 2, an iminocarbonyl group —C(O)N(Y)—, an imino group —N(Y)—, a carbonylimino group —N(Y)C(O)—, a sulfonylimino group —N(Y)S(O)
2
—, whereby Y is a hydrogen atom or a C
1
-C
8
alkyl group, a sulfonyloxy group —OS(O)
2
—, a dimethylsilyloxy group —O—Si(CH
3
)
2
— or a carbonylsulfanyl group —SC(O)—, or B represents a bond between A and C or together with C forms a bond between A and D,
C represents a bond between B and D, or together with B forms a bond between A and D or an unbranched, C
1
-C
6
alkylene group, a phenylene group, a substituted phenylene group, a five-ring or six-ring heteroarylene group, a substituted five-ring or six-ring heteroarylene group or a five-ring or six-ring heteroarylene group that is condensed with a phenyl ring, and
D represents a hydrogen atom, a C
1
-C
4
alkyl group, a vinyl group, a C
1
-C
4
alkoxy group, a C
1
-C
4
alkoxycarbonyl group, a bis(C
1
-C
4
alkoxycarbonyl)methyl group, an acetyl(C
1
-C
4
alkoxycarbonyl)methyl group, a cyano group, a carboxy group, an azide group, a hydroxy group, a halogen atom or a radical of formula C
n
F
m
H
o
, whereby n=1, 2, 3 or 4, m>1 and m+o=2n+1.
In a preferred embodiment of the invention, R
17a
in general formula I means the methyl or ethyl group or the trifluoromethyl or pentafluoroethyl group. Radical R
17b
preferably represents the hydroxy group, a C
1
-C
5
alkoxy group or a C
1
-C
3
alkanoyl group. Quite especially preferably, R
17b
means the hydroxy, methoxy, ethoxy or acetyloxy group. For radical R
6
, a hydrogen atom, the hydroxy group or a halogen atom is preferred. In a quite especially preferred embodiment of the invention, the radical ABCD means 9-hydroxynonyl, 7-(acetylsulfanyl)heptyl or 7-(4-cyanobutoxy)heptyl.
For the purposes of this invention, the alkylene groups that are mentioned for grouping A are the heptane-1,7-diyl, the octane-1,8-diyl, the nonane-1,9-diyl, the decane-1,10-diyl, the undecane-1,11-diyl, the dodecane-1,12-diyl and the tridecane-1,13-diyl group. The equivalent applies for the alkylene groups that are defined as grouping C.
The alkyl groups that are mentioned for substituents Y and D stand both for the unbranched groups, i.e., the methyl, ethyl and propyl group, and the corresponding higher homologues, in so far as they are claimed, and for the branched representatives of the above-mentioned carbon atom numbers, e.g., the 1-methylethyl group, the 1-methylpropyl group, the 2-methylpropyl group, the 1,1-dimethylethyl group, etc. Moreover, alkyl groups are also to be defined as cyclic substituents, depending on the above-mentioned carbon atom number, e.g., the cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cyclopentylmethyl and cyclohexyl radicals.
Alkoxy groups are radicals that are derived from the above-mentioned alkyl groups and extended by one oxygen atom, thus, e.g., the methoxy, ethoxy, propoxy, 1-methylethoxy, 1-methylpropoxy, 2-methylpropoxy and 1,1-dimethylethoxy radicals.
For the purposes of this invention, alkanoyloxy groups are defined as hydroxy groups that are esterified with branched and unbranched carboxylic acids of the above-mentioned numbers of carbon atoms, thus, e.g., the formyloxy, acetyloxy, 1-oxopropoxy, 1-oxobutoxy, and 2-methyl-1-oxopropoxy radical.
The arylene and heteroarylene groups that are indicated for grouping C are linked at a substitutable position with grouping B and substituted at another substitutable position with a radical D. Preferred heteroaromatic compounds are pyrrole, thiophene, imidazole, thiazole, oxazole, triazole, thiadiazole, indole, benzoxazole, benzothiazole, pyridine, and pyrimidine. In addition, the arylene or heteroarylene groups can be substituted with a methyl group or a halogen atom.
If a halogen atom is mentioned as a substituent in one of the radicals, a fluorine, chlorine, bromine or iodine atom is suitable for this purpose. Chlorine and fluorine are preferred.
For the purposes of the invention, the following compounds of general formula I are quite espec
Cleve Arwed
Hoffmann Jens
Huwe Christoph
Parczyk Karsten
Sauer Gerhard
Millen White Zelano & Branigan P.C.
Qazi Sabiha
Schering AG
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