Oxyiminopregnancarbolactones

Details Oxyiminopregnancarbolactones Oxyiminopregnancarbolactones

1999-10-05

2001-01-23

Badio, Barbara (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C540S041000, C540S044000, C540S132000

Reexamination Certificate

active

06177416

ABSTRACT:

The invention relates to the new oxyiminopregnanecarbolactones of general formula I, a process for their production, pharmaceutical preparations that contain these oxyiminopregnanecarbolactones, as well as their use for the production of pharmaceutical agents.
The invention relates to the (E,Z)-mixtures and the isomer-pure (E) and (Z) compounds of formula I,
in which
R means a hydrogen atom or an acyl radical with 2 to 10 C atoms.
As an acyl radical R, a radical C(O)R′, in which R′ is a hydrocarbon radical that is straight-chain or branched-chain or cyclic, saturated, or unsaturated in up to three places; an alkylcycloalkyl or cycloalkenyl radical, in each case with up to 9 carbon atoms; or a benzoyl radical, is suitable.
Preferred radicals for R are either the hydrogen atom or a more linear, saturated alkanoyl radical with 2 to 10 carbon atoms, i.e., R′ is a methyl, ethyl, propyl, butyl, pentyl, hexyl, hepty, octyl, or nonyl group.
As a branched-chain, saturated hydrocarbon radical, for example, the i-propyl or t-butyl radical can be cited.
As a cyclic hydrocarbon radical, primarily the cyclopropyl, cyclopentyl, or cyclohexyl radicals are suitable.
The methylcyclopropyl, methylcyclohexyl, or methylcyclohexenyl radicals can be cited as representatives of an alkylcycloalkyl or cycloalkenyl radical.
The 3-keto compound of formula II (drospirenone) that is analogous to the compounds of general formula I
is described as a compound with
a) an anti-aldosteronic action (DE-A 26 52 761)
b) a gestagenic action (DE-A 30 22 337), as well as
c) a strong antiandrogenic action, and this at a dosage that is sufficient for contraception (DE-A 39 16 112).
Drospirenone is the first synthetic gestagen which, like natural progesterone, exhibits all three partial actions a), b), and c), in a common dose range, but unlike progesterone is also bio-available in a relevant amount after oral administration. Drospirenone can therefore be used either by itself or preferably in combination preparations together with an estrogen for hormonal contraception and/or for hormone replacement therapy. Owing to the antimineralocorticoids and antiandrogenic partial action, these preparations are also suitable for users for whom hormonal combination preparations are otherwise contraindicated (DE-A 39 16 112).
The required daily dose of drospirenone for contraception or hormone replacement therapy is 1 to 10 mg.
For some time now, transdermal administration as well as subcutaneous administration by so-called implants of hormonal active ingredients has been of great interest for hormone replacement therapy and recently also for contraception (Te-Yen Chien et al., “Transdermal Contraceptive Delivery System: Preclinical Development and Clinical Assessment” in Drug Development and Industrial Pharmacy, 20(4), 633-664 (1994)).
To date, drospirenone's disadvantageous physicochemical substance properties, such as, e.g., low solubility in organic polymers, has hampered reasonable use of it via the last-mentioned routes of administration.
The object of this invention therefore consists in converting drospirenone into derivatives that are to have considerably improved physicochemical substance properties, without the very advantageous pharmacological profile being significantly altered.
It has now been found that this can be achieved by converting drospirenone into the 3-oxime derivative (R=H) or the corresponding O-acyl derivative (R=acyl) of general formula I. The derivatives of general formula I are distinguished by, surprisingly enough, several times greater solubility than drospirenone in organic polymers, which are suitable as skin contact adhesives, such as, e.g., polyacrylates, silicone adhesives, synthetic rubber). In the case of transdermal administration, only this greatly increased solubility permits the release of the intact prodrug of general formula I from the matrix in an amount that can ensure an adequate transdermal flow of the active compound (drospirenone) or else its prodrug (compound of general formula I). This is in turn a prerequisite for a more relevant active ingredient level in the serum actually to be brought about.
The compounds thus are the first to actually make it possible to take full advantage of the contraceptive or therapeutic action of drospirenone after transdermal administration of a prodrug. Just like drospirenone itself, they can also be given orally, however.
Contraceptively effective 3-oximes and O-acylates have already been described in the 19-nortestosterone series. Levonorgestrel-oxime-17-acetate has been on the OC market for some years as a combination preparation with ethinylestradiol (DE 16 18 752, DE 16 20 102, DE 26 33 210, U.S. Pat. No. 3,780,073, U.S. Pat. No. 4,027,019, all Ortho Pharmaceutical Corp.).
Pharmacologically active 3-oximes and O-acylates of steroid-spirolactones have not been described to date; only 3-hydroxyimino-5&bgr;,17&agr;-pregnane-21,17-carbolactone is described in DE 43 21 937 as an intermediate compound for the production of the corresponding 3-amino compound that is suitable for treatment of latent and manifest heart failure.
The object of the invention is also the process for the production of the compounds of formula I.
The production of the compounds of formula I is characterized in that the compound of formula II (drospirenone)
is converted into 3-hydroxyimino compounds and the latter are then optionally reacted by esterification with a carboxylic anhydride [(R′C(O)]
2
O or an acid halide R′C(O)X (X=Cl, Br; R′ has the meaning indicated in general formula I) in the presence of a base into the 3-acyloxyimino compounds.
The oxime of general formula I (i.e., R=H) is produced in the reaction of drospirenone with hydroxylamine-hydrochloride/pyridine as an (E,Z)-mixture with an (E,Z) ratio≈4:1.
By reaction with the corresponding acid anhydride or acid halide in the presence of pyridine, optionally with the addition of dimethylaminopyridine, the (E,Z)-mixture of oxime is converted into the acyloxyimino compounds [i.e., R=C(O)R′] of general formula I.
The C=N double bond that is contained in the compounds of formula I gives rise to the production of geometric isomers in the form of (E,Z)-mixtures, which can be separated chromatographically into pure (E) and (Z) isomers.
The compounds according to the invention are extremely active gestagens, which are suitable for maintaining pregnancies when administered transdermally, parenterally, as well as orally. In combination with an estrogen, combination preparations can be obtained that can be used for contraception and with menopausal symptoms.
Owing to their high gestagenic activity, the new compounds of general formula (I) can be used, for example, by themselves or in combination with estrogens in preparations for contraception. The new compounds, however, also open all other possible uses that are now known for gestagens (see, e.g., “Kontrazeption mit Hormonen [Contraception with Hormones],” Hans-Dieter Taubert and Herbert Kuhl, Georg Thieme Verlag Stuttgart—New York, 1995).
The dosage of the active ingredients can vary depending on the method of administration, age and weight of the patient, the desired indication, as well as the type and severity of the disease to be treated and similar factors. The daily dose is 0.1-25 mg, preferably 0.5-5 mg, whereby the dose can be given as a single dose to be administered once or divided into two or more daily doses. In the case of the transdermal systems, up to 14 daily doses can also be given in sequence by a system. In the case of implants, intravaginal systems, such as, e.g., a vaginal ring and intrauterine systems, such as, e.g., mirena, the active ingredients may be administered over a period of up to 3 years.
The gestagenic and estrogenic active ingredient components are preferably administered together in contraception preparations. In the case of oral administration, the daily dose is preferably administered one time.
As estrogens, all na

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