RS50907B - COMPOSITION CONTAINING ONE ANDROGEN 11β-HALOGENSTEROID AND ONE GESTAGEN AS A MAN'S CONTRACEPTIVE BASED ON THIS COMPOSITION - Google Patents

Abstract

A compound containing one androgenic 11βhalogensteroid, selected from the group of compounds of the general formula I in which X-Y-Z represents a group with one of the two structures CH=C-C or CH2-OC, R1 can be α or β in position and stand for hydrogen, R or a ring structure P-Q-R attached via P to the basic ring structure, wherein P and Q represent straight-chain or branched C1 to C8-alkylene-, -alkenylene-, alkynylene groups or their fluorinated derivatives and may be the same or different and wherein R represents one CH3- or CF3-residue, with the recommendation that there is no R1 substituent on Z, as long as X-Y-Z represents the CH2-C=C group, R6 is a hydrogen atom or can have the meanings listed under R, R7 stands for R or for P-Q-R via P related to the basic ring structure, where these groups have the aforementioned meanings, R11 replaces halogen, R13 is methyl or ethyl and R17 is hydrogen or stands for C(O)-R18, where R18 is straight-chain or branched C1- to C18-alkyl -, -alkenyl-, alkynyl residue or and an aryl residue, or stands for T-U-V bonded to a C(O)-group via P, wherein T and U represent straight or branched C1- to C18-alkylene-, -alkenylene-, alkynylene groups, acyclic C3- to C12-groups or aryl groups and are the same or different, and V is a straight or branched C1- to C18-alkyl-, -alkenyl-, alkynyl residue or an aryl residue, or R18 has one of the previously mentioned meanings or is additionally substituted with one or more groups NR19R20 or with one or more groups SOxR21, where x = 0, 1 or 2 and R19, R20 and R21 are each hydrogen or through T to N, S bonded T-U-V with the previously mentioned meaning, with the recommendation that in addition including physiologically tolerable addition salts with inorganic and organic acids, and the gestagen formula that follows, the Application contains 11 more patent claims.

Description

The proposed invention includes in a broader sense a kit containing an androgenic 1 lp-halogen steroid, selected from the group of compounds of the general formula I

in which

X-Y-Z represents a group with one of two structures CH=C-C or CH2-C=C,

R<1>can be a- or P-positional and stand for hydrogen, R or a ring structure P-Q-R bonded via P to the basic ring structure, where P and Q represent straight-chain or branched Ci- to C3-alkylene-, -alkenylene-, alkynylene groups or their fluorinated derivatives and can be the same or different and where R represents one CH3- or CF3-residue, with the recommendation that there is none on Z substituent R<l>, in which X-Y-Z represents the group CH2-C=C,

R6 is a hydrogen atom or can have the meanings listed under R<7>,

R<7>stands for R or for P-Q-R via P attached to the basic ring structure, these groups having the aforementioned meanings,

R<n>represents halogen,

R13 is methyl or ethyl and

R<17> is hydrogen or stands for C(0)-R<18>, wherein

R<18>is a straight or branched Ci- to Cig-alkyl-, -alkenyl-, alkynyl residue or an aryl residue, or stands for T-U-V bonded to a C(0)-group through P, wherein T and U represent straight or branched Ci- to Cig-alkylene-, -alkenylene-, alkynylene groups, acyclic C3- to Cu-groups or aryl groups and are the same or different, and V is straight-chain or branched Ci- to Ci8-alkyl-, -alkenyl-, alkynyl residue or aryl residue, or R18 has any of the aforementioned meanings or is additionally substituted with one or more groups NR<19>R<20> or with one or more groups SOxR<21>, where x = 0, 1 or 2 and R<19>, R<20> and R<21> are each hydrogen or via T to N, S connected T-U-V with previously mentioned meaning, with the recommendation that physiologically tolerable addition salts with inorganic and organic acids are also included,

and the progestogen formula that follows,

This composition is suitable for obtaining pharmaceutical compositions. Therefore, the proposed invention also relates to pharmaceutical compositions, which contain the aforementioned composition of an androgenic 11 P-halogen steroid and a gestagen formula

as well as a pharmacologically tolerable carrier and/or excipient.

Both in the composition and in the pharmaceutical composition, 1 ip-Fluor-17p-hydroxy-7a-methyl-estr-4-en-3-one is favored as an androgenic llp-halogensteroid.

In a further embodiment, the proposed invention relates to a male contraceptive based on the previous pharmaceutical composition. According to a further embodiment of the invention, the male contraceptive contains as androgens 11 p-halogensteroid 1 lp-Fluor-17<p->hydroxy-7a-methyl-estr-4-en-3-one.

In one particular embodiment of the proposed invention in the male contraceptive, both the androgenic 11 P-halogen steroid and the progestagen are formulated in such a way that both can be implanted in the body of the male user as a joint implant or as two separate implants, so that the active compounds are secreted into the body of the male user over a longer period of time.

Continuous release of progestin over a long period of time can also be achieved with a transdermal system, in which progestin is incorporated.

According to the invention, it is also conceivable to administer one active substance in an oral formulation and another active substance as an implant or transdermally. It is also possible to administer both active substances orally. Finally, the possibility of buccal or transmucosal application of one or both components of the composition according to the invention should be mentioned.

The concept of male fertility control is in agreement with the global goals of "Reproductive Health" defined by the WHO.

[Reproductive Health, see WHO task force on methods for the Regulation of Male Fertility (1990) Contraceptive efficacy of testosterone-induced azoospermia in normal men; Lancet 336: 955-959; WHO task Force on methods for the Regulation of Male Fertility (1993) Comparison of two androgens plus depot-medroxyprogesterone acetate for suppression

to azoospermia in Indonesian men; Fertil Steril 60: 1062; WHO task Force on methods for the Regulation of Male Fertility (1995) Rate of testosterone-induced suppression to severe oligozoospermia or azoospermia in two multinational clinical studies; Int J Androl 18:157-165; WHO task force on methods for the regulation of male fertility (1996)

Contraceptive efficacy of testosterone-induced or azoospermia oligozoospermia in normal men; Fertil Steril 65; 821-829]

Integral components of this strategy are male and female contraceptives. Since contraceptives, especially for men, are still lacking, the development of these is seen as absolutely necessary (Andrologie, Grundlagen und Klinik der reproducible gesundheit des Mannes; Hrsg.E. Nieschlag, H.M. Behre; Springer-Verlag, 2. Auflage, S. 442 ff, 2000). Hormonal compounds for male fertility control have gone the furthest in development. They are characterized by proven reversibility and efficiency.

Male hormonal contraceptives are based on the suppression (stop) of spermatogenesis, which ultimately leads to azoospermia and thus male infertility. Mechanically, both gonadotropins LH (Luteinizing Hormone) and FSH (Follicle Stimulating Hormone) are significantly suppressed, which means that serum concentrations of these two hormones can no longer be detected. As a consequence of LH suppression, testicular testosterone production is also suppressed (both hormones belong to the endocrine regulatory cycle). Loss of all three hormones is required to suppress spermatogenesis. An important drawback of the described method is androgen deficiency and the resulting symptoms/consequences for men.

Male contraceptive methods try to suppress LH, FSH and intratesticular testosterone and thus prevent spermatogenesis, while peripheral testosterone is replaced by exogenously supplied androgen. Testosterone or testosteronestar (for example testosterone enanthate, testosterone bucyclate) has been used as an androgen until now. The task of endocrine testosterone consists in maintaining libido, potency, masculine behavior, protein metabolism, erythropoiesis and other functions, such as the exchange of mineral and bone materials.

In short, the goal is to lower the testosterone in the testicles to the level found in the peripheral blood, while the levels in the general circulation should be kept in order.

Suppression of spermatogenesis with only testosterone or testosterone-ester, which at the first moment seemed like an ideal contraceptive, has, however, proven to be insufficiently efficient and has shown, in part, a too long time until the onset of a safe effect (onset of up to 6 months). In addition, ethnic differences were also identified. Too high doses have shown clear and unwanted side effects. When treated with testosterone, it has been shown that side effects occur, especially the enlargement of the prostate through the numerical increase of cells and glands of the stoma (BHP: benign prostatic hyperplasia). 5a-reductase-mediated metabolism of testosterone produces dihydrotestosterone (DHT), which, among other things, can lead to the formation of BHT (Cummings et al., ibid.; WO 99/13883 A1).

There is currently no testosterone for oral use, so alternative forms of administration (i.m., patch, etc.) must be used.

In order to accelerate both the onset of action and efficiency, testosterone is combined with other gonadotropin-suppressing substances, with GnRH-antagonists (GnRH = Gonadotropin Releasing Hormone). The rate of azoospermia as well as the moment of onset of action is clearly improved by this combination. However, currently available GnRH-antagonists must be applied daily (i.m. or s.c., oral application is not available) and their production is expensive. Therefore, this combination is not attractive. Administration of either the progestin cyproteroneacetate or lcvonorgestrel was either ineffective in suppressing spermatogenesis or high doses led to a significant decrease in red blood cells (Merrigiola et al., 1998; Merrigiola et al., 1997; Merrigiola et al., 1996; Bebb et al., 1996).

The use of a mixture of two compounds, one estrogen with one estrogen, in combination is described in US 4,210,644.

A method aimed at inhibiting spermatogenesis through percutaneous or oral administration of norethisterone acetate has also been described (Guerin und Rollet; 1998). To achieve azoospermia, however, quite high doses of both components were required.

To replace testosterone for male contraception, 7a-Methyl-19-nortestosterone (MeNT) has been proposed, which has a higher biological activity than testosterone, since it has a higher binding affinity to androgen receptors. Under two, it persists probably due to steric hindrance of the 7α-Methyl group to 5α-reductase metabolism (Cummings et al., WO 99/13883 A1, WO 99/13812 A1, USA 5,342,834).

Based on the last mentioned feature, a clearly more favorable side effect profile is expected in comparison with testosterone, especially regarding the prostate.

The combination of 7a-Methyl-19-nortestosterone with some progestogen could not be found in these works.

Further compounds, in their selective androgenic action comparable to 7a-Methyl-19-nortestosterone, are those according to the invention applicable androgenic 11 P-halogensteroids of the general formula I, in particular lip-Fluor-17J3-hydroxy-7a-methyl-estr-4-en-3-one.

These compounds were first described in DE 101 04 327.9. The compounds have improved metabolic stability compared to 7a-Methyl-19-nortestosterone. DE 101 04 327.9 is an unpublished document.

For the description and definition of the substituents of the compounds of the general formula I, reference is made to this document.

The compounds are proposed for use in male contraception. They can be used together with gestagens, without being more precise about which gestagens should be used.

The object of the proposed invention is to make available an androgen-/gestagen-based male contraceptive that does not rely on testosterone as an androgen. At the same time, the dose of the applied androgen should be minimized with a progestagen, thus reducing side effects.

The task is solved at the beginning with the mentioned combination of one androgenic 11 P-halogensteroid, especially 1 ip-fluoro-17p-hydroxy-7a-methyl-estr-4-en-3-one.

This progestogen is described in international patent application WO 96/20209 (DE 44 47 401.6). Co-administration with an androgen to achieve male infertility cannot be seen from this application. It is a highly effective progestagen after oral application. In this application, however, other ways of giving are proposed. Thus, a transdermal system containing this progestogen is further described in patent application EP 00250449.6.

With the use of the aforementioned combination as a male contraceptive, sufficient suppression of sperm production in the scrotum can be achieved with a lower substitution dose of androgens. In doing so, a synergistic effect is achieved.

With the help of the composition according to the invention as a male contraceptive, it succeeds, with lower dosages of both components, in suppressing the parameters of LH, FSH and testosterone in areas where they cannot be proven, i.e. in areas where they are no longer effective. Parameters LH and FSH decrease together.

For the reliability and acceptability of the contraceptive according to the invention for men, it is of decisive importance that these parameters, which are decisive for the safety of the contraceptive, fall relatively quickly. "Onset" for the contraceptive according to the invention lies approx. 3 months after the start of application.

The duration of the use of the contraceptive according to the invention can in principle and in the given case be unlimited, which means until the user no longer needs any contraception.

On the other hand, the contraceptive according to the invention guarantees the re-establishment of the user's fertility at any time.

Dosages of androgenic 1ip-halogensteroid of the general formula I, especially 11P-Fluor-17P-hydroxy-7a-methyl-estr-4-en-3-one and progestagen are chosen so that the level of LH, testosterone and FSH no later than 3 months after the start of administration lie in the areas of these parameters that are no longer effective.

For li<p->Fluoro-17<p->hydroxy-7a-methyl-estr-4-en-3-one, a daily effective dose of 0.7 µg to 1.5 µg, preferably 0.7 µg to 1.0 µg, is sufficient.

When determining the effective amount of the androgenic steroid of formula I, it can be taken into account that 1 ip-Fluor-17p-hydroxy-7a-methyl-estr-4-en-3-one is about 10 times more effective than testosterone.

In the case of application by means of an implant or another, during a longer period of time, the dispensing system must be made in such a way that the amount to be dispensed is released daily.

As a norm for dosing the progestogen applied according to the invention, it can be considered that the selected amount has a comparable effect on the suppression of spermatogenesis as a daily dose of levonorgestrel of 200 µg to 300 µg. A single daily oral dose of 240 ug to 260 ug of levonorgestrel is suitable as an equivalently effective amount.

Determining the equieffective amount of levonorgestrel and progestagen applied according to the invention follows the methods known to the expert, for example in the pregnancy maintenance test on rats.

For the formulation of both active substances in the contraceptive according to the invention, reference is made to the aforementioned sources, in which the active components themselves are described. Techniques for the formulation of androgens or progestogens with a long-term constant release of these active substances are known in the state of the art, such as Norplant or Jardelle implant systems for progestogens. For the formulation further according to the invention of the administered progestogen, reference is made to WO 00/21570 (formulation with cyclodextrin) and WO 02/49622 (transdermal system containing the progestogen administered according to the invention).

Determination of LH, FSH and testosterone parameters follows according to known methods.

The effectiveness of the combination according to the invention is confirmed

• determining the LH-concentration in the serum of male juvenile rats after treatment for a period of 1 week with s.c. application of the combination of compounds A and B (diagram 1) as well as • determining the concentration of testosterone in the serum of male adult rats after treatment for a period of 1 week with the s.c. application of the combination of compounds A and B (diagram 2).

In both cases, these parameters are below the detection limit already after one week (quick onset of death).

Compound A is lip-Fluor-17<p->hydroxy-7a-methyl-estr-4-en-3-one and compound B is the progestogen used according to the invention.

The stated doses were given per kg of body weight per day.

In further experiments on male rats, it was possible to prove that with the combination according to the invention (compound A with compound B; identical dosage as in diagrams 1 and 2) after/with a six-week duration of treatment, the relative weight of the organs (prostate, secondary scrotum, seminal sac and scrotum) already decreases according to the hormonal status; • the number of sperm drops to less than 10% of the control value; • LH and testosterone hormone values, even after the treatment that takes place during this period of time, remain constantly below the detection limit (which means both a faster onset of action and a constant effect).

Literary places:

• E. Nieschlag and H. M. Behre; Testosterone in Male Contraception In E. Nieschlag and H. M. Behre eds. Testosterone: action, deficiency, substitution, 1998, Springer, Berlin, pp 513-528. • M.C. Merrigiola, W.J. Bremner, A, Constantino, A. Pavani, M. Capelli and C. Flamigni; Low Dose of Cyproterone Acetate and Testosterone Enanthate for Contraception in Men, Hum Reprod, (1998) 13, 1225-1229.• M.C. Merrigiola, W.J. Bremner, A. Constantino, A. Pavani, M. Capelli and C. Flamigni; An Oral Regimen of Cyproterone Acetate and Testosterone Undecanoate for Spermatogenic Suppression in Men, Ferld. Sterile. (1997). 68,84-850.

M.C. Merrigiola, W.J. Bremner, C. A. Paulsen, A, Valdiserri, L.

Incorvaia, R. Motta, A. Pavani, M. Capelli and C. Flamigni, A Combined Regimen of Cyproterone Acetate and Testosterone Enanthate as a Potentially Highly Effective Male Contraceptive, J.Clin. Endocrinol. (1998). 81, 3018-3023.

RA Bebb, BD Anawalt, RB Cristensen, WJ. Bremner, C. A.

Paulsenand A. M. Matsumoto., Combined Administration of Levonorgestrel and Testosterone Induces More Rapid and Effective Suppression of Spermatogenesis than Testosterone AloneA Promising Contraceptive Approach., J.Clin. Endocrinol.

Metab. (1996) 81, 757-762.

« J. F. Guenn, and J. Rollet, International Journal of Andrology,

1988, 11, pp. 187-199.• Hadgraf and Guy; Transdermal Drug Delivery; Developmental Issues and research initiatives, Marc dekker Inc., 1989. • M. Ottel and E Schillinger (editors), Handbook of Experimental Pharmacology, Vol. 135/11, Androgens and antiestrogens / I,

Pharmacology and Clinical Applications of Estrogens and

Antiestrogens; K. H. Fritzemeier and C. Hegele-Hartung. In Vitro

and In Vivo Models to Characterize estrogens and Antiestrogens;

Springer Verlag, Berlin. Heidelberg, 1999.

F. Neuman, F. Daher, J. Brotherton, F.J. Graf, S.H. hansen. H. J.

Horn A. Hughes, G. W. Oertei, H. Steinheck, H. E. Voss, R. K. Wagner, Androgens // and AntiAndrogens, Springer-Verlag, Berlin, Heidelberg, 1974. • Fuhrmann, Bengston, repenthin, and Schillinger, J.Steroid Biochem. Mol. Biol, 1992, 42(8), 787.

Lancet 336; 1990, 955-959

Fertil Steril 60; 1993,1062

IntJ Androl 18; 1995; 157-165

Fertil Steril 65; 1996, 821-829

• Andrologie, grundlagen und Klinik der reproducible Gesundheit des Mannes; Hrsg. E. Nieschlag, H.M. Behre; Springer-Verlag, 2. Auflage, S. 442 ff, 2000.

Claims (12)

1. A composition containing an androgenic 11 p-halogensteroid selected from groups of compounds of the general formula I in which X-Y-Z represents a group with one of the two structures CH=C-C or CH2-C=C, R<l>can be a- or P-positional and stand for hydrogen, R or a ring structure P-Q-R bonded through P to the basic ring structure, where P and Q represent straight-chain or branched Cp to Cg-alkylene-, -alkenylene-, alkynylene groups or their fluorinated derivatives and can be the same or different and where R represents one CH3- or CF3-residue, with the recommendation that there is none on Z substituent R<1>, in which X-Y-Z represents the group CH2-C=C, R6 is a hydrogen atom or can have the meanings given under R<7>, R<7>stands for R or for P-Q-R via P related to the basic ring structure, where these groups have the aforementioned meanings, R1<1>represents halogen, R<13> is methyl or ethyl and R<17> is hydrogen iii stands for C(0)-R<18>, where R<18> is a straight-chain or branched d- to C1-alkyl-, -alkenyl-, alkynyl residue or an aryl residue, or stands for T-U-V bonded to a C(0)-group via P, wherein T and U represent straight-chain or branched Cr to Cis-alkylene-, -alkenylene-, alkynylene groups, acyclic C3- to C^-groups or aryl groups and are the same or different, and V is straight chain or a branched d- to C1-alkyl-, -alkenyl-, alkynyl residue or an aryl residue, or R18 has any of the aforementioned meanings or is additionally substituted with one or more groups NR<19>R<20> or with one or more groups SOxR<2>\ where are x = 0.1 or 2 and R<19>, R<20> and R<21> are each hydrogen or via T to N, S bonded T-U-V with the previously mentioned meaning, with the recommendation that physiologically tolerable addition salts with inorganic and organic acids are also included, and the progestogen formula that follows, 2. The composition according to claim 1, indicated by the fact that 1 is IfJ-Halogensteroid of the general formula i; compound lip-Fluoro-17p-hydroxy-7a-methyl-estr-4-en-3-one. 3. Pharmaceutical composition, which contains a composition according to claim 1 as well as some pharmaceutically acceptable carrier and/or excipients. 4. Pharmaceutical composition, according to claim 3, characterized in that the llp-Halogensteroid of general formula I, compound 1 is ip-Fluoro-17P-hydroxy-7a-methyl-estr-4-en-3-one. 5. Male contraceptive, containing a pharmaceutical composition according to claim 3. 6. Male contraceptive, containing a pharmaceutical composition according to claim 4. 7. Male contraceptive according to claim 5 or 6, characterized in that the androgenic compound of the general formula I is released in it with the help of an implant over a longer period of time. 8. Male contraceptive according to claim 5 or 6, characterized in that the androgenic compound of the general formula I is intended for oral use. 9. Male contraceptive according to claim 5 or 6, characterized in that the androgenic compound in it is released with the help of a transdermal system for a long period of time. 10. Male contraceptive according to claim 5-9, indicated by the fact that the progestogen in it is released continuously over a long period of time with the help of an implant. 11. Male contraceptive according to claim 5-9, characterized in that the progestogen is formulated in a transdermal system. 12. Male contraceptive according to claim 5-9, characterized in that the gestagen is administered orally.