MXPA97007008A - Use of anti-estrogens for natural control in homb - Google Patents

Abstract

The present invention relates to the use of antiestrogens (aromatase inhibitors, estrogen receptor antagonists) to prepare contraceptive drugs for men.

Description

USE OF ANTI-ESTROGENS FOR NATURAL CONTROL IN MEN DESCRIPTION OF THE INVENTION This invention relates to the use of antiestrogens for the production of pharmaceutical agents for birth control in men. In the narrowest sense, antiestrogens comprise the class of compounds substances that can displace estrogens from their respective receptors (estrogen receptor antagonists) and, in the broadest sense, the compounds also prevent the synthesis of estrogens from their precursors. metabolites in the organism - androgenic compounds with a structure 3-keto-3-ene steroid - inhibiting aromatase enzyme (aromatase inhibitors.) These two groups, which in the final analysis inhibit the biological action of estrogen, fall into the 5 category of both steroidal and non-steroidal compounds in each case In addition, to the so-called pure antiestrogens, such as, for example, 7a- [9- (4,4,5,5,5-pentafluoropentylsulfonyl) -nonyl] -estra-1, 3,5 (10) -triene-3-17β-diol, those compounds which, in addition to their antagonistic action, also have considerable agonistic action, that is, estrogen, are among the antiestrogens competitive The most prominent representative of the latter is tamoxifen. There is a considerable number of indications for which antiestrogens can be used. The best known example is the clinical treatment of breast cancer with tamoxifen, which has been practiced for a long period of time.

The use of antiestrogens (centchroman) for contraception in women in humans is also described in (Nittyanand, S., Kamboj VP [1991] Centchroman: Profile of effectiveness and contraceptive safety, International Conference on the regulation of fertility, November 5-8 , 1992 Bombay, India, Programs and Excerpts). In effective doses, however, undesirable side effects occur, such as, for example, osteoporotic changes, which can be attributed to the systematic action of antiestrogens. Estrogen deprivation, which occurs after long-term treatment with an antiestrogen, limits at least its regulated use for contraception in women. Finally, DE-A 72 13 005 describes the use of aromatase inhibitors for contraception in female primates of reproductive age in a dose, in which the menstrual cycle of the female primate remains basically unaffected. In this case, the absolute level of the daily doses that are required for the contraceptive action depends completely on the type of aromatase inhibitor that is used. For highly active aromatase inhibitors, daily doses are generally between about 0.05 and about 30 mg. In the case of less active aromatase inhibitors, the daily dose may also be high. For male birth control, only condoms and vasectomy have been available so far. The forming substances are only conditionally suitable either in terms of acceptance and contraceptive reliability. Vasectomies are generally irreversible with respect to fertility. A hormonal contraceptive that may be comparable to oral contraceptives for women with respect to its efficacy, reliability, type of use, and acceptance has not been previously offered. An additional main advantage of hormonal contraception in women is its reversibility. A summary of the actual state of the efforts for the development of a contraceptive for men is found in UF Habenicht "Sitzungsberichte der Gesellschaft Naturforschender Freunde zu Beril [Minutes of the Society of Friends of Natural Science in Berlin]", Volume 31, 991, pp . 101-116. Neither the direct inhibition of spermatogenesis by various alkylating agents or the gosipoles that have come to be known as "Chinese pills" nor the direct inhibition of spermatogenesis by blocking the system and hypofiseo-hypothalamic using testosterone derivatives of LHRH analogues (agonists or antagonists) together with testosterone derivatives or with a combination of an androgen with a gestagen have produced the desired success. In the final analysis, the described attempts do not fulfill at least one of the two most important requirements of a modern contraceptive for men, to say the requirement for reversible method and less possible potential for lateral effects. In addition, the use of antigestagens (competitive progesterone receptor antagonists) for birth control in men is also described in (DE-A-40 39 561.8). In the treatment with RU 486 (11β - [(4-N, N-dimethylamino) -phenyl] -17β-hydroxy-17a-propynyl-4,9 (19) -estradien-3-one, from hand-hooded monkeys, ejaculation weight reduction, sperms counted by ejaculation, reduction in sperm motility, morphological abnormalities of sperm, and a loss / inhibition of acrosomes are observed The object of this invention is to provide a pharmaceutical agent for reversible control of fertility in man, which, in comparison to the pharmaceutical agents currently proposed by this indication, exhibit less side effects or better manageability.This object is achieved using antiestrogens for the production of pharmaceutical agents for birth control in men. , surprisingly enough, they alter the acrosomal states of the sperm: In this way, under the influence of antiestrogens, an incipient acrosomal reaction is observed. In time, sperm motility is prevented by antiestrogens. Early induction of the acrosome reaction and limitation of sperm motility may suggest that the latter are unable to fertilize. On the other hand, several parameters of male sexual functions remain unaffected by antiestrogens: the weight of the organ of the male reproductive tract and the concentration of sperm are not altered. In this way, reversible inhibition of sperm functions occurs, which are essential for successful fertilization, by antiestrogens.

These results are all the most amazing as well as antiestrogens, such as, for example, tamoxifen or clomiphene, which have been used in certain male patients to correct fertility disorders [Acosta et al., Fertile. Steril. 55, pp. 1150-6, (1991)]. As a result, the locally increased concentration of estrogen that is assumed to be present in the tests is counter-attacked, which may possibly be the cause of fertility disorders: In these patients, two active components of the antiestrogens used are in work: On the other hand, the antiestrogenic action per se, and on the other hand the endogenic testosterone increased due to the feedback mechanism (counterregulation). The properties described above of antiestrogens are obtained in tests that are performed with the ICI-antiestrogen 7a- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) -nonyl] -estra-1,3,5 (19 ), trien-3,17β-diol in normal male adult rats. This compound can be independent as a standard compound for all compounds of this class of substances. The test design and results are described in the listing below: Normal male animal rats, approximate weight 200 g Group treated with ICI-7a- [9- 2.5 mg / kg in 0.2 ml of (4,4,5,5,5- subcutaneously vehicle pentafluoropentylsulfinyl) - on a nonyl oily base] -estra-1, 3,5 (10) -trien- (benzylbenzoate / 3,17β-diol oil (n = 6; animal castor number vehicle control (n = 6, 0.2 mi vehicle 1 x day number animals) Treatment period 28 days Weight determination of the seminal vesicles, organ of the reproductive tract, testes, male tivo and histology epididymis Extraction of sperm Extraction from the epididymis (epididymal sperm) Determination of: - motility - number - acrosomal state ( corresponding to lines rich in WHO) Observations regarding the weight of the organ of the male reproductive tract and properties of sperm: 1. No effect on the weight or histology of the organ studied 2. Inhibition of motility 3. Induction of an acrosome reaction incipient This observation clearly shows that antiestrogens are suitable for the production of pharmaceutical agents for birth control in men.

Both the compounds having an antiestrogenic action, both competitive antiestrogens (estrogen receptor antagonists) and aromatase inhibitors according to the invention are suitable. The estrogen receptor antagonists and aromatase inhibitors according to this invention can be derived from both steroids or non-steroidal compounds. Compounds having an antiestrogenic action, in the broadest sense, are defined according to this invention only as those compounds which have the most selective selective action, ie, which basically inhibit only the action of estrogens and / or reduce their concentration . Estrogen receptor antagonists have a competitive action, displacing estrogen from the receptor, while aromatase inhibitors inhibit estrogen biosynthesis. According to this invention, the compounds of the aminoglutethimide type, ie 3- (4-aminophenyl) piperidine-2,6-diones which are alkylated in the 3-position, etc., which in addition to the level of estrogen also exert a reduction action in other concentrations of sexual hormone serum are not suitable as compounds having an antiestrogenic action. As non-steroidal estrogen receptor antagonists, there may be mentioned, for example: Tamoxifen «(Z) -2- [p- (1,2-diphenyl-1-butenyl) -phenoxy] -N, N-dimethylethylamine, nafoxidine B 1-2- [4- (6-methoxy-2-phenyl-3,4-dihydro-1-naphthyl) -phenoxy] -ethylpyrrolidine hydrochloride Mer 25 • 1- [p- (2-diethylaminoethoxy) -phenyl] - 2- (p-methoxyphenyl) -1-phenylethanol raloxifene B 6-hydroxy-2- (p-hydroxyphenyl) benzo [b] thien-3-yl-p- (2-piperidino-ethoxy) phenyl ketone centchromane hydrochloride other compounds of the 1,1,2-triphenylbut-1-ene type, especially 1,1-bis- (3'-acetoxyphenyl) -2-phenyl-but-1-ene [J. Cancer Res. Clin. Oncol., (1986), 112, pp. 119-124]; they are also suitable as steroidal estrogen receptor antagonists, for example: 11α-methoxy-17-acetyl-1, 3,5 (10) -estrathien-3,17β-diol and 16β-ethylestradiol, Nn-butyl-N-methyl-11 - (3-17β-dihydroxiestra-1, 3,5 (10) -trien-7a-yl) -undecanamide and 7a- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl] -estra -1, 3,5 (10) -trien-3-17β-diol As aromatase inhibitors, all compounds which are suitable as substrates for aromatase are suitable, such as, for example, 1-methyl-androsta-1, 4-dien-3-17-dione (atamestane) described in German Laid-Open Specification 33 22 285), testolactone (17a-oxa-D-homoandrost-1,4-dien-3-17-dione) which is described in the Journal of Clinical Endocrinology and Metabolism, 49, 672 (1979), the compounds described in "Endocrinology" 1973. Vol. 92, No. 3, page 874: androsta-4,6-dien-3-17 -dione, androsta-4,6-dien-17ß-ol-3-one-acetate, androsta-1, 4,6-trien-3-17-dione, 4-androsten-19-chloro-3-1 -dione , 4-androsten-3,6,17-trlone , the 19-alkynylated steroids described in the German Laid-Open Specification 31 24 780, the 10- (1,2-propadienyl) -steroids described in the German Laid-Open Specification 31 24719, the derivatives of 19- thio-androstane which are described in European Patent Application, Publication No. 100 566, 4-androsten-4-ol-3,17-dione which is described in "Endocrinology" 1977. Vol. 100, No. 6, page 1684 and U.S. Patent 4,235,893 and its esters; the 1-methyl-15a-alkyl-androsta-1,4-dien-3-17-diones described in the German Laid-Open Specification 3539 244, the derivatives of 10β-alkynyl-4,9 (11) -estradiene which are described in the German Laid-Open Specification 36 44 358 and the 1,2-methylene-6-methylene-4-androsten-3,17-dione which is described in European Patent Application 0250262. They can be mentioned as inhibitors of non-steroidal aromatase, for example [4- (5,6,7,8-tetrahydroimidazo [1, 5a] -pyridin-5-yl) benzonitril-mono-hydrochloride] (Cancer Res., 48, pp. 834- 838, 1988) and the cycloalkylenenazoles described in EP-A-0 411 735. The best-known representative of the aforementioned compounds is pentozole which has already been mentioned.

In addition, compounds that are specifically mentioned as aromatase inhibitors in DE-A 42 13 005 can be used within the scope of this invention. This list is not exhaustive; other antiestrogens that are described in the publications mentioned above, as well as those of the publications that are not mentioned here, are also suitable. Antiestrogens can be used according to this invention for suppressed fertility in men according to different treatment schemes. 1. Intermittent treatment Oral treatment once a day to weekly over 4-12 months. Then: a treatment-free interval of 3-5 months. After this, renewed treatment as in the previous. 2. Continuous treatment Oral administration once a day or oral administration every two days for at most regular intervals of seven days or administration of base formulations at regular intervals (for example, 1 x per month, 1 x week, etc.) . To produce a pharmaceutical agent for birth control in men, antiestrogens are used in a daily amount of 0.1 to 100 mg of tamoxifen or an equivalent amount of action of another antiestrogen. In the case where a base formulation is used for the production of the pharmaceutical agent according to the invention, this I I The base formulation is selected in such a way that the daily antiestrogen release ratio is 0.1 to 100 mg of tamoxifen or an equivalent action amount of another antiestrogen. The equivalent action amounts of other antiestrogens, i.e. amounts corresponding to the indicated amount of tamoxifen for the inhibition of fertility in men, can be determined, for example, in tests of growth inhibition in the uterus after stimulation. with estrogen. In the case of the production of oral dose units, the antiestrogen formulation for the purposes of this invention is made completely analogous to the currently known use of tamoxifen (Eur. J. Cancer Clin. Oncol., 1985, 21, 985 and JS Patterson, "10 years of Tamoxifen in breast cancer" in Hormonal Cancer Manipulation, Peptides, Growth Factors, and New (Anti) steroidal Agents, Raven Press, New York (1987). The antiestrogen to be used in a base formulation can be prepared as a microcrystal suspension, as an oily solution, or in the form of a vehicle containing active ingredients (transdermal system). The following examples are used to give a more detailed explanation of the invention.

I2 Example 1 . 0 mg of tamoxifen (antiestrogen with agonistic partial action) 140.0 mg of lactose 55.0 mg of corn starch 2.5 mg of poly-N-vinylpyrrolidone 25 2.0 mg of aerosil 0.5 mg of magnesium stearate 220.0 mg of total tablet weight, which is produced in the usual way in a tablet presser. The active ingredient according to the invention can optionally also be pressed with respectively half of the additives indicated above separately in a two-layer tablet.

Example 2 . 0 g of 7a- [9- (4,4,5,5,5-Pentafluoropentyl-sulfinyl) -nonyl] estra-1, 3,5, (10) -thien-3,17β-diol (pure antiestrogen) 150.0 mg of lactose 60.0 mg of corn starch 2.5 mg of poly-N-vinylpyrrolidone 25 2.0 mg of aerosil 0.5 mg of magnesium stearate 220.0 mg total weight of the tablet, which is produced in the usual way in a tablet presser. The active ingredient according to the invention can optionally also be pressed with respectively half of the additives indicated above separately in a two-layer tablet.

Example 3 0. 2 mg of 5- [Cyclopentylidene- (1-imidazolyl) -methyl] -thiophen-2-carbonitrile (aromatase inhibitor-pentrozole) 160.0 mg of lactose 54.8 mg of corn starch 2.5 mg of poly-N-vinylpyrrolidone 25 2.0 mg of aerosil 0.5 mg of magnesium stearate 220.0 mg total weight of the tablet, which is produced in the usual way in a tablet presser. The active ingredient according to the invention can optionally also be pressed with respectively half of the additives indicated above separately in a two-layer tablet.

Claims (7)

1. Use of antiestrogens for the production of pharmaceutical agents for birth control in men.

2. The use of estrogen receptor antagonists, according to claim 1.

3. The use of aromatase inhibitors, according to claim 1.

4. The use of tamoxifen, according to claim 2.

5. The use of 7a- [9-4,4,5,5,5-pentafluoropentylsulfinyl) nonyl] estra-1,3,5 (10) -trien-3,17β-diol, according to claim 2.

6. The use of atamestane, in accordance with the claim

7. The use of pentrozole, according to claim 3.