DE102011012712A1 - Use of aldosterone receptor antagonists for the treatment of female sexual dysfunction - Google Patents

Abstract

The present invention relates to a new medical indication for aldosterone receptor antagonists.

Description

The present invention relates to a new medical indication for aldosterone receptor antagonists.

A Hypoactive Sexual Desire Disorder (HSDD) disorder is the most prevalent female sexual dysfunction. The symptoms of this disorder include decreased sexual desire (libido weakness), excitability disorder and vaginal dryness. The causes of female sexual dysfunction can usually be of a different nature (relationship problems, oral long-term contraception, menopause, etc.) and there are only a limited number of treatment options of proven benefit.

Therapies for HSDD include the administration of testosterone, both orally and with the aid of a transdermal therapeutic system, which can be used, for example, in WO 96/35427 is described, can take place. Undesirable effects of this therapy include undesirable male-patterned hair growth (hirsutism), which significantly reduces patient acceptance of this therapy.

In addition, topical and systemic estrogen administration may improve vaginal lubrication in postmenopausal patients with vaginal atrophy. However, this therapy does not produce a consistent increase in cravings and arousal.

Another therapeutic strategy for the treatment of female sexual dysfunction is based on the use of a new non-hormonal drug flibanserin, which is disclosed in the patent application WO 03/035072 was disclosed. Flibanserin acts as an agonist at the serotonin receptor 5-HT _1A and as an antagonist at the receptor 5-HT _2A . Among other things, results of Phase III clinical trials demonstrate that HSVD treatment with flibanserin is effective in postmenopausal patients. However, flibanserin has not been previously approved due to common side effects such as dizziness, nausea and fatigue.

Laang et al. (Climacteric 2001, 1, 28-41) reported that therapeutic treatment with tibolone relieves postmenopausal vasomotor symptoms without stimulating endometrium at the same time. Tibolone is a synthetic steroidal drug whose metabolites have estrogenic, gestagenic and androgenic effects. An evaluation of the Million Women Study (Lancet 2005, 365, 1543-51) However, it indicates that long-term use of tibolone is associated with similar carcinoma risks for the uterus and the breast as a therapy with conventional estrogen preparations. In addition, treatment with tibolone increases the risk of recurrence of breast cancer.

US 2003/0212139 discloses that topical prostaglandin administration in the form of a gel or ointment results in an increase in female sexual desire. As active ingredients for corresponding preparations, prostaglandins PGE-1 and PGE-2 were used in this application.

It is also known that symptoms such as libido weakness often occur as side effects of steroidal aldosterone antagonists. These medicines are used as diuretics in patients with elevated levels of aldosterone and are approved, for example, in the treatment of chronic heart failure, kidney failure, high blood pressure and some liver diseases. Spironolactone (IUPAC name: 7α-acetylthio-3-oxo-17α-pregn-4-ene-21,17-carbolactone) is the most commonly used member of this class of drugs. Drug spironolactone-containing are currently commercially available, including under the brands Aldactone ^®, Jena Spiron ^® and Osyrol ^®. However, due to the fact that spironolactone and its active metabolites canrenone, 7α-methylspironolactone and 6β-hydroxy-7α-methylspironolactone have a high affinity for progesterone and androgen receptors, spironolactone therapy is accompanied by undesirable androgenic and progestogenic side effects.

De Gasparo et al. showed that some 9α, 11α-epoxy derivatives of the previously known aldosterone antagonists have a significantly lower affinity for androgen and progesterone receptors and yet are active as potent aldosterone antagonists ( J. steroid. Biochem. 1989, Jan, 32 (1B), 223-7 and J. Pharmacol. Exp. Ther. 1987 Feb, 240, 2, 650-6) , In the context of these studies, the effect of 9α, 11α-epoxyspironolactone (IUPAC name: 9α, 11α-epoxy-7α-acetylthio-3-oxo-17α-pregn-4-ene-21,17-carbolactone), 9α, 11α Epoxyprorenone (IUPAC name: 9α, 11α-epoxy-6β, 7β-methylene-3-oxo-17α-pregna-4-ene-21,17-carbolactone) and 9α, 11α-epoxymexrenone (IUPAC name: 9α, 11α-epoxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-ene-21,17-carbolactone), also known as eplerenone, in in vitro experiments.

Subsequent clinical studies have shown that eplerenone therapy has undesirable side effects such as libido, impotence mediated by androgen and progesterone receptors or menstrual disorders are much less common in patients than in the use of spironolactones. Medicines containing eplerenone are currently commercially available, including under the brand Inspra ^®. Eplerenone is used in addition to standard therapy that includes beta blockers to reduce the risk of cardiovascular mortality and morbidity in stable patients with left ventricular dysfunction and clinical signs of heart failure following a recent myocardial infarction.

Thus, there is still a need for drugs to treat female sexual dysfunction.

worin R¹ ein Wasserstoffatom, eine α-C_1-4-Alkylgruppe, eine α-C_1-4-Alkoxycarbonylgruppe oder zusammen mit R² eine Doppelbindung oder eine 6β,7β-Methylengruppe ist;
R² ein Wasserstoffatom oder zusammen mit R¹ eine Doppelbindung oder eine 6β,7β-Methylengruppe ist;
R³ ein Wasserstoffatom oder zusammen mit R⁴ eine 9α,11α-Epoxygruppe ist; und
R⁴ ein Wasserstoffatom oder zusammen mit R³ eine 9α,11α-Epoxygruppe ist,
zur Steigerung sowohl der Libido als auch der Lubricatio führen. Die vorliegende Erfindung betrifft somit die Verwendung der Verbindungen der genannten Formel I zur Behandlung von weiblicher sexueller Dysfunktion.It has now surprisingly been found that aldosterone receptor antagonists of the general formula I

wherein R ^{1 is} a hydrogen atom, an α-C _1-4 alkyl group, an α-C _1-4 alkoxycarbonyl group or, together with R ^2, a double bond or a 6β, 7β-methylene group;
R ^{2 is} a hydrogen atom or together with R ^{1 is} a double bond or a 6β, 7β-methylene group;
R ^{3 is} a hydrogen atom or, together with R ^4, a 9α, 11α-epoxy group; and
R ^{4 is} a hydrogen atom or, together with R ^3, a 9α, 11α-epoxy group,
to increase both libido and lubricatio. The present invention thus relates to the use of the compounds of said formula I for the treatment of female sexual dysfunction.

These effects were observed in patients of different ages and were found in both young mothers and postmenopausal women. Already with administration of low doses of the drug, these unexpected effects could be detected. The effects also occurred in the week after menstruation, in which vaginal secretion is usually very low.

In addition, these agents have a diuretic effect and thereby reduced the body weight of the patients. In addition, these agents cause an increase in the potassium concentration in the blood and thus protect the body cells physiologically before function restriction.

In particular, the female sexual dysfunction to be treated is a disorder with hypoactive sexual desire disorder (HSDD), a loss of sexual desire, a decreased sexual desire, a lack of sexual desire, a libido loss, a libido disorder, vaginal dryness and frigidity. In particular, the present active compounds are suitable for the treatment of libido loss and at the same time the vaginal dryness.

Among the aldosterone receptor antagonists of the general formula I mentioned, preference is given to those compounds in which R ^{1 is} either an α-C _1-4 -alkoxycarbonyl group or together with R ² a double bond. Particularly suitable α-C _1-4 alkoxycarbonyl groups are methoxycarbonyl and ethyoxycarbonyl, with methoxycarbonyl being particularly preferred. Particularly preferred aldosterone receptor antagonists of the general formula I are eplerenone and mexrenone, in particular eplerenone.

Administration may be by oral route or by intravenous, intramuscular or subcutaneous injection. The preparations can be present, for example, in the form of aqueous or nonaqueous, isotonic, sterile injection solutions or suspensions. These solutions or suspensions may be prepared from sterile powders or from granules with the addition of one or more pharmaceutically acceptable auxiliaries and additives such as carriers, diluents, binders, preservatives, surfactants and dispersants. In addition, the active ingredients may be administered in the form of a transdermal therapeutic system.

In accordance with the invention, the active agent can be employed in any solid state form, either as one or more solid state forms per se or in the form of a pharmaceutical composition comprising one or more solid state forms of active ingredient. These solid state forms include, but are not limited to, solvated crystalline non-solvated crystalline active and amorphous active.

For the oral administration of the active ingredients, a suitable pharmaceutical composition in the form of a tablet, a sachet, a Capsule, a suspension or a liquid dosage form.

A suitable daily dose may range from 0.25 mg to 400 mg, preferably from 5 mg to 200 mg, more preferably from 10 mg to 100 mg, and even more preferably from 10 mg to 50 mg per day. Surprisingly, it has been shown that the desired effect already occurs at a daily dose in the range of less than 40 mg, such as below 20 mg, a dose that is below the usual dose for eplenerone in an infarction prophylaxis.

The dosage regimen for the treatment of female sexual dysfunction may be selected according to a variety of factors such as age, weight, medical condition of the patient, severity of the disorder, the purpose of administration, and the particular active ingredient used, and may therefore vary.

Preferably, a unit dose of the pharmaceutical composition contains the active ingredient in the range of 1 to 200 mg, more preferably in the range of 5 to 100 mg, more preferably in the range of 10 to 50 mg, most preferably in the range of 10 mg to 40 mg. The unit dosage form can be selected to match the desired frequency of administration used so that the desired daily dose is achieved.

The following example illustrates the invention without it being construed restrictively.

example 1

Eight patients of various ages treated for muscle weakness in hypokalemic periodic paralysis participated in the study. The patients were in different stages of fertility (menstruation due to ovulation, menopause, postmenopause).

Patients received regular administration of eplerenone (Inspra ^® ) at a dose of 12.5 to 37.5 mg daily.

Four out of eight patients (31, 48, 51 and 58 years) reported an increase in libido, improved vaginal lubrication and inner balance. This unexpected effect already occurred in the week after menstruation, in which vaginal secretion is usually very low.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 96/35427 [0003]
• WO 03/035072 [0005]
• US 2003/0212139 [0007]

Cited non-patent literature

• Laang et al. (Climacteric 2001, 1, 28-41) [0006]
• Million Women Study (Lancet 2005, 365, 1543-51) [0006]
• De Gasparo et al. [0009]
• J. steroid. Biochem. 1989, Jan, 32 (1B), 223-7 [0009]
• J. Pharmacol. Exp. Ther. 1987 Feb, 240, 2, 650-6) [0009]

Claims (7)

Use of an aldosterone receptor antagonist of the general formula I.

wherein R ^{1 is} a hydrogen atom, an α-C _1-4 alkyl group, an α-C _1-4 alkoxycarbonyl group or, together with R ^2, a double bond or a 6β, 7β-methylene group; R ^{2 is} a hydrogen atom or together with R ^{1 is} a double bond or a 6β, 7β-methylene group; R ^{3 is} a hydrogen atom or, together with R ^4, a 9α, 11α-epoxy group; and R ^{4 is} a hydrogen atom or, together with R ^3, a 9α, 11α-epoxy group for the treatment of female sexual dysfunction. The use of claim 1, wherein the female sexual dysfunction is selected from the group consisting of a Hypoactive Sexual Desire Disorder disorder, a loss of sexual desire, a decreased sexual desire, a lack of sexual desire, a libido - Loss, a libido disorder, vaginal dryness and frigidity. Use according to claim 2, wherein the female sexual dysfunction is selected from the group consisting of libido loss and vaginal dryness. Use according to any one of claims 1-3, wherein the aldosterone receptor antagonist is eplerenone or mexrenone. Use according to claim 4, wherein the aldosterone receptor antagonist is eplerenone. Use according to any one of claims 1-5, wherein the therapeutically effective amount of the aldosterone receptor antagonist to be administered ranges from 0.25 mg to 400 mg per day. Use according to claim 6, wherein the therapeutically effective amount of the aldosterone receptor antagonist to be administered ranges from 10 mg to 50 mg per day.