WO2000067733A2

WO2000067733A2 - Medicament for treating human infertility

Info

Publication number: WO2000067733A2
Application number: PCT/EP2000/003937
Authority: WO
Inventors: Claus Rolf; Eberhard Nieschlag
Original assignee: Claus Rolf; Eberhard Nieschlag
Priority date: 1999-05-05
Filing date: 2000-05-03
Publication date: 2000-11-16
Also published as: DE19920491A1; WO2000067733A3; AU4403700A

Abstract

The invention relates to the use of CNS-stimulating substances for producing medicaments used to treat infertility, orgasmic disturbances, and ejaculatory disturbances in men. The invention also relates to a method for treating infertility, orgasmic disturbances, and ejaculatory disturbances in men consisting of the administration of CNS-stimulating substances.

Description

Medicament to treat male infertility

The invention relates to the use of CNS-stimulating substances for the manufacture of medicaments for the treatment of infertility, orgasmic disorders and ejaculation disorders in men, and a method for the treatment of infertility, orgasm disorders and ejaculation disorders in men, comprising the administration of CNS-stimulating substances.

Background of the Invention

According to the World Health Organization (WHO), the unfulfilled desire to have children is defined as the non-occurrence of pregnancy after one year of unprotected sexual intercourse. In western countries around 40 percent of couples have an unfulfilled desire to have children. Around 40 percent of the cause is in the woman alone, around 20 percent the cause is diagnosed in the man, 25 percent the fertility of both partners is limited, and no disturbance can be determined in the remaining patients (WHO Task Force on the Diagnosis and Treatment of Infertility (1987): Int. J. Androl [Suppl 7]). The majority of men have so-called idiopathic infertility, i.e. H. the cause of the restriction of the ejaculate parameters (sperm concentration, sperm mobility, sperm morphology) is not known. There are no therapeutic curative options. In the case of restricted ejaculate parameters, the only therapy options are to carry out complex and also very expensive assisted fertilization procedures, in particular intracytoplasmic sperm injection with subsequent embryo transfer (> 10,000 DM per therapy attempt). With these therapy methods, pregnancy rates of 20-35% per therapy cycle can be achieved. It is assumed that in approximately 50 percent of the cases, a child is born after 3-4 therapy cycles.

In addition, chemical or hormonal treatment methods are mainly proposed for the treatment of male infertility. This is how it often is Gonadotropin relasing hormone used or administered more intensely (EP-A-0 202 569; WO 91/01747 and BE 904522). This can also be done in combination with a human growth factor in order to increase the number of sperm in the ejaculate (WO 91/01747). It is known, for example, that an increased dose of gonadotropic hormones in birds and mammals increases their sexual activities and also spermatogenesis (BE 904522). EP-A-0 178 841 also discloses the purification of the gonadal regulation protein, which controls the maturation process of the sperm, among other things.

Other hormones are also used to treat male infertility, such as: B. Testosterone, papverine and the like. a. (RO 105546), the somatotrophin releasing factor (EP-A-0 300 982) or a kallikrein polypeptide (EP-A-0 297 913). Further therapeutic options result from the use of the Leydig cell-stimulating polypeptide (EP-A-0 519 889) or the lipid fraction from the Cowper or Bartholini glands, which is able to expand the arterial muscles (WO 85/03441).

In addition, herbal ingredients for treatment, i.e. H. proposed to increase the sperm count, for example radish extract (CA-A-2137219) or Chinese medicine (CN-A-1139002). However, in all the applications mentioned, the cellular mechanism is unknown or the actual active substance is not specified. Furthermore, no efficacy could be demonstrated in any of the substances mentioned in the applications mentioned in published controlled clinical studies with patients with idiopathic infertility.

It is also known that both the spontaneous pregnancy rate and the pregnancy rate in the context of insemination therapies increase almost linearly with increasing sperm count and sperm motility (van der Westeriaken et al., J. Assist. Reprod. Genet. 15: 359-364 (1998) ; Wichman et al., Hum. Reprod. 9: 1102-1108 (1994)). Studies in the Institute for Reproductive Medicine at the Westphalian Wilhelms University in Münster showed that if two or three ejaculates were released within a very short time, only about 50% of the sperm stored in the epididymis in the first Ejaculate can be detected, so that almost the same number of sperm can be found in the following ejaculate (Cooper et al., Hum, Reprod., 8: 1251 - 1258 (1993)). There is therefore great potential to gain an increased sperm concentration by improving the ejaculation power. Since sperm motility also decreases with increasing epididymis storage time, but the older sperm are ejaculated first, increased ejaculation can improve not only the sperm count but also the quality.

Different hormonal, sympathetic and parasympathetic neuronal factors are involved in ejaculation, the exact mechanism is not yet known. The pituitary posterior lobe hormone oxytocin creates a contraction of the smooth muscles of the testes, epididymis and ductus deferens and thus transports the sperm to the ejaculator duct when orgasm. The final semen export (epididymal, seminal vesicle and prostartate secretion) takes place by contraction of the striated pelvic floor muscles (Cooper and Yeung, physiology of sperm maturation and fertilization, Nieschlag Behre HM (ed.), Springer Berlin 65 - 81 (1996)).

In a placebo-controlled double-blind study with oxytocin, which has a peripheral effect on the diverting seminal ducts, this effect could not be reproduced in all infertile men. A dose-dependent increase in the sperm count in the ejaculate could only be achieved in some of the patients, and a dose-dependent decrease in the sperm count was found in 50% of the patients. Even if in this study an improvement in the ejaculate parameters could only be achieved in 30% of the patients with this peripheral hormone, this pilot study shows that in principle an improvement in the ejaculation is possible with pharmacological therapy.

On the other hand, CNS-stimulating substances are used to treat a variety of diseases. For example, DE-A-36 18 627 and A. Colao et al., Eur. J. Endorimol. 1996, 135 (5), 578-552, the use of dopmin agonists for the treatment of hyperprolacinemia. A. Zalata et al., Hum. Reprod. 1995, 10 (12), 3161-5 (Engl.) That endorphins play an immunosuppressive role in seminal plasma.

Surprisingly, it has now been found that a central nervous stimulation reproducibly increases the ability to ejaculate, i.e. that is, the administration of a CNS-stimulating substance (hereinafter also referred to as "substance") increases the orgasm and thus the fertility.

Summary of the invention

The present invention thus relates

(1) the use of a CNS stimulant for the manufacture of a medicament for the treatment of infertility in men; (2) the use of a CNS stimulant for the manufacture of a medicament for the treatment of orgasm and / or ejaculation disorders in men;

(3) the use of a CNS-stimulating substance for the manufacture of a medicament to increase the ability to ejaculate (e.g. by increasing the ability to empty the epididymis) and / or the number of sperm in the ejaculate;

(4) a method of treating infertility in men, which is characterized in that the men to be treated are administered a CNS-stimulating substance; and (5) a method for the treatment of orgasm and / or ejaculation disorders in men, which is characterized in that the men to be treated are administered a CNS-stimulating substance.

Detailed description of the invention

The above-mentioned CNS-stimulating substances (hereinafter also referred to as “substance” for short) are preferably compounds that have serotonin, dopamine and / or NO receptors in the CNS act (serotonin and dopamine are responsible for controlling sexual activity in the CNS).

Particularly preferred substances in the sense of the present invention are amphetamine derivatives, antidepressants, dopamine agonists, nitro preparations and synthetic endorphin agonists. The following compounds are particularly suitable substances for the treatment of male infertility:

1. Amphetamine derivatives: Derivatives of (R, S) -α-methylphenetylamine, the mechanism of which is almost identical, only the receptor selectivity and thus the side effects are different. Particularly preferred amphetamine derivatives are amfetaminil (2- (methylphenetylamino) -2-phenylacetonitrile), dexamphetamine sulfate (S) -α-methylphenethylammonium sulfate) and fenethyllin hydrochloride (7- [2- (α-methylphenethylamino) ethyl] theophyllin- Hydrochloride). Amfetaminil is a preparation that is approved for the treatment of narcolepsy in Germany. Furthermore, amphetamine derivatives in the context of the present invention are also understood to mean compounds which have pharmacologically amphetamine-like properties. Examples include pemoline (2-imino-5-phenyl-oxazidinone), methylphenidate (methyl [α-phenyl-α- (2-piperidyl) acetate]) and its hydrochloride, prolintan hydrochloride (1- (α-propylphenethyl) pyrrolidine -Hydrochloride), Mazindol (5- (4-chlorophenyl) -2,5-dihydro-3H-imidazo [2,1 -α /] isoindol-5-ol) and fipexide hydrochloride (1- (4-chloro - called phenoxyacetyl) -4-piperonylpiperazine hydrochloride).

2. Antidepressants: In particular non-tricyclic antidepressants such as, for. B. the compounds of formula (I) known from DE-A-2059618

or their acid addition salts, wherein X is chlorine or fluorine. The compound of the formula I in which X is chlorine (bupropion) is particularly preferred. Bupropion hydrochloride is an antidepressant drug that was approved in the United States in 1997 as a sustained-release drug to help people quit smoking.

3. Dopamine agonists: Apomorphine (5,6,6a, 7-tetrahydro-6-methyl-4b / -dibenzo [de, g] quinoline-10,11-diol) and those in EP-B-0 139 are particularly preferred 393 described pyrimido (4.5 g) quinoline compounds of the formula (II)

wherein

Is RC ^ alkyl or allyl; R ^{1 is} NH ₂ , NHR ³ or NR ⁴ R ⁵ ;

R ^{2 is} H, CH ₃ , CI or Br;

R ^{3 is} methyl, ethyl, n-propyl or R ⁶ -CO;

R ⁴ and R ^{5 are} independently methyl, ethyl or n-propyl; and

R ^{6 is} C 1-4 alkyl or phenyl, which can be substituted with 1 to 2 groups from Cl, F, Br, CH ₃ , C ₂ H ₅ , CH ₃ O, C ₂ H ₅ O and CF ₃ ; or a pharmacologically acceptable acid addition salt thereof.

Preferred of these are the trans - (-) - stereoisomers of the formula (II) and in particular the compound (5aR, 9aR) -5.5a, 6,7,8,9,9a, 10-octahydro-6-propylpyhdo [2, 3-g] quinazolin-2-amine (Quinelorane). Apomorphine is currently being investigated as a therapeutic agent for erectile dysfunction (ED) therapy in a phase III study.

4. Nitro ^p räparate: Preferred compounds are amyl nitrite, Nitroglycehn, Isosorbidd initrat (1, 4: 3,6-dianhydro-D-glucitol-dinitrate) and 5-isosorbide mononitrate

(1, 4: 3,6-dianhydro-D-glucitol-5-nitrate). The characteristic of nitro preparations is rapid onset of action (reaction to drop in blood pressure). All nitro preparations have the same mechanism of action, the differences are only pharmacokinetic in nature.

Amyl nitrite was the first organic nitro compound to be used to treat coronary heart disease. Because of the pleasure-enhancing effect, the preparation quickly became widespread, particularly in homosexual and artist circles.

5. Synthetic endorphin agonists or enkephalins

6. Other substances: α-adrenergic receptor-active substances such as Adrafinil (2 - [(diphenylmethyl) sulfinyl] acetohydroxamic acid) and Deanol (2-dimethylaminoethanol).

For the purposes of the present application, particular preference is given to the substances mentioned under 1.- 4., in particular the amphetamine derivatives mentioned under 1. and of these in particular amfetaminil.

One or more of the substances mentioned is administered to treat infertility in men. The dose used is dependent on the body weight and physical condition of the patient and is - depending on the substances used in the range from 0.1 to 1000 mg, preferably from 0.5 to 500 mg per day. The dose for substances mentioned under 1 is preferably 10 to 120 mg, depending on the galentics and bioequivalence with respect to (R, S) -α-methylphenetylamine, preferably from 20 to 60 mg as a single oral dose,

- for substances mentioned under 2. at 200 to 450 mg, depending on the galentic system, preferably from 450 mg per day for 3 to 7 days, - for substances mentioned under 3. at 2 to 6 mg, preferably from 4 mg per day over 1 up to 7 days,

- for substances mentioned under 4, at 0.2 to 20 mg, depending on the substance, galentics and type of application, preferably from 0.2 to 1, 6 mg nitroglycerin perlingually, or 4 to 20 mg isosorbide dinitrate orally as a single oral dose , - for substances mentioned under 6 at 50 to 1000 mg, depending on the galenics, preferably from 50 to 100 mg per day (Deanol) for 1 to 7 days.

The duration of treatment for the substances mentioned under 2, 3, 5 and 6 is three to seven days, for the substances mentioned under 1 and 4, a single dose is 15 minutes to 4 hours before the planned sexual intercourse or the planned treatment using assisted fertilization is sufficient; the duration of therapy can be extended to three days.

In addition to the CNS-stimulating substances, the preparations can also contain other pharmacologically active compounds, e.g. B. peripherally influencing ejaculation active substances such as oxytocin and peripherally acting alpha-receptor antagonists such as terazosin or bunazosin and / or commercially available pharmacologically acceptable auxiliaries such as talc, starch, gum arabic, etc.

The invention is illustrated by the following example

Example:

The efficacy of amfetaminil (40 mg) and pemoline (80 mg) to improve ejaculation ability was tested in a placebo-controlled double-blind study. After 13 subjects completed the study, an interim evaluation was carried out. It was shown that a larger volume of ejacuates (4.3 ml versus 3.6 ml) could be obtained 120 min after administration of amfetaminil. The sperm concentration (39.7 x 10 ⁶ ml versus 27.7 x 10 ⁶ ml) and the total number of sperm per ejaculate (164 x 10 ⁶ ejac. Versus 120 x 10 ⁶ ejac.) Were significantly increased. Also in the second ejaculate, obtained approx. 30 min later, a higher sperm count was found after administration of amfetaminil compared to placebo. The total sperm count of both ejaculates after administration of amfetaminil was significantly higher (P = 0.022) than placebo. There was only a minor improvement after pemoline administration. Since according to the majority of the test subjects subjectively the greatest psychostimulating Effect was only achieved after about 3 hours, in a follow-up study the ejaculate was delivered after three hours.

The results are summarized in Tables 1 to 3.

to

Claims

claims

1. Use of a CNS-stimulating substance for the manufacture of a medicament for the treatment of infertility in men.

2. Use according to claim 1, wherein the CNS-stimulating substance is effective via serotonin, dopamine and / or NO receptors.

3. Use according to claim 1 or 2, wherein the CNS-stimulating substance is selected from amphetamine derivatives, antidepressants, dopamine agonists, nitro preparations and synthetic endorphin agonists.

4. Use according to claim 3, wherein the CNS-stimulating substance is an amphetamine vat and in particular amfetaminil or pemoline.

5. Use according to claim 3, wherein the CNS-stimulating substance is selected from bupropion and apomorphine.

6. Use according to claim 3, wherein the CNS-stimulating substance is a nitro preparation, in particular nitroglycerin, where the medicament is to be administered perlingually or orally, or isosorbide dinitrate, where the medication is to be administered orally.

7. Use of the CNS-stimulating substances defined in claims 1 to 6 for the manufacture of a medicament for the treatment of orgasm and / or ejaculation disorders in men.

8. Use of the CNS stimulating substances defined in claims 1 to 6 for the manufacture of a medicament for increasing the ability to ejaculate and / or the number of sperm in the ejaculate.

9. Use according to claim 8, wherein the medicament increases the ability to empty the epididymis stores.

10. A method for treating infertility in men, characterized in that the men to be treated are administered a CNS-stimulating substance as defined in claims 1 to 6.

11. Method for the treatment of orgasm and / or ejaculation disorders in men, characterized in that the men to be treated are administered a CNS-stimulating substance as defined in claims 1 to 6.