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WO2000067733A2 - Medicament pour traiter l'infertilite masculine - Google Patents

Medicament pour traiter l'infertilite masculine Download PDF

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Publication number
WO2000067733A2
WO2000067733A2 PCT/EP2000/003937 EP0003937W WO0067733A2 WO 2000067733 A2 WO2000067733 A2 WO 2000067733A2 EP 0003937 W EP0003937 W EP 0003937W WO 0067733 A2 WO0067733 A2 WO 0067733A2
Authority
WO
WIPO (PCT)
Prior art keywords
cns
men
medicament
stimulating
stimulating substance
Prior art date
Application number
PCT/EP2000/003937
Other languages
German (de)
English (en)
Other versions
WO2000067733A3 (fr
Inventor
Claus Rolf
Eberhard Nieschlag
Original Assignee
Claus Rolf
Eberhard Nieschlag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Claus Rolf, Eberhard Nieschlag filed Critical Claus Rolf
Priority to AU44037/00A priority Critical patent/AU4403700A/en
Publication of WO2000067733A2 publication Critical patent/WO2000067733A2/fr
Publication of WO2000067733A3 publication Critical patent/WO2000067733A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/04—Nitro compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione

Definitions

  • 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.
  • the unfulfilled desire to have children is defined as the non-occurrence of pregnancy after one year of unprotected sexual intercourse.
  • WHO World Health Organization
  • the unfulfilled desire to have children is defined as the non-occurrence of pregnancy after one year of unprotected sexual intercourse.
  • 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 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.
  • 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.
  • 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).
  • 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).
  • radish extract CA-A-2137219
  • Chinese medicine CN-A-1139002
  • the cellular mechanism is unknown or the actual active substance is not specified.
  • 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.
  • 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 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)).
  • CNS-stimulating substances are used to treat a variety of diseases.
  • 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 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.
  • a CNS-stimulating substance hereinafter also referred to as “substance”
  • the present invention thus relates
  • CNS-stimulating substances 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:
  • Amphetamine derivatives Derivatives of (R, S) - ⁇ -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) - ⁇ -methylphenethylammonium sulfate) and fenethyllin hydrochloride (7- [2- ( ⁇ -methylphenethylamino) ethyl] theophyllin- Hydrochloride).
  • Amfetaminil is a preparation that is approved for the treatment of narcolepsy in Germany.
  • 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 [ ⁇ -phenyl- ⁇ - (2-piperidyl) acetate]) and its hydrochloride, prolintan hydrochloride (1- ( ⁇ -propylphenethyl) pyrrolidine -Hydrochloride), Mazindol (5- (4-chlorophenyl) -2,5-dihydro-3H-imidazo [2,1 - ⁇ /] isoindol-5-ol) and fipexide hydrochloride (1- (4-chloro - called phenoxyacetyl) -4-piperonylpiperazine hydrochloride).
  • Antidepressants In particular non-tricyclic antidepressants such as, for. B. the compounds of formula (I) known from DE-A-2059618
  • 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.
  • 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)
  • 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
  • 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.
  • Apomorphine is currently being investigated as a therapeutic agent for erectile dysfunction (ED) therapy in a phase III study.
  • Nitro p räparate Preferred compounds are amyl nitrite, Nitroglycehn, Isosorbidd initrat (1, 4: 3,6-dianhydro-D-glucitol-dinitrate) and 5-isosorbide mononitrate
  • nitro preparations (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.
  • ⁇ -adrenergic receptor-active substances such as Adrafinil (2 - [(diphenylmethyl) sulfinyl] acetohydroxamic acid) and Deanol (2-dimethylaminoethanol).
  • 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) - ⁇ -methylphenetylamine, preferably from 20 to 60 mg as a single oral dose,
  • - 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.
  • 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de substances ayant une action stimulante sur le SNC pour produire des médicaments pour traiter l'infertilité, les troubles orgasmiques et les troubles de l'éjaculation chez l'homme. L'invention concerne également un procédé permettant de traiter l'infertilité, les troubles orgasmiques et les troubles de l'éjaculation chez l'homme, qui se fonde sur l'administration de substances à action stimulante du SNC.
PCT/EP2000/003937 1999-05-05 2000-05-03 Medicament pour traiter l'infertilite masculine WO2000067733A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU44037/00A AU4403700A (en) 1999-05-05 2000-05-03 Medicament for treating human infertility

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19920491.8 1999-05-05
DE1999120491 DE19920491A1 (de) 1999-05-05 1999-05-05 Medikament zur Therapie der männlichen Infertilität

Publications (2)

Publication Number Publication Date
WO2000067733A2 true WO2000067733A2 (fr) 2000-11-16
WO2000067733A3 WO2000067733A3 (fr) 2002-02-28

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/003937 WO2000067733A2 (fr) 1999-05-05 2000-05-03 Medicament pour traiter l'infertilite masculine

Country Status (3)

Country Link
AU (1) AU4403700A (fr)
DE (1) DE19920491A1 (fr)
WO (1) WO2000067733A2 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0248215A2 (fr) * 1986-06-03 1987-12-09 Apotheker Popp oHG Médicament à action dopaminergique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0248215A2 (fr) * 1986-06-03 1987-12-09 Apotheker Popp oHG Médicament à action dopaminergique

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; COLAO, ANNAMARIA ET AL: "Chronic treatment with CV 205-502 restores the gonadal function in hyperprolactinemic males" retrieved from STN Database accession no. 126:69946 CA XP002154548 & EUR. J. ENDOCRINOL. (1996), 135(5), 548-552, 1996, *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; DALLO, JANOS ET AL: "The ejaculatory behavior of sexually sluggish male rats treated with (-)deprenyl, apomorphine, bromocriptine and amphetamine" retrieved from STN Database accession no. 106:188846 XP002154546 & POL. J. PHARMACOL. PHARM. (1986), 38(3), 251-5, *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KAPLAN, JOEL M. ET AL: "Apomorphine induces ejaculation in chronic decerebrate rats" retrieved from STN Database accession no. 115:175782 XP002154545 & NEUROSCI. LETT. (1991), 129(2), 205-8, *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; PAGLIETTI, E. ET AL: "Apomorphine and L-DOPA lower ejaculation threshold in the male rat" retrieved from STN Database accession no. 89:84720 XP002154547 & PHYSIOL. BEHAV. (1978), 20(5), 559-62, *
DATABASE EMBASE [Online] ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL; WALDINGER M.D.: "Use of psychoactive agents in the treatment of sexual dysfunction." retrieved from STN Database accession no. 96284656 XP002154544 & CNS DRUGS, (1996) 6/3 (204-216)., *
DATABASE MEDLINE [Online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; ASHTON A K ET AL: "Bupropion as an antidote for serotonin reuptake inhibitor-induced sexual dysfunction." retrieved from STN Database accession no. 1998200223 XP002154551 & JOURNAL OF CLINICAL PSYCHIATRY, (1998 MAR) 59 (3) 112-5., *
DATABASE MEDLINE [Online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; LABBATE L A: "Bupropion-SR-induced increased libido and spontaneous orgasm Äletter]." retrieved from STN Database accession no. 1998399394 XP002154549 & CANADIAN JOURNAL OF PSYCHIATRY. REVUE CANADIENNE DE PSYCHIATRIE, (1998 AUG) 43 (6) 644-5., *
DATABASE MEDLINE [Online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; MODELL J G ET AL: "Comparative sexual side effects of bupropion, fluoxetine, paroxetine, and sertraline." retrieved from STN Database accession no. 97275795 XP002154550 & CLINICAL PHARMACOLOGY AND THERAPEUTICS, (1997 APR) 61 (4) 476-87., *

Also Published As

Publication number Publication date
WO2000067733A3 (fr) 2002-02-28
AU4403700A (en) 2000-11-21
DE19920491A1 (de) 2000-11-16

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