EP2131842A2 - Use of a compound antagonist to the nk-2-receptors of a neurokinine for the preparation of drugs useful for preventing and treating sexual dysfunction - Google Patents

Use of a compound antagonist to the nk-2-receptors of a neurokinine for the preparation of drugs useful for preventing and treating sexual dysfunction

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Publication number
EP2131842A2
EP2131842A2 EP08761838A EP08761838A EP2131842A2 EP 2131842 A2 EP2131842 A2 EP 2131842A2 EP 08761838 A EP08761838 A EP 08761838A EP 08761838 A EP08761838 A EP 08761838A EP 2131842 A2 EP2131842 A2 EP 2131842A2
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EP
European Patent Office
Prior art keywords
treatment
prevention
use according
sexual
pharmaceutically acceptable
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP08761838A
Other languages
German (de)
French (fr)
Inventor
Lisa Arvanitis
Christiane L'heritier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Original Assignee
Sanofi Aventis France
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Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
Publication of EP2131842A2 publication Critical patent/EP2131842A2/en
Withdrawn legal-status Critical Current

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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of a neurokinin A NK 2 receptor antagonist compound for the preparation of medicaments useful for the prevention and treatment of sexual dysfunction.
  • the neurokinin A NK 2 receptor antagonist is a compound chosen from:
  • a NK 2 receptor antagonist of neurokinin A selected from saredutant and its pharmaceutically acceptable salts, (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo 4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yl] acetamide and its pharmaceutically acceptable salts and (+) - 1 '- [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4'-carboxamide and its pharmaceutically acceptable salts are useful in the prevention and treatment of sexual dysfunction.
  • sexual dysfunction means any pathology as defined by the American Psychiatric Association - DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (Washington DC, 2000), pages 617- 654 and include disorders of sexual desire (that is, disorder: decreased sexual desire and disturbance: sexual aversion), sexual arousal disorders (ie, excitement disorder) sexual dysfunction in women and erectile dysfunction in man), disorders of orgasm (ie orgasmic disorder in women, orgasm disorder in men, and premature ejaculation), sexual disorders with pain (ie dyspareunia and vaginismus), sexual dysfunction due to a general medical condition, substance-induced sexual dysfunction, and unspecified sexual dysfunction.
  • disorders of sexual desire that is, disorder: decreased sexual desire and disturbance: sexual aversion
  • sexual arousal disorders ie, excitement disorder
  • disorders of orgasm ie orgasmic disorder in women, orgasm disorder in men, and premature e
  • the subject of the present invention is the use of a neurokinin A NK 2 receptor antagonist compound chosen from saredutant and its pharmaceutically acceptable salts, the (+) - N- [l- [2- [2- (3,4-dichlorophenyl) -5-oxo-4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yl] acetamide and its pharmaceutically acceptable salts and (+) - [2- [4-Benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4'-carboxamide and pharmaceutically acceptable salts thereof for the preparation of medicaments useful in the prevention and treatment of sexual dysfunction.
  • the present invention relates to the use of saredutant and its pharmaceutically acceptable salts for the preparation of drugs useful in the prevention and treatment of sexual dysfunction
  • the present invention also relates to the use of (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo-4-phenylmorpholin-2-yl] ethyl ] -4- (3-fluorophenyl) piperidin-4-yl] acetamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment of sexual dysfunctions.
  • the present invention also relates to the use of (+) - 1- [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N dimethyl-1,4'-bipiperidine-4'-carboxamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment of sexual dysfunctions.
  • the subject of the present invention is the use of saredutant and its pharmaceutically acceptable salts, (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo] 4-phenylmo ⁇ holin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yljacetamide and its pharmaceutically acceptable salts and (+) - 1 '- [2- [4-benzoyl-2- (3, 4-dichlorophenyl) mo ⁇ olin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4'-carboxamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in preventing and treating sexual desire, especially disorder: decreased sexual desire or disorder: sexual aversion.
  • the subject of the present invention is the use of saredutant and its pharmaceutically acceptable salts, of (+) - N- [1- [2- [2- (3,4- dichlorophenyl) -5-oxo-4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yl] acetamide and its pharmaceutically acceptable salts and (+) - l '- [2- [ 4-Benzoyl-2- (3,4-dichlorophenyl) niorpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidin-4'-carboxamide and pharmaceutically acceptable salts thereof for the preparation of useful medicaments in the prevention and treatment of sexual arousal disorders, in particular sexual arousal disorder in women or erectile dysfunction in men.
  • the subject of the present invention is the use of saredutant and its pharmaceutically acceptable salts, (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo] 4-phenylmorphol-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yl] acetamide and its pharmaceutically acceptable salts and (+) - 1 '- [2- [4-benzoyl-2- ( 3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4'-carboxamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment of disorders of the orgasm, more particularly of the orgasmic disorder in the woman, the disorder of the orgasm in the man or the premature ejaculation.
  • the subject of the present invention is the use of saredutant and its pharmaceutically acceptable salts, (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo] 4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yljacetamide and its pharmaceutically acceptable salts and (+) - 1 '- [2- [4-benzoyl-2- (3, 4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4'-carboxamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment of sexual disorders with pain, more particularly dyspareunia or vaginismus.
  • the subject of the present invention is the use of saredutant and its pharmaceutically acceptable salts, (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo] 4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yljacetamide and its pharmaceutically acceptable salts and (+) - 1 '- [2- [4-benzoyl-2- (3, 4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4'-carboxamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment of dysfunction sexual abuse due to a general medical condition, particularly depressive disorder or major depressive disorder.
  • the subject of the present invention is the use of saredutant and its pharmaceutically acceptable salts, (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo] 4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4- yl] acetamide and its pharmaceutically acceptable salts and (+) - 1 '- [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1 , 4'-bipiperidin-4 l - carboxamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment of sexual dysfunction induced by a substance.
  • the subject of the present invention is the use of saredutant and its pharmaceutically acceptable salts, (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo] 4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yljacetamide and its pharmaceutically acceptable salts and (+) - 1 '- [2- [4-benzoyl-2-
  • (+) - N - [1- [2- [2- (3,4-Dichlorophenyl) -5-oxo-4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4- yl] acetamide and its pharmaceutically acceptable salts may be prepared according to the process described in the international application
  • (+) - r- [2- [4-benzoyl-2- (3 5 4-dichloro ⁇ hényl) morpholin-2-yl] ethyl] -N, N-dimethyl-l, 4'-bipiperidin-4'-carboxamide and its pharmaceutically acceptable salts can be prepared according to the process described in the international application WO 02/094 821.
  • the subject of the present invention is a method for treating or preventing sexual dysfunctions by administering an appropriate dose of saredutant or a pharmaceutically acceptable salt thereof or (+) - N- [ l- [2- [2- (3 3 4-dichloro ⁇ hényl) -5-oxo-4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yl] acetamide or a its pharmaceutically acceptable salts or (+) - r- [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine 4'-carboxamide or a pharmaceutically acceptable salt thereof.
  • the subject of the present invention is also the combination of an NK 2 antagonist compound of neurokinin A according to the invention in combination with another active ingredient that is useful for the treatment of sexual dysfunctions, such as for example : sildenafil, vardenafil, tardalafil, alprostadil, apomorphine, midrodrine, moxisylite, phentolamine, aviptadil, testosterone, dapoxetine, tobolone; thus the invention also relates to pharmaceutical compositions containing this combination.
  • the NK 2 neurokmine A receptor antagonist compound according to the invention and the other active ingredient according to the invention can be administered simultaneously, separately or spread over time.
  • Extended use over time is understood to mean the sequential administration of the first compound of the composition according to the invention, included in a pharmaceutical form, and then of the second compound of the composition according to the invention, included in a pharmaceutical form. separate.
  • the lapse of time elapsed between the administration of the first compound of the composition according to the invention and the administration of the second compound of the same composition according to the invention does not exceed usually not 24 hours.
  • unit dosage forms containing either only one of the constituent compounds of the composition according to the invention, or the combination of the two compounds which can be used in the various types of use described above, may for example be appropriate for the oral, nasal, parenteral or transdermal administration.
  • two different dosage forms may be for the same route of administration or a different route of administration (oral and transdermal). or oral and nasal or parenteral and transdermal etc.).
  • the invention therefore also relates to a kit containing the neurokinin A NK 2 receptor antagonist compound according to the invention and the other active ingredient according to the invention wherein said neurokinin A NK 2 receptor antagonist compound according to the invention, and the other active ingredient according to the invention are in separate compartments and in similar or different packages, and are intended to be administered simultaneously, separately or spread over time.
  • the NK 2 receptor antagonist of neurokinin A, a pharmaceutically acceptable salt thereof should be formulated into a pharmaceutical composition.
  • the active ingredient in the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or local administration, can be administered in particular in unit form, in admixture with conventional pharmaceutical carriers, to animals. and to human beings. Suitable forms of administration include oral forms such as tablets, capsules, pills, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, forms of local administration , intracavernous, transdermal, intramuscular, intravenous.
  • the active ingredient or active ingredients are generally formulated in dosage units.
  • the dosage unit contains 2.5 to 500 mg, preferably 30 to 250 mg, preferably 30 to 150 mg per dosage unit, for daily administrations, one or more times a day.
  • the dosage appropriate to each patient is determined by the physician according to the mode of administration, the age, the weight and the response of said patient.
  • the NK 2 receptor antagonist of neurokinin A is administered orally, in a single dose.
  • saredutant The effects of saredutant were determined in eight-week, multi-center, double-blind, placebo-controlled clinical trials in adult, male or female patients with major depressive disorder.
  • Antidepressants are known to have a deleterious effect on the sexual activity of patients (Montejo-Gonzales AL et al .: J. Sex Marital Ther., 1997, 23 (3), 176-194). Surprisingly, the saredutant has shown a significant improvement
  • a beneficial effect has been observed on the following dysfunctions: the decrease of the sexual desire and the disorders of the sexual arousal.
  • the following nonlimiting examples describe examples of pharmaceutical compositions useful for the use according to the invention of an NK 2 receptor antagonist of neurokine A.
  • Saredutant is used in the form of monosuccinate; (+) - N - [1- [2- [2- (3,4-dichlorophenyl) -5-oxo-4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4- yl] acetamide in hydrochloride form and (+) - r- [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4 Bipiperidine-4'-carboxamide as dihydrochloride.
  • EXAMPLE 1 Capsule 30 mg of saredutant.
  • EXAMPLE 2 Capsule 100 mg of saredutant Saredutant (expressed as base) 100.0 mg lactose monohydrate (200 mesh) QSP 400.0 mg croscarmellose sodium 8.0 mg magnesium stearate 4.0 mg purified water * QS for an opaque capsule of size 0, filled to 400, 0 mg

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to the use of a compound antagonist to the NK<SUB>2 </SUB>receptors of A neurokinine for the preparation of drugs useful for preventing and treating sexual dysfunction.

Description

UTILISATION D'UN COMPOSE ANTAGONISTE DES RECEPTEURS NK2 DE LA NEUROKININE A POUR LA PREPARATION DE MEDICAMENTS UTILES POUR LA PREVENTION ET LE TRAITEMENT DES DYSFONCTIONS SEXUELLES.USE OF ANTAGONIST COMPOUND OF NEUROKININ A NK 2 RECEPTORS FOR THE PREPARATION OF MEDICAMENTS USEFUL IN THE PREVENTION AND TREATMENT OF SEXUAL DYSFUNCTIONS.
La présente invention a pour objet l'utilisation d'un composé antagoniste des récepteurs NK2 de la neurokinine A pour la préparation de médicaments utiles pour la prévention et le traitement des dysfonctions sexuelles. Selon la présente invention, par antagoniste des récepteurs NK2 de la neurokinine A, on entend un composé choisi parmi :The present invention relates to the use of a neurokinin A NK 2 receptor antagonist compound for the preparation of medicaments useful for the prevention and treatment of sexual dysfunction. According to the present invention, the neurokinin A NK 2 receptor antagonist is a compound chosen from:
- le (S)-O)-N- [4-(4-acétamido-4-phénylpipéridin- 1 -yl)-2-(3 ,4-dichlorophényl)butyl] - N-méthylbenzamide, dont la dénomination commune internationale (D.C.I.) est saredutant, et ses sels pharmaceutiquement acceptables décrits dans le brevet EP 0 474 561 et dans le brevet US 5 236 921, ainsi que dans le brevet EP 1 173 179 pour son activité dans les troubles dépressifs majeurs ;(S) -O) -N- [4- (4-acetamido-4-phenylpiperidin-1-yl) -2- (3,4-dichlorophenyl) butyl] -N-methylbenzamide, whose international non-proprietary name ( DCI) is saredutant, and its pharmaceutically acceptable salts described in patent EP 0 474 561 and in patent US 5 236 921, as well as in patent EP 1 173 179 for its activity in major depressive disorders;
- le (+)-N-[l-[2-[2-(3,4-dichlorophényl)-5-oxo-4-phénylmorpholin-2-yl]éthyl]-4-(3- fluorophényl)pipéridin-4-yl] acétamide et ses sels pharmaceutiquement acceptables décrits dans la demande internationale WO 2006/021 654 ; et, - le (+)-r-[2-[4-benzoyl-2-(3,4-dichlorophényl)morpholin-2-yl]éthyl]-N,N-diméthyl- l,4'-bipipéridme-4'-carboxamide et ses sels pharmaceutiquement acceptables, qui possède de plus, la propriété d'être un antagoniste des récepteurs NK3 de la neurokinine B. Ce composé et ses sels sont décrits dans la demande internationale WO 02/094 821. On a maintenant trouvé qu'un antagoniste des récepteurs NK2 de la neurokinine A choisi parmi le saredutant et ses sels pharmaceutiquement acceptables, le (+)-N-[l-[2- [2-(3 ,4-dichlorophényl)-5 -oxo-4-phénylmorpholin-2-yl] éthyl] -4-(3 -fluorophényl) pipéridin-4-yl] acétamide et ses sels pharmaceutiquement acceptables et le (+)-l'-[2- [4-benzoyl-2-(3,4-dichlorophényl)morpholin-2-yl]éthyl]-N,N-diméthyl-l,4'- bipipéridine-4'-carboxamide et ses sels pharmaceutiquement acceptables sont utiles dans la prévention et le traitement des dysfonctions sexuelles.(+) - N- [1- [2- [2- (3,4-Dichlorophenyl) -5-oxo-4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4 -yl] acetamide and its pharmaceutically acceptable salts described in international application WO 2006/021 654; and, (+) - r- [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidin-4 carboxyamide and its pharmaceutically acceptable salts, which furthermore has the property of being an antagonist of the NK 3 receptors of neurokinin B. This compound and its salts are described in the international application WO 02/094 821. found that a NK 2 receptor antagonist of neurokinin A selected from saredutant and its pharmaceutically acceptable salts, (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo 4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yl] acetamide and its pharmaceutically acceptable salts and (+) - 1 '- [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4'-carboxamide and its pharmaceutically acceptable salts are useful in the prevention and treatment of sexual dysfunction.
Par dysfonctions sexuelles on entend toutes pathologies telles que définies par l'American Psychiatrie Association - DSM-IV-TR, Manuel diagnostique et statistique des troubles mentaux, 4ème édition, texte révisé (Washington DC, 2000), pages 617- 654 et qui incluent les troubles du désir sexuel (c'est-à-dire le trouble : baisse du désir sexuel et le trouble : aversion sexuelle), les troubles de l'excitation sexuelle (c'est-à- dire le trouble de l'excitation sexuelle chez la femme et le trouble de l'érection chez l'homme), les troubles de l'orgasme (c'est-à-dire le trouble de l'orgasme chez la femme, le trouble de l'orgasme chez l'homme, et l'éjaculation précoce), les troubles sexuels avec douleurs (c'est-à-dire la dyspareunie et le vaginisme), la dysfonction sexuelle due à une affection médicale générale, la dysfonction sexuelle induite par une substance, et les dysfonctions sexuelles non spécifiées.For sexual dysfunction means any pathology as defined by the American Psychiatric Association - DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (Washington DC, 2000), pages 617- 654 and include disorders of sexual desire (that is, disorder: decreased sexual desire and disturbance: sexual aversion), sexual arousal disorders (ie, excitement disorder) sexual dysfunction in women and erectile dysfunction in man), disorders of orgasm (ie orgasmic disorder in women, orgasm disorder in men, and premature ejaculation), sexual disorders with pain (ie dyspareunia and vaginismus), sexual dysfunction due to a general medical condition, substance-induced sexual dysfunction, and unspecified sexual dysfunction.
Ainsi, selon un de ses aspects, la présente invention a pour objet l'utilisation d'un composé antagoniste des récepteurs NK2 de la neurokinine A choisi parmi le saredutant et ses sels pharmaceutiquement acceptables, le (+)-N-[l-[2-[2-(3,4- dichlorophényl)-5-oxo-4-phénylmorpholin-2-yl]éthyl]-4-(3-fiuorophényl)pipéridin-4- yl]acétamide et ses sels pharmaceutiquement acceptables et le (+)-l'-[2-[4-benzoyl-2- (3,4-dichlorophényl)morpholin-2-yl]éthyl]-N,N-diméthyl-l,4'-bipipéridine-4'- carboxamide et ses sels pharmaceutiquement acceptables pour la préparation de médicaments utiles dans la prévention et le traitement des dysfonctions sexuelles. En particulier, la présente invention a pour objet l'utilisation du saredutant et de ses sels pharmaceutiquement acceptables pour la préparation de médicaments utiles dans la prévention et le traitement des dysfonctions sexuelles.Thus, according to one of its aspects, the subject of the present invention is the use of a neurokinin A NK 2 receptor antagonist compound chosen from saredutant and its pharmaceutically acceptable salts, the (+) - N- [l- [2- [2- (3,4-dichlorophenyl) -5-oxo-4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yl] acetamide and its pharmaceutically acceptable salts and (+) - [2- [4-Benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4'-carboxamide and pharmaceutically acceptable salts thereof for the preparation of medicaments useful in the prevention and treatment of sexual dysfunction. In particular, the present invention relates to the use of saredutant and its pharmaceutically acceptable salts for the preparation of drugs useful in the prevention and treatment of sexual dysfunction.
En particulier aussi, la présente invention a pour objet l'utilisation du (+)-N-[l-[2- [2-(3,4-dichlorophényl)-5-oxo-4-phénylmorpholin-2-yl]éthyl]-4-(3-fluorophényl) pipéridin-4-yl]acétamide et ses sels pharmaceutiquement acceptables pour la préparation de médicaments utiles dans la prévention et le traitement des dysfonctions sexuelles.In particular, the present invention also relates to the use of (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo-4-phenylmorpholin-2-yl] ethyl ] -4- (3-fluorophenyl) piperidin-4-yl] acetamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment of sexual dysfunctions.
En particulier également, la présente invention a pour objet l'utilisation du (+)-l'- [2-[4-benzoyl-2-(3,4-dichlorophényl)morpholin-2-yl]éthyl]-N,N-diméthyl-l,4'- bipipéridine-4'-carboxamide et ses sels pharmaceutiquement acceptables pour la préparation de médicaments utiles dans la prévention et le traitement des dysfonctions sexuelles.In particular, the present invention also relates to the use of (+) - 1- [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N dimethyl-1,4'-bipiperidine-4'-carboxamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment of sexual dysfunctions.
En particulier également, la présente invention a pour objet l'utilisation du saredutant et de ses sels pharmaceutiquement acceptables, du (+)-N-[l-[2-[2-(3,4- dichlorophényl)-5-oxo-4-phénylmoφholin-2-yl]éthyl]-4-(3-fluorophényl) pipéridin-4- yljacétamide et ses sels pharmaceutiquement acceptables et du (+)-l'-[2-[4-benzoyl-2- (3,4-dichlorophényl)moφholin-2-yl]éthyl]-N,N-diméthyl-l,4'-bipipéridine-4'- carboxamide et ses sels pharmaceutiquement acceptables pour la préparation de médicaments utiles dans la prévention et le traitement du trouble du désir sexuel, plus particulièrement du trouble : baisse du désir sexuel ou du trouble : aversion sexuelle.In particular also, the subject of the present invention is the use of saredutant and its pharmaceutically acceptable salts, (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo] 4-phenylmoφholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yljacetamide and its pharmaceutically acceptable salts and (+) - 1 '- [2- [4-benzoyl-2- (3, 4-dichlorophenyl) moφolin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4'-carboxamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in preventing and treating sexual desire, especially disorder: decreased sexual desire or disorder: sexual aversion.
En particulier également, la présente invention a pour objet l'utilisation du saredutant et de ses sels pharmaceutiquement acceptables, du (+)-N-[l-[2-[2-(3,4- dichlorophényl)-5-oxo-4-phénylmorpholin-2-yl]éthyl]-4-(3-fluorophényl) pipéridin-4- yl]acétamide et ses sels pharmaceutiquement acceptables et du (+)-l'-[2-[4-benzoyl-2- (3,4-dichlorophényl)niorpholin-2-yl]éthyl]-N,N-diméthyl-l,4'-bipipéridme-4'- carboxamide et ses sels pharmaceutiquement acceptables pour la préparation de médicaments utiles dans la prévention et le traitement des troubles de l'excitation sexuelle, plus particulièrement du trouble de l'excitation sexuelle chez la femme ou du trouble de l'érection chez l'homme.In particular also, the subject of the present invention is the use of saredutant and its pharmaceutically acceptable salts, of (+) - N- [1- [2- [2- (3,4- dichlorophenyl) -5-oxo-4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yl] acetamide and its pharmaceutically acceptable salts and (+) - l '- [2- [ 4-Benzoyl-2- (3,4-dichlorophenyl) niorpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidin-4'-carboxamide and pharmaceutically acceptable salts thereof for the preparation of useful medicaments in the prevention and treatment of sexual arousal disorders, in particular sexual arousal disorder in women or erectile dysfunction in men.
En particulier également, la présente invention a pour objet l'utilisation du saredutant et de ses sels pharmaceutiquement acceptables, du (+)-N-[l-[2-[2-(3,4- dichlorophényl)-5 -oxo-4~phénylmorpholm-2-yl] éthyl] -4-(3 -fluorophényl) pipéridin-4- yl]acétamide et ses sels pharmaceutiquement acceptables et du (+)-l'-[2-[4-benzoyl-2- (3,4-dichlorophényl)morpholin-2-yl]éthyl]-N,N-diméthyl-l,4'-bipipéridine-4'- carboxamide et ses sels pharmaceutiquement acceptables pour la préparation de médicaments utiles dans la prévention et le traitement des troubles de l'orgasme, plus particulièrement du trouble de l'orgasme chez la femme, du trouble de l'orgasme chez l'homme ou de l'éjaculation précoce.In particular also, the subject of the present invention is the use of saredutant and its pharmaceutically acceptable salts, (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo] 4-phenylmorphol-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yl] acetamide and its pharmaceutically acceptable salts and (+) - 1 '- [2- [4-benzoyl-2- ( 3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4'-carboxamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment of disorders of the orgasm, more particularly of the orgasmic disorder in the woman, the disorder of the orgasm in the man or the premature ejaculation.
En particulier également, la présente invention a pour objet l'utilisation du saredutant et de ses sels pharmaceutiquement acceptables, du (+)-N-[l-[2-[2-(3,4- dichlorophényl)-5-oxo-4-phénylmorpholin-2-yl]éthyl]-4-(3-fluorophényl) pipéridin-4- yljacétamide et ses sels pharmaceutiquement acceptables et du (+)-l'-[2-[4-benzoyl-2- (3,4-dichlorophényl)morpholin-2-yl] éthyl] -N,N-diméthyl- 1 ,4'-bipipéridine-4'- carboxamide et ses sels pharmaceutiquement acceptables pour la préparation de médicaments utiles dans la prévention et le traitement des troubles sexuels avec douleurs, plus particulièrement de la dyspareunie ou du vaginisme.In particular also, the subject of the present invention is the use of saredutant and its pharmaceutically acceptable salts, (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo] 4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yljacetamide and its pharmaceutically acceptable salts and (+) - 1 '- [2- [4-benzoyl-2- (3, 4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4'-carboxamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment of sexual disorders with pain, more particularly dyspareunia or vaginismus.
En particulier également, la présente invention a pour objet l'utilisation du saredutant et de ses sels pharmaceutiquement acceptables, du (+)-N-[l-[2-[2-(3,4- dichlorophényl)-5-oxo-4-phénylmorpholin-2-yl]éthyl]-4-(3-fluorophényl) pipéridin-4- yljacétamide et ses sels pharmaceutiquement acceptables et du (+)-l'-[2-[4-benzoyl-2- (3 ,4-dichlorophényl)morpholin-2-yl] éthyl] -N,N-diméthyl- 1 ,4'-bipipéridine-4'- carboxamide et ses sels pharmaceutiquement acceptables pour la préparation de médicaments utiles dans la prévention et le traitement de la dysfonction sexuelle due à une affection médicale générale, particulièrement à un trouble dépressif ou à un trouble dépressif majeur. En particulier également, la présente invention a pour objet l'utilisation du saredutant et de ses sels pharmaceutiquement acceptables, du (+)-N-[l-[2-[2-(3,4- dichlorophényl)-5-oxo-4-phénylmorpholin-2-yl]éthyl]-4-(3-fiuorophényl) pipéridin-4- yl]acétamide et ses sels pharmaceutiquement acceptables et du (+)-l'-[2-[4-benzoyl-2- (3,4-dichlorophényl)morpholin-2-yl]éthyl]-N,N-diméthyl-l,4'-bipipéridine-4l- carboxamide et ses sels pharmaceutiquement acceptables pour la préparation de médicaments utiles dans la prévention et le traitement de la dysfonction sexuelle induite par une substance.In particular also, the subject of the present invention is the use of saredutant and its pharmaceutically acceptable salts, (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo] 4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yljacetamide and its pharmaceutically acceptable salts and (+) - 1 '- [2- [4-benzoyl-2- (3, 4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4'-carboxamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment of dysfunction sexual abuse due to a general medical condition, particularly depressive disorder or major depressive disorder. In particular also, the subject of the present invention is the use of saredutant and its pharmaceutically acceptable salts, (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo] 4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4- yl] acetamide and its pharmaceutically acceptable salts and (+) - 1 '- [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1 , 4'-bipiperidin-4 l - carboxamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment of sexual dysfunction induced by a substance.
En particulier également, la présente invention a pour objet l'utilisation du saredutant et de ses sels pharmaceutiquement acceptables, du (+)-N-[l-[2-[2-(3,4- dichlorophényl)-5 -oxo-4-phénylmorpholin-2-yl] éthyl] -4-(3 -fluorophényl) pipéridin-4- yljacétamide et ses sels pharmaceutiquement acceptables et du (+)-l'-[2-[4-benzoyl-2-In particular also, the subject of the present invention is the use of saredutant and its pharmaceutically acceptable salts, (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo] 4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yljacetamide and its pharmaceutically acceptable salts and (+) - 1 '- [2- [4-benzoyl-2-
(3,4-dichlorophényl)morpholin-2-yl]éthyl]-N,N-diméthyl-l,4'-bipipéridine-4'- carboxamide et ses sels pharmaceutiquement acceptables pour la préparation de médicaments utiles dans la prévention et le traitement des dysfonctions sexuelles non spécifiées. Le saredutant et ses sels pharmaceutiquement acceptables peuvent être préparés selon le procédé décrit dans le brevet EP 0474 561 ou celui décrit dans le brevet EP 0 698 601.(3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4'-carboxamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment unspecified sexual dysfunctions. The saredutant and its pharmaceutically acceptable salts can be prepared according to the process described in patent EP 0474 561 or that described in patent EP 0 698 601.
Le (+)-N-[l-[2-[2-(3,4-dichlorophényl)-5-oxo-4-phénylmorpholin-2-yl]éthyl]-4- (3 -fluorophényl) pipéridin-4-yl]acétamide et ses sels pharmaceutiquement acceptables peuvent être préparés selon le procédé décrit dans la demande internationale(+) - N - [1- [2- [2- (3,4-Dichlorophenyl) -5-oxo-4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4- yl] acetamide and its pharmaceutically acceptable salts may be prepared according to the process described in the international application
WO 2006/021 654.WO 2006/021 654.
Le (+)-r-[2-[4-benzoyl-2-(354-dichloroρhényl)morpholin-2-yl]éthyl]-N,N- diméthyl-l,4'-bipipérîdine-4'-carboxamide et ses sels pharmaceutiquement acceptables peuvent être préparés selon le procédé décrit dans la demande internationale WO 02/094 821.The (+) - r- [2- [4-benzoyl-2- (3 5 4-dichloroρhényl) morpholin-2-yl] ethyl] -N, N-dimethyl-l, 4'-bipiperidin-4'-carboxamide and its pharmaceutically acceptable salts can be prepared according to the process described in the international application WO 02/094 821.
Selon un autre de ses aspects, la présente invention a pour objet une méthode de traitement ou de prévention des dysfonctions sexuelles par administration d'une dose appropriée du saredutant ou d'un de ses sels pharmaceutiquement acceptables ou du (+)-N-[l-[2-[2-(334-dichloroρhényl)-5-oxo-4-phénylmorpholin-2-yl]éthyl]-4-(3- fluorophényl) pipéridin-4-yl]acétamide ou d'un de ses sels pharmaceutiquement acceptables ou du (+)-r-[2-[4-benzoyl-2-(3,4-dichlorophényl)morpholin-2-yl]éthyl]- N,N-diméthyl-l,4'-bipipéridine-4'-carboxamide ou d'un de ses sels pharmaceutiquement acceptables.According to another of its aspects, the subject of the present invention is a method for treating or preventing sexual dysfunctions by administering an appropriate dose of saredutant or a pharmaceutically acceptable salt thereof or (+) - N- [ l- [2- [2- (3 3 4-dichloroρhényl) -5-oxo-4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yl] acetamide or a its pharmaceutically acceptable salts or (+) - r- [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine 4'-carboxamide or a pharmaceutically acceptable salt thereof.
Selon un autre de ses aspects, la présente invention a également pour objet l'association d'un composé antagoniste NK2 de la neurokinine A selon l'invention en association avec un autre principe actif utile pour le traitement des dysfonctions sexuelles tel que par exemple : sildenafil, vardenafïl, tardalafil, alprostadil, apomorphine, midrodrine, moxisylite, phentolamine, aviptadil, testosterone, dapoxetine, tobolone ; ainsi l'invention concerne également les compositions pharmaceutiques contenant cette association.According to another of its aspects, the subject of the present invention is also the combination of an NK 2 antagonist compound of neurokinin A according to the invention in combination with another active ingredient that is useful for the treatment of sexual dysfunctions, such as for example : sildenafil, vardenafil, tardalafil, alprostadil, apomorphine, midrodrine, moxisylite, phentolamine, aviptadil, testosterone, dapoxetine, tobolone; thus the invention also relates to pharmaceutical compositions containing this combination.
Selon un autre aspect de l'invention, le composé antagoniste des récepteurs NK2 neurokmine A selon l'invention et l'autre principe actif selon l'invention peuvent être administrés de manière simultanée, séparée ou étalée dans le temps.According to another aspect of the invention, the NK 2 neurokmine A receptor antagonist compound according to the invention and the other active ingredient according to the invention can be administered simultaneously, separately or spread over time.
On entend par "utilisation simultanée", l'administration des composés de la composition selon l'invention compris dans une seule et même forme pharmaceutique. On entend par "utilisation séparée" l'administration, en même temps, des deux composés de la composition selon l'invention, chacun compris dans une forme pharmaceutique distincte.By "simultaneous use" is meant the administration of the compounds of the composition according to the invention included in one and the same pharmaceutical form. By "separate use" is meant the administration, at the same time, of the two compounds of the composition according to the invention, each comprised in a separate pharmaceutical form.
On entend par "utilisation étalée dans le temps", l'administration successive du premier composé de la composition selon l'invention, compris dans une forme pharmaceutique, puis, du deuxième composé de la composition selon l'invention, compris dans une forme pharmaceutique distincte."Extended use over time" is understood to mean the sequential administration of the first compound of the composition according to the invention, included in a pharmaceutical form, and then of the second compound of the composition according to the invention, included in a pharmaceutical form. separate.
Dans le cas de cette "utilisation étalée dans le temps", le laps de temps écoulé entre l'administration du premier composé de la composition selon l'invention et l'administration du deuxième composé de la même composition selon l'invention n'excède généralement pas 24 heures.In the case of this "use spread over time", the lapse of time elapsed between the administration of the first compound of the composition according to the invention and the administration of the second compound of the same composition according to the invention does not exceed usually not 24 hours.
Les formes pharmaceutiques unitaires contenant soit un seul des composés constitutifs de la composition selon l'invention, soit l'association des 2 composés qui peuvent être mis en œuvre dans les différents types d'utilisation décrits ci-dessus peuvent par exemple être appropriées à l'administration orale, nasale, parentérale ou transdermique.The unit dosage forms containing either only one of the constituent compounds of the composition according to the invention, or the combination of the two compounds which can be used in the various types of use described above, may for example be appropriate for the oral, nasal, parenteral or transdermal administration.
Aussi, dans le cas d'une "utilisation séparée" et d'une "utilisation étalée dans le temps", deux formes pharmaceutiques distinctes peuvent être destinées à la même voie d'administration ou à une voie d'administration différente (orale et transdermique ou orale et nasale ou parentérale et transdermique etc.). L'invention concerne donc également une trousse contenant le composé antagoniste des récepteurs NK2 de la neurokinine A selon l'invention et l'autre principe actif selon l'invention dans laquelle ledit composé antagoniste des récepteurs NK2 neurokinine A selon l'invention, et l'autre principe actif selon l'invention sont dans des compartiments distincts et dans des conditionnements semblables ou différents, et sont destinés à être administrés de manière simultanée, séparée ou étalée dans le temps. Pour son utilisation en tant que médicament, l'antagoniste des récepteurs NK2 de la neurokinine A, un de ses sels pharmaceutiquement acceptables doit être formulé en composition pharmaceutique. Dans les compositions pharmaceutiques de la présente invention pour l'administration orale, sublinguale, sous-cutanée, intramusculaire, intraveineuse, transdermique ou locale, le principe actif peut être administré en particulier sous forme unitaire, en mélange avec des supports pharmaceutiques classiques, aux animaux et aux êtres humains. Les formes d'administration appropriées comprennent les formes par voie orale telles que les comprimés, les gélules, les pilules, les poudres, les granules et les solutions ou suspensions orales, les formes d'administration sublinguale et buccale, les formes d'administration locale, intracaverneuse, transdermique, intramusculaire, intraveineuse. Dans les compositions pharmaceutiques de la présente invention, le principe actif ou les principes actifs sont généralement formulés en unités de dosage. L'unité de dosage contient 2,5 à 500 mg, avantageusement de 30 à 250 mg, de préférence de 30 à 150 mg par unité de dosage, pour les administrations quotidiennes, une ou plusieurs fois par jour. Bien que ces dosages soient des exemples de situations moyennes, il peut y avoir des cas particuliers où des dosages plus élevés ou plus faibles sont appropriés, de tels dosages appartiennent également à l'invention. Selon la pratique habituelle, le dosage approprié à chaque patient est déterminé par le médecin selon le mode d'administration, l'âge, le poids et la réponse dudit patient.Also, in the case of "separate use" and "spread use over time", two different dosage forms may be for the same route of administration or a different route of administration (oral and transdermal). or oral and nasal or parenteral and transdermal etc.). The invention therefore also relates to a kit containing the neurokinin A NK 2 receptor antagonist compound according to the invention and the other active ingredient according to the invention wherein said neurokinin A NK 2 receptor antagonist compound according to the invention, and the other active ingredient according to the invention are in separate compartments and in similar or different packages, and are intended to be administered simultaneously, separately or spread over time. For its use as a drug, the NK 2 receptor antagonist of neurokinin A, a pharmaceutically acceptable salt thereof, should be formulated into a pharmaceutical composition. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or local administration, the active ingredient can be administered in particular in unit form, in admixture with conventional pharmaceutical carriers, to animals. and to human beings. Suitable forms of administration include oral forms such as tablets, capsules, pills, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, forms of local administration , intracavernous, transdermal, intramuscular, intravenous. In the pharmaceutical compositions of the present invention, the active ingredient or active ingredients are generally formulated in dosage units. The dosage unit contains 2.5 to 500 mg, preferably 30 to 250 mg, preferably 30 to 150 mg per dosage unit, for daily administrations, one or more times a day. Although these assays are examples of average situations, there may be special cases where higher or lower dosages are appropriate, such assays also belong to the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the age, the weight and the response of said patient.
De façon préférentielle, l'antagoniste des récepteurs NK2 de la neurokinine A est administré par la voie orale, en une prise unique.Preferably, the NK 2 receptor antagonist of neurokinin A is administered orally, in a single dose.
Les effets du saredutant ont été déterminés au cours d'études cliniques de huit semaines, multicentrique, en double-aveugle, versus placebo, chez les patients adultes, maie ou femelle, présentant un trouble dépressif majeur. Les patients ont reçu par voie orale, une dose de 100 mg par jour de saredutant pendant huit semaines, sous forme de gélules (Exemple 2).The effects of saredutant were determined in eight-week, multi-center, double-blind, placebo-controlled clinical trials in adult, male or female patients with major depressive disorder. The patients received orally, a dose of 100 mg per day of saredutant for eight weeks in capsule form (Example 2).
Les effets du saredutant par rapport au placebo ont été évalués en utilisant le questionnaire CSFQ comprenant 14 items (de l'anglais : Changes in SexualThe effects of saredutant compared to placebo were assessed using the CSFQ Questionnaire with 14 items: Changes in Sexual
Functioning Questionnaire) selon Clayton AH et al., Psychopharmacol. Bull., 1997, 33, 731-745.Functioning Questionnaire) according to Clayton AH et al., Psychopharmacol. Bull., 1997, 33, 731-745.
Il est connu que les antidépresseurs ont un effet délétère sur l'activité sexuelle des patients (Montejo-Gonzales AL et al. : J. Sex Marital Ther., 1997, 23(3), 176- 194). Or, de façon surprenante, le saredutant a démontré une amélioration significativeAntidepressants are known to have a deleterious effect on the sexual activity of patients (Montejo-Gonzales AL et al .: J. Sex Marital Ther., 1997, 23 (3), 176-194). Surprisingly, the saredutant has shown a significant improvement
(p<0,05) du score total CSFQ entre la dernière visite (prévue au 56ème jour) et la première visite (avant le début du traitement) par rapport au groupe placebo (p<0,05). Le tableau ci-dessous indique pour chaque groupe traité la variation moyenne par rapport à la valeur de base avant traitement du score total CSFQ et sa variabilité entre parenthèses obtenues sur l'analyse de l'ensemble des études. Une augmentation du score total CSFQ correspond à une amélioration de la fonction sexuelle.(p <0.05) total score CSFQ between the last visit (under 56th day) and the first visit (before start of treatment) compared with the placebo group (p <0.05). The table below indicates, for each treatment group, the average variation from baseline before treatment of the total CSFQ score and its variability in parentheses obtained on the analysis of all the studies. An increase in the total CSFQ score corresponds to an improvement in sexual function.
TABLEAU I Score total CSFQTABLE I Total CSFQ score
* p < 0,05 versus placebo dans ANCOVA (analyse de covariance, incluant la valeur de base du score total CSFQ, le facteur sexe, et le facteur étude traité comme un facteur aléatoire), n = nombre de patients. Ces études montrent de manière surprenante, une amélioration significative du score CSFQ des dysfonctions sexuelles chez les patients traités par le saredutant versus les patients recevant le placebo.* p <0.05 versus placebo in ANCOVA (covariance analysis, including the baseline value of the total CSFQ score, the sex factor, and the study factor treated as a random factor), n = number of patients. These studies show, surprisingly, a significant improvement in the CSFQ score of sexual dysfunctions in patients treated with saredutant versus patients receiving placebo.
Plus particulièrement, un effet bénéfique a été observé sur les dysfonctionnements suivants : la baisse du désir sexuel et les troubles de l'excitation sexuelle. Les exemples suivants, non limitatifs, décrivent des exemples de compositions pharmaceutiques, utiles pour l'utilisation selon l'invention d'un antagoniste des récepteurs NK2 de la neurokine A. Le saredutant est utilisé sous forme de monosuccinate ; le (+)-N-[l-[2-[2-(3,4-dichlorophényl)-5-oxo-4-phénylmorpholin-2- yl]éthyl]-4-(3-fluorophényl) pipéridin-4-yl]acétamide sous forme de chlorhydrate et le (+)-r-[2-[4-benzoyl-2-(3,4-dichlorophényl)morpholin-2-yl]éthyl]-N,N-diméthyl-l,4'- bipipéridine-4'-carboxamide sous forme de dichlorhydrate.More particularly, a beneficial effect has been observed on the following dysfunctions: the decrease of the sexual desire and the disorders of the sexual arousal. The following nonlimiting examples describe examples of pharmaceutical compositions useful for the use according to the invention of an NK 2 receptor antagonist of neurokine A. Saredutant is used in the form of monosuccinate; (+) - N - [1- [2- [2- (3,4-dichlorophenyl) -5-oxo-4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4- yl] acetamide in hydrochloride form and (+) - r- [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4 Bipiperidine-4'-carboxamide as dihydrochloride.
EXEMPLE 1 : Gélule à 30 mg de saredutant.EXAMPLE 1: Capsule 30 mg of saredutant.
Saredutant (exprimé en base) 30,0 mg lactose monohydrate (200 mesh) QSP 400,0 mg croscarmellose sodium 8,0 mg stéarate de magnésium 4,0 mg eau purifiée* QS pour une gélule opaque de taille 0, remplie à 400,0 mg * évaporée au séchage après la granulation humide.Saredutant (expressed as base) 30.0 mg lactose monohydrate (200 mesh) QSP 400.0 mg croscarmellose sodium 8.0 mg magnesium stearate 4.0 mg purified water * QS for an opaque capsule of size 0, filled to 400, 0 mg * evaporated on drying after wet granulation.
EXEMPLE 2 : Gélule à 100 mg de saredutant. Sarédutant (exprimé en base) 100,0 mg lactose monohydrate (200 mesh) QSP 400,0 mg croscarmellose sodium 8,0 mg stéarate de magnésium 4,0 mg eau purifiée* QS pour une gélule opaque de taille 0, remplie à 400,0 mgEXAMPLE 2 Capsule 100 mg of saredutant Saredutant (expressed as base) 100.0 mg lactose monohydrate (200 mesh) QSP 400.0 mg croscarmellose sodium 8.0 mg magnesium stearate 4.0 mg purified water * QS for an opaque capsule of size 0, filled to 400, 0 mg
* évaporée au séchage après la granulation humide.* evaporated on drying after wet granulation.
EXEMPLE 3 : Gélule à 50 mg de (+)-N-[l-[2-[2-(3,4-dichlorophényl)-5-oxo-4- phénylmorpholin-2-yl]éthyl]-4-(3-fluorophényl)pipéridin-4-yl]acétamideEXAMPLE 3: 50 mg capsule of (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo-4-phenylmorpholin-2-yl] ethyl] -4- (3) fluorophenyl) piperidin-4-yl] acetamide
(exprimé en base) 50,0 mg lactose monohydrate (200 mesh) 44,0 mg hydroxypropylméthylcellulose 2,0 mg carboxyméthylamidon sodique 3,0 mg stéarate de magnésium 1,0 mg eau purifiée* QS pour une gélule opaque remplie à 100,0 mg(expressed as base) 50.0 mg lactose monohydrate (200 mesh) 44.0 mg hydroxypropyl methylcellulose 2.0 mg sodium carboxymethyl starch 3.0 mg magnesium stearate 1.0 mg purified water * QS for an opaque capsule filled to 100.0 mg
* évaporée au séchage après la granulation humide.* evaporated on drying after wet granulation.
EXEMPLE 4 : Comprimé à 50 mg de (+)-l'-[2-[4-benzoyl-2-(3,4- dichlorophényl)morpholin-2-yl] éthyl] -N,N-diméthyl- 1 ,4'-bipipéridine-4'-carboxamideEXAMPLE 4: 50 mg tablet of (+) - 1 '- [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4 '-bipipéridine-4'-carboxamide
(exprimé en base) 50,0 mg(expressed as base) 50.0 mg
Mannitol 223,75 mgMannitol 223.75 mg
Croscarmellose sodique 6,0 mg Amidon de maïs 15,0 mgCroscarmellose sodium 6.0 mg Corn starch 15.0 mg
Hydroxypropylméthylcellulose 2,25 mg stéarate de magnésium 3,0 mg pour un comprimé terminé à 300,0 mg Hydroxypropyl methylcellulose 2.25 mg magnesium stearate 3.0 mg for a 300 mg tablet

Claims

REVENDICATIONS
1. Utilisation d'un composé antagoniste des récepteurs NK2 de la neurokinine A choisi parmi le saredutant et ses sels pharmaceutiquement acceptables, le (+)-N-1. Use of a neurokinin A NK 2 receptor antagonist compound selected from saredutant and its pharmaceutically acceptable salts, the (+) - N-
[l-[2-[2-(354-dichlorophényl)-5-oxo-4-ρhénylmorpholin-2-yl]éthyl]-4-(3- fluorophényl) pipéridin-4-yl]acétamide et ses sels pharmaceutiquement acceptables et le (+)-r-[2-[4-benzoyl-2-(3,4-dichlorophényl)morpholin-2- yl] éthyl] -N,N-diméthyl- 1 ,4'-bipipéridine-4'-carboxamide et ses sels pharmaceutiquement acceptables pour la préparation de médicaments utiles dans la prévention et le traitement des dysfonctions sexuelles.[l- [2- [2- (3 5 4-dichlorophenyl) -5-oxo-4-ρhénylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yl] acetamide and pharmaceutically salts and (+) - r- [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4 ' carboxamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment of sexual dysfunctions.
2. Utilisation selon la revendication 1 du saredutant et de ses sels pharmaceutiquement acceptables pour la préparation de médicaments utiles dans la prévention et le traitement des dysfonctions sexuelles.2. Use according to claim 1 saredutant and its pharmaceutically acceptable salts for the preparation of drugs useful in the prevention and treatment of sexual dysfunction.
3. Utilisation selon la revendication 1 du (+)-N-[l-[2-[2-(3,4-dichlorophényl)-5-oxo- 4-phénylmorpholin-2-yl] éthyl] -4-(3-fluorophényl) pipéridin-4-yl]acétamide et ses sels pharmaceutiquement acceptables pour la préparation de médicaments utiles dans la prévention et le traitement des dysfonctions sexuelles. 4. Utilisation selon la revendication 1 du (+)-l'-[2-[4-benzoyl-2-(3,4- dichlorophényl)morpholin-2-yl]éthyl]-N,N-diméthyl-l,3. Use according to claim 1 of (+) - N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo-4-phenylmorpholin-2-yl] ethyl] -4- -fluorophenyl) piperidin-4-yl] acetamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment of sexual dysfunctions. 4. Use according to claim 1 of (+) - 1 - [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,
4'-bipipéridine-4'- carboxamide et ses sels pharmaceutiquement acceptables pour la préparation de médicaments utiles dans la prévention et le traitement des dysfonctions sexuelles.4'-Bipiperidine-4'-carboxamide and its pharmaceutically acceptable salts for the preparation of medicaments useful in the prevention and treatment of sexual dysfunctions.
5. Utilisation selon l'une quelconque des revendications 1 à 4 dans la prévention et le traitement du trouble du désir sexuel.5. Use according to any one of claims 1 to 4 in the prevention and treatment of sexual desire disorder.
6. Utilisation selon la revendication 5 dans la prévention et le traitement de la baisse du désir sexuel.6. Use according to claim 5 in the prevention and treatment of decreased sexual desire.
7. Utilisation selon la revendication 5 dans la prévention et le traitement de l'aversion sexuelle. Use according to claim 5 in the prevention and treatment of sexual aversion.
8. Utilisation selon l'une quelconque des revendications 1 à 4 dans la prévention et le traitement des troubles de l'excitation sexuelle.8. Use according to any one of claims 1 to 4 in the prevention and treatment of disorders of sexual arousal.
9. Utilisation selon la. revendication 8 dans la prévention et le traitement du trouble de l'excitation sexuelle chez la femme.9. Use according to the. claim 8 in the prevention and treatment of sexual arousal disorder in women.
10. Utilisation selon la revendication 8 dans la prévention et le traitement de l'érection chez l'homme.10. Use according to claim 8 in the prevention and treatment of erection in humans.
11. Utilisation selon l'une quelconque des revendications 1 à 4 dans la prévention et le traitement des troubles de l'orgasme. 11. Use according to any one of claims 1 to 4 in the prevention and treatment of disorders of orgasm.
12. Utilisation selon la revendication 11 dans la prévention et le traitement du trouble de l'orgasme chez la femme.12. Use according to claim 11 in the prevention and treatment of orgasm disorder in women.
13. Utilisation selon la revendication 11 dans la prévention et le traitement du trouble de l'orgasme chez l'homme. 13. Use according to claim 11 in the prevention and treatment of the orgasm disorder in humans.
14. Utilisation selon la revendication 11 dans la prévention et le traitement de l'éjaculation précoce. 14. Use according to claim 11 in the prevention and treatment of premature ejaculation.
15. Utilisation selon l'une quelconque des revendications 1 à 4 dans la prévention et le traitement des troubles sexuels avec douleurs. 15. Use according to any one of claims 1 to 4 in the prevention and treatment of sexual disorders with pain.
16. Utilisation selon la revendication 15 dans la prévention et le traitement de la dyspareunie.16. Use according to claim 15 in the prevention and treatment of dyspareunia.
17. Utilisation selon la revendication 15 dans la prévention et le traitement du vaginisme.17. Use according to claim 15 in the prevention and treatment of vaginismus.
18. Utilisation selon l'une quelconque des revendications 1 à 4 dans la prévention et le traitement de la dysfonction sexuelle due à une affection médicale générale.18. Use according to any one of claims 1 to 4 in the prevention and treatment of sexual dysfunction due to a general medical condition.
19. Utilisation selon la revendication 18 dans la prévention et le traitement de la dysfonction sexuelle due à un trouble dépressif.19. Use according to claim 18 in the prevention and treatment of sexual dysfunction due to depressive disorder.
20. Utilisation selon la revendication 19 dans la prévention et le traitement de la dysfonction sexuelle due à un trouble dépressif majeur. 20. Use according to claim 19 in the prevention and treatment of sexual dysfunction due to major depressive disorder.
21. Utilisation selon l'une quelconque des revendications 1 à 4 dans la prévention et le traitement de la dysfonction sexuelle induite par une substance.21. Use according to any one of claims 1 to 4 in the prevention and treatment of substance-induced sexual dysfunction.
22. Utilisation selon l'une quelconque des revendications 1 à 4 dans la prévention et le traitement des dysfonctions sexuelles non spécifiées.22. Use according to any one of claims 1 to 4 in the prevention and treatment of unspecified sexual dysfunctions.
23. Association d'un composé antagoniste des récepteurs NK2 de la neurokinine A choisi parmi le saredutant et ses sels pharmaceutiquement acceptables, le (+)-N-23. Association of an NK 2 receptor antagonist compound of neurokinin A selected from saredutant and its pharmaceutically acceptable salts, the (+) - N-
[l-[2-[2-(3,4-dichlorophényl)-5-oxo-4-phénylmorpholin-2-yl]éthyl]-4-(3- fluorophényl) pipéridin-4-yl]acétamide et ses sels pharmaceutiquement acceptables et le (+)-l'-[2-[4-benzoyl-2-(3,4-dichlorophényl)morpholin-2- yl]éthyl]-N,N-diméthyl-l,4'-bipipéridine-4'-carboxamide et ses sels pharmaceutiquement acceptables avec un autre principe actif utile pour le traitement des dysfonctions sexuelles choisi parmi : sildenafil, vardenafil, tardalafïl, alprostadil, apomorphine, midrodrine, moxisylite, phentolamine, aviptadil, testosterone, dapoxetine, tobolone.[1- [2- [2- (3,4-dichlorophenyl) -5-oxo-4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yl] acetamide and its pharmaceutically acceptable salts and (+) - 1- [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4 carboxyamide and its pharmaceutically acceptable salts with another active ingredient useful for the treatment of sexual dysfunctions chosen from: sildenafil, vardenafil, tardalafil, alprostadil, apomorphine, midrodrine, moxisylite, phentolamine, aviptadil, testosterone, dapoxetine, tobolone.
24. Trousse contenant un composé antagoniste des récepteurs NK2 de la neurokinine A choisi parmi le saredutant et ses sels pharmaceutiquement acceptables, le (+)-24. A kit containing a neurokinin A NK 2 receptor antagonist compound selected from saredutant and its pharmaceutically acceptable salts, the (+) -
N-[l-[2-[2-(3,4-dichlorophényl)-5-oxo-4-phénylmorpholin-2-yl]éthyl]-4-(3- fluorophényl) pipéridin-4-yl]acétamide et ses sels pharmaceutiquement acceptables et le (+)-r-[2-[4-benzoyl-2-(3,4-dichlorophényl)morpholin-2- yl]éthyl]-N,N-diméthyl-l,4'-bipipéridine-4'-carboxamide et ses sels pharmaceutiquement acceptables et un autre principe actif utile pour le traitement des dysfonctions sexuelles choisi parmi : sildenafil, vardenafil, tardalafil, alprostadil, apomorphine, midrodrine, moxisylite, phentolamine, aviptadil, testosterone, dapoxetine, tobolone dans laquelle lesdits composés sont dans des compartiments distincts et dans des conditionnements semblables ou différents et sont destinés à être administrés de manière simultanée, séparée ou étalée dans le temps. N- [1- [2- [2- (3,4-dichlorophenyl) -5-oxo-4-phenylmorpholin-2-yl] ethyl] -4- (3-fluorophenyl) piperidin-4-yl] acetamide and its pharmaceutically salts and (+) - r- [2- [4-benzoyl-2- (3,4-dichlorophenyl) morpholin-2-yl] ethyl] -N, N-dimethyl-1,4'-bipiperidine-4 ' -carboxamide and its pharmaceutically acceptable salts and another active ingredient useful for the treatment of sexual dysfunctions chosen from: sildenafil, vardenafil, tardalafil, alprostadil, apomorphine, midrodrine, moxisylite, phentolamine, aviptadil, testosterone, dapoxetine, tobolone wherein said compounds are in separate compartments and in similar or different packages and are intended to be administered simultaneously, separately or spread over time.
EP08761838A 2007-02-07 2008-02-04 Use of a compound antagonist to the nk-2-receptors of a neurokinine for the preparation of drugs useful for preventing and treating sexual dysfunction Withdrawn EP2131842A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0700856A FR2912058A1 (en) 2007-02-07 2007-02-07 Treatment or prevention of sexual dysfunction, e.g. lack of sexual desire or erectile dysfunction, uses neurokinin A NK2 receptor antagonist, e.g. sareductant
PCT/FR2008/000135 WO2008110697A2 (en) 2007-02-07 2008-02-04 Use of a compound antagonist to the nk2 receptors of a neurokinine for the preparation of drugs useful for preventing and treating sexual dysfunction

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JP (1) JP2010518052A (en)
AR (1) AR065178A1 (en)
CL (1) CL2008000383A1 (en)
FR (1) FR2912058A1 (en)
TW (1) TW200906406A (en)
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WO (1) WO2008110697A2 (en)

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FR2792835B3 (en) * 1999-04-27 2001-05-25 Sanofi Sa USE OF SAREDUTANT FOR THE PREPARATION OF MEDICINES USEFUL IN THE TREATMENT OR PREVENTION OF ALL MOOD DISORDERS, ADAPTATION DISORDERS OR MIXED ANXIETY-DEPRESSION DISORDERS
FR2824828B1 (en) * 2001-05-21 2005-05-20 Sanofi Synthelabo NOVEL DERIVATIVES OF PIPERIDINECARBOXAMIDE, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
FR2873373B1 (en) * 2004-07-23 2006-09-08 Sanofi Synthelabo DERIVATIVES OF 4-ARYLMORPHOLIN-3-ONE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
CN101065014A (en) * 2004-09-23 2007-10-31 亚历山大·米哈洛 Methods for regulating neurotransmitter systems by inducing counteradaptations
WO2006096435A1 (en) * 2005-03-04 2006-09-14 Boehringer Ingelheim International Gmbh Pharmaceutical compositions for the treatment and/or prevention of depression
FR2912057B1 (en) * 2007-02-07 2009-04-17 Sanofi Aventis Sa PHARMACEUTICAL COMPOSITION COMPRISING SAREDUTANT AND A SELECTIVE SEROTONIN RECAPTURE INHIBITOR OR SEROTONIN / NOREPINEPHRINE RECAPTURE INHIBITOR

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UY30899A1 (en) 2008-09-30
TW200906406A (en) 2009-02-16
US20100173879A1 (en) 2010-07-08
JP2010518052A (en) 2010-05-27
FR2912058A1 (en) 2008-08-08
CL2008000383A1 (en) 2008-07-04
WO2008110697A3 (en) 2008-11-13
AR065178A1 (en) 2009-05-20

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