WO2000066117A1 - Use of (2s)-1- [(2r,3s)-5-chloro-3- (2-chlorophenyl)- 1-(3,4-dimethoxybenzenesulfonyl)- 3-hydroxy-2,3- dihydro-1h- indole-2-carbonyl] pyrrolidine- 2-carboxamide in the production of medicaments used to treat raynaud's phenomenon - Google Patents

Use of (2s)-1- [(2r,3s)-5-chloro-3- (2-chlorophenyl)- 1-(3,4-dimethoxybenzenesulfonyl)- 3-hydroxy-2,3- dihydro-1h- indole-2-carbonyl] pyrrolidine- 2-carboxamide in the production of medicaments used to treat raynaud's phenomenon Download PDF

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Publication number
WO2000066117A1
WO2000066117A1 PCT/FR2000/001085 FR0001085W WO0066117A1 WO 2000066117 A1 WO2000066117 A1 WO 2000066117A1 FR 0001085 W FR0001085 W FR 0001085W WO 0066117 A1 WO0066117 A1 WO 0066117A1
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WO
WIPO (PCT)
Prior art keywords
raynaud
phenomenon
carboxamide
pyrrolidine
indole
Prior art date
Application number
PCT/FR2000/001085
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French (fr)
Inventor
Rémi BROUARD
Original Assignee
Sanofi-Synthelabo
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Filing date
Publication date
Priority to FR99/05434 priority Critical
Priority to FR9905434A priority patent/FR2792834A1/en
Application filed by Sanofi-Synthelabo filed Critical Sanofi-Synthelabo
Publication of WO2000066117A1 publication Critical patent/WO2000066117A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404Indoles, e.g. pindolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/08Vasodilators for multiple indications
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The invention relates to the use of (2S)-1- [(2R,3S)-5- chloro-3-(2-chlorophenyl)- 1-(3,4-dimethoxybenzenesulfonyl)- 3-hydroxy- 2,3-dihydro-1H-indole-2-carbonyl] pyrrolidine-2-carboxamide, the solvates thereof and/or pharmaceutically acceptable hydrates thereof in the production of medicaments used to treat or prevent Raynaud's phenomenon.

Description

       

  
 



     UTILISATION DU (2S)-1- [ (2R, 3S)-5-CHLORO-3- (2-CHLOROPHENYL)-1-    (3,4-DIMETHOXYBENZENESULFONYL)-3-HYDROXY-2, 3-DIHYDRO1H-INDOLE-2-CARBONYL] PYRROLIDINE-2-CARBOXAMIDE POUR LA
PREPARATION DE MEDICAMENTS UTILES DANS LE TRAITEMENT
DU PHENOMENE DE RAYNAUD.



   La présente invention a pour objet une nouvelle utilisation d'un antagoniste sélectif des récepteurs Via de   I'arginine-vasopressine.   



   Le   (2S)-1-[(2R, 3S)-5-chloro-3-(2-chlorophényl)-1-(3,4-      diméthoxybenzènesulfonyl)-3-hydroxy-2, 3-dihydro-1 H-indole-2-      carbonyl]    pyrrolidine-2-carboxamide, dont le nom de code est SR 49059, de formule :
EMI1.1     

 ci-après dénommé composé A, a été décrit dans la littérature comme étant un antagoniste puissant et sélectif des récepteurs Via de   I'arginine-    vasopressine chez différentes espèces, en particulier des récepteurs Via humains, (C. Serradeil-Le Gal   et al.,    J. Clin. Invest., 1993,92,224-231). 11 ne possède qu'une faible affinité pour les récepteurs V2. Le composé A est le plus puissant antagoniste sélectif des récepteurs Via humains connu à ce jour.

   Les effets du composé A sur la vasoconstriction chez
I'homme induite par injection d'arginine-vasopressine ont été décrits dans la littérature par R. Weber et al., Hypertension, 1997,30 (5), 1121-1127.



   On a maintenant trouvé que le composé A, ainsi que ses   solvats et/ou    hydrates pharmaceutiquement acceptables, sont utiles dans le traitement ou la prévention du phénomène de Raynaud.



   Le phénomène de Raynaud comprend la maladie de Raynaud (primaire) et le syndrome de Raynaud (secondaire).



   Ainsi, selon un de ses aspects, la présente invention a pour objet l'utilisation du   (2S)-1-[(2R, 3S)-5-chioro-3-(2-chlorophényl)-1-(3,4-       diméthoxybenzènesulfonyl)-3-hydroxy-2, 3-dihydro-1 H-indole-2-carbonyl]    pyrrolidine-2-carboxamide, de ses solvats et/ou hydrates pharmaceutiquement acceptables, pour la préparation de médicaments utiles dans le traitement ou la prévention du phénomène de Raynaud.



   En particulier, la présente invention a pour objet l'utilisation du   (2S)-1-       [ (2R, 3S)-5-chloro-3- (2-chlorophényl)-1- (3, 4-diméthoxybenzènesulfonyl)-3-    hydroxy-2,3-dihydro-1 H-indole-2-carbonyl] pyrrolidine-2-carboxamide, de ses solvats et/ou hydrates pharmaceutiquement acceptables, pour la préparation de médicaments utiles dans le traitement ou la prévention de la maladie de Raynaud.



   En particulier aussi, la présente invention a pour objet l'utilisation du    (2S)-1-[(2 R, 3S)-5-chloro-3-(2-chlorophényl)-1-(3,4diméthoxybenzènesulfonyl)-3-hydroxy-2, 3-dihydro-1 H-indole-2-carbonyl]      pyrrolidine-2-carboxamide,    de ses solvats et/ou hydrates pharmaceutiquement acceptables, pour la préparation de médicaments utiles dans le traitement ou la prévention du syndrome de Raynaud.



   Selon un autre de ses aspects, la présente invention a pour objet une méthode de traitement ou de prévention du phénomène de Raynaud par administration d'une dose appropriée du composé A, de ses   solvats et/ou    hydrates pharmaceutiquement acceptables.



   Le composé A, ses   solvats et/ou    hydrates, sont préparés selon le procédé décrit dans le brevet EP-526 348 B1 et dans le brevet US 5 338 755.



   Pour leur utilisation en tant que médicaments, le composé A et ses   solvats et/ou    hydrates pharmaceutiquement acceptables sont généralement administrés en unités de dosage. Lesdites unités de dosage sont de préférence formulées dans des compositions pharmaceutiques dans lesquelles le principe actif est mélangé avec un exipient pharmaceutique.



   Dans les compositions pharmaceutiques de la présente invention pour !'administration orale, sublinguale, inhalée, sous-cutanée, intramusculaire, intraveineuse, transdermique, locale ou rectale, le principe actif seul ou en association avec un autre principe actif peut tre administré sous forme unitaire d'administration, en mélange avec des supports pharmaceutiques classiques, aux animaux et aux tres humains. Les formes unitaires d'administration appropriées comprennent les formes par voie orale telles que les comprimés, les gélules, les poudres, les granules et les solutions ou suspensions orales, les formes d'administration sublinguale et buccale,  les aérosols, les formes d'administration topiques, les implants, les formes d'administration sous-cutanée, transdermique, intramusculaire, intraveineuse, intranasale et les formes d'administration rectale.



   Selon la présente invention, les formes orales d'administration sont préférées.



   Le dosage journalier du composé A est de 0,05 à 5 mg/kg, avantageusement de 1 à 2,5 mg/kg, préférentiellement de 2 à 2,5 mg/kg, à administrer en une ou plusieurs fois. Le composé A et ses solvats et/ou hydrates sont généralement formulés en unité de dosage contenant de 2,5 à 1000 mg, avantageusement de 2,5 à 500 mg, préférentiellement de 2,5 à 250 mg, de principe actif par unité de dosage, à administrer une fois, deux fois ou plusieurs fois en mme temps, selon la nécessité. Bien que ces dosages soient des exemples de situation 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,   t'âge, te    poids et la réponse dudit patient.



   Les compositions pharmaceutiques peuvent tre préparées selon le brevet EP 526 348 B1 et le brevet US 5 338 755 ou la demande internationale WO 98/24430.



   Les effets du composé A ont été déterminés au cours d'une étude clinique réalisée en double aveugle, versus placebo, chez des patients âgés de 24 à 67 ans, présentant un phénomène de Raynaud primaire ou secondaire, en utilisant un test au froid, selon G.   Bizzini    Pezzetta et   al.,    (Quantification of vasomotor alteration in Raynaud's Phenomenon by digital   plethysmography    versus   chronothermobiology    in Proceedings of the   20th European Conference    on   Microcirculation,    Paris, France, August   30-September2,1998).   



   Les patients ont reçu, par voie orale, une dose de 300 mg par jour de composé A, pendant une période de sept jours en plan croisé versus placebo, avec une période d'élimination de 21 jours. On a mesuré les effets sur la pression systolique digitale et la température digitale avant et après le test au froid.



   On a observé que le composé A, administré par voie orale pendant 7 jours, à des patients présentant un phénomène de Raynaud, montrait des effets positifs, comparé au placebo, sur la pression systolique digitale et le réchauffement digital.  



   Les exemples suivants illustrent l'invention, sans toutefois la limiter.



  EXEMPLE 1 : Gélule dosée à 5 mg de composé A.



   Composé A   micronisé    5,00 mg
 Lactose monohydrate 344,40 mg
 Amidon de maïs modifié 60,77 mg
 Silice colloïdale anhydre 2,125 mg
 Stéarate de magnésium 4,25 mg
 Talc 8,50 mg
 Pour une gélule blanc opaque   n     0 remplie à 425 mg.



  EXEMPLE 2 : Gélule dosée à 25 mg de composé A
 Composé A   micronisé    25,00 mg
 Lactose monohydrate 327,40 mg
 Amidon de maïs modifié 57,77 mg
 Silice colloïdale anhydre 2,125 mg
 Stéarate de magnésium 4,25 mg
 Talc 8,50 mg
 Pour une gélule blanc opaque   n     0 remplie à 425 mg.



  EXEMPLE 3 : Gélule dosée à 100 mg de composé A
 Composé A   micronisé    100,00 mg
 Lactose monohydrate 263,60 mg
 Amidon de maïs modifié 46,52 mg
 Silice colloïdale anhydre 2,125 mg
 Stéarate de magnésium 4,25 mg
 Talc 8,50 mg
 Pour une gélule blanc opaque   n     0 remplie à 425 mg.
  



  
 



     USE OF (2S) -1- [(2R, 3S) -5-CHLORO-3- (2-CHLOROPHENYL) -1- (3,4-DIMETHOXYBENZENESULFONYL) -3-HYDROXY-2, 3-DIHYDRO1H-INDOLE-2 -CARBONYL] PYRROLIDINE-2-CARBOXAMIDE FOR THE
PREPARATION OF MEDICINES USEFUL IN TREATMENT
OF THE RAYNAUD PHENOMENON.



   The present invention relates to a new use of a selective antagonist of the Via receptors for arginine-vasopressin.



   (2S) -1 - [(2R, 3S) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxybenzenesulfonyl) -3-hydroxy-2,3-dihydro-1 H-indole -2- carbonyl] pyrrolidine-2-carboxamide, whose code name is SR 49059, of formula:
EMI1.1

 hereinafter called compound A, has been described in the literature as being a powerful and selective antagonist of the Via receptors for arginine-vasopressin in various species, in particular human Via receptors, (C. Serradeil-Le Gal et al. , J. Clin. Invest., 1993, 92, 224-231). It has only a weak affinity for the V2 receptors. Compound A is the most potent selective human Via receptor antagonist known to date.

   The effects of compound A on vasoconstriction in
Human induced injection of arginine-vasopressin have been described in the literature by R. Weber et al., Hypertension, 1997.30 (5), 1121-1127.



   It has now been found that compound A, as well as its pharmaceutically acceptable solvates and / or hydrates, are useful in the treatment or prevention of Raynaud's phenomenon.



   Raynaud's phenomenon includes Raynaud's disease (primary) and Raynaud's syndrome (secondary).



   Thus, according to one of its aspects, the subject of the present invention is the use of (2S) -1 - [(2R, 3S) -5-chioro-3- (2-chlorophenyl) -1- (3,4- dimethoxybenzenesulfonyl) -3-hydroxy-2,3-dihydro-1 H-indole-2-carbonyl] pyrrolidine-2-carboxamide, its pharmaceutically acceptable solvates and / or hydrates, for the preparation of medicaments useful in the treatment or prevention of Raynaud's phenomenon.



   In particular, the subject of the present invention is the use of (2S) -1- [(2R, 3S) -5-chloro-3- (2-chlorophenyl) -1- (3, 4-dimethoxybenzenesulfonyl) -3- hydroxy-2,3-dihydro-1 H-indole-2-carbonyl] pyrrolidine-2-carboxamide, of its pharmaceutically acceptable solvates and / or hydrates, for the preparation of medicaments useful in the treatment or prevention of Raynaud's disease .



   Also in particular, the subject of the present invention is the use of (2S) -1 - [(2 R, 3S) -5-chloro-3- (2-chlorophenyl) -1- (3,4dimethoxybenzenesulfonyl) -3- hydroxy-2, 3-dihydro-1 H-indole-2-carbonyl] pyrrolidine-2-carboxamide, its pharmaceutically acceptable solvates and / or hydrates, for the preparation of medicaments useful in the treatment or prevention of Raynaud's syndrome.



   According to another of its aspects, the subject of the present invention is a method of treatment or prevention of Raynaud's phenomenon by administration of an appropriate dose of compound A, of its pharmaceutically acceptable solvates and / or hydrates.



   Compound A, its solvates and / or hydrates, are prepared according to the process described in patent EP-526,348 B1 and in US patent 5,338,755.



   For their use as medicaments, compound A and its pharmaceutically acceptable solvates and / or hydrates are generally administered in dosage units. Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.



   In the pharmaceutical compositions of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active ingredient alone or in combination with another active ingredient can be administered in unit form administration, in admixture with conventional pharmaceutical carriers, to animals and humans. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, aerosols, administration forms topical, implants, subcutaneous, transdermal, intramuscular, intravenous, intranasal and rectal administration forms.



   According to the present invention, oral forms of administration are preferred.



   The daily dosage of compound A is from 0.05 to 5 mg / kg, advantageously from 1 to 2.5 mg / kg, preferably from 2 to 2.5 mg / kg, to be administered in one or more times. Compound A and its solvates and / or hydrates are generally formulated in dosage units containing from 2.5 to 1000 mg, advantageously from 2.5 to 500 mg, preferably from 2.5 to 250 mg, of active principle per unit of dosage, to be administered once, twice or several times at the same time, as necessary. Although these dosages are examples of average situations, there may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention.

   According to usual practice, the appropriate dosage for each patient is determined by the doctor according to the method of administration, the age, the weight and the response of said patient.



   The pharmaceutical compositions can be prepared according to patent EP 526,348 B1 and US patent 5,338,755 or international application WO 98/24430.



   The effects of compound A were determined during a double-blind, placebo-controlled clinical study in patients aged 24 to 67 with primary or secondary Raynaud's phenomenon, using a cold test, according to G. Bizzini Pezzetta et al., (Quantification of vasomotor alteration in Raynaud's Phenomenon by digital plethysmography versus chronothermobiology in Proceedings of the 20th European Conference on Microcirculation, Paris, France, August 30-September2,1998).



   The patients received, orally, a dose of 300 mg per day of compound A, for a period of seven days in crossed plan versus placebo, with a elimination period of 21 days. The effects on digital systolic pressure and digital temperature were measured before and after the cold test.



   Compound A, administered orally for 7 days, to patients with Raynaud's phenomenon, has been observed to show positive effects, compared to placebo, on digital systolic pressure and digital warming.



   The following examples illustrate the invention without, however, limiting it.



  EXAMPLE 1 Capsule dosed at 5 mg of compound A.



   Compound A micronized 5.00 mg
 Lactose monohydrate 344.40 mg
 Modified corn starch 60.77 mg
 Anhydrous colloidal silica 2.125 mg
 Magnesium stearate 4.25 mg
 Talc 8.50 mg
 For an opaque white capsule No. 0 filled to 425 mg.



  EXAMPLE 2 Capsule Dosed at 25 mg of Compound A
 Micronized Compound A 25.00 mg
 Lactose monohydrate 327.40 mg
 Modified corn starch 57.77 mg
 Anhydrous colloidal silica 2.125 mg
 Magnesium stearate 4.25 mg
 Talc 8.50 mg
 For an opaque white capsule No. 0 filled to 425 mg.



  EXAMPLE 3 Capsule Dosed at 100 mg of Compound A
 Compound A micronized 100.00 mg
 Lactose monohydrate 263.60 mg
 Modified corn starch 46.52 mg
 Anhydrous colloidal silica 2.125 mg
 Magnesium stearate 4.25 mg
 Talc 8.50 mg
 For an opaque white capsule No. 0 filled to 425 mg.
  


    

Claims

REVENDICATIONS 1. Utilisation du (2S)-1-[(2R, 3S)-5-chloro-3-(2-chlorophényl)-1-(3,4- diméthoxybenzènesulfonyl)-3-hydroxy-2, 3-dihydro-1 H-indole-2- carbonyl] pyrrolidine-2-carboxamide, de ses solvats et/ou hydrates pharmaceutiquement acceptables, pour la préparation de médicaments utiles dans le traitement ou la prévention du phénomène de Raynaud.  CLAIMS 1. Use of (2S) -1 - [(2R, 3S) -5-chloro-3- (2-chlorophenyl) -1- (3,4- dimethoxybenzenesulfonyl) -3-hydroxy-2,3-dihydro- 1 H-indole-2-  carbonyl] pyrrolidine-2-carboxamide, its solvates and / or hydrates    pharmaceutically acceptable, for the preparation of  drugs useful in the treatment or prevention of the phenomenon  by Raynaud.
2. Utilisation selon la revendication 1 dans le traitement ou la prévention de la maladie de Raynaud. 2. Use according to claim 1 in treatment or prevention  Raynaud's disease.
3. Utilisation selon la revendication 1 dans le traitement ou la prévention du syndrome de Raynaud. 3. Use according to claim 1 in treatment or prevention  Raynaud's syndrome.
PCT/FR2000/001085 1999-04-29 2000-04-25 Use of (2s)-1- [(2r,3s)-5-chloro-3- (2-chlorophenyl)- 1-(3,4-dimethoxybenzenesulfonyl)- 3-hydroxy-2,3- dihydro-1h- indole-2-carbonyl] pyrrolidine- 2-carboxamide in the production of medicaments used to treat raynaud's phenomenon WO2000066117A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
FR99/05434 1999-04-29
FR9905434A FR2792834A1 (en) 1999-04-29 1999-04-29 USE OF SR 49059, ITS PHARMACEUTICALLY ACCEPTABLE SOLVATES AND / OR HYDATES FOR THE PREPARATION OF MEDICINES USEFUL IN THE TREATMENT OR PREVENTION OF RAYNAUD PHENOMENON

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
AU43035/00A AU4303500A (en) 1999-04-29 2000-04-25 Use of (2s)-1- ((2r,3s)-5-chloro-3- (2-chlorophenyl)- 1-(3,4-dimethoxybenzenesulfonyl)- 3-hydroxy-2,3- dihydro-1(h)- indole-2-carbonyl) pyrrolidine- 2-carboxamide in the production of medicaments used to treat raynaud's phenomenon

Publications (1)

Publication Number Publication Date
WO2000066117A1 true WO2000066117A1 (en) 2000-11-09

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AR (1) AR023617A1 (en)
AU (1) AU4303500A (en)
FR (1) FR2792834A1 (en)
WO (1) WO2000066117A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0526348A1 (en) * 1991-08-02 1993-02-03 Sanofi Indoline derivatives carrying an amide function, their preparation and pharmaceutical compositions containing them
US5338755A (en) * 1990-07-31 1994-08-16 Elf Sanofi N-sulfonylindoline derivatives, their preparation and the pharmaceutical compositions in which they are present
WO1995018105A1 (en) * 1993-12-24 1995-07-06 Sanofi 1,3-dihydroindol-2-one derivatives substituted in position 3 by a nitrogen group as vasopressin and/or ocytocine agonists and/or antagonists
WO1999044613A1 (en) * 1998-03-06 1999-09-10 Sanofi-Synthelabo Pharmaceutical compositions containing in combination two antagonists selective of arginine-vassopressin v receptors, even of v1a and v2 receptors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5338755A (en) * 1990-07-31 1994-08-16 Elf Sanofi N-sulfonylindoline derivatives, their preparation and the pharmaceutical compositions in which they are present
EP0526348A1 (en) * 1991-08-02 1993-02-03 Sanofi Indoline derivatives carrying an amide function, their preparation and pharmaceutical compositions containing them
WO1995018105A1 (en) * 1993-12-24 1995-07-06 Sanofi 1,3-dihydroindol-2-one derivatives substituted in position 3 by a nitrogen group as vasopressin and/or ocytocine agonists and/or antagonists
WO1999044613A1 (en) * 1998-03-06 1999-09-10 Sanofi-Synthelabo Pharmaceutical compositions containing in combination two antagonists selective of arginine-vassopressin v receptors, even of v1a and v2 receptors

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"SR 49059", DATABASE PHAR (ONLINE) RETRIEVED FROM STN; AN=11309, XP002128619 *
C. SERRADEIL-LE GAL ET AL.: "Effects of SR 49059, a non-peptide antagonist of vasopressin V1a receptors, on vasopressin-induced coronary vasoconstriction in conscious rabbits", FUNDAMENTAL & CLINICAL PHARMACOLOGY, vol. 9, no. 1, 1995, pages 17 - 24, XP000866522 *
M. METZLER ET AL.: "Vasospastic disorders", POSTGRADUATE MEDICINE, vol. 65, no. 2, 1979, pages 79 - 88, XP000870196 *

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FR2792834A1 (en) 2000-11-03
AR023617A1 (en) 2002-09-04

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