WO2003011281A1 - Traitement de l'hyperactivite avec deficit de l'attention ou du trouble deficitaire de l'attention - Google Patents

Traitement de l'hyperactivite avec deficit de l'attention ou du trouble deficitaire de l'attention Download PDF

Info

Publication number
WO2003011281A1
WO2003011281A1 PCT/GB2002/003545 GB0203545W WO03011281A1 WO 2003011281 A1 WO2003011281 A1 WO 2003011281A1 GB 0203545 W GB0203545 W GB 0203545W WO 03011281 A1 WO03011281 A1 WO 03011281A1
Authority
WO
WIPO (PCT)
Prior art keywords
trifluoromethyl
methoxy
indoline
compound
attention deficit
Prior art date
Application number
PCT/GB2002/003545
Other languages
English (en)
Inventor
Pascal Jean Denis Goetghebeur
Guy Anthony Kennett
Sean Lightowler
Original Assignee
Vernalis Research Limited
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 Vernalis Research Limited filed Critical Vernalis Research Limited
Publication of WO2003011281A1 publication Critical patent/WO2003011281A1/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
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/40—Heterocyclic 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
    • 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
    • A61K31/40—Heterocyclic 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
    • A61K31/407—Heterocyclic 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 other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to the use of compounds having antagonistic, inverse agonistic activity or negative allosteric modulatory activity at the 5-HT 2 c receptor as a novel treatment of attention deficit hyperactivity disorder (ADHD) or attention deficit disorder (ADD).
  • ADHD attention deficit hyperactivity disorder
  • ADD attention deficit disorder
  • ADHD is the most common behavioural disorder of childhood, with a prevalence of 5-10% of the general population (Swanson et al., 1998, Lancet, 351: 429-433).
  • ADHD is characterised by a number of symptoms, including consistent impairment in attention (i.e. poor attention span); and/or excessive motor activity (i.e. hyperactivity) optionally in association with impulsivity (i.e. weak impulse control).
  • ADD is characterised by similar symptoms in the absence of hyperactivity.
  • Amphetamine derivatives such as the dextroamphetamine (d-amphetamine)/ amphetamine composite medication have been one of the main treatments for ADD and ADHD, with methylphenidate as an alternative therapy.
  • the amphetamine drug class has traditionally been linked with a high abuse potential and other side-effects.
  • 5-HT 5-hydroxytryptamine
  • WO 01/32660 (NPS Allelix Co.) claims a series of 5-HT 6 receptor antagonists to be useful in the treatment of various CNS disorders including schizophrenia, depression, ADHD, impaired cognition, and memory dysfunction.
  • WO 01/32625 claims a series of aryl- and heteroaryl -substituted tetrahydroisoquinolines as blockers of the re-uptake of norepinephrine, dopamine and serotonin as being useful in the treatment of neurological and psychiatric disorders, such as ADHD, anxiety, depression, and addiction disorders.
  • WO 00/12073 (Smithkline Beecham P.L.C., UK) claims the use of 5-HT 6 antagonists containing arylsulfamide or arylaminosulfonyl groups in the manufacture of a medicament for the treatment of ADHD.
  • WO 99/25364 claims a method using a tachykinin receptor antagonist as useful for treating or preventing ADD, optionally associated with hyperactivity, in a patient.
  • WO 01/36428 (Novartis A.-G., Switz.; Novartis-Erfindungen etc.) claims a series of silylated benzo[g]quinoline or naphth[2,3-b]-l,4-oxazine derivatives, their preparation and use as pharmaceuticals for treatment of depression and ADHDs.
  • WO 01/41701 (H. Lundbeck A/S, Denmark) claims the use of compounds having serotonin reuptake inhibiting activity and 5-HT 2 c antagonistic, partial agonistic or inverse agonistic activity for the treatment of depression and other affective disorders.
  • the 5-HT 2 c receptor is one of the 5-HT 2 receptor family of seven trans-membrane spanning proteins. 5-HT 2 c receptors have been found to be present at a high level in the choroid plexus with lower level in the cerebral cortex, hippocampus, hypothalamus, striatum and substantia nigra in rats and show a similar distribution in man (Kennett, 1993, Curr. Opin. Invest. Drugs, 2: 317-362).
  • a compound selected from an antagonist of, an inverse agonist of or a negative allosteric modulator of the 5-HT 2 c receptor in the manufacture of a medicament for the treatment of attention deficit hyperactivity disorder (ADHD) or attention deficit disorder (ADD).
  • the invention provides a method of treatment of attention deficit hyperactivity disorder (ADHD) or attention deficit disorder (ADD) comprising the administration to a subject in need thereof of an effective amount of a compound selected from an antagonist of, an inverse agonist of or a negative allosteric modulator of the 5- HT 2C receptor.
  • ADHD attention deficit hyperactivity disorder
  • ADD attention deficit disorder
  • the use or method of the present invention encompasses the co-administration of two or more compounds having the above-noted activity at the 5-HT 2 c receptor.
  • Such a combination of compounds may be administered sequentially or simultaneously, and in the same or separate formulations.
  • a 5-HT 2 c receptor antagonist is used in the use or method of the invention.
  • said antagonist of, inverse agonist of or negative allosteric modulator of the 5-HT 2 c receptor is the sole active agent used in the treatment of ADHD or ADD. In a further embodiment, said antagonist of, inverse agonist of or negative allosteric modulator of the 5-HT 2 c receptor is used in the absence of a serotonin re-uptake inhibitor.
  • the subject is a human subject, particularly a human in childhood.
  • a 5HT 2 c antagonist refers to any molecule which acts directly at the 5HT 2 c receptor to attenuate the effect of an agonist acting at the same receptor.
  • a 5HT 2 c inverse agonist refers to any molecule acting at the 5-HT 2 c receptor to attenuate the constituitive activity of that receptor.
  • a 5HT 2 c negative allosteric modulator refers to any molecule that attenuates the effect of a 5-HT 2 c receptor agonist by interacting with the receptor at a site which is distinct from that at which 5-HT acts.
  • a 5HT 2 c antagonist, inverse agonist or negative allosteric modulator refers to a compound which, at a concentration of l ⁇ M, inhibits by at least 30% the response produced by 5HT at a concentration that produces 70% of the maximal response to 5-HT alone, at any mammalian 5-HT 2 c receptor.
  • treatment includes prophylactic treatment.
  • ADHD attention deficit hyperactivity disorder
  • the term "attention deficit hyperactivity disorder” or “ADHD” refers to the syndrome characterised by excessive motor control (i.e. hyperactivity) and/or consistent impairment in attention (i.e. poor attention span), optionally in association with impulsivity (i.e. weak impulse control).
  • ADHD attention deficit hyperactivity disorder
  • the term "attention deficit hyperactivity disorder” or “ADHD” as used herein refers to the syndrome characterised by all three of the above-mentioned symptoms.
  • ADHD attention deficit hyperactivity disorder
  • GROUP 1 (Inattention): six (or more) of the following symptoms of inattention have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level:
  • Hyperactivity six (or more) of the following symptoms of hyperactivity-impulsivity have persisted for at least 6 months to a degree that is maladaptive and inconsistent with developmental level: Hyperactivity:
  • the term "attention deficit disorder” or "ADD” refers to the syndrome characterised by consistent impairment in attention (i.e. poor attention span) optionally in association with impulsivity (i.e. weak impulse control).
  • the term ADD refers to the presence of the symptoms of "Inattention” optionally in association with the symptoms of "Impulsivity" of the DSM-IV criteria referred to above.
  • a 5-HT 2 c receptor antagonist is selected from:
  • (xi) a compound described either generically or specifically in WO-94/04533.
  • Other compounds useful in the invention include: l-[(3-Pyridyl)-3-phenyl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[(4-Pyridyl)-3-phenyl carbamoyl]-5-methylthio-6-trifluoromethyl indoline, l-[(3-Pyridyl)-3-phenyl carbamoyl]-5-methylthio-6-trifluoromethyl indoline, l-[(3-Pyridyl)-4-phenyl carbamoyl]-5-methoxy-6-trifluoromethylindoline, l-[(4-Pyridyl)-4-phenyl carbamoyl]-5-methoxy-6-trifluoromethylindoline, l-[(2-Pyridyl)-3-phenyl carb
  • the invention relates to use of SB-242082, SB-247853 and SB- 243213.
  • a pharmaceutical composition based on the invention may be prepared by admixture suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parental or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administerable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non- aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
  • fluid unit dosage forms are prepared ultilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parental suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • the composition may contain from 0.1 to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • suitable unit doses may be 0.05 to lOOOmg, more suitable 1.0 to 200 mg, and such unit doses may administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
  • Figure 1 shows the effect of chlordiazepoxide (CDP 1-5 mg/kg i.p., 30 min pretest) on the number of shocks taken in the Vogel test (0.8mA shock level). The results marked as * and ** show a significant difference at p ⁇ 0.1 and 0.05, respectively, from vehicle by Dunnett's test following significant 1 way ANOVA (analysis of variance).
  • Figure 2 shows the effect of methylphenidate (Mphen - 1 mg/kg i.p. 40 min pretest), d- amphetamine (Amph - 0.75 mg/kg i.p.
  • Figure 3 shows the effect of SB-242084 (3 mg/kg s.c, 40 min pretest) and chlordiazepoxide (CDP- 4 mg/kg i.p., 30 min pretest) on the number of shocks taken in the Vogel test (0.8mA shock level).
  • the results marked as ** and ## show a significant difference at p ⁇ 0.01 from veh-veh and veh-CDP groups, respectively, by Tukey's test following a significant 2-way ANOVA.
  • Figure 4 shows the effect of -i-amphetamine (0.25-1 kg i.p. 30 min pretest) on the number of shocks taken in the Vogel test (0.4mA shock level). The results marked as * show a significant difference at p ⁇ 0.05 from vehicle by Dunnett's test following significant 1 way ANOVA.
  • Figure 5 shows the effect of methylphenidate (0.1-5 mg/kg i.p. 30 min pretest) and d- amphetamine (0.5 mg/kg i.p. 30 min pretest) on the number of shocks taken in the Vogel test (0.4mA shock level).
  • the results marked as * and ** show a significant difference at p ⁇ 0.05 and 0.01 respectively from vehicle by Dunnett's test following significant 1 way ANOVA.
  • Figure 6 shows the effect of SB-242084 (1-10 mg/kg i.p. 30 min pretest) on the number of shocks taken in the Vogel test (0.4mA shock level).
  • the results marked as * and ** show a significant difference at p ⁇ 0.05 and 0.01 respectively from vehicle by Dunnett's test following significant 1 way ANOVA.
  • nonspecific 5-HT 2 c receptor antagonists such as ritanserin and mianserin
  • ritanserin and mianserin are reportedly anxiolytic in man (Bressa et al., 1987, Int. J. Clin. Pharmacol. Res., 7: 111-119; Ceulemans et al., 1985, Pharmacopsychiatr., 18: 303-3055; Conti, et al., 1979, J. Int. Med. Res., 7: 285-289).
  • selective 5-HT 2B/2C receptor antagonists, SB-200646 and SB-206553 are anxiolytic-like in a number of rodent models, such as the rat social interaction, Geller-Seifter conflict test and the marmoset operant procedure (Kennett et al., 1994, Br. J. Pharmacol., I ll: 797-802; Kennett et al., 1995, Psychopharmacol., 118: 178- 182; Kennett, et al., 1996, Br. J. Pharmacol., 117: 427-434).
  • the highly selective 5-HT 2 c receptor antagonist assessed for anti-impulsive activity SB-242084, has an anxiolytic-like profile in the social interaction and Geller-Seifter tests (Kennett et al., 1997, Neuropharmacology, 36: 609-620).
  • mice Male Sprague-Dawley rats (Charles River) weighing 220-300g were used. The animals were group housed, 5 per cage (cage size: 40x40x20cm), and kept in a temperature controlled environment (20 ⁇ 2°C) in a 12 hour light-dark cycle. Animals had free access to food and water until testing, they were then deprived of water 16-18 hours prior to the familiarisation session.
  • the Vogel chamber consists of a plastic box (30cm x 25cm x 32cm) with a grid floor.
  • the water bottle is attached to the outside wall of the box and a hole allows the rat access to the water bottle spout.
  • Chlordiazepoxide (Sigma), d-amphetamine sulfate (Sigma) and methylphenidate (MacFarlan Smith Ltd) were administered in 0.9% saline.
  • SB-242084 (Vernalis Chemistry Department) was administered in 20% PEG-400 : 8% cyclodextrin in distilled water. The volume administered was 1 ml /kg.
  • each rat 16-18 hours after water deprivation each rat was introduced to a chamber as part of a familiarisation session. During this session the animals were allowed up to 150 licks of the water spout, during a maximum 3 minute period. On removal, the rats were then further water deprived for 3 hours prior to testing. During the test session the rats were allowed 75 unpunished licks of the water spout, before they entered a shocked phase. An animal only entered the shocked phase if the initial unshocked 75 licks were completed within 3 minutes. During the shocked phase the animals were shocked (0.8 mA, figs 1-3; 0.4 mA, figs 4-6), via the water spout, following each 20th subsequent lick. The number of shocks delivered were recorded for each rat that entered the shocked phase.

Abstract

L'invention porte sur l'utilisation d'un composé sélectionné parmi un antagoniste, un agoniste inverse ou un modulateur allostérique négatif du récepteur de la 5HT2C, et entrant dans la composition d'un médicament traitant l'hyperactivité avec déficit de l'attention (ADHD) ou le trouble déficitaire de l'attention (ADD); et sur un procédé de traitement de ces mêmes troubles.
PCT/GB2002/003545 2001-08-02 2002-08-02 Traitement de l'hyperactivite avec deficit de l'attention ou du trouble deficitaire de l'attention WO2003011281A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0118892.9A GB0118892D0 (en) 2001-08-02 2001-08-02 Method of treatment
GB0118892.9 2001-08-02

Publications (1)

Publication Number Publication Date
WO2003011281A1 true WO2003011281A1 (fr) 2003-02-13

Family

ID=9919696

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2002/003545 WO2003011281A1 (fr) 2001-08-02 2002-08-02 Traitement de l'hyperactivite avec deficit de l'attention ou du trouble deficitaire de l'attention

Country Status (2)

Country Link
GB (1) GB0118892D0 (fr)
WO (1) WO2003011281A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007132841A1 (fr) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et utilisation
WO2009063992A1 (fr) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
EP2248524A2 (fr) 2004-08-25 2010-11-10 Takeda Pharmaceutical Company Limited Agents préventifs/remèdes pour l'incontinence de stress et procédé de séléction de ceux-ci
WO2011071136A1 (fr) 2009-12-11 2011-06-16 アステラス製薬株式会社 Agent thérapeutique pour la fibromyalgie
TWI406866B (zh) * 2004-09-03 2013-09-01 Athersys Inc 作為血清素受體調節劑之三環雜芳哌嗪，吡咯啶和氮雜環丁烷
WO2019131902A1 (fr) 2017-12-27 2019-07-04 武田薬品工業株式会社 Agent thérapeutique pour incontinence urinaire de stress et incontinence fécale

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5663191A (en) * 1994-07-06 1997-09-02 Adir Et Compagnie Benzopyran compounds as 5HT2C receptor antagonists
WO2000059489A2 (fr) * 1999-04-06 2000-10-12 Sepracor Inc. Methodes et compositions pour le traitement des troubles neuroleptiques et associes au moyen de metabolites de ziprasidone
WO2001041701A2 (fr) * 1999-12-06 2001-06-14 H. Lundbeck A/S Combinaison d'un inhibiteur du recaptage de la serotonine et d'un antagoniste, d'un agoniste inverse ou d'un agoniste partiel de 5-ht¿2c?

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5663191A (en) * 1994-07-06 1997-09-02 Adir Et Compagnie Benzopyran compounds as 5HT2C receptor antagonists
US5723484A (en) * 1994-07-06 1998-03-03 Adir Et Compagnie Benzopyran compounds as 5-HT2C receptor antagonists
WO2000059489A2 (fr) * 1999-04-06 2000-10-12 Sepracor Inc. Methodes et compositions pour le traitement des troubles neuroleptiques et associes au moyen de metabolites de ziprasidone
WO2001041701A2 (fr) * 1999-12-06 2001-06-14 H. Lundbeck A/S Combinaison d'un inhibiteur du recaptage de la serotonine et d'un antagoniste, d'un agoniste inverse ou d'un agoniste partiel de 5-ht¿2c?

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GROTTICK ET AL.: "Studies to investigate the role of 5-HT2c receptors on cocaine- and food maintained behavior", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 295, no. 3, pages 1183 - 1191, XP002225463 *
MCMAHON ET AL.: "Role of 5-HT2a and 5HT2b/2c receptors in the behavioral interactions between serotonin and catecholamine reuptake inhibitors", NEUROPYSCHOPHARMACOLOGY, vol. 24, no. 3, pages 319 - 329, XP002225464 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2248524A2 (fr) 2004-08-25 2010-11-10 Takeda Pharmaceutical Company Limited Agents préventifs/remèdes pour l'incontinence de stress et procédé de séléction de ceux-ci
EP2400300A1 (fr) 2004-08-25 2011-12-28 Takeda Pharmaceutical Company Limited Procédé de sélection d'agents préventifs/remèdes pour l'incontinence de stress
TWI406866B (zh) * 2004-09-03 2013-09-01 Athersys Inc 作為血清素受體調節劑之三環雜芳哌嗪，吡咯啶和氮雜環丁烷
WO2007132841A1 (fr) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et utilisation
EP2727585A1 (fr) 2006-05-16 2014-05-07 Takeda Pharmaceutical Company Limited Méthode de dépistage in-vivo
EP2742936A1 (fr) 2006-05-16 2014-06-18 Takeda Pharmaceutical Company Limited Composé hétérocyclique condensé et son utilisation
WO2009063992A1 (fr) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
EP2789338A2 (fr) 2007-11-15 2014-10-15 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
WO2011071136A1 (fr) 2009-12-11 2011-06-16 アステラス製薬株式会社 Agent thérapeutique pour la fibromyalgie
WO2019131902A1 (fr) 2017-12-27 2019-07-04 武田薬品工業株式会社 Agent thérapeutique pour incontinence urinaire de stress et incontinence fécale

Also Published As

Publication number Publication date
GB0118892D0 (en) 2001-09-26

Similar Documents

Publication Publication Date Title
JP6203781B2 (ja) Ｃ−ｆｍｓおよび／またはｃ−ｋｉｔ活性を調節する化合物およびその用途
Britton et al. Evidence for involvement of both D1 and D2 receptors in maintaining cocaine self-administration
EP0279114B2 (fr) Médicaments pour le traitement ou la prévention du syndrome associé à un état de manque
JP2009514941A (ja) 血小板減少症を治療する化合物および方法
CN102958540B (zh) 含取代的2,3-二氢咪唑并[1,2-c]喹唑啉的组合
MX2007011436A (es) Ligando del receptor nicotinico neuronal 7 y composiciones antipsicoticas.
JP2009518423A (ja) 統合失調症の副作用および陰性症状を治療するためのｃｂ１アンタゴニストの使用
EP0279990A2 (fr) Emploi de dérivés hétérocycliques pour le traitement de troubles de la démence
CA2488311A1 (fr) Traitement combine de la depression et de l'anxiete a l'aide d'antagonistes nk1 et nk3
WO2012161301A1 (fr) Agent prophylactique ou thérapeutique pour la douleur neuropathique associée au syndrome de guillain-barré
CN105142623A (zh) 用于改善认知功能的方法和组合物
US20020049211A1 (en) Combination treatment for depression and anxiety
WO2003011281A1 (fr) Traitement de l'hyperactivite avec deficit de l'attention ou du trouble deficitaire de l'attention
JP2001502311A (ja) 抗鬱及び／又は抗不安薬としてのｃｎｓ浸透性ｎｋ―１受容体拮抗薬
US20040048869A1 (en) Combination treatment for depression, anxiety and psychosis
CA2357901A1 (fr) Traitement combine contre la depression et l'anxiete
RU2009136331A (ru) Индоловые и бензотиофеновые соединения в качестве модуляторов гистаминового н3-рецептора
CN102482271A (zh) 焦虑障碍治疗剂
US5574053A (en) Method for treating anxiety
JPH07165612A (ja) 禁煙による症状を軽減するための医薬
US20040001895A1 (en) Combination treatment for depression and anxiety
EP0709093A2 (fr) Utilisation d'une oxadiazole ou thiadiazole azabicyclique dans le traitement de l'anxiété
RU2508106C2 (ru) Способы и композиции для лечения шизофрении с использованием атипичной нейролептической комбинированной терапии
RU2508096C2 (ru) Способы и композиции для лечения шизофрении с использованием нейролептической комбинированной терапии
WO2004078177A1 (fr) Medicament contre la dependance aux drogues et aux substances toxiques

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR LC LK LR LS LT LU LV MA MD MG MN MW MX MZ NO NZ OM PH PL PT RU SD SE SG SI SK SL TJ TM TN TR TZ UA UG US UZ VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ UG ZM ZW AM AZ BY KG KZ RU TJ TM AT BE BG CH CY CZ DK EE ES FI FR GB GR IE IT LU MC PT SE SK TR BF BJ CF CG CI GA GN GQ GW ML MR NE SN TD TG

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP