WO2003011281A1 - Treatment of attention deficit hyperactivity disorder or attention deficit disorder - Google Patents
Treatment of attention deficit hyperactivity disorder or attention deficit disorder Download PDFInfo
- 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
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- WO
- WIPO (PCT)
- Prior art keywords
- trifluoromethyl
- methoxy
- indoline
- compound
- attention deficit
- Prior art date
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Classifications
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-
- 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.
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Abstract
Description
Claims
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GBGB0118892.9A GB0118892D0 (en) | 2001-08-02 | 2001-08-02 | Method of treatment |
GB0118892.9 | 2001-08-02 |
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WO2007132841A1 (en) | 2006-05-16 | 2007-11-22 | Takeda Pharmaceutical Company Limited | Fused heterocyclic compound and use thereof |
WO2009063992A1 (en) | 2007-11-15 | 2009-05-22 | Takeda Pharmaceutical Company Limited | Condensed pyridine derivative and use thereof |
EP2248524A2 (en) | 2004-08-25 | 2010-11-10 | Takeda Pharmaceutical Company Limited | Preventives/remedies for stress urinary incontinence and method of screening the same |
WO2011071136A1 (en) | 2009-12-11 | 2011-06-16 | アステラス製薬株式会社 | Therapeutic agent for fibromyalgia |
TWI406866B (en) * | 2004-09-03 | 2013-09-01 | Athersys Inc | Tricyclic heteroaryl piperazines, pyrrolidines and azetidines as serotonin receptor modulators |
WO2019131902A1 (en) | 2017-12-27 | 2019-07-04 | 武田薬品工業株式会社 | Therapeutic agent for stress urinary incontinence and fecal incontinence |
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2001
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Cited By (10)
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EP2248524A2 (en) | 2004-08-25 | 2010-11-10 | Takeda Pharmaceutical Company Limited | Preventives/remedies for stress urinary incontinence and method of screening the same |
EP2400300A1 (en) | 2004-08-25 | 2011-12-28 | Takeda Pharmaceutical Company Limited | Method of screening preventives/remedies for stress urinary incontinence |
TWI406866B (en) * | 2004-09-03 | 2013-09-01 | Athersys Inc | Tricyclic heteroaryl piperazines, pyrrolidines and azetidines as serotonin receptor modulators |
WO2007132841A1 (en) | 2006-05-16 | 2007-11-22 | Takeda Pharmaceutical Company Limited | Fused heterocyclic compound and use thereof |
EP2727585A1 (en) | 2006-05-16 | 2014-05-07 | Takeda Pharmaceutical Company Limited | In-vivo screening method |
EP2742936A1 (en) | 2006-05-16 | 2014-06-18 | Takeda Pharmaceutical Company Limited | Fused heterocyclic compound and use thereof |
WO2009063992A1 (en) | 2007-11-15 | 2009-05-22 | Takeda Pharmaceutical Company Limited | Condensed pyridine derivative and use thereof |
EP2789338A2 (en) | 2007-11-15 | 2014-10-15 | Takeda Pharmaceutical Company Limited | Condensed pyridine derivate and use thereof |
WO2011071136A1 (en) | 2009-12-11 | 2011-06-16 | アステラス製薬株式会社 | Therapeutic agent for fibromyalgia |
WO2019131902A1 (en) | 2017-12-27 | 2019-07-04 | 武田薬品工業株式会社 | Therapeutic agent for stress urinary incontinence and fecal incontinence |
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