WO2003011281A1

WO2003011281A1 - Treatment of attention deficit hyperactivity disorder or attention deficit disorder

Info

Publication number: WO2003011281A1
Application number: PCT/GB2002/003545
Authority: WO
Inventors: Pascal Jean Denis Goetghebeur; Guy Anthony Kennett; Sean Lightowler
Original assignee: Vernalis Research Ltd
Current assignee: Ligand UK Research Ltd
Priority date: 2001-08-02
Filing date: 2002-08-02
Publication date: 2003-02-13
Anticipated expiration: 2004-02-02
Also published as: GB0118892D0

Abstract

Use of a compound selected from an antagonist of, an inverse agonist of or a negative allosteric modulator of the 5HT2C receptor in the manufacture of a medicament for the treatment of attention deficit hyperactivity disorder (ADHD) or attention deficit disorder (ADD); and a method for treating the same.

Description

METHOD OF TREATMENT OF ATTENTION DEFICIT HYPERACTIVITY DISORDER OR ATTENTION DEFICIT DISORDER

The present invention relates to the use of compounds having antagonistic, inverse agonistic activity or negative allosteric modulatory activity at the 5-HT₂c receptor as a novel treatment of attention deficit hyperactivity disorder (ADHD) or attention deficit disorder (ADD).

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. However, the amphetamine drug class has traditionally been linked with a high abuse potential and other side-effects.

During the last decade, multiple 5-hydroxytryptamine (5-HT) subtypes have been characterised. On the basis of the receptor binding profiles, common second messenger coupling and the functional activity of selective ligands, seven main groups of 5-HT receptor, termed 5-HT], 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₅, 5-HT₆ and 5-HT₇, have been identified.

WO 01/32660 (NPS Allelix Co.) claims a series of 5-HT₆ receptor antagonists to be useful in the treatment of various CNS disorders including schizophrenia, depression, ADHD, impaired cognition, and memory dysfunction.

WO 01/32625 (Du Pont Pharmaceuticals Company, USA) 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-HT₆ antagonists containing arylsulfamide or arylaminosulfonyl groups in the manufacture of a medicament for the treatment of ADHD.

WO 99/25364 (Merck & Co. Inc. USA) 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 Verwaltungsgesellschaft m.b.H.) 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-HT₂c antagonistic, partial agonistic or inverse agonistic activity for the treatment of depression and other affective disorders.

It is an object of this invention to provide an alternative treatment for the treatment of ADHD which does not suffer from the disadvantages of existing treatments.

It has now been found that treatments which decrease 5-HT₂c receptor function, such as administration of 5-HT₂c receptor antagonists, inverse agonists of the 5HT₂c receptor, or negative allosteric modulators of the 5-HT₂c receptor (i.e. attenuators acting at modulating sites) are effective in the treatment of ADHD. These 5-HT₂c receptor ligands have been shown to produce an anti-impulsive effect in the Vogel conflict model comparable to that produced by drugs effective in the treatment of ADHD.

The 5-HT₂c receptor is one of the 5-HT₂ receptor family of seven trans-membrane spanning proteins. 5-HT₂c 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).

According to the present invention there is provided use of a compound selected from an antagonist of, an inverse agonist of or a negative allosteric modulator of the 5-HT₂c receptor in the manufacture of a medicament for the treatment of attention deficit hyperactivity disorder (ADHD) or attention deficit disorder (ADD).

In a further aspect, 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.

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-HT₂c receptor. Such a combination of compounds may be administered sequentially or simultaneously, and in the same or separate formulations.

In one embodiment, a 5-HT₂c receptor antagonist is used in the use or method of the invention.

In one embodiment, said antagonist of, inverse agonist of or negative allosteric modulator of the 5-HT₂c 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-HT₂c receptor is used in the absence of a serotonin re-uptake inhibitor.

Preferably the subject is a human subject, particularly a human in childhood.

As used herein, a 5HT₂c antagonist refers to any molecule which acts directly at the 5HT₂c receptor to attenuate the effect of an agonist acting at the same receptor. As used herein, a 5HT₂c inverse agonist refers to any molecule acting at the 5-HT₂c receptor to attenuate the constituitive activity of that receptor.

As used herein, a 5HT₂c negative allosteric modulator refers to any molecule that attenuates the effect of a 5-HT₂c receptor agonist by interacting with the receptor at a site which is distinct from that at which 5-HT acts.

As used herein, a 5HT₂c antagonist, inverse agonist or negative allosteric modulator refers to a compound which, at a concentration of lμM, 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-HT₂c receptor.

As used herein, the term "treatment" includes prophylactic treatment.

As used herein, 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). In one embodiment, the term "attention deficit hyperactivity disorder" or "ADHD" as used herein refers to the syndrome characterised by all three of the above-mentioned symptoms.

In an alternative embodiment, the term "attention deficit hyperactivity disorder" or "ADHD" as used herein refers to the syndrome characterised by the presence of either Group 1 or Group 2 of the following diagnostic criteria for ADHD provided by the Diagnostic and Statistical Manual of Mental Disorders (4th Edition, American Psychiatric Association; hereinafter referred to as "DSM-IV):

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:

(a) often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities;

(b) often has difficulty sustaining attention in tasks or play activities; (c) often does not seem to listen when spoken to directly;

(d) often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behaviour or failure to understand instructions); (e) often has difficulty organizing tasks and activities;

(f) often avoids, dislikes, or is reluctant to engage in tasks that require; sustained mental effort (such as schoolwork or homework);

(g) often loses things necessary for tasks or activities (e.g. toys, school assignments, pencils, books, or tools); and (h) is often easily distracted by extraneous stimuli.

Group 2 (hyperactivity-impulsivity): 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:

(a) often fidgets with hands or feet or squirms in seat;

(b) often leaves seat in classroom or in other situations in which remaining seated is expected;

(c) often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness);

(d) often has difficulty playing or engaging in leisure activities quietly;

(e) is often "on the go" or often acts as if "driven by a motor"; and

(f) often talks excessively

Impulsivity:

(g) often blurts out answers before questions have been completed; (h) often has difficulty awaiting turn; and

(i) often interrupts or intrudes on others (e.g. butts into conversations or games).

As used herein, 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). In an alternative embodiment, 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.

Any suitable antagonists of, inverse agonist of or negative allosteric modulator of the 5- HT₂c receptor may be used in the present invention. In one embodiment, a 5-HT₂c receptor antagonist is selected from:

(i) a compound disclosed either genetically or specifically in WO-96/23783, particularly 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]- lH-indole-1-carboxamide}, which is also known as SB-242084.

(ii) a compound disclosed in WO-97/48699, particularly {2,3-dihydro-5-methyl-Ν-[6- [(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-6-(trifluoromethyl)-lH-Indole-l-carboxamide}, which is also known as SB-243213;

(iii) a compound disclosed either generically or specifically in WO-A-97/48700, particularly 2,3-dihydro-5-methyl-N-[6-(2-pyridinylmethoxy)-3-pyridinyl]-6-(trifluoro- methyl)-lH-indole-l-carboxamide, which is also known as SB-247853;

(iv) N-[3-fluoro-5-(3-pyridinyl)phenyl]-2,3-dihydro-5-methoxy-6-(trifluoro-methyl)- lH-indole-1-carboxamide, which is also known as SB-228357;

(v) {N-[5-[5-(2,4-dioxo-l,3,8-triazasρiro[4.5]dec-8-yl)-l-oxopentyl]-2,4- dimethoxyphenyl]-4-(trifluoromethyl)-benzenesulfonamide}, which is also known as RS 102221;

(vi) O-Methylasparvenone (I):

(vii) 0-Methylasparvenone-derived compounds of formula (II):

described by Boes, M. et al. in 1998, Helv. Chim. Acta, 81(3), 525-538, particularly Ro 60- 0795 and Ro 60-0491, also described by Misane, I. et al. In Neuropsychopharmacology (1999), Volume Date 2000, 22(2), 168-190;

(viii) A substituted [2,3,4,4a,5,10b-hexahydro-benz[h]isoquinoline-6(lH)-one] 5HT₂c antagonist disclosed by Stadler, H. et al. in 2000, Chimia, 54 (11) 669 - 671; .

(ix) A compound selected from:

(+)-l-[2-[4-[(lR,3S)-5-chloro-3-(4-fluorophenyl)-2,3-dihydro-lH-inden-l-yl]-l- piperazinyl]ethyl]-3-(l-methylethyl)-2-imidazolidinone; and l-[2-[4-[(lR,3S)-5-chloro-3-(4-fluorophenyl)-2,3-dihydro-lH-inden-l-yl]-l- piperazinyl]ethyl]-3-(l-methylethyl)-2-imidazolidinone, (2Z)-2-butenedioate;

(x) a pyridoindolyl cycloalkanecarboxylate 5HT_2c antagonist as described either generically or specifically in EP-A-1070716, particularly one of formula (III):

(HI)

(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 carbamoyl]-5-methoxy-6-trifluoromethylindoline, l-[4-Methyl-3-(3-Pyridyl)-phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[3-Fluoro-5-(3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[2-Fluoro5-(3-pyridyl) phenyl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-(5-Phenyl pyrid-3-yl carbamoyl)-5-methoxy-6trifluoromethyl indoline, l-(5-Phenyl pyrid-3-yl carbamoyl)-5-methylthio-6-trifluoromethyl indoline, l-[5-(3-Pyridyl)-pyrid-3-yl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[5-(4-Trifluoromethylphenyl)-pyrid-3-yl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[5-(4-Methylphenyl)-pyrid-3yl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[5-(2-Thienyl)-pyrid-3-yl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[5-(3-Thienyl)-pyrid-3-yl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[5-(2-Pyrrolyl)-pyrid-3-yl carbamoyl)-5-methoxy-6-trifluoromethyl indoline, l-[5-(4-Pyridyl)-pyrid-3-yl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[2-(3-Pyridyl)-thiazol-4-yl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[2-(2-Pyridyl)-thien-5-yl carbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-(3-Fluoro-5-(4-methyl-3-pyridyl)phenylcarbamoyl)-5-methoxy-6trifluoromethylindoline, l-(5-(2,6-Difluorophenyl)-3-pyridylcarbamoyl)-5-methoxy-6- trifluoromethylindoline, 6-Chloro-5-methyl-l-(4-methyl-3-(pyrid-3-yl)-phenylcarbamoyl) indoline, l-(4-Methyl-3-(pyrid-3-yl) phenylcarbamoyl)-5-thiomethyl-6-trifluoromethyl indoline, l-(3-Fluoro-5-(pyrid-3-yl)phenylcarbamoyl)-5-thiomethyl-6-trifluoromethylindoline, l-(4-Chloro-3-(pyrid-3-yl)phenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline, 5-Methoxy-l-(5-methyl-(l,2-4-oxadiazol-3-yl)-phenylcarbamoyl)-6-trifluoromethyl indoline, l-[4-Methyl-3-(4-methyl-3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[5-Bromo-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline, l-[4-t-Butyl-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline, l-[4-Methoxy-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline, l-[5-Fluoro-4-methoxy-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[3-Bromo-4-methyl-5-(3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[3-(4-Isoquinolyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[5-(4-Methyl-3-pyridyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[6-(3-Pyridyl)-pyrid-3-ylcarbamoyl]-5-methoxy-6-trifluoromethylindoline, l-[5-(2-Furyl)-pyrid-3-ylcarbamoyl-5-methoxy-6-trifluoromethyl indoline, l-[2-(Pyrazinyl)-thiazol-4-ylcarbamoyl]-5-methoxy-6-trifluoromethyl-indoline, l-[3-(5-Pyrimidyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl-indoline, l-[3-(4-Methyl-3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline, l-[5-Ethyl-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline, 5-Methoxy-l-[5-phenyl-3-(pyrid-3-yl)phenylcarbamoyl]-6-trifluoromethyl indoline, 6-Chloro-5-methyl-l-[4-methyl-3-(4-methyl-3-pyridyl)phenyl carbamoyl] indoline, l-[3-(pyrid-3-ylaminocarbonyl)-phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline, l-[3-(pyrid-3-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-trifluoromethyl indoline, l-[3-(Pyrid-4-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-trifluoromethyl indoline, l-[4-(Pyrid-3-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-trifluoromethyl indoline, l-[4-(Pyrid-4-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-trifluoromethyl indoline, l-[3-(3-pyridylcarbonyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[3-(Pyrid-3-yl-aminosulphonyl)-phenylcarbamoyl]5-methoxy-6-trifluoromehtylindoline, 5-Methylthio-6-trifluoromethyl-l-[6-(pyridin-3-yloxy)pyridin-3-ylcarbamoyl)indoline, 5-Methoxy-trifluoromethyl-l-[6-(pyridin-3-yloxy)pyridin-3-ylcarbamoyl]indoline, 5-Methoxy-6-trifluoromethyl-l-[4-(pyridin-4ylmethyloxy)phenyl carbamoyl]indoline, 5-Methoxy-6-trifluoromethyl-l-[6-(pyridin-4-ylmethyloxy)pyridin-3-ylcarbamoyl] indoline, 5-Methylthio-6-trifluoromethyl-l-[4-(pyrid-4-yl-methylamino carbonyl)phenyl carbamoyl] indoline,

Trans-5-Methylthio-6-trifluoromethyl-l-(4-[2-ethenyl-(4-pyridyl)]-phenylcarbamoyl)- indoline, 5-Methylthio-6-trifluoromethyl-l-(4-[2-ethyl(4-pyridyl)]phenyl carbamoyl ) indoline, l-(l-(4-Pyridyl)-5-indolylcarbamoyl)-5-methoxy-6-trifluoromethylindoline, 5-Methoxy-6-trifluoromethyl-l-[4-(pyridin-4-ylthiomethyl)phenyl carbamoyl] indoline, 5-Methoxy-6-trifiuoromethyl-l-[4-(pyridin-4ylsulphonylmethyl)phenylcarbamoyl] indoline, 5-Methoxy-6-trifluoromethyl-l-[4-(pyridin-4-ylmethylthio)phenyl carbamoyl]indoline, 5-Methylthio-6-trifluoromethyl-l-[(6-phenoxy)-3-pyridylcarbamoyl]indoline, 5-Methoxy-6-trifluoromethyl-l-[2-(pyridin-3-yloxy)pyridin-4-ylcarbamoyl)indoline, 5-Methylthio-6-trifluoromethyl-l-[6-(2-methylpyridin-3-yloxy)pyridin-3ylcarbamoyl] indoline, 5-Methylthio-6-trifluoromethyl-l-[6-(6-methylpyridin-3-yloxy)pyridin-3ylcarbamoyl] indoline,

5-Methoxy-6-trifluoromethyl-l-[6-(pyridin-3-ylthio)pyridin-3-ylcarbamoyl] indoline, 5-Methylthio-6-trifluoromethyl-l-[4-(pyrid-3-ylmethyl)amido phenyl carbamoyl]indoline, 5-Methylthio-6-trifluoromethyl-l-[3-(pyrid-4ylmethyl) amidophenylcarbamoyl] indoline, 5-Methylthio-6-trifluoromethyl-l-[4(pyrid-2-ylmethyl) amidophenylcarbamoyl] indoline, l-(l-(3-Pyridylmethyl)-5-indolylcarbamoyl)-5-methoxy-6-trifluoromethylindoline, l-(l-(4-Pyridylmethyl)-5-indolylcarbamoyl)-5-methoxy-6-trifluoromethylindoline, l-(l-(3-pyridyl)-5-indolylcarbamoyl)-5-methoxy-6-trifluoromethyl indoline, 5-Methylthio-6-trifluoromethyl-l-[4-[2-(4-pyridyl)-thiazol-4-yl]phenylcarbamoyl) indoline,

5-Methylthio-6-trifluoromethy]-l-(4-[2-(3-pyridyl)-thiazol-4-yl]phenylcarbamoyl) indoline, l-[4-Fluoro-3-(3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[3-Fluoro-5-(pyrimidin-5-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[4-Chloro-3-(4-methyl-3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, l-[2,3-Dihydro-7-(pyrid-3-yl)benzofuran-5-ylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline, 5-Methoxy-6-trifluoromethyl-l-[6-(2-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl] indoline, and other specific examples disclosed in WO-96/23783, and pharmaceutically acceptable salts thereof.

In a preferred embodiment, the invention relates to use of SB-242082, SB-247853 and SB- 243213.

The disclosures of the documents referenced above under items (i) to (ix) are incorporated herein for their descriptions of the above-mentioned compounds, including their methods of preparation.

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.

For parental administration, 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. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, 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. Advantageously, 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.

The dose of the compound used in the treatment of ADHD will vary in the usual way with the seriousness of the disorder, the weight of the sufferer, and other similar factors. However, as a general guide 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.

The invention will now be illustrated by way of example. It will be apparent to those skilled in the art that modifications to the examples can be made without departing from the scope of the invention.

In the following exemplification section, the results are displayed graphically in Figures 1 to 6 in which:

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. 40 min pretest) and chlordiazepoxide (CDP - 6 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 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.

In each of Figures 1 to 6, the term "veh" refers to the results obtained for vehicle-only administration. EXAMPLES

The production of an anti-impulsive effect via selective 5-HT₂c receptor antagonism has been investigated in the rat Vogel test. In the Vogel conflict test, thirsty rats are trained to drink from a water-spout. On the test day, drinking may result in the delivery of an electric shock from the water-spout. In a study by Pappas et al. (1981, Pharmacol. Biochem. Behav., 15: 743-6), chlordiazepoxide was reported to produce a deficit in impulse control, indicated by an increase in punished responding. This finding is consistent with the reported ability of benzodiazepines to increase impulsivity in human patients (Mathew et al., 2000, Can. J. Psychiatr., 45: 89-90.) and cause unfavourable effects in children with ADHD (Werry, 1977, Drugs, 11: 81-89; Zrull, et al., 1964, Am. J. Psychiatr., 121: 388- 389.). Further evidence that responding in the Vogel model reflects impulsivity is provided by the observation that male rats exposed to high levels of the pro-impulsive hormone testosterone for 8 weeks, or to one high dose 24 hours before testing, display an increase in punished responding (Bing, et al., 1998, Eur. Neuropsychopharmacol., 8: 321- 323). Insofar as persistence in punished responding may be analagous to lack of impulse control, the Vogel model thus mimics one of the central features of ADHD. Furthermore, stimulants effective in the treatment of ADHD, including -i-amphetamine and methylphenidate reverse the benzodiazepine-induced increase in punished responding in the Vogel model, and phenobarbital, which worsens ADHD symptoms, enhances the deficit in impulse control (Pappas et al., 1981, Pharmacol. Biochem. Behav., 15: 743-6). The Vogel model may therefore be used as a model of ADHD.

The reported pro-impulsive effect of chlordiazepoxide in the Vogel model, characterised by an increase in the number of shocks taken, has been replicated (see fig 1), as was its reversal by d-amphetamine and methylphenidate (fig 2). At doses reportedly selective and non-sedating, the 5-HT₂c receptor antagonist, SB-242084 (Kennett et al., 1997, Neuropharmacology, 36: 609-620) also reversed the pro-impulsive increase in number of shocks taken produced by chlordiazepoxide in the Vogel test (fig 3).

In order to demonstrate that the apparent anti-impulsive effects of -i-amphetamine, methylphenidate and SB-242084 are not dependent upon the presence of chlordiazepoxide, their effects were also assessed against a high baseline of punished responding, produced by lowering the shock level. Under these conditions, d-amphetamine (fig 4), methylphenidate (fig 5) and SB-242084 (fig 6) again produced anti-impulsive reductions in punished responding in the Vogel test.

Another possible interpretation of data is that a reduction in punished responding in the Vogel test, either in the presence or absence of chlordiazepoxide, is due to anxiogenesis. However, neither -/-amphetamine nor methylphenidate are associated with anxiogenesis (Ahmann et al., 2001. Pediatrics, 107: E10001; Barkley, et al., 1990, Pediatrics, 86: 184-92). Furthermore, there is strong clinical and preclinical evidence that 5-HT₂c receptor antagonism produces anxiolytic activity, and not anxiogenesis. Thus, the nonspecific 5-HT₂c receptor antagonists, such as 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). In keeping with this, 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). Furthermore, the highly selective 5-HT₂c 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).

The data presented in figures 1-6 thus illustrate that 5-HT₂c receptor antagonism produces an anti-impulsive effect in the Vogel model comparable to that produced by drugs effective in the treatment of ADHD. The data therefore illustrate that the administration of a 5HT₂c receptor antagonist or other treatments which decrease 5HT₂c receptor function, are effective in the treatment of ADHD.

Experimental Methods

Animals

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.

Apparatus

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.

Drug administration

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.

Procedure

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.

Data Analysis

One-way ANOVA or two-way ANOVA followed by Dunnett's or Tukey's test respectively, were carried out to analyse the data. The data are presented as the mean ± standard error of the mean. N = 7-15 per group.

Claims

Claims:

1. Use of a compound selected from an antagonist of, an inverse agonist of or a negative allosteric modulator of the 5HT₂c receptor in the manufacture of a medicament for the treatment of attention deficit hyperactivity disorder (ADHD) or attention deficit disorder (ADD).

2. 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-HT₂c receptor.

3. A use or method according to claim 1 or 2 wherein said compound is a 5-HT_2c receptor antagonist.

4. A use or method according to claim 1 or 2 wherein the compound is 5-methyl-l-[[2- [(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethyl-indoline.

5. A use or method according to claim 1 or 2 wherein the compound is 6-chloro-5- methyl-l-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]indoline.

6. A use or method according to claim 1 or 2 wherein the compound is selected from 2,3- dihydro-5-methyl-N-[6-(2-pyridinylmethoxy)-3-pyridinyl]-6-(trifluoromethyl)-lH- indole-1-carboxamide, and N-[3-fluoro-5-(3-pyridinyl)phenyl]-2,3-dihydro-5-methoxy- 6-(trifluoromethyl)-lH-indole-l-carboxamide.

7. A use or method according to claim 1 or 2 wherein the compound is selected from:

{N-[5-[5-(2,4-dioxo-l,3,8-triazaspiro[4.5]dec-8-yl)-l-oxopentyl]-2,4- dimethoxyphenyl]-4-(trifluoromethyl)-benzenesulfonamide } ; O-Methylasparvenone;

(+)-l-[2-[4-[(lR,3S)-5-chloro-3-(4-fluorophenyl)-2,3-dihydro-lH-inden-l-yl]-l- piperazinyl]ethyl]-3-(l-methylethyl)-2-imidazolidinone; l-[2-[4-[(lR,3S)-5-chloro-3-(4-fluorophenyl)-2,3-dihydro-lH-inden-l-yl]-l- piperazinyl]ethyl]-3-(l-methylethyl)-2-imidazolidinone, (2Z)-2-butenedioate; and a compound of formula (HI):

(in⁾.

8. A use or method according to any preceding claim for the treatment of ADHD or ADD characterised by symptoms selected from the group consisting of excessive motor control and/or consistent impairment in attention, optionally in association with impulsivity.

9. A use or method according to claim 8 wherein the symptoms are excessive motor control, consistent impairment in attention and impulsivity.

10. A use or method according to claim 8 for the treatment of ADD characterised by consistent impairment in attention optionally in association with impulsivity.