Use of Sulfamate Derivatives for Treating Impulse Control Disorders

Europäisches Patentamt *EP001158973B1* (19) European Patent Office

Office européen des brevets (11) EP 1 158 973 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.7: A61K 31/255, A61K 31/35, of the grant of the patent: A61K 31/7048, A61P 25/00, 04.05.2005 Bulletin 2005/18 A61P 25/30, A61P 25/32, (21) Application number: 00914630.9 A61P 25/34

(22) Date of filing: 18.02.2000 (86) International application number: PCT/US2000/004187

(87) International publication number: WO 2000/050020 (31.08.2000 Gazette 2000/35)

(54) USE OF SULFAMATE DERIVATIVES FOR TREATING IMPULSE CONTROL DISORDERS VERWENDUNG VON SULFAMAT DERIVATEN ZUR BEHANDLUNG VON IMPULSIVEN STÖRUNGEN TRAITEMENT DES TROUBLES DU CONTROLE DES IMPULSIONS A BASE DE DERIVES SULFAMATES

(84) Designated Contracting States: • POTTER D ET AL: "SUSTAINED WEIGHT LOSS AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU ASSOCIATED WITH 12-MONTH TOPIRAMATE MC NL PT SE THERAPY" EPILEPSIA,US,RAVEN PRESS LTD., Designated Extension States: NEW YORK, vol. 38, no. SUPPL. 08, 1997, page AL LT LV MK RO SI 97 XP000923402 ISSN: 0013-9580 • MARCOTTE D: "USE OF TOPIRAMATE, A NEW (30) Priority: 24.02.1999 US 121339 P ANTI-EPILEPTIC AS A MOOD STABILIZER" JOURNAL OF AFFECTIVE (43) Date of publication of application: DISORDERS,NL,ELSEVIER BIOCHEMICAL 05.12.2001 Bulletin 2001/49 PRESS, AMSTERDAM, vol. 50, no. 2/03, September 1998 (1998-09), pages 245-251, (73) Proprietor: UNIVERSITY OF CINCINNATI XP000881514 ISSN: 0165-0327 Cincinnati, OH 45267-0829 (US) • MCELROY S.L. ET AL: "Are impulse -control disorders related to bipolar disorder?." (72) Inventor: MCELROY, Susan, L. COMPREHENSIVE PSYCHIATRY, (1996) 37/4 Cincinnati, OH 45243-1441 (US) (229-240). , XP000951526 • K.T. BRADY ET AL.: "The Relationship Between (74) Representative: Müller-Boré & Partner Substance Use Disorders, Impulse Control Patentanwälte Disorders, and Pathological Aggression" Grafinger Strasse 2 AMERICAN JOURNAL ON ADDICTIONS, vol. 7, 81671 München (DE) no. 3, 1998, pages 221-230, XP000951530 • KUZIECKY R ET AL: "TOPIRAMATE INCREASE (56) References cited: CEREBRAL GABA IN HEALTHY HUMANS" EP-A- 0 568 306 WO-A-00/07583 NEUROLOGY,LIPPINCOTT WILLIAMS & WO-A-00/23059 WO-A-00/44374 WILKINS, PHILADELPHIA,US, no. 51, August WO-A-98/00123 WO-A-98/00130 1998 (1998-08), pages 627-629, XP000923467 US-A- 4 513 006 ISSN: 0028-3878

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 158 973 B1

Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 158 973 B1

• DEWEY S L ET AL: "A PHARMACOLOGIC STRATEGY FOR THE TREATMENT OF NICOTINE ADDICTION" SYNAPSE,GB,WILEY AND SONS, CHICHESTER, vol. 31, no. 1, January 1999 (1999-01), pages 76-86, XP000856613 ISSN: 0887-4476

2 EP 1 158 973 B1

Description

Technical Field

5 [0001] The present invention generally relates to the use of drugs for the treatment of mental disorders. More specifically, the invention describes the use for the manufacture of a medicament for the treatment and prevention of Impulse Control Disorders (ICD's) of sulfamate derivatives.

Background of the Invention 10 [0002] Sulfamate derivatives having useful pharmaceutical activity in the areas of epilepsy, glaucoma, peptic ulcers and male infertility are disclosed in U.S. Pat. Nos. 4,075,351, 4,513,006, 4,591,601, 4,792,569, and 5,760,007. One of these compounds 2,3:4,5-bis-O-(1-methylethylidene)- beta -D-fructopyranose sulfamate known as topiramate has been demonstrated in clinical trials of human epilepsy to be effective as adjunctive therapy or as monotherapy in 15 treating simple and complex partial seizures and secondarily generalized seizures and is currently marketed for the treatment of simple and complex partial seizure epilepsy with or without secondary generalized seizures. [0003] Other pertinent references include:

WO 98/00130 describes the use of Topiramate and related derivatives to treat obesity and the condition of being 20 overweight;

WO 98/00123 describes the use of Topiramate and related derivatives for the treatment of manic depressive bipolar disorder;

25 Journal of Effective Disorders, Vol. 50, 1998, pp. 241-251, D. Marcotte, discusses the use of Topiramate as a mood stabilizer effective in the treatment of bipolar disorders;

Comprehensive Psychiatry, Vol. 37(4), 1996, pp. 229-240, S. McElroy, discusses whether impulse control disorders are related to bipolar disorders. 30 [0004] Binge eating disorder (BED) is characterized by discrete periods of binge eating during which large amounts of food are consumed in a discrete period of time and a sense of control over eating is absent. Persons with bulimia nervosa have been reported to have electroencephalographic abnormalities and to display reduced binge eating in response to the anti-epileptic drug phenytoin. Also, in controlled trials in patients with epilepsy, topiramate was asso- 35 ciated with suppression of appetite and weight loss unreleated to binge eating. [0005] Binge eating disorder is a subset of a larger classification of mental disorders broadly defined as Impulse Control Disorders (ICDs) characterized by harmful behaviors performed in response to irresistible impulses. It has been suggested that ICDs may be related to obsessive-compulsive disorder or similarly, maybe forms of obsessive- compulsive disorders. It has also been hypothesized that ICDs may be related to mood disorder or may be forms of 40 affective spectrum disorder, a hypothesized family of disorders sharing at least one common physiologic abnormality with major depression. In the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), the essential feature of an ICD is the failure to resist an impulse, drive, or temptation to perform an act that is harmful to the person or to others. For most ICDs, the individual feels an increasing sense of tension or arousal before committing the act, and then experiences pleasure, gratification, or release at the time of committing the act. After the act is performed, there may 45 or may not be regret or guilt. ICDs are listed in a residual category, the ICDs Not Elsewhere Classi fied, which includes intermittent explosive disorder (IED), kleptomania, pathological gambling, pyromania, trichotillomania, and ICD not otherwise specified (NOS). Examples of ICDs NOS are compulsive buying or shopping, repetitive self-mutilation, nonparaphilic sexual addictions, severe nail biting, compulsive skin picking, personality disorders with impulsive features, attention deficit/hyperactivity disorder, eating disorders characterized by binge eating, and substance use disorders. 50 [0006] WO 00 44374 A relates to anticonvulsant derivatives of formula (I), wherein x is CH2 or oxygen, for treating bulimia nervosa. [0007] WO 00 07583 A provides methods for treating substance addiction and changing addiction-related behaviour of a mammal suffering from substance addiction by administering to the mammal an effective amount of a pharmaceutical composition or medicament including gamma vinyl GABA. 55 Summary of the Invention

[0008] It is an object of the present invention to describe the use of sulfamate derivatives for the manufacture of a

3 EP 1 158 973 B1

medicament for the treatment of Impulse Control Disorders. [0009] The present invention comprises uses for the manufacture of a medicament for the treatment or prevention of Impulse Control Disorders of the compounds of formula (I), pharmaceutical compositions containing one or more of the compounds of formula (I), or pharmaceutical compositions containing one or more of the compounds of formula 5 (I) in addition to a safe and effective amount of one or more additional agents to treat related symptoms and conditions.

Detailed Description of the Invention

[0010] The sulfamates of use in the present invention are of the following formula (I): 10

X is CH2 or oxygen; R1 is hydrogen or alkyl; and R2,R3,R4and R5 are independently hydrogen or lower alkyl and, when X is CH2,R4and 25 R5 may be alkene groups joined to form a benzene ring and, when X is oxygen, R2 and R3 and/or R4 and R5 together may be a methylenedioxy group of the following formula (II):

35 wherein R6 and R7 are the same or different and are hydrogen, lower alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring. R1 in particular is hydrogen or alkyl of 1 to 4 carbons, such as methyl, ethyl and iso-propyl. Alkyl throughout this specification includes straight and branched chain alkyl. Alkyl groups for R2,R3,R4,R5,R6and R7 are 40 of 1 to 3 carbons and include methyl, ethyl, iso-propyl and n-propyl. When X is CH2,R4and R5 may combine to form a benzene ring fused to the 6-membered X-containing ring, i.e.,R4and R5 are defined by the alkatrienyl group =C-CH=CH-CH=. [0011] A particular group of compounds of formula (I) is that wherein X is oxygen and both R2 and R3 and R4 and R5 together are methylenedioxy groups of the formula (II), wherein R6 and R7 are both hydrogen, both alkyl or combine 45 to form a spiro cyclopentyl or cyclohexyl ring, in particular where R6 and R7 are both alkyl such as methyl. A second group of compounds is that wherein X is CH2 and R4 and R5 are joined to form a benzene ring. A third group of compounds of formula (I) is that wherein both R2 and R3 are hydrogen. [0012] The compounds of formula 1: maybe made by the processes disclosed in U.S. Pat. Nos. 4,075,351, 4,513,006, 4,591,601, 4,792,569 , 5,242,942, 5,387,700. 50 [0013] The compounds of formula I include the various individual isomers as well as the racemates thereof. For treating ICDs, a compound of formula (I) may be employed at a daily dosage in the range of 15 to 1400 mg administered orally, for an average adult human. [0014] To prepare the pharmaceutical compositions used in this invention, one or more sulfamate compounds of formula (I) are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding 55 techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral, by suppository, or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives,

4 EP 1 158 973 B1

coloring agents and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar 5 coated or enteric coated by standard techniques. Suppositories may be prepared, in which case cocoa butter could be used as the carrier. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Topiramate is currently available for oral administration in round tablets containing 25 mg, 100 mg or 200 mg of active agent. The 10 tablets contain the following inactive ingredients: lactose hydrous, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, synthetic iron oxide, and polysorbate 80. [0015] The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder injection, teaspoonful, suppository and the like from 5 to 1000 mg of the active ingredient. 15 [0016] The activity of the compounds of formula I in treating ICD's was first evidenced in clinical studies conducted to evaluate the efficacy of topiramate in treating mood disorders. Several patients who coincidentally had binge eating disorder reported that there was a marked reduction in their binging and a concurrent loss in weight. [0017] Examples of specific compounds of formula (I) are:

20 2,3 :4,5-bis-O-(1-methylethylidene)- beta -D-fructopyranose sulfamate 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl- beta -D-fructopyranose sulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl- beta -L-fructopyranose sulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl- beta -D-fructopyranose methylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl- beta -D-fructopyranose butylsulfamate; 25 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl- beta -D-fructopyranose ethylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl- beta -D-fructopyranose octylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl- beta -D-fructopyranose 2-propenylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl- beta -D-fructopyranose phenylmethylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl- beta -D-fructopyranose cyclopropylsulfamate; 30 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl- beta -D-fructopyranose cyclobutylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl- beta -D-fructopyranose (2,2,2-trifluoroethyl)sulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl- beta -D-fructopyranose dimethylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl- beta -D-fructopyranose diethylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl- beta -D-fructopyranose azidosulfate; 35 (S)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl- beta -D-fructopyranose sulfamate; (R)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl- beta -D-fructopyranose sulfamate; 2,3-O-(1-ethylpropylidene)-4,5-O-sulfonyl- beta -D-fructopyranose sulfamate; 2,3-O-(1-methylethylidene)-4,5-O-[N-(4-methylbenzenesulfonyl)imidosulfinyl]- beta -D-fructopyranose sulfamate; 2,3-O-(1-methylethylidene)-4,5-O-[N-(4-methylbenzenesulfonyl)imidosulfonyl]- beta -D-fructopyranose sulfa- 40 mate; 2,3-O-(cyclohexylidene)-4,5-O-sulfonyl- beta -D-fructopyranose sulfamate; (S)-4,5-O-[N-(1,1-dimethylethoxycarbonyl)imidosulfinyl]-2,3-O-(1-methylethylidene)- beta -D-fructopyranose sulfamate;

45 and the pharmaceutically acceptable salts thereof. [0018] Other suitable compounds are selected from the group consisting of (1R,2R,3S,4S)-(1,2:3,4-di-O-methyl- ethylidenecyclohexan-1,2,3,4-tetraol-4-yl)methyl sulfamate and (1R,2S,3S,4S)-(3,4-O-methylethylidene-1,2-O-sulfi- nylcyclohexan 1,2,3,4-tetraol-4-yl)methyl sulfamate. [0019] Included within the scope of this invention are the various individual anomers, diastereomers and enantiomers 50 as well as mixtures thereof. Such compounds are included within the definition of formula (I). In addition, the compounds of this invention also include any pharmaceutically acceptable salts, for example: alkali metal salts, such as sodium and potassium; ammonium salts; monoalkylammonium salts; dialkylammonium salts; trialkylammonium salts; tetraalkylammonium salts; and tromethamine salts. Hydrates and other solvates of the compound of the formula (I) are included within the scope of this invention. 55 [0020] Pharmaceutically acceptable salts of the compounds of formula (I) can be prepared by reacting the sulfamate of formula (I) with the appropriate base and recovering the salt. [0021] The sulfamate derivatives may be used in conjunction with one or more other drug compound and used according to the methods of the present invention so long as the pharmaceutical agent has a use that is also effective

5 EP 1 158 973 B1

in treating ICD's and/or concurrent illnesses. Pharmaceutical agents include the following categories and specific examples. Those of ordinary skill in the art will be able to identify readily those pharmaceutical agents that have utility with the present invention. Those of ordinary skill in the art will recognize also numerous other compounds that fall within the categories and that are useful according to the invention. 5 [0022] Adrenergic: Adrenalone; Amidephrine Mesylate; Apraclonidine Hydrochloride; Brimonidine Tartrate; Dapipra- zole Hydrochloride; Deterenol Hydrochloride; Dipivefrin; Dopamine Hydrochloride; Ephedrine Sulfate; Epinephrine; Epinephrine Bitartrate; Epinephryl Borate; Esproquin Hydrochloride; Etafedrine Hydrochloride; Hydroxyamphetamine Hydrobromide; Levonordefrin; Mephentermine Sulfate; Metaraminol Bitartrate; Metizoline Hydrochloride; Naphazoline Hydrochloride; Norepinephrine Bitartrate; Oxidopamine; Oxymetazoline Hydrochloride; Phenylephrine Hydrochloride; 10 Phenylpropanolamine Hydrochloride; Phenylpropanolamine Polistirex; Prenalterol Hydrochloride; Propylhexedrine; Pseudoephedrine Hydrochloride; Tetrahydrozoline Hydrochloride; Tramazoline Hydrochloride; Xylometazoline Hydro- chloride. [0023] Adrenocortical steroid: Ciprocinonide; Desoxycorticosterone Acetate; Desoxycorticosterone Pivalate; Dex- amethasone Acetate; Fludrocortisone Acetate; Flumoxonide; Hydrocortisone Hemisuccinate; Methylprednisolone 15 Hemisuccinate; Naflocort; Procinonide; Timobesone Acetate; Tipredane. [0024] Adrenocortical suppressant: Aminoglutethimide; Trilostane. [0025] Alcohol deterrent: Disulfiram. [0026] Aldosterone antagonist: Canrenoate Potassium; Canrenone; Dicirenone; Mexrenoate Potassium; Prorenoate Potassium; Spironolactone. 20 [0027] Amino acid: Alanine; Aspartic Acid; Cysteine Hydrochloride; Cystine; Histidine; Isoleucine; Leucine; Lysine; Lysine Acetate; Lysine Hydrochloride; Methionine; Phenylalanine; Proline; Serine; Threonine; Tryptophan; Tyrosine; Valine. [0028] Analeptic: Modafinil. [0029] Analgesic: Acetaminophen; Alfentanil Hydrochloride; Aminobenzoate Potassium; Aminobenzoate Sodium; 25 Anidoxime; Anileridine; Anileridine Hydrochloride; Anilopam Hydrochloride; Anirolac; Antipyrine; Aspirin; Benoxapro- fen; Benzydamine Hydrochloride; Bicifadine Hydrochloride; Brifentanil Hydrochloride; Bromadoline Maleate; Brom- fenac Sodium; Buprenorphine Hydrochloride; Butacetin; Butixirate; Butorphanol; Butorphanol Tartrate; Car- bamazepine; Carbaspirin Calcium; Carbiphene Hydrochloride; Carfentanil Citrate; Ciprefadol Succinate; Ciramadol; Ciramadol Hydrochloride; Clonixeril; Clonixin; Codeine; Codeine Phosphate; Codeine Sulfate; Conorphone Hydrochlo- 30 ride; Cyclazocine; Dexoxadrol Hydrochloride; Dexpemedolac; Dezocine; Diflunisal; Dihydrocodeine Bitartrate; Dime- fadane; Dipyrone; Doxpicomine Hydrochloride; Drinidene; Enadoline Hydrochloride; Epirizole; Ergotamine Tartrate; Ethoxazene Hydrochloride; Etofenamate; Eugenol; Fenoprofen; Fenoprofen Calcium; Fentanyl Citrate; Floctafenine; Flufenisal; Flunixin; Flunixin Meglumine; Flupirtine Maleate; Fluproquazone; Fluradoline Hydrochloride; Flurbiprofen; Hydromorphone Hydrochloride; Ibufenac; Indoprofen; Ketazocine; Ketorfanol; Ketorolac Tromethamine; Letimide Hy- 35 drochloride; Levomethadyl Acetate; Levomethadyl Acetate Hydrochloride; Levonantradol Hydrochloride; Levorphanol Tartrate; Lofemizole Hydrochloride; Lofentanil Oxalate; Lorcinadol; Lomoxicam; Magnesium Salicylate; Mefenamic Acid; Menabitan Hydrochloride; Meperidine Hydrochloride; Meptazinol Hydrochloride; Methadone Hydrochloride; Methadyl Acetate; Methopholine; Methotrimeprazine; Metkephamid Acetate; Mimbane Hydrochloride; Mirfentanil Hy- drochloride; Molinazone; Morphine Sulfate; Moxazocine; Nabitan Hydrochloride; Nalbuphine Hydrochloride; Nalmex- 40 one Hydrochloride; Namoxyrate; Nantradol Hydrochloride; Naproxen; Naproxen Sodium; Naproxol; Nefopam Hydro- chloride; Nexeridine Hydrochloride; Noracymethadol Hydrochloride; Ocfentanil Hydrochloride; Octazamide; Olvanil; Oxetorone Fumarate; Oxycodone; Oxycodone Hydrochloride; Oxycodone Terephthalate; Oxymorphone Hydrochlo- ride; Pemedolac; Pentamorphone; Pentazocine; Pentazocine Hydrochloride; Pentazocine Lactate; Phenazopyridine Hydrochloride; Phenyramidol Hydrochloride; Picenadol Hydrochloride; Pinadoline; Pirfenidone; Piroxicam Olamine; 45 Pravadoline Maleate; Prodilidine Hydrochloride; Profadol Hydrochloride; Propirarn Fumarate; Propoxyphene Hydro- chloride; Propoxyphene Napsylate; Proxazole; Proxazole Citrate; Proxorphan Tartrate; Pyrroliphene Hydrochloride; Remifentanil Hydrochloride; Salcolex; Salethamide Maleate; Salicylamide; Salicylate Meglumine; Salsalate; Sodium Salicylate; Spiradoline Mesylate; Sufentanil; Sufentanil Citrate; Talmetacin; Talniflumate; Talosalate; Tazadolene Suc- cinate; Tebufelone; Tetrydamine; Tifurac Sodium; Tilidine Hydrochloride; Tiopinac; Tonazocine Mesylate; Tramadol 50 Hydrochloride; Trefentanil Hydrochloride; Trolamine; Veradoline Hydrochloride; Verilopam Hydrochloride; Volazocine; Xorphanol Mesylate; Xylazine Hydrochloride; Zenazocine Mesylate; Zomepirac Sodium; Zucapsaicin. [0030] Anorectic compounds including dexfenfluramine. [0031] Anorexic: Aminorex; Amphecloral; Chlorphentermine Hydrochloride; Clominorex; Clortermine Hydrochloride; Diethylpropion Hydrochloride; Fenfluramine Hydrochloride; Fenisorex; Fludorex; Fluminorex; Levamfetamine Succi- 55 nate; Mazindol; Mefenorex Hydrochloride; Phenmetrazine Hydrochloride; Phentermine; Sibutramine Hydrochloride. [0032] Anti-anxiety agent: Adatanserin Hydrochloride; Alpidem; Binospirone Mesylate; Bretazenil; Glemanserin; Ip- sapirone Hydrochloride; Mirisetron Maleate; Ocinaplon; Ondansetron Hydrochloride; Panadiplon; Pancopride; Pazi- naclone; Serazapine Hydrochloride; Tandospirone Citrate; Zalospirone Hydrochloride.

6 EP 1 158 973 B1

[0033] Antidepressant: Adatanserin Hydrochloride; Adinazolam; Adinazolam Mesylate; Alaproclate; Aletamine Hy- drochloride; Amedalin Hydrochloride; Amitriptyline Hydrochloride; Amoxapine; Aptazapine Maleate; Azaloxan Fuma- rate; Azepindole; Azipramine Hydrochloride; Bipenamol Hydrochloride; Bupropion Hydrochloride; Butacetin; Butriptyl- ine Hydrochloride; Caroxazone; Cartazolate; Ciclazindol; Cidoxepin Hydrochloride; Cilobamine Mesylate; Clodazon 5 Hydrochloride; Clomipramine Hydrochloride; Cotinine Fumarate; Cyclindole; Cypenamine Hydrochloride; Cyprolidol Hydrochloride; Cyproximide; Daledalin Tosylate; Dapoxetine Hydrochloride; Dazadrol Maleate; Dazepinil Hydrochlo- ride; Desipramine Hydrochloride; Dexamisole; Deximafen; Dibenzepin Hydrochloride; Dioxadrol Hydrochloride; Doth- iepin Hydrochloride; Doxepin Hydrochloride; Duloxetine Hydrochloride; Eclanamine Maleate; Encyprate; Etoperidone Hydrochloride; Fantridone Hydrochloride; Fehmetozole Hydrochloride; Fenmetramide; Fezolamine Fumarate; Fluotra- 10 cen Hydrochloride; Fluoxetine; Fluoxetine Hydrochloride; Fluparoxan Hydrochloride; Gamfexine; Guanoxyfen Sulfate; Imafen Hydrochloride; Imiloxan Hydrochloride; Imipramine Hydrochloride; Indeloxazine Hydrochloride; Intriptyline Hy- drochloride; Iprindole; Isocarboxazid; Ketipramine Fumarate; Lofepramine Hydrochloride; Lortalamine; Maprotiline; Maprotiline Hydrochloride; Melitracen Hydrochloride; Milacemide Hydrochloride; Minaprine Hydrochloride; Mirtazap- ine; Moclobemide; Modaline Sulfate; Napactadine Hydrochloride; Napamezole Hydrochloride; Nefazodone Hydrochlo- 15 ride; Nisoxetine; Nitrafudam Hydrochloride; Nomifensine Maleate; Nortriptyline Hydrochloride; Octriptyline Phosphate; Opipramol Hydrochloride; Oxaprotiline Hydrochloride; Oxypertine; Paroxetine; Phenelzine Sulfate; Pirandamine Hy- drochloride; Pizotyline; Pridefine Hydrochloride; Prolintane Hydrochloride; Protriptyline Hydrochloride; Quipazine Maleate; Rolicyprine; Seproxetine Hydrochloride; Sertraline Hydrochloride; Sibutramine Hydrochloride; Sulpiride; Suri- tozole; Tametraline Hydrochloride; Tampramine Fumarate; Tandamine Hydrochloride; Thiazesim Hydrochloride; Tho- 20 zalinone; Tomoxetine Hydrochloride; Trazodone Hydrochloride; Trebenzomine Hydrochloride; Trimipramine; Trimi- pramine Maleate; Venlafaxine Hydrochloride; Viloxazine Hydrochloride; Zimeldine Hydrochloride; Zometapine. [0034] Antihypertensive: Alfuzosin Hydrochloride; Alipamide; Althiazide; Amiquinsin Hydrochloride; Amlodipine Be- sylate; Amlodipine Maleate; Anaritide Acetate; Atiprosin Maleate; Belfosdil; Bemitradine; Bendacalol Mesylate; Bend- roflumethiazide; Benzthiazide; Betaxolol Hydrochloride; Bethanidine Sulfate; Bevantolol Hydrochloride; Biclodil Hydro- 25 chloride; Bisoprolol; Bisoprolol Fumarate; Bucindolol Hydrochloride; Bupicomide; Buthiazide: Candoxatril; Candoxat- rilat; Captopril; Carvedilol; Ceronapril; Chlorothiazide Sodium; Cicletanine; Cilazapril; Clonidine; Clonidine Hydrochlo- ride; Clopamide; Cyclopenthiazide; Cyclothiazide; Darodipine; Debrisoquin Sulfate; Delapril Hydrochloride; Diapamide; Diazoxide; Dilevalol Hydrochloride; Diltiazem Malate; Ditekiren; Doxazosin Mesylate; Ecadotril; Enalapril Maleate; Enalaprilat; Enalkiren; Endralazine Mesylate; Epithiazide; Eprosartan; Eprosartan Mesylate; Fenoldopam Mesylate; 30 Flavodilol Maleate; Flordipine; Flosequinan; Fosinopril Sodium; Fosinoprilat; Guanabenz; Guanabenz Acetate; Gua- nacline Sulfate; Guanadrel Sulfate; Guancydine; Guanethidine Monosulfate; Guanethidine Sulfate; Guanfacine Hy- drochloride; Guanisoquin Sulfate; Guanoclor Sulfate; Guanoctine Hydrochloride; Guanoxabenz; Guanoxan Sulfate; Guanoxyfen Sulfate; Hydralazine Hydrochloride; Hydralazine Polistirex; Hydroflumethiazide; Indacrinone; Indapamide; Indolaprif Hydrochloride; Indoramin; Indoramin Hydrochloride; Indorenate Hydrochloride; Lacidipine; Leniquinsin; Lev- 35 cromakalim; Lisinopril; Lofexidine Hydrochloride; Losartan Potassium; Losulazine Hydrochloride; Mebutamate; Mecamylamine Hydrochloride; Medroxalol; Medroxalol Hydrochloride; Methalthiazide; Methyclothiazide; Methyldopa; Methyldopate Hydrochloride; Metipranolol; Metolazone; Metoprolol Fumarate; Metoprolol Succinate; Metyrosine; Minoxidil ; Monatepil Maleate; Muzolimine; Nebivolol; Nitrendipine; Ofornine; Pargyline Hydrochloride; Pazoxide; Pe- lanserin Hydrochloride; Perindopril Erbumine; Phenoxybenzamine Hydrochloride; Pinacidil; Pivopril; Polythiazide; Pra- 40 zosin Hydrochloride; Primidolol; Prizidilol Hydrochloride; Quinapril Hydrochloride; Quinaprilat; Quinazosin Hydrochlo- ride; Quinelorane Hydrochloride; Quinpirole Hydrochloride; Quinuclium Bromide; Ramipril; Rauwolfia Serpentina; Re- serpine; Saprisartan Potassium; Saralasin Acetate; Sodium Nitroprusside; Sulfinalol Hydrochloride; Tasosartan; Tel- udipine Hydrochloride; Temocapril Hydrochloride; Terazosin Hydrochloride; Terlakiren; Tiamenidine; Tiamenidine Hy- drochloride; Ticrynafen; Tinabinol; Tiodazosin; Tipentosin Hydrochloride; Trichlormethiazide; Trimazosin Hydrochlo- 45 ride; Trimethaphan Camsylate; Trimoxamine Hydrochloride; Tripamide; Xipamide; Zankiren Hydrochloride; Zofenopri- lat Arginine. [0035] Anti-inflammatory: Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazone; Balsalazide Dis- odium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; 50 Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; Dexamethasone Dipropionate; Di- clofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate; Diflumidone Sodium; Diflunisal; Difluprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone; Enlimomab; Enolicam Sodium; Epirizole; Etodolac; Etofena- mate; Felbinac; Fenamole; Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluaza- 55 cort; Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin; Flunixin Meglumine; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen; Fluretofen; Fluticasone Propionate; Furaprofen; Furobufen; Halcinonide; Halobeta- sol Propionate; Halopredone Acetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indometh- acin; Indomethacin Sodium; Indoprofen; Indoxole; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen;

7 EP 1 158 973 B1

Lofemizole Hydrochloride; Lomoxicam; Loteprednol Etabonate; Meclofenamate Sodium; Meclofenamic Acid; Meclori- sone Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone; Methylprednisolone Suleptanate; Momiflumate; Nabumetone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein; Orpanoxin; Oxapro- zin; Oxyphenbutazone; Paranyline Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate; 5 Pirfenidone; Piroxicam; Piroxicam Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone; Proxazole; Proxazole Citrate; Rimexolone; Romazarit; Salcolex; Salnacedin; Salsalate; Sanguinarium Chloride; Seclazone; Sermetacin; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tesimide; Tetrydamine; Tiopinac; Tixocortol Pivalate; Tolmetin; Tol- metin Sodium; Triclonide; Triflumidate; Zidometacin; Zomepirac Sodium. 10 [0036] Antinauseant: Buclizine Hydrochloride; Cyclizine Lactate; Naboctate Hydrochloride. [0037] Antineutropenic: Filgrastim; Lenograstim; Molgramostim; Regramostim; Sargramostim. [0038] Antiobsessional agent: Fluvoxamine Maleate. [0039] Antiparkinsonian: Benztropine Mesylate; Biperiden; Biperiden Hydrochloride; Biperiden Lactate; Carmanta- dine; Ciladopa Hydrochloride; Dopamantine; Ethopropazine Hydrochloride; Lazabemide; Levodopa; Lometraline Hy- 15 drochloride; Mofegiline Hydrochloride; Naxagolide Hydrochloride; Pareptide Sulfate; Procyclidine Hydrochloride; Qui- netorane Hydrochloride; Ropinirole Hydrochloride; Selegiline Hydrochloride; Tolcapone; Trihexyphenidyl Hydrochlo- ride. Antiperistaltic: Difenoximide Hydrochloride; Difenoxin; Diphenoxylate Hydrochloride; Fluperamide; Lidamidine Hydrochloride; Loperamide Hydrochloride; Malethamer; Nufenoxole; Paregoric. [0040] Antipsychotic: Acetophenazine Maleate; Alentemol Hydrobromide; Alpertine; Azaperone; Batelapine Maleate; 20 Benperidol; Benzindopyrine Hydrochloride; Brofbxine; Bromperidol; Bromperidol Decanoate; Butaclamol Hydrochlo- ride; Butaperazine; Butaperazine Maleate; Carphenazine Maleate; Carvotroline Hydrochloride; Chlorpromazine; Chlo- rpromazine Hydrochloride; Chlorprothixene; Cinperene; Cintriamide; Clomacran Phosphate; Clopenthixol; Clopimoz- ide; Clopipazan Mesylate; Cloroperone Hydrochloride; Clothiapine; Clothixamide Maleate; Clozapine; Cyclophenazine Hydrochloride; Droperidol; Etazolate Hydrochloride; Fenimide; Flucindole; Flumezapine; Fluphenazine Decanoate; 25 Fluphenazine Enanthate; Fluphenazine Hydrochloride; Fluspiperone; Fluspirilene; Flutroline; Gevotroline Hydrochlo- ride; Halopemide; Haloperidol; Haloperidol Decanoate; Iloperidone; Imidoline Hydrochloride; Lenperone; Mazapertine Succinate; Mesoridazine; Mesoridazine Besylate; Metiapine; Milenperone; Milipertine; Molindone Hydrochloride; Nar- anol Hydrochloride; Neflumozide Hydrochloride; Ocaperidone; Olanzapine; Oxiperomide; Penfluridol; Pentiapine Maleate; Perphenazine; Pimozide; Pinoxepin Hydrochloride; Pipamperone; Piperacetazine; Pipotiazine Palniitate; 30 Piquindone Hydrochloride; Prochlorperazine Edisylate; Prochlorperazine Maleate; Promazine Hydrochloride; Remox- ipride; Remoxipride Hydrochloride; Rimcazole Hydrochloride; Seperidol Hydrochloride; Sertindole; Setoperone; Spiperone; Thioridazine; Thioridazine Hydrochloride; Thiothixene; Thiothixene Hydrochloride; Tioperidone Hydrochlo- ride; Tiospirone Hydrochloride; Trifluoperazine Hydrochloride; Trifluperidol; Triflupromazine; Triflupromazine Hydro- chloride; Ziprasidone Hydrochloride. 35 [0041] Appetite suppressant: Dexfenfluramine Hydrochloride; Phendimetrazine Tartrate; Phentermine Hydrochlo- ride. [0042] Blood glucose regulators: Human insulin; Glucagon; Tolazamide; Tolbutamide; Chloropropamide; Acetohex- amide and Glipizide. [0043] Carbonic anhydrase inhibitor: Acetazolamide; Acetazolamide Sodium, Dichlorphenamide; Dorzolamide Hy- 40 drochloride; Methazolamide; Sezolamide Hydrochloride. [0044] Cardiac depressant: Acecainide Hydrochloride; Acetylcholine Chloride; Actisomide; Adenosine; Amiodarone; Aprindine; Aprindine Hydrochloride; Artilide Fumarate; Azimilide Dihydrochloride; Bidisomide; Bucainide Maleate; Bucromarone; Butoprozine Hydrochloride; Capobenate Sodium; Capobenic Acid; Cifenline; Cifenline Succinate; Clofil- ium Phosphate; Disobutamide; Disopyramide; Disopyramide Phosphate; Dofetilide; Drobuline; Edifolone Acetate; Emil- 45 ium Tosylate; Encainide Hydrochloride; Flecainide Acetate; Ibutilide Fumarate; Indecainide Hydrochloride; Ipazilide Fumarate; Lorajmine Hydrochloride; Lorcainide Hydrochloride; Meobentine Sulfate; Mexiletine Hydrochloride; Mo- decainide; Moricizine; Oxiramide; Pirmenol Hydrochloride; Pirolazamide; Pranolium Chloride; Procainamide Hydro- chloride; Propafenone Hydrochloride; Pyrinoline; Quindonium Bromide; Quinidine Gluconate; Quinidine Sulfate; Re- cainam Hydrochloride; Recainam Tosylate;Risotilide Hydrochloride; Ropitoin Hydrochloride; Sematilide Hydrochloride; 50 Suricainide Maleate; Tocainide; Tocainide Hydrochloride; Transcainide. [0045] Cardiotonic: Actodigin; Amrinone; Bemoradan; Butopamine; Carbazeran; Carsatrin Succinate; Deslanoside; Digitalis; Digitoxin; Digoxin; Dobutamine; Dobutamine Hydrochloride; Dobutamine Lactobionate; Dobutamine Tartrate; Enoximone; Imazodan Hydrochloride; Indolidan; Isomazole Hydrochloride; Levdobutamine Lactobionate; Lixazinone Sulfate; Medorinone; Milrinone; Pelrinone Hydrochloride; Pimobendan; Piroximone; Prinoxodan; Proscillaridin; Quazi- 55 none; Tazolol Hydrochloride; Vesnarinone. [0046] Cardiovascular agent: Dopexamine; Dopexamine Hydrochloride. [0047] Choleretic: Dehydrocholic Acid; Fencibutirol; Hymecromone; Piprozolin; Sincalide; Tocamphyl. [0048] Cholinergic: Aceclidine; Bethanechol Chloride; Carbachol; Demecarium Bromide; Dexpanthenol; Echothi-

8 EP 1 158 973 B1

ophate Iodide; Isoflurophate; Methacholine Chloride; Neostigmine Bromide; Neostigmine Methylsulfate; Physostig- mine; Physostigmine Salicylate; Physostigmine Sulfate; Pilocarpine; Pilocarpine Hydrochloride; Pilocarpine Nitrate; Pyridostigmine Bromide. [0049] Cholinergic agonist: Xanomeline; Xanomeline Tartrate. 5 [0050] Cholinesterase Deactivator: Obidoxime Chloride; Pralidoxime Chloride; Pralidoxime Iodide; Pralidoxime Me- sylate. [0051] Coccidiostat: Arprinocid; Narasin; Semduramicin; Semduramicin Sodium. [0052] Cognition adjuvant: Ergoloid Mesylates; Piracetam; Pramiracetam Hydrochloride; Pramiracetam Sulfate; Ta- crine Hydrochloride. 10 [0053] Cognition enhancer: Besipirdine Hydrochloride; Linopirdine; Sibopirdine. [0054] Hormone: Diethylstilbestrol; Progesterone; 17 hydroxy progesterone; Medroxyprogesterone; Norgestrel; Norethynodrel; Estradiol; Megestrol (Megace); Norethindrone; Levonorgestrel; Ethyndiol; Ethinyl estradiol; Mestranol; Estrone; Equilin; 17 alpha dihydroequilin; equilenin; 17 alpha dihydroequilenin; 17 alpha estradiol; 17 beta estradiol; Leuprolide (lupron); Glucagon; Testolactone; Clomiphene; Han memopausal gonadotropins; Human chorionic gona- 15 dotropin; Urofollitropin; Bromocriptine; Gonadorelin; Luteinizing hormone releasing hormone and analogs; Gonadotro- pins; Danazol; Testosterone; Dehydroepiandrosterone; Androstenedione; Dihydroestosterone; Relaxin; Oxytocin; Va- sopressin; Folliculostatin; Follicle regulatory protein; Gonadoctrinins; Oocyte maturation inhibitor; Insulin growth factor; Follicle Stimulating Hormone; Luteinizing hormone; Tamoxifen.; Corticorelin Ovine Triftutate; Cosyntropin; Metogest; Pituitary, Posterior; Seractide Acetate; Somalapor; Somatrem; Somatropin; Somenopor; Somidobove. 20 [0055] Memory adjuvant: Dimoxamine Hydrochloride; Ribaminol. [0056] Mental performance enhancer: Aniracetam. [0057] Mood regulator: Fengabine. [0058] Neuroleptic: Duoperone Fumarate; Risperidone. [0059] Neuroprotective: Dizocilpine Maleate. 25 [0060] Psychotropic: Minaprine. [0061] Relaxant: Adiphenine Hydrochloride; Alcuronium Chloride; Aminophylline; Azumolene Sodium; Baclofen; Benzoctamine Hydrochloride; Carisoprodol; Chlorphenesin Carbamate; Chlorzoxazone; Cinflumide; Cinnamedrine; Clodanolene; Cyclobenzaprine Hydrochloride; Dantrolene; Dantrolene Sodium; Fenalamide; Fenyripol Hydrochloride; Fetoxylate Hydrochloride; Flavoxate Hydrochloride; Fletazepam; Flumetramide;-Flurazepam Hydrochloride; Hexaflu- 30 orenium Bromide; Isomylamine Hydrochloride; Lorbamate; Mebeverine Hydrochloride; Mesuprine Hydrochloride; Metaxalone; Methocarbamol; Methixene Hydrochloride; Nafomine Malate; Nelezaprine Maleate; Papaverine Hydro- chloride; Pipoxolan Hydrochloride; Quinctolate; Ritodrine; Ritodrine Hydrochloride; Rolodine; Theophylline Sodium Glycinate; Thiphenamil Hydrochloride; Xilobam. [0062] Sedative-hypnotic: Allobarbital; Alonimid; Alprazolam; Amobarbital Sodium; Bentazepam; Brotizolam; Buta- 35 barbital; Butabarbital Sodium; Butalbital; Capuride; Carbocloral; Chloral Betaine; Chloral Hydrate; Chlordiazepoxide Hydrochloride; Cloperidone Hydrochloride; Clorethate; Cyprazepam; Dexclamol Hydrochloride; Diazepam; Dichloral- phenazone; Estazolam; Ethchlorvynol; Etomidate; Fenobam; Flunitrazepam; Fosazepam; Glutethimide; Halazepam; Lormetazepam; Mecloqualone; Meprobamate; Methaqualone; Midaflur; Paraldehyde; Pentobarbital; Pentobarbital So- dium; Perlapine; Prazepam; Quazepam; Reclazepam; Roletamide; Secobarbital; Secobarbital Sodium; Suproclone; 40 Thalidomide; Tracazolate; Trepipam Maleate; Triazolam; Tricetamide; Triclofos Sodium; Trimetozine; Uldazepam; Za- leplon; Zolazepam Hydrochloride; Zolpidem Tartrate. [0063] Serotonin antagonist: Altanserin Tartrate; Amesergide; Ketanserin; Ritanserin. [0064] Serotonin inhibitor: Cinanserin Hydrochloride; Fenclonine; Fonazine Mesylate; Xylamidine Tosylate. [0065] Serotonin receptor antagonist: Tropanserin Hydrochloride. 45 [0066] Stimulant: Amfonelic Acid; Amphetamine Sulfate; Ampyzine Sulfate; Arbutamine Hydrochloride; Azabon; Caf- feine; Ceruletide; Ceruletide Diethylamine; Cisapride; Dazopride Fumarate; Dextroamphetamine; Dextroamphetamine Sulfate; Difluanine Hydrochloride; Dimefline Hydrochloride; Doxapram Hydrochloride; Etryptamine Acetate; Ethamivan; Fenethylline Hydrochloride; Flubanilate Hydrochloride; Flurothyl; Histamine Phosphate; Indriline Hydro- chloride; Mefexamide; Methamphetamine Hydrochlo ride; Methylphenidate Hydrochloride; Pemoline; Pyrovalerone 50 Hydrochloride; Xamoterol; Xamoterol Fumarate. Synergist: Proadifen Hydrochloride. [0067] Thyroid hormone: Levothyroxine Sodium; Liothyronine Sodium; Liotrix. [0068] Thyroid inhibitor: Methimazole; Propyithiouracil. [0069] Thyromimetic: Thyromedan Hydrochloride. 55 [0070] Cerebral ischemia agents: Dextrorphan Hydrochloride. [0071] Vasoconstrictor: Angiotensin Amide; Felypressin; Methysergide; Methysergide Maleate. [0072] Vasodilator: Alprostadil; Azaclorzine Hydrochloride; Bamethan Sulfate; Bepridil Hydrochloride; Buterizine; Ce- tiedil Citrate; Chromonar Hydrochloride; Clonitrate; Diltiazem Hydrochloride; Dipyridamole; Droprenilamine; Erythrityl

9 EP 1 158 973 B1

Tetranitrate; Felodipine; Flunarizine Hydrochloride; Fostedil; Hexobendine; Inositol Niacinate; Iproxamine Hydrochlo- ride; Isosorbide Dinitrate; Isosorbide Mononitrate; Isoxsuprine Hydrochloride; Lidoflazine; Mefenidil; Mefenidil Fuma- rate; Mibefradil Dihydrochloride; Mioflazine Hydrochloride; Mixidine; Nafronyl Oxalate; Nicardipine Hydrochloride; Nicergoline; Nicorandil; Nicotinyl Alcohol; Nifedipine; Nimodipine; Nisoldipine; Oxfenicine; Oxprenolol Hydrochloride; 5 Pentaerythritol Tetranitrate; Pentoxifylline; Pentrinitrol; Perhexiline Maleate; Pindolol; Pirsidomine; Prenylamine; Propatyl Nitrate; Suloctidil; Terodiline Hydrochloride; Tipropidil Hydrochloride; Tolazoline Hydrochloride; Xanthinol Ni- acinate. [0073] Specifically, topiramate may be administered in combination with other medications to treat certain symptoms and disorders including: 10 I. Treatment of Binge Eating (Binge Eating Disorder, Anorexia Nervosa with Binge eating) with serotonin re-uptake inhibitors (e.g., citalopram (CELEXA), clomipramine (ANAFRANIL)), fluoxetine (PROZAC), fluvoxamine (LUVOX), venlafaxine (EFFEXOR), other antidepressants (e.g., bupropion (WELLBUTRIN) nefazodone (SERZONE), tricy- clics (e.g., NORPRAMIN and PAMELOR), trazodone (DESYREL), Substance P antagonists), psychostimulants, 15 (e.g., d-amphetamine, phentermine; and sibutramine (MERIDIA)) and orlistat. II. Treatment of overweight/obesity condition with sibutramine (MERIDIA); psychostimulants, (e.g., d-amphetamine, phentermine) and orlistat. III. Treatment of other impulse control disorders (behavioral addictions) with serotonin reuptake inhibitors, lithium, valproic acid or divalproex sodium (e.g., DEPAKENE or DEPAKOTE), other antidepressants, naltrexone, atypical 20 antipsychotics, (e.g., olanzapine (ZYPREXA), quetiapine (SEROQUEL), risperidone (RISPERDAL), ziprasidone) and other mood stabilizers (e.g., carbamazepine) IV. Treatment of paraphilias/sexual addictions with serotonin reuptake inhibitors, lithium, divalproex sodium/valproic acid, antiandrogen medications (e.g., medroxyprogesterone, gonadotropin-releasing hormone (GnRH) agonists), other antidepressants, and other mood stabilizers (e.g., carbamazepine). 25 [0074] When administered, the formulations used in the invention are applied in pharmaceutically acceptable amounts and in pharmaceutically acceptable compositions. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic ingredients. When used in medicine the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to 30 prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the invention. Such phar- macologically and pharmaceutically acceptable salts include those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulfonic, tartaric, citric, methane sulfonic, formic, malonic, succinic, naphthalene-2-sulfonic, and benzene sulfonic. Also, pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts. 35 [0075] Suitable buffering agents include: acetic acid and a salt (1-2% W/V); citric acid and a salt (1-3% W/V); boric acid and a salt (0.5-2.5% W/V); and phosphoric acid and a salt (0.8-2% W/V). Suitable preservatives include benzal- konium chloride (0.003-0.03% W/V); chlorobutanol (0.3-0.9% W/V); parabens (0.01-0.25% W/V) and thimerosal (0.004-0.02% W/V). [0076] In the present invention, the sulfamide derivatives are administered in safe and effective amounts. An effective 40 amount means that amount necessary to delay the onset of, inhibit the progression of, halt altogether the onset or progression of or diagnose the particular condition being treated. In general, an effective amount for treating an ICD will be that amount necessary to inhibit mammalian symptoms of the particular ICD in-situ. When administered to a subject, effective amounts will depend, of course, on the particular condition being treated; the severity of the condition; individual patient parameters including age, physical condition, size and weight; concurrent treatment; frequency of 45 treatment; and the mode of administration. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is preferred generally that a minimum dose be used, that is, the lowest safe dosage that provides appropriate relief of symptoms. [0077] Dosage may be adjusted appropriately to achieve desired drug levels, locally or systemically. Generally, daily oral doses of active compounds will be from 0.01 mg/kg per day to 2000 mg/kg per day. Preferred doses range from 50 15 to 2000 mg per day and more preferred are doses ranging from 25 to 750 mg per day. It is expected that IV doses in the range of 1 to 1000 mg/cm3 per day will be effective. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Continuous IV dosing over, for example 24 hours or multiple doses per day is contemplated to achieve appropriate systemic levels of compounds. 55 [0078] A variety of administration routes are available. The particular mode selected will depend of course, upon the particular drug selected, the severity of the disease state(s) being treated and the dosage required for therapeutic efficacy. The methods of this invention, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clin-

10 EP 1 158 973 B1

ically unacceptable adverse effects. Such modes of administration include oral, rectal, sublingual, topical, nasal, transdermal or parenteral routes. The term "parenteral" includes subcutaneous, intravenous, intramuscular, or infusion. Intravenous routes are preferred. [0079] The compositions may conveniently be presented in unit dosage form and may be prepared by any of the 5 methods well known in the art of pharmacy. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product. [0080] Compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active compound. Other compositions include 10 suspensions in aqueous liquors or non-aqueous liquids such as a syrup, an elixir, or an emulsion. [0081] Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the active compounds of the invention, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer based systems such as polylactic and polyglycolic acid, polyanhydrides and 15 polycaprolactonc; nonpolymer systems that are lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-, di and triglycerides; hydrogel release systems; silastic systems; peptide based systems; wax coatings, compressed tablets using conventional binders and excipients, partially fused implants and the like. In addition, a pump-based hardware delivery system can be used, some of which are adapted for implantation. [0082] A long-term sustained release implant also may be used. "Long-term" release, as used herein, means that 20 the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 30 days, and preferably 60 days. Long-term sustained release implants are well known to those of ordinary skill in the art and include some of the release systems described above.

Examples. 25 [0083] In the examples, patients were treated with open-label topiramate starting at 25 mg/ every evening at bedtime (qHS) and the dosage increased by the patient in 25 mg increments as tolerated by the subjects until a response is seen up to a maximum of 1200 mg.

30 Table 1. Patients with Binge Eating Disorder (BED) Treated Clinically with Open-Label Topiramate (as of 12/16/98) Pt # Pt ID Reasons Topiramate Begun Max Dose Response (mg/day) 35 1 LJM BD 1200 Remission of BD (BED) Remission of BED (Obesity) Loss of 49 kg (107 lbs.)

40 2 CEJ BD 150 Mild improvement of BD, BED Moderate decrease of BED, Overweight Loss of 2 kg (5lbs.) Discontinued due to sedation, 45 cognitive dulling

3 JAC BD 1200 Moderate improvement of BD. BED Remission of BED 50 Obesity Loss of 23 kg (50.5 lbs.)

4 JEB BD 900 Moderate improvement of BD, BED Marked improvement of BED, 55 Overweight Loss of 14 kg (30.5 lbs.)

11 EP 1 158 973 B1

Table 1. (continued) Patients with Binge Eating Disorder (BED) Treated Clinically with Open-Label Topiramate (as of 12/16/98) Pt # Pt ID Reasons Topiramate Begun Max Dose Response 5 (mg/day) 5 KCW BED 100 First trial: No response of BED, Obesity discontinued due to GI distress Compulsive Buying 100 10 (BD, in remission) Second Trial: Worsening of BD Remission of BED Loss of 5 kg (11 lbs.) Remission of Compulsive Buying 15

6 JB BED 100 No response of BED Overweight No weight change Key: BD=Bipolar Disorder; BED=Binge Eating Disorder; Pt.=patient; D/C= topiramate treatment discontinued; 20 Cont.= topiramate treatment continued; GI=gastrointestinal

Table 2.

25 Patients with Overeating, Overweight, and Obesity Treated Clinically with Topiramate (as of 12/16/98) Pt. # Pt. ID Reasons Topiramate Begun Max dose Response (mg/day)

30 1 BAA BD 700 No response of BD Obesity Loss of 4 kg (133-129 kg) (BED,in remission) [9 lbs. (293-284)]

35 2 HTB BD 300 Remission of BD Overeating Remission of overeating Overweight Loss of 7 kg. (113-106 kg) [16 lbs. (248-232)]

40 Discontinued 2°illness in remission

3 ADJ BD 400 Moderate improvement of BD Overeating, Moderate improvement of 45 overeating Overweight Loss of 3 kg. (108-105 kg) [7 lbs. (239-232)]

50 4 TK BD 350 No response of BD Overeating Mild improvement in overeating Overweight Loss of 2 kg. (108-106 kg) [5 lbs. (238-233)] 55

12 EP 1 158 973 B1

Table 2. (continued) Patients with Overeating, Overweight, and Obesity Treated Clinically with Topiramate (as of 12/16/98)

5 Pt. # Pt. ID Reasons Topiramate Begun Max dose Response (mg/day) 5 JCJ BD 1. 250 First Trial: Worsening of BD Overeating 2. 200 Mild decrease of overeating 10 Overweight Loss of 3 kg. (69-66 kg) [7 lbs. (152-145)] Second Trial Mild improvement of BD; 15 Mild decrease of overeating Gain of 1 kg. (70-71 kg) [1 lb. (154-155 lbs.)]

6 KDC Overeating 800 Worsening of BD 20 Overweight Loss of 4 kg. (94-90 kg) (BD, in remission) [9 lbs. (208-199 lbs.)]

7 NLR BD 300 Worsening of BD 25 Overweight Loss of 21 kg. (89-68 kg.) [46 lbs. (195-150 lbs.)] Discontinued due to anorexia

8 PR BD 700 Moderate improvement of BD 30 Overeating Marked improvement in overeating Overweight Loss of 9 kg (84-75 kg) [19 lbs. (185-166)] 35 Discontinued due to G.I. Distress Key: Pt.=patient; BD=Bipolar Disorder; BED=Binge Eating Disorder; D/C=topiramate treatment discontinued; cont=topiramate treatment continued;GI=gastrointestinal

40 Claims

1. Use of a compound of the formula I:

55 wherein X is CH2 or oxygen; R1 is hydrogen, methyl, ethyl, or iso-propyl; and

13 EP 1 158 973 B1

R2,R3,R4and R5 are independently hydrogen, methyl, ethyl, iso-propyl or n-propyl, and, when X is CH2,R4and R5 may be alkene groups joined to form a benzene ring and, when X is oxygen, R2 and R3 and/or R4 and R5 together may be a methylenedioxy group of the following formula (II):

wherein R6 and R7 are the same or different and are hydrogen, methyl, ethyl, iso-propyl or n-propyl, or are alkyl and are 15 joined to form a cyclopentyl or cyclohexyl ring; in a therapeutically effective amount for the preparation of a pharmaceutical composition for treating an Impulse Control Disorder in a mammal, wherein the Impulse Control Disorder is selected from the group consisting of intermittent explosive disorder (IED), kleptomania, pathological gambling, pyromania, trichotillomania, compulsive buying or shopping, repetitive self-mutilation, nonparaphilic sexual addictions, severe nail biting, compulsive skin 20 picking, personality disorders with impulsive features, attention deficit/hyperactivity disorder, Binge Eating Disor- der, and anorexia nervosa with binge eating.

2. The use of a compound selected from the group consisting of 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose sulfamate; 25 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-L-fructopyranose sulfamate, 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose methylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose butylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose ethylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose octylsulfamate; 30 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose 2-propenylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose phenylmethylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose cyclopropylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose cyclobutylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose (2,2,2-trifluoroethyl)sulfamate; 35 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose dimethylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose diethylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D-fructopyranose azidosulfate; (S)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl-beta-D-fructopyranose sulfamate; (R)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl-beta-D-fructopyranose sulfamate; 40 2,3-O-(1-ethylpropylidene)-4,5-O-sulfonyl-beta-D-fructopyranose sulfamate; 2,3-O-(1-methylethylidene)-4,5-O-[N-(4-methylbenzenesulfonyl)imidosulfinyl]-beta-D-fructopyranose sulfamate; 2,3-O-(1-methylethylidene)-4,5-O-[N-(4-methylbenzenesulfonyl)imidosulfonyl]-beta-D-fructopyranose sulfamate; 2,3-O-(cyclohexylidene)-4,5-O-sulfonyl-beta-D-fructopyranose sulfamate; (S)-4,5-O-[N-(1,1-dimethylethoxycarbonyl)imidosulfinyl]-2,3-O-(1-methylethylidene)-beta-D-fructopyranose sul- 45 famate, and the pharmaceutically acceptable salts thereof, in a therapeutically effective amount for the preparation of a pharmaceutical composition for treating an Impulse Control Disorder in a mammal, wherein the Impulse Control Disorder is selected from the group consisting of intermittent explosive disorder (IED), kleptomania, pathological gambling, pyromania, trichotillomania, compulsive buying or shopping, repetitive self-mutilation, nonparaphilic sexual addictions, severe nail biting, compulsive skin 50 picking, personality disorders with impulsive features, attention deficit/hyperactivity disorder, Binge Eating Disor- der, and anorexia nervosa with binge eating.

3. The use of a compound selected from the group consisting or (1R, 2R, 3S, 4S)-(1,2:3,4-di-O-methylethylidenecy- clohexane-1,2,3,4-tetraol-4-yl)methyl sulfamate and (1R,2S,3S,4S)-(3,4-O-methylethylidene-1,2-O-sulfinylcy- 55 clohexane-1,2,3,4-tetraol-4-yl)methyl sulfamate, in a therapeutically effective amount for the preparation of a pharmaceutical composition for treating an Impulse Control Disorder in a mammal, wherein the Impulse Control Dis- order is selected from the group consisting of intermittent explosive disorder (IED), kleptomania, pathological gambling, pyromania, trichotillomania, compulsive buying or shopping, repetitive self-mutilation, nonparaphilic sexual

14 EP 1 158 973 B1

addictions, severe nail biting, compulsive skin picking, personality disorders with impulsive features, attention deficit/hyperactivity disorder, Binge 7Eating Disorder, and anorexia nervosa with binge eating.

4. The use of claim 1 wherein the compound is topiramate. 5 5. The use of any one of claims 1 to 4, wherein the therapeutically effective amount is of from 15 to 2000 mg per day.

6. The use of any one of claims 1 to 4, wherein the therapeutically effective amount is of from 25 to 750 mg per day.

10 7. The use of any one of claims 1 to 6, wherein the compound is used in conjunction with one or more other drug compounds selected from the group consisting of adrenergics, adrenocortical steroids, adrenocortical suppressants, aldosterone antagonists, amino acids, analeptics, analgesics, anorectic compounds, anorexics, anti-anxiety agents, antidepressants, antihypertensives, anti-inflammatories, antinauscants, antineutropenics, antiobsessional agents, antiparkinsonians, antipsychotics, apptite suppressants, blood glucose regulators, carbonic anhydrase 15 inhibitors, cardiotronics, cardiovascular agents, choleretics, cholinergics, cholinergic agonists, cholinesterase de- activators, cognition adjuvants, cognition enhancers, hormones, memory adjuvants, mental performance enhancers, mood regulators, neuroleptics, neuroprotectives, psychotropics, relaxants, sedative-hypnotics, serotonin antagonists, serotonin inhibitors, serotonin receptor antagonists, stimulants, thyroid hormones, thyroid inhibitors, thyromimetics, cerebral ischemia agents, vasoconstrictors, and vasodilators. 20 8. The use of any one of claims 1 to 7, wherein the Impulse Control Disorder is a binge eating disorder or anorexia nervosa with binge eating and the compound is used in conjunction with one or more other drug compounds selected from the group consisting of serotonin re-uptake inhibitors, antidepressants, psychostimulants, and orlistat. 25 9. The use of claim 8, wherein the compound is topiramate and the disorder is anorexia nervosa with binge eating.

10. The use of any one of claims 1 to 7, wherein the Impulse Control Disorder is intermittent explosive disorder (IED), kleptomania, pathological gambling, pyromania, trichotillomania, compulsive buying or stopping, repetitive self- 30 mutilation, severe nail biting, compulsive skin picking, personality disorders with impulsive features, attention deficit/hyperactivity disorder and the compound is used in conjunction with one or more other drug compounds selected from the group consisting of serotonin re-uptake inhibitors, lithium, valproic acid or divalproex sodium, other antidepressants, naltrexone, atypical antipsychotics, and other mood stabilizers.

35 11. The use of any one of claims 1 to 7, wherein the Impulse Control Disorder is a nonparaphilic sexual addiction and the compound is used in conjunction with one or more other drug compounds selected from the group consisting of serotonin re-uptake inhibitors, lithium, divalproex sodium/valproic acid, antiandrogen agents, other antidepressants, and other mood stabilizers.

40 Patentansprüche

1. Verwendung einer Verbindung der Formel I:

55 worin X CH2 oder Sauerstoff ist, R1 Wasserstoff, Methyl, Ethyl oder Isopropyl ist, und

15 EP 1 158 973 B1

R2,R3,R4und R5 unabhängig voneinander Wasserstoff, Methyl, Ethyl, Isopropyl oder n-Propyl sind, und wenn X CH2 ist, R4 und R5 Alkengruppen sein können, die verknüpft sind, um einen Benzolring zu bilden, und wenn X Sauerstoff ist, R2 und R3 und/oder R4 und R5 zusammen eine Methylendioxygruppe der folgenden Formel (II) sein können: 5

worin 15 R6 und R7 gleich oder unterschiedlich sind und Wasserstoff, Methyl, Ethyl, Isopropyl oder n-Propyl sind, oder Alkyl sind und verknüpft sind, um einen Cyclopentyl- oder Cyclohexylring zu bilden, in einer therapeutisch wirksamen Menge zur Herstellung einer pharmazeutischen Zusammensetzung zur Behand- lung einer Impulskontrollerkrankung in einem Säugetier, wobei die Impulskontrollerkrankung aus der Gruppe, bestehend aus intermittierender explosiver Erkrankung (IED), Kleptomanie, krankhafter Spielsucht, Pyromanie, 20 Haarrupfsucht, Kaufsucht oder Einkaufssucht, repetitiver Selbstverstümmelung, nicht-paraphiler Sexsüchtigkeit, schwerem Nägelkauen, Zwangshautkratzen, Persönlichkeitserkrankungen mit Impulseigenschaften, hyperkinetischem Syndrom des Kindesalters, Freßerkrankung und Magersucht mit Fressen, ausgesucht ist.

2. Verwendung einer Verbindung, ausgewählt aus der Gruppe, bestehend aus 25 2,3-O-(1-Methylethyliden)-4,5-O-sulfonyl-beta-D-fructopyranosesulfamat, 2,3-O-(1-Methylethyliden)-4,5-O-sulfonyl-beta-L-fructopyranosesulfamat, 2,3-O-(1-Methylethyliden)-4,5-O-sulfonyl-beta-D-fructopyranosemethylsulfamat, 2,3-O-(1-Methylethyliden)-4,5-O-sulfonyl-beta-D-fructopyranosebutylsulfamat, 2,3-O-(1-Methylethyliden)-4,5-O-sulfonyl-beta-D-fructopyranoseethylsulfamat, 30 2,3-O-(1-Methylethyliden)-4,5-O-sulfonyl-beta-D-fructopyranoseoctylsulfamat, 2,3-O-(1-Methylethyliden)-4,5-O-sulfonyl-beta-D-fructopyranose-2-propenylsulfamat, 2,3-O-(1-Methylethyliden)-4,5-O-sulfonyl-beta-D-fructopyranosephenylmethylsulfamat, 2,3-O-(1-Methylethyliden)-4,5-O-sulfonyl-beta-D-fructopyranosecyclopropylsulfamat, 2,3-O-(1-Methylethyliden)-4,5-O-sulfonyl-beta-D-fructopyranosecyclobutylsulfamat, 35 2,3-O-(1-Methylethyliden)-4,5-O-sulfonyl-beta-D-fructopyranose (2,2,2-trifluorethyl)sulfamat, 2,3-O-(1-Methylethyliden)-4,5-O-sulfonyl-beta-D-fructopyranosedimethylsulfamat, 2,3-O-(1-Methylethyliden)-4,5-O-sulfonyl-beta-D-fructopyranosediethylsulfamat, 2,3-O-(1-Methylethyliden)-4,5-O-sulfonyl-beta-D-fructopyranoseazidosulfat, (S)-2,3-O-(1-Methylethyliden)-4,5-O-sulfinyl-beta-D-fructopyranosesulfamat, 40 (R )-2,3-O-(1-Methylethyliden)-4,5-O-sulfinyl-beta-D-fructopyranosesulfamat, 2,3-O-(1-Ethylpropyliden)-4,5-O-sulfonyl-beta-D-fructopyranosesulfamat, 2,3-O-(1-methylethyliden)-4,5-O-[N-(4-methylbenzolsulfonyl)imidosulfinyl]-beta-D-fructopyranosesulfamat, 2,3-O-(1-Methylethyliden)-4,5-O-[N-(4-methylbenzolsulfonyl)imidosulfonyl]-beta-D-fructopyranosesulfamat, 2,3-O-(Cyclohexyliden)-4,5-O-sulfonyl-beta-D-fructopyranosesulfamat, 45 (S)-4,5-O-[N-(1,1-Dimethylethoxycarbonyl)imidosulfinyl]-2,3-O-(1-methylethyliden)-beta-D-fructopyranosesulfamat und die pharmazeutisch verträglichen Salze davon in einer therapeutisch wirksamen Menge zur Herstellung einer pharmazeutischen Zusammensetzung zur Behand- lung einer Impulskontrollerkrankung in einem Säugetier, wobei die Impulskontrollerkrankung aus der Gruppe, bestehend aus intermittierender explosiver Erkrankung (IED), Kleptomanie, krankhafter Spielsucht, Pyromanie, 50 Haarrupfsucht, Kaufsucht oder Einkaufssucht, repetitiver Selbstverstümmlung, nicht-paraphiler Sexsüchtigkeit, schwerem Nägelkauen, Zwangshautkratzen, Persönlichkeitserkrankungen mit Impulseigenschaften, hyperkinetischem Syndrom des Kindesalters, Freßerkrankung und Magersucht mit Fressen, ausgesucht ist.

3. Verwendung einer Verbindung, welche aus der Gruppe, bestehend aus (1R, 2R, 3S, 4S)-(1,2:3,4-Di-O-methyle- 55 thylidencyclohexan-1,2,3,4-tetraol-4-yl)methylsulfamat und (1R, 2S, 3S, 4S)-(3,4-O-Methylethyliden-1,2-Osulfi- nylcyclohexan-1,2,3,4-tetraol-4-yl)methylsulfamat, ausgewählt ist, in einer therapeutisch wirksamen Menge zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung einer Impulskontrollerkrankung in einem Säugetier, wobei die Impulskontrollerkrankung aus der Gruppe, bestehend aus intermittierender explosiver Er-

16 EP 1 158 973 B1

krankung (IED), Kleptomanie, krankhafter Spielsucht, Pyromanie, Haarrupfsucht, Kaufsucht oder Einkaufssucht, repetitiver Selbstverstümmlung, nicht-paraphiler Sexsüchtigkeit, schwerem Nägelkauen, Zwangshautkratzen, Persönlichkeitserkrankungen mit Impulseigenschaften, hyperkinetischem Syndrom des Kindesalters, Freßerkran- kung und Magersucht mit Fressen, ausgewählt ist. 5 4. Verwendung nach Anspruch 1, wobei die Verbindung Topiramat ist.

5. Verwendung nach einem der Ansprüche 1 bis 4, wobei die therapeutisch wirksame Menge von 15 bis 2000 mg pro Tag ist. 10 6. Verwendung nach einem der Ansprüche 1 bis 4, wobei die therapeutisch wirksame Menge von 25 bis 750 mg pro Tag ist.

7. Verwendung nach einem der Ansprüche 1 bis 6, wobei die Verbindung zusammen mit einer oder mehreren anderen 15 Arzneimittelverbindungen, ausgewählt aus der Gruppe, bestehend aus Sympathomimetika, Nebennierenrinden- steroiden, Nebennierenrinden-Hemmagentien, Aldosteronantagonisten, Aminosäuren, Analeptica, Schmerzmit- teln, appetitzügelnden Verbindungen, Appetithemmem, Anti-Angstmitteln, Antidepressiva, Blutdrucksenkern, Ent- zündungshemmem, gegen Nausea wirkenden Mitteln, Anti-Neutropenien, Anti-Obsessionsmitteln, Antiparkinson- mitteln, Antipsychotika, Appetitzüglern, Blutzuckerregulatoren, Kohlesäureanhydrase-Inhibitoren, stärkenden 20 Herzmitteln, Herzkreislaufmitteln, Choleretika, Cholinergika, cholinergischen Agonisten, Cholinesterasedeaktiva- toren, Wahmehmungshilfsmitteln, Wahmehmungsverstärkem, Hormonen, Gedächtnishilfsmitteln, geistigen Lei- stungsverstärkem, Stimmungsregulatoren, Neuroleptika, Neuroprotektiva, Psychotropika, Relaxantien, sedativen Hypnotika, Serotoninantagonisten, Serotonininhibitoren, Serotoninrezeptorantagonisten, Stimulantien, Thyroid- hormonen, Thyroidinhibitoren, Thyromimetika, zerebralen Ischämiemitteln, Vasokonstriktoren und Vasodilatato- 25 ren, verwendet wird.

8. Verwendung nach einem der Ansprüche 1 bis 7, wobei die Impulskontrollerkrankung eine Freßerkrankung oder Magersucht mit Fressen ist, und die Verbindung zusammen mit einer oder mehreren anderen Arzneimittelverbin- dungen, ausgewählt aus der Gruppe, bestehend aus Serotonin-Wiederaufnahmeinhibitoren, Antidepressiva, Psy- 30 chostimulantien und Orlistat, verwendet wird.

9. Verwendung nach Anspruch 8, wobei die Verbindung Topiramat ist und die Erkrankung Magersucht mit Fressen ist.

10. Verwendung nach einem der Ansprüche 1 bis 7, wobei die Impulskontrollerkrankung intermittierende explosive 35 Erkrankung (IED), Kleptomanie, krankhafte Spielsucht, Pyromanie, Haarrupfsucht, Kaufsucht oder Einkaufssucht, repetitive Selbstverstümmlung, schweres Nägelkauen, Zwangshautkratzen, Persönlichkeitserkrankungen mit Im- pulseigenschaften, hyperkinetisches Syndrom des Kindesalters ist, und die Verbindung zusammen mit einer oder mehreren anderen Arzneimittelverbindungen, ausgewählt aus der Gruppe, bestehend aus Serotonin-Wiederauf- nahmeinhibitoren, Lithium, 2-Propylvaleriansäure oder Divalproexnatrium, anderen Antidepressiva, Naltrexon, 40 atypischen Antipsychotika und anderen Stimmungsstabilisatoren, verwendet wird.

11. Verwendung nach einem der Ansprüche 1 bis 7, wobei die Impulskontrollerkrankung eine nicht-paraphile Sex- süchtigkeit ist, und die Verbindung zusammen mit einer oder mehreren anderen Arzneimittelverbindungen, aus- gewählt aus der Gruppe, bestehend aus Serotonin-Wiederaufnahmeinhibitoren, Lithium, Divalproexnatrium/2-Pro- 45 pylvaleriansäure, Antiandrogenmitteln, anderen Antidepressiva und anderen Stimmungsstabilisatoren, verwendet wird.

Revendications 50 1. Utilisation d'un composé de formule I :

17 EP 1 158 973 B1

10 dans laquelle X est CH2 ou l'oxygène ; R1 est l'hydrogène, un groupe méthyle, éthyle ou isopropyle ; et R2,R3,R4et R5 sont indépendamment l'hydrogène, un groupe méthyle, éthyle, isopropyle ou n-propyle, et 15 quand X est CH2,R4et R5 peuvent être des groupes alcène reliés pour former un noyau benzénique, et quand X est l'oxygène, R2 et R3 et/ou R4 et R5 ensemble peuvent être un groupe méthylènedioxy ayant la formule (II) suivante :

dans laquelle R6 et R7 sont identiques ou différents et sont l'hydrogène, un groupe méthyle, éthyle, isopropyle ou n-propyle, ou ils sont un groupe alkyle et sont reliés pour former un noyau cyclopentyle ou cyclohexyle ; 30 en une quantité thérapeutiquement efficace pour la préparation d'une composition pharmaceutique pour traiter un trouble du contrôle des impulsions chez un mammifère, ledit trouble du contrôle des impulsions étant choisi dans l'ensemble constitué de : trouble explosif intermittent (TEI), cleptomanie, passion pathologique pour les jeux d'argent, pyromanie, trichotillomanie, achat ou "shopping" compulsif, automutilation répétitive, addictions sexuelles non paraphiliques, onychophagie sévère, écorchures compulsives de la peau, troubles de la personnalité 35 avec des particularités impulsives, trouble de déficit/hyperactivité de l'attention, trouble de la boulimie et anorexie mentale avec boulimie.

2. Utilisation d'un composé choisi dans l'ensemble constitué de sulfamate de 2,3-O-(1-méthyléthylidène)-4,5-O-sulfonyl-bêta-D-fructopyrannose ; 40 sulfamate de 2,3-O-(1-méthyléthylidène)-4,5-O-sulfonyl-bêta-L-fructopyrannose ; méthylsulfamate de 2,3-O-(1-méthyléthylidène)-4,5-O-sulfonyl-bêta-D-fructopyrannose ; butylsulfamate de 2,3-O-(1-méthyléthylidène)-4,5-O-sulfonyl-bêta-D-fructopyrannose ; éthylsulfamate de 2,3-O-(1-méthyléthylidène)-4,5-O-sulfonyl-bêta-D-fructopyrannose ; octylsulfamate de 2,3-O-(1-méthyléthylidène)-4,5-O-sulfonyl-bêta-D-fructopyrannose ; 45 2-propénylsulfamate de 2,3-O-(1-méthyléthylidène)-4,5-O-sulfonyl-bêta-D-fructopyrannose ; phénylméthylsulfamate de 2,3-O-(1-méthyléthylidène)-4,5-O-sulfonyl-bêta-D-fructopyrannose ; cyclopropylsulfamate de 2,3-O-(1-méthyléthylidène)-4,5-O-sulfonyl-bêta-D-fructopyrannose ; cyclobutylsulfamate de 2,3-O-(1-méthyléthylidène)-4,5-O-sulfonyl-bêta-D-fructopyrannose ; (2,2,2-trifluoroéthyl)sulfamate de 2,3-O-(1-méthyléthylidène)-4,5-0-sulfonyl-bêta-D-fructopyrannose ; 50 diméthylsulfamate de 2,3-O-(1-méthyléthylidène)-4,5-O-sulfonyl-bêta-D-fructopyrannose ; diéthylsulfamate de 2,3-O-(1-méthyléthylidène)-4,5-O-sulfonyl-bêta-D-fructopyrannose ; azidosulfate de 2,3-O-(1-méthyléthylidène)-4,5-O-sulfonyl-bêta-D-fructopyrannose ; sulfamate de (S)-2,3-O-(1-méthyléthylidène)-4,5-O-sulfinyl-bêta-D-fructopyrannose ; sulfamate de (R)-2,3-O-(1-méthyléthylidène)-4,5-O-sulfinyl-bêta-D-fructopyrannose ; 55 sulfamate de 2,3-O-(1-éthylpropylidène)-4,5-O-sulfonyl-bêta-D-fructopyrannose ; sulfamate de 2,3-O-(1-méthyléthylidène)-4,5-O-[N-(4-méthylbenzènesulfonyl)imidosulfinyl]-bêta-D- fructopyrannose ; sulfamate de 2,3-O-(1-méthyléthylidène)-4,5-O-[N-(4-méthylbenzènesulfonyl)imidosulfonyl]-bêta-D-

18 EP 1 158 973 B1

fructopyrannose ; sulfamate de 2,3-O-(cyclohexylidène)-4,5-O-sulfonyl-bêta-D-fructopyrannose ; sulfamate de (S)-4,5-O-[N-(1,1-diméthyléthoxycarbonyl)-imidosulfinyl]-2,3-O-(1-méthyléthylidène)-bêta-D- fructopyrannose, 5 et leurs sels pharmaceutiquement acceptables, en une quantité thérapeutiquement efficace pour la préparation d'une composition pharmaceutique pour traiter un trouble du contrôle des impulsions chez un mammifère, ledit trouble du contrôle des impulsions étant choisi dans l'ensemble constitué de : trouble explosif intermittent (TEI), cleptomanie, passion pathologique pour les jeux d'argent, pyromanie, trichotillomanie, achat ou "shopping" compulsif, automutilation répétitive, addictions 10 sexuelles non paraphiliques, onychophagie sévère, écorchures compulsives de la peau, troubles de la personnalité avec des particularités impulsives, trouble de déficit/hyperactivité de l'attention, trouble de la boulimie et anorexie mentale avec boulimie.

3. Utilisation d'un composé choisi dans l'ensemble constitué du sulfamate de (1R,2R,3S,4S)-(1,2:3,4-di-O-méthylé- 15 thylidènecyclohexane-1,2,3,4-tétraol-4-yl)méthyle et du sulfamate de (1R,2S,3S,4S)-(3,4-O-méthyléthylidène- 1,2-O-sulfinylcyclohexane-1,2,3,4-tétraol-4-yl)méthyle, en une quantité thérapeutiquement efficace pour la prépa- ration d'une composition pharmaceutique pour traiter un trouble du contrôle des impulsions chez un mammifère, ledit trouble du contrôle des impulsions étant choisi dans l'ensemble constitué de : trouble explosif intermittent (TEI), cleptomanie, passion pathologique pour les jeux d'argent, pyromanie, trichotillomanie, achat ou "shopping" 20 compulsif, automutilation répétitive, addictions sexuelles non paraphiliques, onychophagie sévère, écorchures compulsives de la peau, troubles de la personnalité avec des particularités impulsives, trouble de déficit/hyperac- tivité de la tension, trouble de la boulimie et anorexie mentale avec boulimie.

4. Utilisation selon la revendication 1, dans laquelle le composé est du topiramate. 25 5. Utilisation selon l'une quelconque des revendications 1 à 4, dans laquelle la quantité thérapeutiquement efficace est de 15 à 2000 mg par jour.

6. Utilisation selon l'une quelconque des revendications 1 à 4, dans laquelle la quantité thérapeutiquement efficace 30 est de 25 à 750 mg par jour.

7. Utilisation selon l'une quelconque des revendications 1 à 6, dans laquelle on utilise le composé conjointement avec un ou plusieurs autres composés médicamenteux choisis dans l'ensemble constitué des adrénergiques, corticostéroïdes, suppresseurs corticostéroïdiens, antagonistes de l'aldostérone, acides aminés, analeptiques, 35 analgésiques, composés anorexiques, anorexiques, agents antianxiété, antidépresseurs, antihypertenseurs, an- tiinflammatoires, antinauséeux, antineutropéniques, agents anti-obsessionnels, antiparkinsoniens, antipsychotiques, anorexiants, régulateurs du glucose dans le sang, inhibiteurs de l'anhydrase carbonique, cardiotoniques, agents cardio-vasculaires, cholérétiques, cholinergiques, agonistes cholinergiques, désactivateurs de cholinesté- rase, adjuvants de cognition, stimulateurs de cognition, hormones, adjuvants de la mémoire, stimulateurs de la 40 performance mentale, régulateurs de l'humeur, neuroleptiques, neuroprotecteurs, psychotropes, relaxants, séda- tifs-hypnotiques, antagonistes de la sérotonine, inhibiteurs de la sérotonine, antagonistes des récepteurs de la sérotonine, stimulants, hormones thyroïdiennes, inhibiteurs thyroïdiens, thyromimétiques, agents anti-ischémie cérébrale, vasoconstricteurs et vasodilatateurs.

45 8. Utilisation selon l'une quelconque des revendications 1 à 7, dans laquelle le trouble du contrôle des impulsions est un trouble de la boulimie ou une anorexie mentale avec trouble de la boulimie, et on utilise le composé conjointement avec un ou plusieurs autres composés médicamenteux choisis dans l'ensemble constitué d'inhibiteurs de réabsorption de sérotonine, d'antidépresseurs, de psychostimulants et d'orlistat.

50 9. Utilisation selon la revendication 8, dans laquelle le composé est du topiramate et le trouble est une anorexie mentale avec boulimie.

10. Utilisation selon l'une quelconque des revendications 1 à 7, dans laquelle le trouble du contrôle des impulsions est un trouble explosif intermittent (TEI), la cleptomanie, la passion pathologique pour les jeux d'argent, la pyro- 55 manie, la trichotillomanie, l'achat ou le "shopping" compulsif, une automutilation répétitive, l'onychophagie sévère, des écorchures compulsives de la peau, des troubles de la personnalité avec des particularités impulsives, un trouble de déficit/hyperactivité de l'attention, et on utilise le composé conjointement avec un ou plusieurs autres composés médicamenteux choisis dans l'ensemble constitué d'inhibiteurs de réabsorption de sérotonine, lithium,

19 EP 1 158 973 B1

acide valproïque ou divalproex sodique, autres antidépresseurs, naltrexone, antipsychotiques atypiques et autres stabilisants de l'humeur.

11. Utilisation selon l'une quelconque des revendications 1 à 7, dans laquelle le trouble du contrôle des impulsions 5 est une addiction sexuelle non paraphilique, et on utilise le composé conjointement avec un ou plusieurs autres composés médicamenteux choisis dans l'ensemble constitué d'inhibiteurs de réabsorption de sérotonine, lithium, divalproex sodique/acide valproïque, agents antiandrogènes, autres antidépresseurs et autres stabilisants de l'humeur.