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USOO6323236B2 (12) United States Patent (10) Patent No.: US 6,323,236 B2 McElroy (45) Date of Patent: *Nov. 27, 2001

(54) USE OF SULFAMATE DERIVATIVES FOR Marcotte D, “Use of , A New Anti-Epileptic As TREATING IMPULSE CONTROL a Mood Stabilizer”, Journal of Affective Disorders, NL, DSORDERS Elsevier Biochemical Press, Amsterdam, vol. 50. No. 2/03, Sep. 1998 (1998–09), pp. 245-251. (75) Inventor: Susan McElroy, Cincinnati, OH (US) Dewey S.L. et al., “A Pharmacologic Strategy For The Treatment of Nicotine Addiction”, Synapse, G.B., Wiley and Sons, Chichester, vol. 31, No. 1, Jan. 1999 (1999-01), pp. (73) Assignee: University of Cincinnati, Cincinnati, 76-86. OH (US) R.L. Spitzer, S. Yanovski, T. Wadden, et al., Binge Eating Disorder: Its Further Validation in a Multisite Study, Inter (*) Notice: This patent issued on a continued pros national Journal of Eating Disorders, vol. 13, pp. 137-153, ecution application filed under 37 CFR 1993. 1.53(d), and is subject to the twenty year M.D. Privitera, Topiramate: A New Antiepileptic , patent term provisions of 35 U.S.C. Annals of Pharmacotherapy, vol. 31, pp. 1164-1173, 1997. 154(a)(2). B.G. Stanley, L.H. Ha, L.C. Spears, et al., Lateral Hypotha lamic Injections of Glutamate, Kainic Acid, Subject to any disclaimer, the term of this D.L-alpha-amino-3-hydroxy-5-methyl-isoxazole propri patent is extended or adjusted under 35 onic acid or N-methyl-D-aspartic acid Rapidly Elicit U.S.C. 154(b) by 0 days. Intense Transient Eating in Rats, Brain Research, vol. 613, pp. 88–95, 1993. (21) Appl. No.: 09/506,991 B. G. Stanley, V.L. Willett, III, H.W. Donias, et al., the Lateral Hypothalamus: a Primary Site Mediating Excitatory (22) Filed: Feb. 18, 2000 Amino Acid-elicited Eating, Brain Research, vol. 630, pp. 1-49, 1993. Related U.S. Application Data R.S. Green, J.H. Rau, Treatment of Compulsive Eating (60) Provisional application No. 60/121,339, filed on Feb. 24, Disturbances with , American 1999. Journal of PsySchiatry, vol. 131, pp. 428-432, 1974. (51) Int. Cl." ...... A61K 31/385; A61K 31/35; J. L. Hudson, S.L. McElroy N.C. Raymond, et al., Fluvox A61K 31/335 amine in the Treatment of Binge Eating Disorder: a Multi (52) U.S. Cl...... 514/439; 514/455; 514/459; Center Placebo-Controlled Double-Blind Trial, American 514/463 Journal of Psychiatry, vol. 155, pp. 1756–1762, 1998. (58) Field of Search ...... 514/455, 439, 514/459, 463 (List continued on next page.) (56) References Cited Primary Examiner William R. A. Jarvis (74) Attorney, Agent, or Firm-Frost Brown Todd LLC U.S. PATENT DOCUMENTS (57) ABSTRACT 4,513,006 4/1985 Maryanoff et al.. 6,071,537 6/2000 Shank. Impulse Control Disorders (ICD's) are characterized by harmful behaviors performed in response to irresistible FOREIGN PATENT DOCUMENTS impulses. The essential feature of an ICD is the failure to 0568306A 11/1993 (WO). resist an impulse, drive, or temptation and to perform an act WO9800123A 1/1998 (WO). that is harmful to the person or to others. The present WO9800130A 1/1998 (WO). invention comprises methods for the treatment or prevention WO0007583A 2/2000 (WO). of ICD's using a class of sulfamates of the following (List continued on next page.) formula: OTHER PUBLICATIONS (I) McElroy, S. L. et al., “Are Impulse-Control Disorders CHOSONHR Related To Bipolar Disorder?', Comprehensive Psychiatry, (1996) 37/4 (229–240). Potter, D. et al., “Sustained Weight Loss Associated with 12-month Topiramate Therapy”, Epilepsia, U.S., Raven Press Ltd., New York, vol. 38, No. Suppl. 08, 1997, p. 97. K.T. Brady et al., “The Relationship Between Subtance Use wherein X is CH or oxygen, and R, R2, R, R and Rs Disorders, Impulse Control Disorders, and Pathological are as herein defined. Further, pharmaceutical compo Aggression', American Journal of Addictions, Vol. 7, No. 3, Sitions containing a compound of formula (I) as well as 1998, pp. 221-230. methods for their use and intermediates form part of the Kuziecky R. et al., “Topiramate Increase Cerebral Gaba in present invention are also disclosed. Healthy Humans”, Neurology, Lippincott Williams, & Wilkins, Philadelphia, U.S., No. 51, Aug. 1998 (1998–08), pp. 627–629. 16 Claims, No Drawings US 6,323,236 B2 Page 2

FOREIGN PATENT DOCUMENTS American Psychiatric ASSociation, Diagnostic and Statisti WOOO23059A 4/2000 (WO). cal Manual for Mental Disorders, American Psychiatric WOOO44374A 8/2000 (WO). ASSociation, 4th Ed. Washington, DC, 1994, Table of Con WO061140A 10/2000 (WO). tents only. WO0066108A 11/2000 (WO). M. Mitchell DeZwaan, J.E. Mitchell, N.C. Raymond, et al., WO0076943 12/2000 (WO). Binge Eating Disorder: Clinical Features and Treatment of a New Diagnosis, Harvard Review of Psychiatry, Vol. 1, pp. OTHER PUBLICATIONS 310-325, 1994. L.L. Alshuler, R.M. Post, G.S. Leverich, et al., Antidepres R.L. Spitzer, M. Devlin, B.T. Walsh, et al., Binge Eating Sant-induced Mania and Cycle Acceleration: a Controversy Disorder: a multisite field trial of the diagnostic criteria, Revisited, American Journal of Psychiatry, vol. 152, pp. International Journal of Eating Disorders, vol. 11, pp. 1130–1138, 1996. 191-203, 1992. F. Benazzi, -ASSociated Hypomania in Out J.R. Calabrese, M.D. Shelton, III, P.E. Keck, Jr., et al., patient Depression: a 203-Case Study in Private Practice, Topiramate in Severe Treatment-Refractory Mania, New Journal of Affectic Disorders, vol. 46, pp. 73–77, 1997. Research Program and Abstracts of the 151 Annual Meet S. Kruger, G. Shugar, R.G. Cooke, Comorbidity of Binge ing of the American Psychiatry ASSociation; Tononto, Eating Disorder and the Partial Binge Eating Syndrome with Canada Abstract NR 202:121–122, Jun. 2, 1998. Bipolar Syndrome, International Journal of Eating Disor J.J.I. Hudson, H.G. Pope, The role of in the ders, vol. 19, pp. 45–52, 1996. Treatment of Bulimia, S.L. McElroy, H.G. Pope, eds. “Use A.J. Stunkard, Eating Pattern and Obesity, Psychiatric of Anticonvulsants in Psychiatry: Recent Advances,” Clif Quarterly, vol. 33, pp. 284–292, 1959. ton, NJ, Oxford Health Care, pp. 141-145, 1988. US 6,323,236 B2 1 2 USE OF SULFAMATE DERIVATIVES FOR SUMMARY OF THE INVENTION TREATING IMPULSE CONTROL It is an object of the present invention to describe the use DISORDERS of sulfamate derivatives for the treatment of Impulse Control Disorders. This application claims priority to U.S. Provisional The present invention comprises methods for the treat Patent Application Ser. No. 60/121,339, filed Feb. 24, 1999. ment or prevention of Impulse Control Disorders using the compounds of formula (I), pharmaceutical compositions TECHNICAL FIELD containing one or more of the compounds of formula (I), or The present invention generally relates to the use of pharmaceutical compositions containing one or more of the for the treatment of mental disorders. More specifically, the compounds of formula (I) in addition to a safe and effective invention describes methods for the treatment and preven amount of one or more additional agents to treat related tion of Impulse Control Disorders (ICD's) by administering Symptoms and conditions. Sulfamate derivatives. DETAILED DESCRIPTION OF THE INVENTION BACKGROUND OF THE INVENTION 15 The Sulfamates of use in the present invention are of the Sulfamate derivatives having useful pharmaceutical activ following formula (I): ity in the areas of epilepsy, glaucoma, peptic ulcers and male infertility are disclosed in U.S. Pat. Nos. 4,075,351, 4.513, (I) 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- CHOSONHR1 fructopyranose Sulfamate known as topiramate has been demonstrated in clinical trials of human epilepsy to be effective as adjunctive therapy or as monotherapy in treating Simple and complex partial Seizures and Secondarily gener 25 alized Seizures and is currently marketed for the treatment of Simple and complex partial Seizure epilepsy with or without wherein Secondary generalized Seizures. X is CH or oxygen; Binge eating disorder (BED) is characterized by discrete R is hydrogen or alkyl, and R, R, R and Rs are periods of binge eating during which large amounts of food independently hydrogen or lower alkyl and, when X is are consumed in a discrete period of time and a Sense of CH, R and Rs may be alkene groups joined to form control over eating is absent. Persons with bulimia nervosa a ring and, when X is oxygen, R and R have been reported to have electroencephalographic abnor and/or R and Rs together may be a methylenedioxy malities and to display reduced binge eating in response to group of the following formula (II): the anti-epileptic drug . Also, in controlled trials in 35 patients with epilepsy, topiramate was associated with Sup (II) pression of appetite and weight loSS unreleated to binge eating. Binge eating disorder is a Subset of a larger classification of mental disorders broadly defined as Impulse Control 40 Disorders (ICDS) characterized by harmful behaviors per formed in response to irresistible impulses. It has been wherein Suggested that ICDS may be related to obsessive-compulsive Re and R7 are the same or different and are hydrogen, disorder or similarly, maybe forms of obsessive-complusive lower alkyl or are alkyl and are joined to form a disorders. It has also been hypothesized that ICDS may be 45 cyclopentyl or cyclohexyl ring. R in particular is related to mood disorder or may be forms of affective hydrogen or alkyl of about 1 to 4 carbons, Such as Spectrum disorder, a hypothesized family of disorders Shar methyl, ethyl and iso-propyl. Alkyl throughout this ing at least one common physiologic abnormality with major Specification includes Straight and branched chain depression. In the Diagnostic and Statistical Manual of alkyl. Alkyl groups for R, R., R., R., R and R, are Mental Disorders (DSM-IV), the essential feature of an ICD 50 of about 1 to 3 carbons and include methyl, ethyl, is the failure to resist an impulse, drive, or temptation to iso-propyl and n-propyl. When X is CH, R and Rs perform an act that is harmful to the perSon or to others. For may combine to form a benzene ring fused to the most ICDS, the individual feels an increasing Sense of 6-membered X-containing ring, i.e., R and Rs are tension or arousal before committing the act, and then defined by the alkatrienyl group =C-CH=CH experiences pleasure, gratification, or release at the time of 55 CH=. committing the act. After the act is performed, there may or A particular group of compounds of formula (I) is that may not be regret or guilt. ICDS are listed in a residual wherein X is oxygen and both R- and R and R and Rs category, the ICDs Not Elsewhere Classified, which includes together are methylenedioxy groups of the formula (II), intermittent explosive disorder (IED), kleptomania, patho wherein R and R7 are both hydrogen, both alkyl or combine logical gambling, pyromania, trichotillomania, and ICD not 60 to form a Spiro cyclopentyl or cyclohexyl ring, in particular otherwise specified (NOS). Examples of ICDs NOS are where R and R7 are both alkyl Such as methyl. A Second compulsive buying or shopping, repetitive Self-mutilation, group of compounds is that wherein X is CH and R and Rs nonparaphilic Sexual addictions, Severe nail biting, compul are joined to form a benzene ring. A third group of com Sive skin picking, personality disorders with impulsive pounds of formula (I) is that wherein both R- and R are features, attention deficit/hyperactivity disorder, eating dis 65 hydrogen. orders characterized by binge eating, and Substance use The compounds of formula I; may be made by the disorders. processes disclosed in U.S. Pat. Nos. 4,075,351, 4,513,006, US 6,323,236 B2 3 4 4,591,601, 4,792,569, 5,242.942, 5,387,700, which are 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- incorporated in their entirety herein by reference. fructopyranose octylsulfamate; The compounds of formula I include the various indi 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- vidual isomers as well as the racemates thereof. For treating fructopyranose 2-propenylsulfamate; ICDs, a compound of formula (I) may be employed at a daily 5 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- dosage in the range of about 15 to 1400 mg administered fructopyranose phenylmethylsulfamate; orally, for an average adult human. 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- To prepare the pharmaceutical compositions of this fructopyranose cyclopropylsulfamate; invention, one or more Sulfamate compounds of formula (I) 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- are intimately admixed with a pharmaceutical carrier fructopyranose cyclobutylsulfamate; according to conventional pharmaceutical compounding 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- techniques, which carrier may take a wide variety of forms fructopyranose (2,2,2-trifluoroethyl)sulfamate; depending on the form of preparation desired for 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- administration, e.g., oral, by Suppository, or parenteral. In fructopyranose dimethylsulfamate; preparing the compositions in oral dosage form, any of the 15 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- usual pharmaceutical media may be employed. Thus, for fructopyranose diethylsulfamate; liquid oral preparations, Such as for example, Suspensions, 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- elixirs and Solutions, Suitable carriers and additives include fructopyranose azidoSulfamate; water, glycols, oils, , flavoring agents, preservatives, (S)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl-beta-D- coloring agents and the like; for Solid oral preparations Such fructopyranose Sulfamate; as, for example, powders, capsules and tablets, Suitable (R)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl-beta-D- carriers and additives include Starches, Sugars, diluents, fructopyranose Sulfamate; granulating agents, lubricants, binders, disintegrating agents 2,3-O-(1-ethylpropylidene)-4,5-O-sulfonyl-beta-D- and the like. Because of their ease in administration, tablets fructopyranose Sulfamate; and capsules represent the most advantageous oral dosage 25 2,3-O-(1-methylethylide ne)-4, 5-O-N-(4- unit form, in which case Solid pharmaceutical carriers are methylbenzenesulfonyl)imidosulfinyl)-beta-D- obviously employed. If desired, tablets may be Sugar coated fructopyranose Sulfamate; or enteric coated by Standard techniques. Suppositories may 2,3-O-(1-methylethylide ne)-4, 5-O-N-(4- be prepared, in which case cocoa butter could be used as the methylbenzenesulfonyl)imidosulfonyl)-beta-D- carrier. For parenterals, the carrier will usually comprise fructopyranose Sulfamate; Sterile water, though other ingredients, for example, for 2,3-O-(cyclohexylidene)-4,5-O-sulfonyl-beta-D- purposes Such as aiding Solubility or for preservation, may fructopyranose Sulfamate; be included. Injectable Suspensions may also be prepared in (S)-4,5-O-N-(1,1-dimethylethoxycarbonyl)imidosulfinyl which case appropriate liquid carriers, Suspending agents 2,3-O-(1-methylethylidene)-beta-D-fructopyranose sulfa and the like may be employed. Topiramate is currently 35 mate, available for oral administration in round tablets containing 25 mg, 100 mg or 200 mg of active agent. The tablets and the pharmaceutically acceptable Salts thereof contain the following inactive ingredients: lactose hydrous, Included within the scope of this invention are the various pregelatinized Starch, microcrystalline cellulose, Sodium individual anomers, diastereomers and enantiomers as well Starch glycolate, Stearate, purified water, car 40 as mixtures thereof. Such compounds are included within nauba wax, hydroxypropyl methylcellulose, titanium the definition of formula (I). In addition, the compounds of dioxide, polyethylene glycol, Synthetic iron oxide, and this invention also include any pharmaceutically acceptable polysorbate 80. Salts, for example: alkali metal Salts, Such as Sodium and The pharmaceutical compositions herein will contain, per potassium, ammonium Salts, monoalkylammonium Salts; dosage unit, e.g., tablet, capsule, powder injection, 45 dialkylammonium Salts, trialkylammonium Salts, tetraalky teaspoonful, Suppository and the like from about 5 to about lammonium Salts, and tromethamine Salts. Hydrates and 1000 mg of the active ingredient. other solvates of the compound of the formula (I) are The activity of the compounds of formula I in treating included within the scope of this invention. ICD's was first evidenced in clinical studies conducted to Pharmaceutically acceptable Salts of the compounds of evaluate the efficacy of topiramate in treating mood disor 50 formula (I) can be prepared by reacting the Sulfamate of derS. Several patients who coincidentally had binge eating formula (I) with the appropriate base and recovering the Salt. disorder reported that there was a marked reduction in their The Sulfamate derivatives may be used in conjunction binging and a concurrent loSS in weight. with one or more other drug compound and used according Examples of Specific compounds of formula (I) are: to the methods of the present invention So long as the 55 pharmaceutical agent has a use that is also effective in 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose treating ICD's and/or concurrent illnesses. Pharmaceutical Sulfamate agents include the following categories and Specific 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- examples. It is not intended that the category be limited by fructopyranose Sulfamate; the specific examples. Those of ordinary skill in the art will 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-L- 60 be able to identify readily those pharmaceutical agents that fructopyranose Sulfamate; have utility with the present invention. Those of ordinary 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- skill in the art will recognize also numerous other com fructopyranose methylsulfamate; pounds that fall within the categories and that are useful 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- according to the invention. fructopyranose butylsulfamate; 65 Adrenergic: Adrenalone, Amidephrine MeSylate; Apra 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- Hydrochloride; Brimonidine Tartrate; Dapiprazole fructopyranose ethylsulfamate; Hydrochloride; Deterenol Hydrochloride; Dipivefrin; US 6,323,236 B2 S 6 Hydrochloride; Ephedrine Sulfate; Epinephrine; Hydrochloride; Terephthalate; Epinephrine Bitaritrate; Epinephryl Borate; Esproquin Hydrochloride; Pemedolac, Pentamorphone; ; Hydrochloride; Etafedrine Hydrochloride; Hydroxyamphet Pentazocine Hydrochloride; Pentazocine Lactate; amine Hydrobromide; Levonordefrin; Mephentermine Sul Hydrochloride; Phenyramidol Hydrochlo fate; Metaraminol Bitartrate; Metizoline Hydrochloride; ride; Hydrochloride; Pinadoline; Pirfenidone; Naphazoline Hydrochloride; Bitartrate; Olamine; Pravadoline Maleate; Prodilidine Oxidopamine; Oxymetazoline Hydrochloride; Phenyleph Hydrochloride; Profadol Hydrochloride; Propirarn Fuma rine Hydrochloride; Phenylpropanolamine Hydrochloride; rate; Propoxyphene Hydrochloride; Propoxyphene Napsy Phenylpropanolamine Polistirex, Prenalterol Hydrochloride; late; Proxazole; Proxazole Citrate; Tartrate; Propylhexedrine; Pseudoephedrine Hydrochloride; Tetrahy Pyrroliphene Hydrochloride; Hydrochloride; drozoline Hydrochloride; Tramazoline Hydrochloride; Salcolex; Salethamide Maleate; ; Salicylate Xylometazoline Hydrochloride. Meglumine; ; Sodium Salicylate; Adrenocortical : ; DeSoxycorticOS Mesylate; ; Sufentanil Citrate; Talmetacin; Talni terone Acetate, DeSoxycorticosterone Pivalate; Dexametha flumate; Talosalate; Tazadolene Succinate; Tebufelone; Some Acetate, Acetate, ; 15 Tetrydamine; Tifurac Sodium; Hydrochloride; Hemisuccinate; Tiopinac; Mesylate; Hydrochloride; Hemisuccinate; ; ; Trefentanil Hydrochloride; Trolamine; Veradoline Hydro Acetate, . chloride; Verilopam Hydrochloride; Volazocine; Adrenocortical SuppreSSant: Aminoglutethimide; Trilos Mesylate; Hydrochloride; Mesylate; tane. Sodium, Zucapsaicin. deterrent: Disulfiram. Anorectic compounds including . antagonist: Canrenoate Potassium, Can Anorexic: , Amphecloral; renone; Dicirenone; ; Prorenoate Hydrochloride; Clominorex; Clortennine Hydrochloride; Potassium, . Diethylpropion Hydrochloride; Hydrochlo Amino acid: Alanine; ASpartic Acid, Cysteine Hydrochlo 25 ride; Fenisorex, Fludorex, Fluminorex, Levamfetamine Suc ride, Cystine, Histidine; Isoleucine; Leucine; ; Lysine cinate; ; Mefenorex Hydrochloride; Phenmetra Acetate; Lysine Hydrochloride; Methionine; ; Zine Hydrochloride; Phentermine; Sibu tramine Proline; Serine; Threonine; ; ; Valine. Hydrochloride. Analeptic: . Anti-anxiety agent: Hydrochloride; ; : Acetaminophen; Hydrochloride; MeSylate; ; ; Aminobenzoate Potassium; Aminobenzoate Sodium; Ani Hydrochloride; Mirisetron Male ate; ; doXime, , Anileridine Hydrochloride; Anilopam Hydrochloride; ; Pancopride; Pazi Hydrochloride; Anirolac, Antipyrine; ; Benoxapro naclone; Hydrochloride; Citrate; fen; Hydrochloride; Biciifadine Hydrochlo Hydrochloride. ride; Brifentanil Hydrochloride; Bromadoline Maleate; Bro 35 Antidepressant: Adatanserin Hydrochloride, ; mfenac Sodium; Hydrochloride; Butacetin; Adinazolam MeSylate; Alaproclate; Aletamine Hydrochlo Butixirate; ; Butorphanol Tartrate; Carbam ride; Amedalin Hydrochloride; Hydrochlo aZepine, Carbaspirin ; Carbiphene Hydrochloride; ride, , Maleate, AZaloxan Fumarate; Citrate; Succinate; Ciramadol; Cira ; Hydrochloride; Bipenarinol Hydro madol Hydrochloride; Clonixeril; Clonixin; ; 40 chloride; Hydrochloride; Butacetin; Codeine Phosphate; Codeine Sulfate; Conorphone Hydro Hydrochloride; CaroXaZone; , ; chloride; ; Dexoxadrol Hydrochloride; Dex Hydrochloride; Mesylate; Clodazon pemedolac, ; ; Bitar Hydrochloride; Hydrochloride; Cotinine trate; Dimefadane; Dipyrone; Doxpicomine Hydrochloride; Fumarate; Cyclindole; Cypenamine Hydrochloride; Cypro Drinidene; Hydrochloride; Epirizole; 45 lidol Hydrochloride; Cyproximide; Daledalin Tosylate; Tartrate; Ethoxazene Hydrochloride; Etofenamate; Eugenol; Dapoxetine Hydrochloride; Dazadrol Maleate; Dazepinil ; Fenoprofen Calcium; Citrate; Floc Hydrochloride; Hydrochloride; Dexamisole; tafenine; Flufenisal; Flunixin; Flunixin Meglumine; Flupir Deximafen; Hydrochloride; Dioxadrol Hydro tine Maleate; FluproduaZone; Fluradoline Hydrochloride; chloride; Dothiepin Hydrochloride; Hydrochlo ; Hydrochloride; Ibufenac; 50 ride; Duloxetine Hydrochloride; Maleate; Indoprofen; Keta Zo cine; Ketorfanol; Encyprate; Hydrochloride; Fantridone Hydro Tromethamine; Letimide Hydrochloride; Levomethadyl chloride; Fehmetozole Hydrochloride; Fenmetramide; Acetate; Levomethadyl Acetate Hydrochloride; Levonant Fezolamine Fumarate; Hydrochloride; Fluoxet radol Hydrochloride; Tartrate; Lofemizole ine; Hydrochloride; Fluparoxan Hydrochloride; Hydrochloride; Oxalate; Lorcinadol; Lomoxi 55 Gamfexine; Guanoxyfen Sulfate; Imafen Hydrochloride; cam; ; , Menabitan Imiloxan Hydrochloride; Hydrochloride; Inde Hydrochloride; Meperidine Hydrochloride; loxazine Hydrochloride; Hydrochloride; Iprin Hydrochloride; Hydrochloride; Methadyl dole; Isocarboxazid; Ketipramine Fumarate, Acetate; Methopholine; Methotrimeprazine; Metkephamid Hydrochloride; Lortalamine; ; Maprotiline Acetate; Mimbane Hydrochloride; Mirfentanil Hydrochlo 60 Hydrochloride; Hydrochloride; Milacemide ride; Molinazone; Sulfate; ; Nabitan Hydrochloride; Minaprine Hydrochloride; ; Hydrochloride; Hydrochloride; Moclobemide; Modaline Sulfate; Napacitadine Hydrochlo Hydrochloride; Namoxyrate; Nantradol Hydrochloride; ride; Napamezole Hydrochloride; Hydrochlo ; Naproxen Sodium; Naproxol; Hydro ride; Nisoxetine; Nitrafudam Hydrochloride; Nomifensine chloride; Nexeridine Hydrochloride; Noracy methadol 65 Maleate; Hydrochloride; Phos Hydrochloride; Ocfentanil Hydrochloride; Octazamide; phate; Hydrochloride; Hydrochlo Olvanil; Fumarate; Oxycodone; Oxycodone ride; ; Paroxetine; Phenelzine Sulfate; Piran US 6,323,236 B2 7 8 damine Hydrochloride; Pizotyline; Pridefine Hydrochloride; chloride; Bromelains, Broperamole; , Carpro Prolintane Hydrochloride; Hydrochloride; fen; Cicloprofen; Cintazone; Cliprofen; Propi Maleate; Rolicyprine; Hydrochlo onate; Butyrate; Clopirac, ride; Hydrochloride; Sibutramine Hydrochloride; Propionate; Cormethasone Acetate; Cortodoxone, Deflaza ; Suritozole; Hydrochloride; Tam cort, , ; Dipropi pramine Fumarate; Hydrochloride; Thiazesim onate; Potassium; Diclofenac Sodium; Diflo Hydrochloride; Thozalinone; Tomoxetine Hydrochloride; rasone Diacetate; Diflumidone Sodium; Diflunisal; Hydrochloride; Trebenzomine Hydrochloride; ; Diftalone; Dimethyl Sulfoxide; ; ; Trimipramine Maleate; Hydro Endrysone; Enlimomab, Enolicam Sodium; Epirizole; Etod chloride; Hydrochloride; Zimeldine Hydrochlo olac, Etofenamate; Felbinac, Fenamole, Fenbufen, Fen ride, Zometapine. clofenac, Fenclorac, Fendosal, Fenpipalone, Fentiazac, Antihypertensive: AflyZosin Hydrochloride; Alipamide; Flazalone; , , Flumizole; Althiazide; Amiquinsin Hydrochloride; Besy Acetate; Flumixin; Flunixin Meglumine; Fluo late, Amlodipine Maleate; Anaritide Acetate; cortin Butyl; Acetate; FluguaZone; Flurbi Maleate; Belfosdil; Bemitradine; Bendacalol Mesylate; 15 profen; Fluretofen; Propionate; Furaprofen; Bendroflumethiazide; Benzthiazide, Betaxolol Hydrochlo Furobufen; ; Halobetasol Propionate; Halopre ride; Bethanidine Sulfate; Bevantolol Hydrochloride; done Acetate, Ibufenac, ; Ibuprofen Aluminum; Biclodil Hydrochloride; Bisoprolol; Bisoprolol Fumarate; Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin Bucindolol Hydrochloride; Bupicomide; Buthiazide: Can Sodium; Indoprofen; Indoxole; Intrazole; doXatril; CandoXatrilat, Captopril; , Ceronapril; Acetate; ISOXepac, , , Lofemizole Chlorothiazide Sodium; Cicletanine; CilaZapril; Clonidine; Hydrochloride; , Lote prednol Etabonate; Clonidine Hydrochloride; Clopamide; Cyclopenthiazide; Meclofenamate Sodium; , Cyclothiazide; Darodipine; Debrisoquin Sulfate; Delapril Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone; Hydrochloride; Diapamide; Diazoxide; Dilevalol Hydro Methylprednisolone Suleptanate; Momiflumate; Nabume chloride; Diltiazem Malate; Ditekiren; Doxazosin Mesylate; 25 tone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; , Enalapril Maleate; Enalaprilat, Enalkiren; Olsalazine Sodium; Orgotein; Orpanoxin; , Endralazine MeSylate, Epithiazide, EproSartan; Eprosartan Oxyphenbutazone; Paranyline Hydrochloride; Pentosan Mesylate; Mesylate; Flavodilol Maleate; Flo Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pir rdipine, FloSequinan; Fosinopril Sodium; Fosinoprilat, Gua fenidone; PiroXicam, Piroxicam Cinnamate; Piroxicam Ola nabenz, Guanabenz. Acetate; Guanacline Sulfate; Guanadrel mine; Pirprofen; ; Prifelone; Prodolic Acid; Pro Sulfate; Guancydine; Guanethidine Monosulfate; Guanethi quaZone; Proxazole; Proxazole Citrate; ; dine Sulfate; Hydrochloride; Guanisoquin Sul Romazarit; Salcolex, Salnacedin, Salsalate, Sanguinarium fate; Guanoclor Sulfate; Guanoctine Hydrochloride; Guan Chloride; SeclaZone, Sermetacin; Sudoxicam, , oXabenz, Guanoxan Sulfate; Guanoxy fen Sulfate; ; Talmetacin; Talniflumate; Talosalate; Tebufelone; Hydralazine Hydrochloride; Hydralazine Polistirex; 35 Tenidap; Tenidap Sodium, , TeSicam, Tesimide; Hydroflumethiazide; Indacrinone; Indapamide; Indolaprif Tetrydamine; Tiopinac; Pivalate; Tolimetin; Tol Hydrochloride; Indoramin; Indoramin Hydrochloride; metin Sodium; ; Triflumidate; Zidometacin; Hydrochloride, Lacidipine; Leniquinsin; Levcro Zomepirac Sodium. makalim; Lisinopril, Hydrochloride; LOSartan Antinauseant: Buclizine Hydrochloride; Cyclizine Lac Potassium; Losulazine Hydrochloride; ; 40 tate; Naboctate Hydrochloride. Mecamylamine Hydrochloride; Medroxalol; Medroxalol Antineutropenic: Filgrastim; Lenograstim; Molgra Hydrochloride; Methalthiazide; Methyclothiazide; Methyl moStim; RegramoStim; SargramoStim. dopa; Methyldopate Hydrochloride; Metipranolol; Metola Antiobsessional agent: Maleate. Zone; Metoprolol Fumarate; Metoprolol Succinate; Mety Antiparkinsonian: Benztropine MeSylate; Biperiden; rosine; Minoxidil ; Maleate; Muzolimine; 45 Biperiden Hydrochloride; Biperiden Lactate; Carmantadine; Nebivolol; ; Ofornine; Pargyline Hydrochlo Hydrochloride; Dopamantine; Ethopropazine ride; Pazoxide; Hydrochloride; Perindopril Erbu Hydrochloride; LaZabemide; Levodopa, Lometraline mine; Hydrochloride; Pinacidil; Pivo Hydrochloride; Mofegiline Hydrochloride; Naxagolide pril; Polythiazide; Prazosin Hydrochloride; Primidolol; Hydrochloride; Pareptide Sulfate; Procyclidine Hydrochlo Prizidilol Hydrochloride; Quinapril Hydrochloride; Quinap 50 ride; Quinetorane Hydrochloride; Hydrochlo rilat; Quinazosin Hydrochloride; Hydrochlo ride; Hydrochloride; Tolcapone; Trihexyphenidyl ride; Hydrochloride; Quinuclium ; Hydrochloride. Antiperistaltic: Difenoximide Hydrochlo Ramipril; Rauwolfia Serpentina; , Saprisartan ride; Difenoxin; Hydrochloride; Fluperam Potassium; Saralasin Acetate; Sodium Nitroprusside; Sulfi ide; Lidamidine Hydrochloride; Hydrochloride; malol Hydrochloride; Tasosartan; Teludipine Hydrochloride; 55 Malethamer; Nufenoxole; . Temocapril Hydrochloride; Terazosin Hydrochloride; Terla : Maleate; kiren; Tiamenidine; Tiamenidine Hydrochloride; Tic Hydrobromide, Alpertine, ; Maleate; rynafen; Tinabinol; Tiodazosin; Tipentosin Hydrochloride; ; BenZindopyrine Hydrochloride; Brofbxine; Trichlormethiazide; Trimazosin Hydrochloride; Tri ; Bromperidol Decanoate; Hydro methaphan Camsylate; Trimoxamine Hydrochloride; Tripa 60 chloride; ; Butaperazine Maleate; Carphena mide; Xipamide; Zankiren Hydrochloride; Zofenoprilat zine Maleate; Carvotroline Hydrochloride; ; Arginine. Chlorpromazine Hydrochloride; ; Cin Anti-inflammatory: Alclofenac; Dipropi perene, Cintriamide; Clomacran Phosphate, ; onate, AlgeStone Acetonide; Alpha Amylase, ; ; Clopipazan Mesylate; Cloroperone Hydro ; Amfenac Sodium; Amiprilose Hydrochloride; 65 chloride; Clothiapine; Clothixamide Maleate; ; Anakinra, Anirolac, AnitraZafen; ApaZone; BalsalaZide Cyclophenazine Hydrochloride; ; Disodium; Bendazac, ; Benzydamine Hydro Hydrochloride; Fenimide; ; ; US 6,323,236 B2 9 10 Decanoate, Flu phena Zine Enant hate; Pilocarpine Hydrochloride; Pilocarpine Nitrate; Pyridostig Fluphenazine Hydrochloride; Fluspiperone; ; mine Bromide. Flutroline; Hydrochloride; Halopemide; Halo Cholinergic agonist: Xanomeline, Xanomeline Tartrate. peridol; Decanoate, , Imidoline Cholinesterase Deactivator: Obidoxime Chloride; Prali Hydrochloride; ; Succinate; doxime Chloride; Pralidoxime Iodide; Pralidoxime Mesy ; Mesoridazine Besylate; ; Milenper late. one; Milipertine; Hydrochloride; CoccidioStat: Arprinocid; Narasin; Semduramicin; Sem Hydrochloride; Neflumozide Hydrochloride; ; duramicin Sodium. ; Oxiperomide; ; Pentiapine Maleate; Cognition adjuvant: MeSylates, Piracetam; ; ; Hydrochloride; Pipam 1O Pramiracetam Hydrochloride; Pramiracetam Sulfate; perone, , Palnitate; Tacrine Hydrochloride. Hydrochloride; Edisylate; Prochlorpera Cognition enhancer: Besipirdine Hydrochloride; Linopir zine Maleate; Hydrochloride; ; dine, Sibopirdine. Remoxipride Hydrochloride; Hydrochloride; Hormone: Diethylstilbestrol; ; 17 hydroxy Seperidol Hydrochloride; ; ; Spiper 15 progesterone; Medroxyprogesterone, ; Nor one; ; Thioridazine Hydrochloride; Thiothix ethynodrel; ; Megestrol (Megace); Norethindrone; ene; Thiothixene Hydrochloride; Tioperidone Hydrochlo ; Ethyndiol; Ethinyl estradiol; Mestranol; ride; Hydrochloride; Estrone, Equilin; 17 alpha dihydroequilin; equilenin; 17 Hydrochloride; ; Triflu promazine; Triflupro alpha dihydroequilenin; 17 alpha estradiol; 17 beta estradiol; mazine Hydrochloride; Hydrochloride. Leuprolide (lupron); Glucagon; ; Clomiphene; Appetite Suppressant: Dexfenfluramine Hydrochloride; Han memopausal gonadotropins, Human chorionic gona Phendimetrazine Tartrate; Phentermine Hydrochloride. dotropin; Urofollitropin; ; Gonadorelin; Blood glucose regulators: Human insulin; Glucagon; Luteinizing hormone releasing hormone and analogs, Gona TolaZamide, Tolbutamide; Chloropropamide, Acetohexam dotropins; ; , ; ide and Glipizide. 25 , Dihydroestosterone, Relaxin, Oxytocin, Carbonic anhydrase inhibitor: Acetazolamide, Acetazola Vasopressin; Folliculostatin; Follicle regulatory protein; mide Sodium, Dichlorphenamide; Dorzolamide Hydrochlo Gonadoctrinins, Oocyte maturation inhibitor; Insulin growth ride; Methazolamide; Sezolarmide Hydrochloride. factor, Follicle Stimulating Hormone, Luteinizing hormone; Cardiac depressant: Acecainide Hydrochloride, Acetyl Tamoxifen.; Corticorelin Ovine Triftutate; Cosyntropin; Chloride; Actisomide, Adenosine, Amiodarone; ; Pituitary, Posterior; Seractide Acetate; Somal Aprindine; Aprindine Hydrochloride; Artilide Fumarate; apor, Somatrem; Somatropin; Somenopor, Somidobove. Azimilide Dihydrochloride; Bidisomide; Bucainide Male Memory adjuvant: Dimoxamine Hydrochloride; Ribami ate; Bucromarone; Butoprozine Hydrochloride; Capobenate nol. Sodium; Capobenic Acid; Cifenline; Cifenline Succinate; Mental performance enhancer: Aniracetam. Clofilium Phosphate; Disobutamide; Disopyramide; Dis 35 Mood regulator: Fengabine. opyramide Phosphate; Dofetilide; Drobuline; Edifolone Neuroleptic: Duoperone Fumarate; . Acetate; Emilium Tosylate; Encainide Hydrochloride; Neuroprotective: Maleate. Flecainide Acetate; Ibutilide Fumarate; Indecainide Hydro Psychotropic: Minaprine. chloride; Ipazilide Fumarate; Lorajmine Hydrochloride; Relaxant: Adiphenine Hydrochloride; Alcuronium Chlo Lorcainide Hydrochloride; Meobentine Sulfate; 40 ride; Aminophylline; Azumolene Sodium; ; Ben Hydrochloride; Modecainide; Moricizine; Oxiramide; Pir Zoctamine Hydrochloride; ; Chlorphenesin menol Hydrochloride; Pirolazamide; Pranolium Chloride; ; ; Cinflumide, Cinnamedrine; Procainamide Hydrochloride; Propafenone Hydrochloride; Clodanolene; Hydrochloride; ; Pyrinoline; Quindonium Bromide; Gluconate; Dantrolene Sodium; Fenalanide; Fenyripol Hydrochloride; Quinidine Sulfate; Recainam Hydrochloride; Recainam 45 Fetoxylate Hydrochloride; Flavoxate Hydrochloride; Fle Tosylate; Risotilide Hydrochloride; Ropitoin Hydrochlo tazepam, Flumetramide;- Hydrochloride; ride; Sematilide Hydrochloride; Suricainide Maleate; Hexafluorenium Bromide; Isomylamine Hydrochloride; Tocainide; Tocainide Hydrochloride; Transcainide. Lorbamate; Mebeverine Hydrochloride; Mesuprine Hydro Cardiotonic: Actodigin; Amrinone; Bemoradan; Buto chloride; ; ; Methixene Hydro pamine; CarbaZeran; CarSatrin Succinate, Deslanoside; 50 chloride; Nafomine Malate; NeleZaprine Maleate; Papaver Digitalis, Digitoxin; Digoxin; Dobutamine; Dobutamine ine Hydrochloride; Pipoxolan Hydrochloride; Quinctolate; Hydrochloride; Dobutamine Lactobionate; Dobutamine Tar Ritodrine; Ritodrine Hydrochloride; Rolodine; Theophylline trate; Enoximone, ImaZodan Hydrochloride; Indolidan; Iso Sodium Glycinate; Thiphenamil Hydrochloride; Xilobam. mazole Hydrochloride; Levdobutamine Lactobionate; Lix -: ; Alonimid; ; azinone Sulfate; Medorinone; Milrinone; Pelrinone 55 Sodium; ; ; Butabar Hydrochloride; Pimobendan; Piroximone; Prinoxodan; bital; Sodium; ; Capuride; Carboclo Proscillaridin; Quazinone; Tazolol Hydrochloride; ral; Betaine; ; Vesnarinone. Hydrochloride; Cloperidone Hydrochloride; Clore thate; Cardiovascular agent: ; Dopexamine Hydro , Dexclamol Hydrochloride; , chloride. 60 ; ; ; ; Choleretic: Dehydrocholic Acid, Fencibutirol; Hymec Fenobam; , , Glute thimide; romone, Piprozolin; Sincalide, Tocamphyl. , , ; ; Cholinergic: Aceclidine; Bethanechol Chloride; Carba ; ; ; ; Pen chol; Demecarium Bromide; Dexpanthenol; Echothiophate tobarbital Sodium; , , , Iodide; Isoflurophate; Methacholine Chloride; Neostigmine 65 ; Roletamide; ; Secobarbital Bromide; Neostigmine Methylsulfate; Physostigmine; Phy Sodium; ; ; ; SoStigmine Salicylate; PhySoStigmine Sulfate; Pilocarpine; Maleate; ; Tricetamide; Sodium; Trime US 6,323,236 B2 11 12 toZine, , ; Hydrochloride; V. Treatment of other impulse control disorders Tartrate. (behavioral addictions) with reuptake Serotonin antagonist: Tartrate; , inhibitors, lithium, Valproic acid or divalproex Sodium ; . Serotonin inhibitor: Hydrochloride; Fenclo (e.g., DEPAKENE or DEPAKOTE), other nine; Fonazine Mesylate; Tosylate. , , atypical , Serotonin : Hydrochlo (e.g., Olanzapine (ZY PREXA), quetia pine ride. (SEROQUEL), risperidone (RISPERDAL), Stimulant: Amfonelic Acid; Sulfate; Ziprasidone) and other mood Stabilizers (e.g., Ampyzine Sulfate; Arbutamine Hydrochloride; Azabon; ) Caffeine; Ceruletide; Ceruletide Diethylamine; ; VI. Treatment of paraphilias/sexual addictions with sero Fumarate; Dextroamphetamine, Dextroamphet tonin reuptake inhibitors, lithium, divalproex Sodium/ amine Sulfate; Difluanine Hydrochloride; Dimefline Hydro chloride; Doxapram Hydrochloride; Etryptamine Acetate; Valproic acid, (e.g., Ethamivan; Fenethylline Hydrochloride; Flubanilate Hydro medroxyprogesterone, gonadotropin-releasing hor chloride; Flurothyl; Histamine Phosphate; Indriline Hydro 15 mone (GnRH) agonists), other antidepressants, and chloride; Mefexamide; Hydrochloride; other mood Stabilizers (e.g., carbamazepine). Hydrochloride; Pemoline; Pyrovalerone When administered, the formulations of the invention are Hydrochloride; Xamoterol; Xamoterol Fumarate. Synergist: applied in pharmaceutically acceptable amounts and in Hydrochloride. pharmaceutically acceptable compositions. Such prepara Thyroid hormone: Levothyroxine Sodium; Liothyronine tions may routinely contain Salts, buffering agents, Sodium; Liotrix. preservatives, compatible carriers, and optionally other Thyroid inhibitor: Methimazole; Propyithiouracil. Thyromimetic: Thyromedan Hydrochloride. therapeutic ingredients. When used in medicine the Salts Cerebral ischemia agents: Hydrochloride. should be pharmaceutically acceptable, but non Vasoconstrictor: Angiotensin Amide, Felypressin, Methy pharmaceutically acceptable Salts may conveniently be used Sergide, Maleate. 25 to prepare pharmaceutically acceptable Salts thereof and are Vasodilator: Alprostadil; AZaclorzine Hydrochloride; not excluded from the Scope of the invention. Such phar Bamethan Sulfate; Bepridil Hydrochloride; Buterizine; macologically and pharmaceutically acceptable Salts Cetiedil Citrate; Chromonar Hydrochloride; Clonitrate; Dil include, but are not limited to, those prepared from the tiazem Hydrochloride; Dipyridamole; Droprenilamine; following acids: hydrochloric, hydrobromic, Sulfuric, nitric, Erythrityl Tetranitrate; ; Hydrochlo phosphoric, maleic, acetic, Salicylic, p- Sulfonic, ride; Fostedil; Hexobendine; Inositol Niacinate; Iproxamine tartaric, citric, methane Sulfonic, formic, malonic, Succinic, Hydrochloride; Isosorbide Dinitrate; Isosorbide Mononi naphthalene-2-Sulfonic, and benzene Sulfonic. Also, phar trate; IsoxSuprine Hydrochloride; Lidoflazine; Mefenidil; maceutically acceptable Salts can be prepared as alkaline Mefenidil Fumarate; Mibefradil Dihydrochloride; Miofla 35 metal or alkaline earth Salts, Such as Sodium, potassium or zine Hydrochloride; Mixidine; Nafronyl Oxalate; Nicar calcium Salts. dipine Hydrochloride; ; Nicorandil; Nicotinyl Suitable buffering agents include: acetic acid and a Salt Alcohol; ; ; Nisoldipine; Oxfenicine; Hydrochloride; Pentaerythritol Tetranitrate; (1-2% W/V); citric acid and a salt (1–3% W/V); boric acid Pentoxifylline; Pentrinitrol; Perhexiline Maleate; ; and a salt (0.5-2.5% W/V); and phosphoric acid and a salt Pirsidomine; Prenylamine; Propatyl Nitrate; Suloctidil; 40 (0.8–2% W/V). Suitable preservatives include benzalko Terodiline Hydrochloride; Tipropidil Hydrochloride; Tola nium chloride (0.003–0.03% W/V); Zoline Hydrochloride; Xanthinol Niacinate. (0.3–0.9% W/V); parabens (0.01-0.25% W/V) and thime Specifically, topiramate may be administered in combi rosal (0.004–0.02% W/V). nation with other medications to treat certain Symptoms and In the present invention, the Sulfamide derivatives are disorders including: 45 administered in Safe and effective amounts. An effective I. Treatment of Binge Eating (Binge Eating Disorder, amount means that amount necessary to delay the onset of, Bulimia Nervosa, Anorexia Nervosa with Binge eating) inhibit the progression of, halt altogether the onset or with Serotonin re-uptake inhibitors (e.g., progression of or diagnose the particular condition being (CELEXA), clomipramine (ANAFRANIL)), fluoxet 50 treated. In general, an effective amount for treating an ICD ine (PROZAC), fluvoxamine (LUVOX), venlafaxine will be that amount necessary to inhibit mammalian Symp (EFFEXOR), other antidepressants (e.g., bupropion toms of the particular ICD in-situ. When administered to a (WELLBUTRIN) nefazodone (SERZONE), Subject, effective amounts will depend, of course, on the (e.g., NORPRAMIN and PAMELOR), trazodone particular condition being treated; the Severity of the con (DESY REL), Substance P antagonists), 55 dition; individual patient parameters including age, physical psychoStimulants, (e.g., d-amphetamine, phentermine; condition, Size and weight, concurrent treatment; frequency and sibutramine (MERIDIA)) and orlistat. of treatment; and the mode of administration. These factors II. Treatment of overweight/obesity condition with are well known to those of ordinary skill in the art and can Sibutramine (MERIDIA); psychostimulants, (e.g., be addressed with no more than routine experimentation. It d-amphetamine, phentermine) and orlistat. 60 is preferred generally that a minimum dose be used, that is, III. Treatment of nicotine addiction/smoking cessation the lowest Safe dosage that provides appropriate relief of with bupropion (ZYBAN), serotonin reuptake Symptoms. inhibitors, nicotine patches and gun, and other antide Dosage may be adjusted appropriately to achieve desired preSSants. drug levels, locally or Systemically. Generally, daily oral IV. Treatment of alcohol abuse/dependence (alcoholism) 65 doses of active compounds will be from about 0.01 mg/kg with naltrexone (REVIA), serotonin reuptake per day to 2000 mg/kg per day. It is expected that IV doses inhibitors, and other antidepressants. in the range of about 1 to 1000 mg/cm per day will be US 6,323,236 B2 13 14 effective. In the event that the response in a Subject is insufficient at Such doses, even higher doses (or effective TABLE 1. higher doses by a different, more localized delivery route) Patients with Binge Eating Disorder (BED) Treated Clinically with may be employed to the extent that patient tolerance permits. Open-Label Topiramate (as of 12/16/98 Continuous IV dosing over, for example 24 hours or mul Reasons Max tiple doses per day is contemplated to achieve appropriate Pt Topiramate Dose Systemic levels of compounds. # Pt ID Begun (mg/day) Response

A variety of administration routes are available. The 1 LM BD 12OO Remission of BD particular mode Selected will depend of course, upon the 1O (BED) Remission of BED particular drug selected, the Severity of the disease State(s) (Obesity) Loss of 107 lbs. being treated and the dosage required for therapeutic effi 2 CE BD 150 Mild improvement of BD, cacy. The methods of this invention, generally speaking, BED Moderate decrease of BED, Overweight Loss of 5 lbs. may be practiced using any mode of administration that is Discontinued due to sedation, medically acceptable, meaning any mode that produces 15 cognitive dulling effective levels of the active compounds without causing 3 JAC BD 12OO Moderate improvement of B.D. clinically unacceptable adverse effects. Such modes of BED Remission of BED Obesity Loss of 50.5 lbs administration include oral, rectal, Sublingual, topical, nasal, 4 JEB BD 900 Moderate improvement of BD, transdermal or parenteral routes. The term "parenteral' BED Marked improvement of BED, includes Subcutaneous, intravenous, intramuscular, or infu Overweight Loss of 30.5 lbs. Sion. Intravenous routes are preferred. 5 KCW BED 1OO First trial: No response of BED, Obesity discontinued due to GI distress The compositions may conveniently be presented in unit Compulsive dosage form and may be prepared by any of the methods Buying well known in the art of pharmacy. In general, the compo (BD, in 1OO Sitions are prepared by uniformly and intimately bringing 25 remission) the compounds into association with a liquid carrier, a finely Second Trial: Worsening of BD Remission of BED divided Solid carrier, or both, and then, if necessary, Shaping Loss of 11 lbs. the product. Remission of Compulsive Compositions Suitable for oral administration may be Buying presented as discrete units Such as capsules, cachets, tablets, 6 JB BED 1OO No response of BED or lozenges, each containing a predetermined amount of the Overweight No weight change active compound. Other compositions include Suspensions Key: BD = Bipolar Disorder: BED = Binge Eating Disorder; Pt. = patient; in aqueous liquors or non-aqueous liquids Such as a Syrup, DfC = topiramate treatment discontinued; Cont.= topiramate treatment an elixir, or an emulsion. 35 continued; GI = gastrointestinal Other delivery Systems can include time-release, delayed release or Sustained release delivery Systems. Such Systems TABLE 2 can avoid repeated administrations of the active compounds of the invention, increasing convenience to the Subject and Patients with Overeating, Overweight, and Obesity Treated Clinically with the physician. Many types of release delivery Systems are 40 Topiramate (as of 12/16/98 available and known to those of ordinary skill in the art. Reasons Max They include polymer based Systems. Such as polylactic and Pt Topiramate dose polyglycolic acid, polyanhydrides and polycaprolactone; # Pt ID Begun (mg/day) Response nonpolymer Systems that are lipids including Sterols Such as 1 BAA BD 700 No response of BD 45 Obesity Loss of 9 lbs. (293-284) , cholesterol esters and fatty acids or neutral fats (BED, in Such as mono-, di and triglycerides, hydrogel release SyS remission) tems, Silastic Systems, peptide based Systems, wax coatings, 2 HTB BD 3OO Remission of BD compressed tablets using conventional binders and Overeating Remission of overeating Overweight Loss of 16 lbs. (248-232) excipients, partially fused implants and the like. In addition, 50 Discontinued 2 illness in a pump-based hardware delivery System can be used, Some remission of which are adapted for implantation. 3 AD, BD 400 Moderate improvement of BD Along-term Sustained release implant also may be used. Overeating, Moderate improvement of "Long-term' release, as used herein, means that the implant Overeating is constructed and arranged to deliver therapeutic levels of 55 Overweight Loss of 7 lbs. (239-232) the active ingredient for at least 30 days, and preferably 60 4 TK BD 350 No response of BD Overeating Mild improvement in overeating days. Long-term Sustained release implants are well known Overweight Loss of 5 lbs. (238-233) to those of ordinary skill in the art and include some of the 5 JCJ BD 1. 250 First Trial: Worsening of BD release Systems described above. Overeating 2. 200 Mild decrease of overeating Overweight Loss of 7 lbs. (152-145) 60 Second Trial Mild improvement of EXAMPLES BD Mild decrease of overeating In the examples, patients were treated with open-label Gain of 1 lb. (154–155 lbs.) 6 KDC Overeating 800 Worsening of BD topiramate Starting at 25 mg/qHS and the dosage increased Overweight Loss of 9 lbs. (208-199 lbs) by the patient in 25 mg increments as tolerated by the 65 (BD, in Subjects until a response is seen up to a maximum of 1200 remission) mg. US 6,323,236 B2 15 16 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-L- TABLE 2-continued fructopyranose Sulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- Patients with Overeating, Overweight, and Obesity Treated Clinically with fructopyranose methylsulfamate; Topiramate (as of 12/16/98 5 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- Reasons Max fructopyranose butylsulfamate; Pt Topiramate dose 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- # Pt ID Begun (mg/day) Response fructopyranose ethylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- 7 NLR BD 3OO Worsening of BD fructopyranose octylsulfamate; Overweight Loss of 46 lbs. (196-150 lbs.) Discontinued due to anorexia 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- 8 PR BD 700 Moderate improvement of BD fructopyranose 2-propenylsulfamate; Overeating Marked improvement in overeating 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- Overweight Loss of 19 lbs. (185-166) fructopyranose phenylmethylsulfamate; Discontinued due to 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- G.I. Distress 15 fructopyranose cyclopropylsulfamate; Key: Pt. = patient; BD = Bipolar Disorder; BED = Binge Eating Disorder; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- DfC = topiramate treatment discontinued; cont = topiramate treatment con fructopyranose cyclobutylsulfamate; tinued; GI = gastrointestinal 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- What is claimed is: fructopyranose (2,2,2-trifluoroethyl)sulfamate; 1. A method for treating an Impulse Control Disorder 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- comprising administering to a mammal afflicted with Such fructopyranose dimethylsulfamate; condition a therapeutically effective amount for treating 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- Such condition of a compound of the formula I: fructopyranose diethylsulfamate; 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- (I) 25 fructopyranose azido Sulfamate; (S)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl-beta-D- CHOSONHR1 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-methylethylide ne)-4, 5-O-N-(4- wherein methylbenzenesulfonyl)imidosulfonyl)-beta-D X is CH or oxygen; -fructopyranose Sulfamate; R is hydrogen or alkyl, and 35 2,3-O-(1-methylethylide ne)-4, 5-O-N-(4- R2, R, R and Rs are independently hydrogen or lower methylbenzenesulfonyl)imidosulfonyl)-beta-D- alkyl and, when X is CH, R and Rs may be alkene fructopyranose Sulfamate; groups joined to form a benzene ring and, when X is 2,3-O-(cyclohexylidene)-4,5-O-sulfonyl-beta-D- oxygen, R and R and/or R and Rs together may be fructopyranose Sulfamate; a methylenedioxy group of the follow formula (II): 40 (S)-4,5-O-N-(1,1-dimethylethoxycarbonyl)imidosulfinyl 2,3-O-(1-methylethylidene)-beta-D-fructopyranose (II) Sulfamate, and the pharmaceutically acceptable Salts R N/O thereof. C N 45 3. The method of claim 1 wherein the compound is R7 O selected from the group consisting of (1R,2R,3S,4S)-(1,2:3, 4-di-O-methylethylidenecyclohexan-1,2,3,4-tetrahydroxy 4-yl)methyl sulfamate and (1R,2S,3S,4S)-(3,4-O- wherein methylethylidene-1,2-O-sulfinylcyclohexan-1,2,3,4- Re and R7 are the same or different and are hydrogen, tetrahydroxy-4-yl)methyl sulfamate. lower alkyl or are alkyl and are joined to form a 50 4. The method of claim 1 wherein the compound of cyclopentyl or cyclohexyl ring; formula I is topiramate. wherein the Impulse Control Disorder is selected from the 5. The method of claim 1, wherein the therapeutically group consisting of intermittent explosive disorder (ED), effective amount is of from about 15 to about 2000 mg per kleptomania, pathological gambling, pyromania, day. trichotillomania, compulsive buying or Shopping, repetitive 55 6. The method of claim 1, wherein the therapeutically Self-mutilation, nonparaphilic Sexual addictions, Severe nail effective amount is of from about 25 to about 750 mg per biting, compulsive skin picking, personality disorders with day. impulsive features, attention deficit/hyperactivity disorder, 7. The method of claim 1 wherein the compound is used Binge Eating Disorder, bulimia nervosa, anorexia nervosa in conjunction with one or more other drug compounds with binge eating and Substance use disorders. 60 Selected from the group consisting of adrenergics, adreno 2. The method of claim 1 wherein the compound is cortical , adrenocortical SuppreSSants, aldosterone Selected from the group consisting of antagonists, amino acids, analeptics, , anorectic compounds, anorexics, anti-anxiety agents, antidepressants, 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose antihypertensives, anti-inflammatoryS, antinause ants, Sulfamate; 65 antineutropenics, antiobsessional agents, antiparkinsonians, 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-beta-D- antipsychotics, appetite Suppressants, blood glucose fructopyranose Sulfamate; regulators, carbonic anhydrase inhibitors, cardiotonics, car US 6,323,236 B2 17 18 diovascular agents, choleretics, cholinergics, cholinergic wherein agonists, cholinesterase deactivators, cognition adjuvants, R and R, are the same or different and are hydrogen, cognition enhancers, hormones, memory adjuvants, mental lower alkyl or are alkyl and are joined to form a performance enhancers, mood regulators, neuroleptics, cyclopentyl or cyclohexyl ring; neuroprotectives, psychotropics, relaxants, Sedative 5 , Serotonin antagonists, Serotonin inhibitors, Sero wherein the Impulse Control Disorder is selected from the tonin receptor antagonists, Stimulants, thyroid hormones, group consisting of intermittent explosive disorder (IED), thyroid inhibitors, thyromimetics, cerebral ischemia agents, kleptomania, pathological gambling, pyromania, vasoconstrictors, and vasodilators. trichotillomania, compulsive buying or Shopping, repetitive 8. The method of claim 1 wherein the Impulse Control Self-mutilation, nonparaphilic Sexual addictions, Severe nail Disorder is an eating disorder and the compound is used in biting, compulsive skin picking, personality disorders with conjunction with one or more other drug compounds impulsive features, attention deficit/hyperactivity disorder, Selected from the group consisting of Serotonin re-uptake Binge Eating Disorder, anorexia nervosa with binge eating inhibitors, antidepressants, psychoStimulants, and orlistat. and Substance use disorders. 9. The method of claim 1 wherein the Impulse Control 14. A method for treating an Impulse Control Disorder Disorder is a nicotine addiction condition and the compound 15 comprising administering to a mammal afflicted with Such is used in conjunction with one or more other drug com condition a therapeutically effective amount for treating pounds Selected from the group consisting of bupropion, Such condition of a compound of the formula I: Serotonin reuptake inhibitors, nicotine, and antidepressants. 10. The method of claim 1 wherein the Impulse Control (I) Disorder is an alcohol abuse/dependence condition and the compound is used in conjunction with one or more other CHOSONHR drug compounds Selected from the group consisting of naltrexone, Serotonin reuptake inhibitors, and other antide preSSants. 11. The method of claim 1 wherein the Impulse Control 25 Disorder is a behavioral addiction condition and the com pound is used in conjunction with one or more other drug compounds Selected from the group consisting of Serotonin wherein reuptake inhibitors, lithium, Valproic acid or divalproex X is CH or oxygen; Sodium, other antidepressants, naltrexone, atypical R is hydrogen or alkyl, and antipsychotics, and other mood Stabilizers. 12. The method of claim 1 wherein the Impulse Control R2, R, R and Rs are independently hydrogen or lower Disorder is a paraphilias/sexual addiction condition and the alkyl and, when X is CH2, R and Rs may be alkene compound is used in conjunction with one or more other groups joined to form a benzene ring and, when X is drug compounds Selected from the group consisting of Oxygen, R2 and R and/or R and Rs together may be Serotonin reuptake inhibitors, lithium, divalproex Sodium/ 35 a methylenedioxy group of the following formula (II): Valproic acid, antiandrogen agents, other antidepressants, and other mood Stabilizers. (II) 13. A method for treating an Impulse Control Disorder comprising administering to a mammal afflicted with Such condition a therapeutically effective amount for treating 40 Such condition of a compound of the formula I: (I) wherein Re and R7 are the same or different and are hydrogen, CHOSONHR1 45 lower alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring, wherein the Impulse Control Disorder is bulimia nervosa. 15. A method for treating an Impulse Control Disorder characterized by binge eating, wherein the Impulse Control 50 Disorder is Selected from the group consisting of Binge wherein Eating Disorder, Bulimia Nervosa and Anorexia Nervosa with Binge Eating, Said method comprising administering to X is CH or oxygen; a human afflicted with Such a disorder, a therapeutically R is hydrogen or alkyl, and effective amount of topiramate in combination with one or R2, R, R and Rs are independently hydrogen or lower more drug compounds Selected from the group consisting of alkyl and, when X is CH2, R and Rs may be alkene 55 Serotonin re-uptake inhibitors, antidepressants, groups joined to form a benzene ring and, when X is psychoStimulants, orlistat, and Sibutramine. oxygen, R2 and R and/or R and Rs together may be 16. A method for treating an Impulse Control Disorder a methylenedioxy group of the following formula (II): characterized by binge eating, wherein the Impulse Control Disorder is Selected from the group consisting of Binge (II) 60 Eating Disorder, Bulimia Nervosa and Anorexia Nervosa with Binge Eating, Said method comprising administering to Re a human afflicted with Such a disorder, a therapeutically N effective amount of topiramate in combination with a Sero R7 O tonin re-uptake inhibitor.

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