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Wo 2007/128674 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 15 November 2007 (15.11.2007) PCT WO 2007/128674 A2 (51) International Patent Classification: Houtenlaan 36, NL-1381 CP Weesp (NL). KRUSE, Cor- A61K 31/00 (2006.01) A61K 31/551 (2006.01) nelis G. [NL/NL]; c/o SOLVAY PHARMACEUTICALS A61K 31/439 (2006.01) A61P 25/18 (2006.01) B.V., IPSI Department, CJ. Van Houtenlaan 36, NL-1381 A61K 31/4439 (2006.01) CP Weesp (NL). (21) International Application Number: (74) Agent: VERHAGE, Marinus; Octrooibureau Zoan B.V., PCT/EP2007/053934 NL-1380 AC Weesp (NL). (22) International Filing Date: 23 April 2007 (23.04.2007) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, (25) Filing Language: English CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, (26) Publication Language: English IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY,MA, MD, MG, MK, MN, MW, MX, MY, (30) Priority Data: MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, 061 13476.3 4 May 2006 (04.05.2006) EP RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, 60/797,355 4 May 2006 (04.05.2006) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (71) Applicant (for all designated States except US): SOLVAY (84) Designated States (unless otherwise indicated, for every PHARMACEUTICALS B.V. [NL/NL]; CJ. Van Houten kind of regional protection available): ARIPO (BW, GH, laan 36, NL-1381 CP Weesp (NL). GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (72) Inventors; and European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (75) Inventors/Applicants (for US only): DE BRUIN, FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, MT, NL, PL, Natasja M.WJ. [NL/NL]; c/o SOLVAY PHARMACEU PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, TICALS B.V, IPSI Department, Cj. Van Houtenlaan 36, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). NL-1383 CP Weesp (NL). VAN DRIMMELEN, Marlies L. [NL/NL]; c/o SOLVAY PHARMACEUTICALS B.V, Published: IPSI Department, CJ. Van Houtenlaan 36, NL-1381 CP — without international search report and to be republished Weesp (NL). HERREMANS, Arnoldus HJ. [NL/NL]; upon receipt of that report c/o SOLVAY PHARMACEUTICALS B.V, IPSI D e partment, CJ. Van Houtenlaan 36, NL-1381 CP Weesp For two-letter codes and other abbreviations, refer to the "G uid (NL). TULP, Martinus ThJVI. [NL/NL]; c/o SOLVAY ance Notes on Codes and Abbreviations" appearing at the beg in PHARMACEUTICALS B.V, IPSI Department, CJ. Van ning of each regular issue of the PCT Gazette. (54) Title: MUSCARINIC AGONISTS TO TREAT IMPULSE CONTROL DISORDERS (57) Abstract: The invention relates to a novel use of compounds and pharmaceutically acceptable salts thereof, which are mus carinic, in particular muscarine- 1 (M 1) agonists. These compounds are useful for the preparation of medicaments for treatment, amelioration or prevention of impulse control disorders. These include impulse control disorders "Not Elsewhere Classified' such as intermittent explosive disorder, pyromania, kleptomania, pathological gambling and trichotillomania; and impulse control disorders "Not Otherwise Specified' such as: compulsive buying disorder, binge eating and binge drinking disorder, impulsive self-injurious behaviour such as pathological skin picking, nail-biting and nose-picking, gouging, head banging and self- biting; paraphilic sexual addictions, including exhibitionism, fetishism, frotteurism, pedophilia, masochism, sadism, transvestic fetishism and voyeurism; compulsive Internet use and excessive mobile phone use. MUSCARINIC AGONISTS TO TREAT IMPULSE CONTROL DISORDERS BACKGROUND OF THE INVENTION An impulsive person is apt to be moved by a sudden impulse. This behaviour often is associated with a lack of self-control. Impulsivity therefore, has a substantial impact on individuals as well as on society. Impulse control disorders (ICD's) are characterized by failure to resist an impulse, drive or temptation to perform an act that is harmful to the person or to others. In most cases, 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 or may not be regret or guilt. Impulse control disorders are a separate group of psychiatric disorders, listed in the "Diagnostic and Statistical Manual of Mental Disorders" (DSM-IV) of the American Psychiatric Association as a residual category consisting of impulse control disorders 'Not Elsewhere Classified' (NEC) and impulse control disorders 'Not Otherwise Specified' (NOS). The first consist of: intermittent explosive disorder, pyromania, kleptomania, pathological gambling and trichotillomania. No specific disorders are mentioned in DSM-IV under the heading: 'impulse control disorders NOS', but this group is defined as "a category for disorders of impulse control that do not meet the criteria for any specific impulse control disorder or for any other mental disorder having features involving impulse control (such as borderline, antisocial, histrionic and narcissistic personality disorders)". In the scientific and patent literature a number of such impulse control disorders, also referred to as 'atypical impulse control disorders', are described, for instance: compulsive buying disorder, binge eating and binge drinking disorder, impulsive self-injurious behaviour such as pathological skin picking, nail-biting and nose-picking, gouging, head banging and self- biting; paraphilic sexual addictions, lack of control of a person's sexual impulses, include exhibitionism, fetishism, frotteurism, pedophilia, masochism, sadism, transvestic fetishism and voyeurism, as well as compulsive Internet use and excessive mobile phone use. Patients suffering form impulse control disorder have been treated by psychotherapy, behaviour modification, hypnosis, relaxation therapy and administration of varied pharmaceutical preparations, the latter with little or no success. Historically, impulse control disorders have been considered refractory to known pharmacological or psychotherapeutic treatments. Therefore, a continuing need exists for agents thatt will be effective to treat the symptoms associated with ICD's, either by eliminating or by reducing them. In different patent and patent applications a variety of molecular mechanisms are claimed to be of therapeutic value in impulse control disorders: opioid antagonists (US 5,780,479), anticonvulsants (WO 02/43731 ); (US serotonin antagonists 2001023254); 5-HT 1A agonists (WO 94/13659), serotonin reuptake inhibitors (WO 92/18005) and cannabinoid antagonists (US 2004/ 0077650). Muscarinic agonists have been claimed as treatment for cognitive impairment, psychosis, affective disorders, mania, and behavioural disorders (WO 2006/067494, WO 2006/017614 and EP 0525 879) as well as for the treatment of tics, tremors and related disorders (US 2004/1 16505). These disorders are quite distinct from impulse control disorders (DSM-IV) DETAILED DESCRIPTION OF THE INVENTION The goal of the present invention is to develop drugs for the therapy of impulse control disorders, which have a mechanism of action different from that of drugs currently on the market, and which are likely to improve impulsivity control without negative effects on attention and concentration. Surprisingly, muscarinic agonists were found active in an animal model predictive of impulsive behavior in humans: the attenuation of MK801 induced increase of anticipatory responses of rats in the -Choice-Serial-Reaction-Time task, an effect associated with impulsive behavior (Cole, 1987; Ruotsalainen, 2000). Muscarinic agonists are active at doses in the range of 0.1 - 100 mg/kg after oral administration, and their unique pharmacological profile clearly indicates therapeutic potential in impulse control disorders. In a preferred embodiment, the invention embraces the following muscarinic agonists: AF-150, AF-151 , alvameline, ACP-104, CDD-34, CDD-98, CDD-0097, CDD-0102, CDD-190, CDD-0199- J, CDD-0235-J, CDD-0304, cevimeline, CPR-2006, CS-932, desmethylclozapine, FPL-14995, FPL-15467, KAD-193R, L-680648, L-687306, L-689660, MCNa-343, milameline, nebracetam, NGX-267, PD-151832, sabcomeline, SDZ-21 0-086, SR-46559A, talsaclidine fumarate, tazomeline, xanomeline, YM-796 and YM-954. Most preferred is the use of the muscarinic agonist xanomeline The compounds of the invention of the general formula ( 1 ), as well as the pharmacologically acceptable salts thereof, have muscarinic receptor agonistic activity. They are useful in treating impulse control disorders, including intermittent explosive disorder, pyromania, kleptomania, pathological gambling, trichotillomania, compulsive buying disorder, binge eating and binge drinking disorder, impulsive self-injurious behaviour such as pathological skin picking, nail-biting and nose-picking, gouging, head banging and self-biting; paraphilic sexual addictions, including exhibitionism, fetishism, frotteurism, pedophilia, masochism, sadism, transvestic fetishism and voyeurism; compulsive Internet use and excessive mobile phone use. DEFINITIONS DSM-IV: IMPULSE CONTROL DISORDERS NOT ELSEWHERE CLASSIFIED (NEC) Intermittent explosive
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