(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 12 April 2007 (12.04.2007) WO 2007/039869 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/16 (2006.01) A61P 25/32 (2006.01) kind of national protection available): AE, AG, AL, AM, A61P 25/30 (2006.01) A61P 25/36 (2006.01) AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, (21) International Application Number: GB, GD, GE, GH, GM, HN, HR, HU, ID, IL, IN, IS, JP, PCT/IB2006/053603 KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LV,LY,MA, MD, MG, MK, MN, MW, MX, MY, MZ, (22) International Filing Date: 3 October 2006 (03.10.2006) NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, (25) Filing Language: Italian TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (30) Priority Data: ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), TO2005A000691 4 October 2005 (04. 10.2005) IT European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, (71) Applicant (for all designated States except US): ROT- RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, TAPHARM S.p.A. [IT/IT]; Galleria Unione 5, 1-20122 GN, GQ, GW, ML, MR, NE, SN, TD, TG). Milano (IT). Declarations under Rule 4.17: (72) Inventors; and — as to applicant's entitlement to apply for and be granted a (75) Inventors/Applicants (for US only): MAKOVEC, patent (Rule 4.17(U)) Francesco [IT/IT]; Via Silvio Pellico 14, 1-20050 Lesmo — of inventor ship (Rule 4.17 (iv)) (milano) (IT). CASELLI, Gianfranco [IT/IT]; Via Giu- ditta Sidoli 22, 1-20129 Milano (IT). ROVATI, Lucio Published: Claudio [IT/IT]; Via Ramazzotti 1, 1-20052 Monza (m i — without international search report and to be republished lano) (IT). GIORDANI, Antonio [IT/IT]; Via Cesare upon receipt of that report Angelini 64/d, 1-27100 Pavia (IT). For two-letter codes and other abbreviations, refer to the "G uid (74) Agents: RAMBELLI, Paolo et al.; Corso Emilia 8, ance Notes on Codes and Abbreviations" appearing at the beg in 1-10152 Torino (IT). ning of each regular issue of the PCT Gazette. (54) Title: USE OF NEBOGLAMINE IN THE TREATMENT OF TOXICODEPENDENCY (57) Abstract: Use of neboglamine, (S)-4-amino-N (4, 4-dimethyl-cyclohexyl) glutamic acid (CR 2249) (CAS Registry Number 163000-63-3) , the racemic mixture thereof or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in the treatment of toxicodependency induced by drugs such as CNS sedatives such as opiates, barbiturates, benzodiazepines, alcohol, stimulants such as amphetamines and cocaine, and hallucinogens such as LSD, mescalin, cannabis (marijuana) or fencyclidine. Use of neboglamine in the treatment of toxicodependency The present invention relates to a novel use of (S) -4-amino- N- (4,~4-dimethylcyclohexyl) glutamic acid (CR 2249-neboglamine) (CAS Registry Number 163000-63-3) , the racemic mixture thereof or a pharmaceutically acceptable salt thereof, for use in the treatment of toxicodependency induced by drugs such as Central Nervous System (CNS) sedatives such as opiates, benzodiazepines, barbiturates, alcohol, stimulants such as amphetamines and cocaine, and hallucinogens such as LSD, mescalin, cannabis (marijuana) or fencyclidine. The term "toxicodependency", whether physical or psychological, means the continued and totally implicit use of a drug. Such a use involves the risk of physical damage and the need to stop or limit the consumption of the substance, whether or not the drug taker is in agreement. The term "psychological dependency" means an irresistible impulse (compulsion) to continue self-administering the drug in order to find pleasure. For certain drugs, the psychological dependency is the most important factor in their compulsive use. The term "physical dependency" means a state of habituation to the drug accompanied by tolerance and that is manifested by abstinence syndromes . Tolerance is the need to increase the dose of the drug in order to obtain the same effects as were initially obtained with lower doses; the abstinence syndrome is characterized by painful physical sensations that are manifested when the taking of the drug is stopped. The substances commonly used b y drug takers all induce psychological dependency, while others (the majority) also induce physical dependency. The following groups may b e distinguished: CNS sedatives such a s opiates, benzodiazepines, barbiturates and alcohol, which also all induce physical dependency and tolerance; CNS stimulants, for instance amphetamine and cocaine which induce physical dependency t o a minor extent, if at all; hallucinogens such a s LSD, mescalin, cannabis (marijuana) and fencyclidine. O n the basis o f published preclinical data, the compound neboglamine (CR 224 9 ) has been shown t o have significant modulatory properties on the glycine site (strychnine- insensitive) coupled t o the NMDA receptor complex [Lanza e t a l ., Neuropharmacology 3j5_, 1057-64 (1997)], and also advantageous properties o f promoting memory and learning in various animal models [Garofalo et al. J . Pharm. Pharmacol. 8_, 1290-97 (1996)]. The facilitatory activity exerted b y neboglamine on the NMDA receptor complex should b e o f therapeutic use in conditions o f glutamatergic hypof unctionality . It has been suggested that the NMDA receptor complex may b e involved in a variety o f functional responses t o cocaine, for instance locomotor activity, dependency (continued reinforcement o f self-administration) , tolerance and toxicity (Rockhold R .W., Progress in Drug Research 50j_ 155-92, 1998). It has also recently been demonstrated that glycine i s capable o f inhibiting the locomotor hyperactivity, tolerance and dependency induced b y morphine in mice (K. W . Shin e t a l ., Arch. Pharm. Res. _26 _ 1074-1078, 2003). Thus, neboglamine was evaluated in animal experimental models that may b e considered as predictive for the evaluation of toxicodependency induced by various drugs such as cocaine, morphine and benzodiazepines, which are widely representative of the syndromes caused b y toxicodependency. In the first model used, the inhibitory effect of neboglamine and glycine on the hypermotility induced by cocaine and morphine in rats was evaluated. T-he .motor activity was measured with a video camera and recorded using the Videotrack 512 system as described b y Garofalo (J. Pharm. Pharmacol. 48j_ 1290-1297, 1996). Physiological saline, neboglamine (30 mg/kg) or glycine (300 mg/kg) were administered via the i.p. route 30 minutes before physiological saline, morphine (10 mg/kg s.c.) or cocaine (20 mg/kg s.c). The locomotor activity was recorded for 15 minutes and the total distance covered (in cm) by the animal was recorded b y the computer connected to the video camera. The results thus obtained are collated in Table 1 . Table 1 : Inhibitory activity of neboglamine and glycine on the locomotor hyperactivity induced by cocaine and morphine Glycine (G) 300+F 2900 (-)12.1 - Cocaine (C) F+20 5800 75.7 - Morphine (M) F+10 5300 60.6 - N+C 30+20 3600 9.1 88 .0 ' N+M 30+10 3750 13.6 77 .5 U I G+M 300+10 4250 28.8 52 .5 (1) : The %inhibition i s calculated by the formula: <2) : The % inhibition is calculated by the formula: C + )J Dn -Fπ x m From the data given in Table 1 , it may be seen that both cocaine and morphine show a marked increase in locomotor activity (75.7% and 60.6%, respectively), whereas neboglamine and glycine do not significantly alter the spontaneous motility of the animal. The motor activity accelerated by both •the drugs cocaine and morphine is almost completely antagonized by doses of 30 mg/kg i.p. of neboglamine (88% and 77 .5%, respectively). Glycine also inhibits the morphine-induced hyperkinetic activity, but with a smaller effect (52.5%) and at doses 10 times higher (300 mg/kg as opposed to 30 mg/kg of neboglamine) . In a second experiment, the capacity of neboglamine to inhibit the increased sensitivity (inverse tolerance) induced in rats was evaluated by chronic treatment with morphine. Neboglamine (30 mg/kg) or physiological saline were administered via the i.p. route 30 minutes before morphine (10 mg/kg s.c.) for 6 days. On the seventh day, the test was performed, as described in the preceding experiment, in comparison with a group of animals treated with the same dose of morphine given acutely only on the 7th day (final day of the experiment) . The results thus obtained are collated in Table 2 . Table 2 : Inhibitory activity of neboglamine on the inverse tolerance induced by chronic treatment with morphine in rats The % inhibition is calculated b y the formula: [MC -(MC +N)] Chronic treatment with morphine induces an increase in the motor activity of the rat, compared with the acute effect of the drug, by about 50% (128.6% as opposed to 80.3%). Chronic pre-treatment with neboglamine (30 mg/kg i.p for 7 days) succeeds in almost- completely antagonizing (70.8%) the development of the inverse tolerance induced by the chronic treatment with morphine.