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WO 2017/037079 Al 9 March 2017 (09.03.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/037079 Al 9 March 2017 (09.03.2017) P O P C T (51) International Patent Classification: (74) Agent: COLLIN, Matthieu; 7 rue Watt, 75013 Paris (FR). A61K 31/55 (2006.01) A61P 25/02 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/EP20 16/070449 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (22) Date: International Filing DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 3 1 August 2016 (3 1.08.2016) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (26) Publication Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (30) Priority Data: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 15306342.5 1 September 2015 (01.09.2015) EP TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicants: INSERM (INSTITUT NATIONAL DE LA (84) Designated States (unless otherwise indicated, for every SANTE ET DE LA RECHERCHE MEDICALE) kind of regional protection available): ARIPO (BW, GH, [FR/FR]; 101, rue de Tolbiac, 75013 Paris (FR). UNI- GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, VERSITE DE MONTPELLIER [FR/FR]; 163, rue Au- TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, guste Broussonnet, 34090 Montpellier (FR). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventors: SCAMPS, Frederique; INSERM - UMR LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 1051, Hopital Saint Eloi, 80 rue Augustin Fliche, 34090 SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Montpellier (FR). RAOUL, Cedric; INSERM - UMR GW, KM, ML, MR, NE, SN, TD, TG). 1051, Hopital Saint Eloi, 80 rue Augustin Fliche, 34090 Montpellier (FR). BOWERMAN, Melissa; INSERM - Published: UMR 105 1, Hopital Saint Eloi, 80 rue Augustin Fliche, — with international search report (Art. 21(3)) 34090 Montpellier (FR). o o o (54) Title: A 5-H-DIBENZ[B,F]AZEPINE-5-CARBOXAMIDE DERIVATIVE FOR USE IN A METHOD FOR PREVENTING OR TREATING ANDERMANN SYNDROME (57) Abstract: The invention relates to a 5H-dibenz[b,fJazepine-5-carboxamide derivative such as carbamazepine (CBZ) for use in a method for preventing or treating Andermann syndrome. A 5-H-DIBENZ[B,F]AZEPINE-5-CARBOXAMIDE DERIVATIVE FOR USE IN A METHOD FOR PREVENTING OR TREATING ANDERMANN SYNDROME FIELD OF THE INVENTION: The invention relates to a 5H-dibenz[b,fJazepine-5-carboxamide derivative such as carbamazepine (CBZ) for use in a method for preventing or treating Andermann syndrome. BACKGROUND OF THE INVENTION: Andermann syndrome is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by peripheral neuropathy with variable agenesis of the corpus callosum (ACCPN) , hypotonia and amyotrophy and is caused by mutations within the cation-chloride cotransporter KCC3 4. KCC3-deficient mice reproduce the typical ACCPN sensorimotor histophysiopathology 4 6 , displaying impaired locomotor and sensorimotor gating capacities and decreased peripheral nerve conduction 4 . Axonal swelling, neurodegeneration and hypomyelination of the sciatic nerve seem to account for the peripheral neuropathy 4 6' . Both enveloping glial cells and demyelinating events were proposed as responsible for reduced nerve conduction and neurodegeneration in ubiquitously-deleted KCC3 mice and patients 4' ' . However, sciatic nerve analysis from neuron-specific KCC3-deleted mice reveals that neuronal loss of KCC3 is sufficient to induce peripheral neuropathy . These findings thus support a cell-autonomous role for KCC3 in neurons, implying that the phenotype of ubiquitous mutant mice illustrates a primarily neuronal-dependent neuropathy. KCC3 belongs to the family of cation-chloride cotransporters coded by the Slcl2a genes 10 . In the nervous system, the Slcl2a gene family comprises five members coding for one inwardly directed Na+-K+-2C1 cotransporter (Slcl2a2 for NKCC1), and four outwardly directed K+-C1 cotransporters, (Slcl2a4-7 for KCCl-4, respectively) . These membrane proteins are responsible for various functions such as cell volume regulation and maintenance of intracellular chloride concentration [Cl ]i. In neurons, only NKCC1, KCC2 and KCC3 have been shown to regulate the [Cl ]i (reviewed in 12). As a regulator of [Cl ]i, KCC3 could participate in the establishment and/or maintenance of spinal cord synaptic networks 5' 13 ' 14 . Indeed, additional molecular mechanisms linking KCCs to electrical activity and ionic homeostasis have recently emerged. Of interest is the demonstrated interaction between Na+/K+-ATPase a2 and KCC2 in synaptic membrane fractions 15 as well as between the KCC3a isoform and the Na+/K+-ATPase a l in gastric parietal cells . The Na+/K+-ATPase is an ion pump essential for the maintenance of cellular electrochemical gradients (reviewed in 17) and neuromuscular junction (NMJ) organization 18 . Moreover, although axonal swelling is a hallmark of Andermann syndrome, it is surprising that the functionally related volume regulators KCC1 and KCC4 do not compensate for the loss of KCC3. In addition, impaired locomotor and sensorimotor gating capacities occur prior to axonal degeneration, suggesting that neuronal loss is in fact a consequence of the primary pathological mechanisms that cause Andermann syndrome 4. SUMMARY OF THE INVENTION: In a first aspect, the invention relates to a 5H-dibenz[b,f]azepine-5-carboxamide derivative for use in a method for preventing or treating Andermann syndrome. DETAILED DESCRIPTION OF THE INVENTION: The invention relies on the unexpected discovery that KCC3 deletion induces profound structural modifications at the NMJ and skeletal muscle atrophy, prior to any spinal motoneuron degeneration. The inventors show that Andermann syndrome is not related to a chloride imbalance but most likely due to aberrant localization and decreased activity of the Na+/K+-ATPase a l in the motoneuron soma. Thus, combined with the functional analysis of nerve-evoked muscle contraction in ACCPN patients, the present results highlight motoneuron-dependent defects as central in Andermann syndrome. More importantly, the inventors show that chronic carbamazepine (CBZ) treatment in vivo restores the normal expression of the Na+/K+-ATPase l at the plasma membrane of spinal motoneuron of Slcl2a6 mice and prevents, in vitro, the loss of activity-dependent plateau accommodation that occurs in Slcl2a6 ' motoneurons at a concentration ineffective on action potential amplitude. Importantly, CBZ partly prevents the denervation at the neuromuscular junction which makes this compound a therapeutically valuable tool for the treatment of Andermann syndrome. Accordingly, in a first aspect, the invention relates to a 5H-dibenz[b,f]azepine-5- carboxamide derivative for use in a method for preventing or treating Andermann syndrome. In one embodiment of the invention, said derivative is a voltage-gated sodium channel (VGSC) blocker. In one embodiment of the invention, said derivative is an anticonvulsant or antiepileptic drug. In one embodiment of the invention, said derivative is a tricyclic antidepressant. In one embodiment of the invention, said derivative is a compound of Formula (I): wherein Rl and R2 are independently selected from H, alkyl, hydroxyalkyl, amino, alkylamino, nitro, oxo, cyano, acyloxy preferably acetoxy, halogen, trifluoromethyl and hydroxy groups, and pharmaceutically acceptable salts thereof. 5H-dibenz[b,f]azepine-5-carboxamide derivatives and the syntheses for preparing them are known in the art and have been extensively described (see for instance U.S. Pat. No. 3,643,775; U.S. Pat. No. 3,367,667) and U.S. Pat. No. 4,076,812). In one particular embodiment, the compound of Formula (I) is carbamazepine (5H- dibenz[b,f]azepine-5-carboxamide, CBZ, marketed as Tegretol® by Novartis), which is a widely used anticonvulsant agent having the structural formula: The 5H-dibenz[b,f]azepine-5-carboxamide derivatives may be substituted or unsubstituted at the 10- or 11-position. The 10 or 11-positions may be substituted with, alkyl, hydroxyalkyl, amino, alkylamino, nitro, oxo, cyano, acyloxy such as acetoxy, halogen, trifluoromethyl and hydroxy groups, preferably oxo, acetoxy, or hydroxy groups. When there is an oxo, acetoxy or a hydroxy group at the 10-position, the 11-position is preferably unsubstituted and vice versa. Accordingly, in addition to carbamazepine (5H-dibenz[b,f]azepine-5-carboxamide), examples of suitable compounds of the general formula I are: 10-oxo-10,l l-dihydro-5H- dibenz[b,f]azepine-5-carboxamide (cf. U.S. Pat. No. 3,643,775) and 10-hydroxy-10,l 1- dihydro-5H-dibenz[b,f]azepine-5-carboxamide (cf. U.S. Pat. No. 3,367,667) as well as 10- fluoro-, 10-chloro- and 10-bromo-5H-dibenz[b,fJazepine-5-carboxamide (cf. U.S. Pat. No. 4,076,812), and 10-cyano-5H-dibenz[b,fJazepine-5-carboxamide. Preferred compounds are selected from carbamazepine (Tegretol®) (CBZ), oxacarbazepine (Trileptal ®), eslicarbazepine acetate (Zebinix®) (ESL). In one embodiment, the compound of Formula (I) is oxcarbazepine (10-oxo-10,ll- dihydro-5H-dibenz[b,f]azepine-5-carboxamide, OXC, marketed as Trileptal® by Novartis), which is also used as an anticonvulsant agent having the structural formula: In one embodiment, the compound of Formula (I) is eslicarbazepine acetate ((S)-(-)- 10-Acetoxy-10,ll-dihydro-5H-dibenz[b,fJazepine-5-carboxamide, ESL, marketed as Aptiom® or Zebinix® by Eisai) which is an also used anticonvulsant agent having the structural formula: Oral forms of 5H-dibenz[b,f]azepine-5-carboxamide derivatives arc well known to the skilled i the art and are suitable for repeated administration over a prolonged period of treatment to ensure a uniform concentration of active agent in the blood.
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