(19) TZZ Z _T (11) EP 2 540 295 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 02.01.2013 Bulletin 2013/01 A61K 31/404 (2006.01) A61P 25/00 (2006.01) A61P 25/28 (2006.01) (21) Application number: 11171532.2 (22) Date of filing: 27.06.2011 (84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • Briault, Sylvain GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO 45000 ORLEANS (FR) PL PT RO RS SE SI SK SM TR • Perche, Olivier Designated Extension States: 45380 LA CHAPELLE SAINT MESMIN (FR) BA ME (74) Representative: Thomas, Dean et al (71) Applicants: Cabinet Ores • Centre national de la recherche scientifique 36 rue de St Pétersbourg 75016 Paris (FR) 75008 Paris (FR) • Centre Hospitalier Régional d’Orléans 45032 Orléans Cédex 1 (FR) (54) Compositions for the treatment of Fragile X syndrome (57) The present invention relates to a composition a fluoro-oxindole or a chloro- oxindole for use in the treat- comprising a maxi-K potassium channel opener the use ment of fragile X syndrome. in the treatment of fragile X syndrome. More specifically the present invention relates to a composition comprising EP 2 540 295 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 540 295 A1 2 Description ularly shyness, limited eye contact, memory problems and difficulty with facial encoding and recognition. Many [0001] The present invention relates to compositions individuals with FXS also meet the diagnostic criteria for for the alleviation of neuropsychiatric symptoms and in autism. Most females who have the syndrome experi- particular those of Fragile X syndrome. 5 ence symptoms to a lesser degree because of their sec- [0002] Neuropsychiatry is the branch of medicine deal- ond X-chromosome; however, females can develop ing with mental disorders attributable to diseases of the symptoms just as severe as their male counterparts. nervous system, this discipline is closely related to neu- While full mutation males tend to present with severe rology but neurology and neuropsychiatry are typically intellectual disability, the symptoms of full mutation fe- practiced separately. Neurology is a medical specialty 10 males run the gamut of minimally affected to severe in- dealing with disorders of the nervous system such as tellectual disability, which may explain why females are pathologies of the central, peripheral and autonomic under diagnosed relative to males, leading to the persist- nervous systems, as well as the connective tissue asso- ence of the anomaly in the population. ciated with the nervous system. [0009] At the present time no medicament has been [0003] The basis of neuropsychiatric conditions can be 15 approved for the treatment of FXS. due to a single gene aberration or a combination of sev- [0010] FXS is considered an important therapeutic tar- eral mutations and/or environmental cues. get firstly as it is the most common form of mental retar- [0004] An example of a neuropsychiatric disorder dation attributable to a single gene mutation and also caused by a single gene aberration is Fragile X syndrome because as the development of drugs to treat neuropsy- (FXS). FXS or Martin-Bell syndrome, is a genetic syn- 20 chiatric diseases such as mental retardation or autism is drome which results in a spectrum of characteristic phys- becoming an increasingly important commercial objec- ical and intellectual limitations as well as a number of tive, an approach based upon looking at single- gene dis- emotional and behavioral aberrations which range from orders and the use of these as a window into the field severe to mild in manifestation. In particular sufferers of treating of neuropsychiatric diseases such as mental re- FXS can present symptoms of mental disorder upon the 25 tardation or autism is one of the most attractive develop- autism spectrum as well as epilepsy. ment strategies available. [0005] FXS is the most common form of mental disa- [0011] Workers seeking the means to treat FXS have bility (MD) due to a genetic defect. In 5 to 25% MD is shown that excessive glutamate accumulates at the syn- associated with behavioral disorders in the autism spec- apse of a mouse model of FXS and is responsible for the trum. With a prevalence of 1/1000 males and 1/4000 fe- 30 cognitive deficits seen in this mouse model of FXS (Huber males, in France a country of approximately 60 million K.M. et al. Proc. Natl. Acad. Sci. U. S. A. 99, 7746-7750 people, more than 40,000 FXS patients are currently un- (2002)). Workers also found that reducing expression of dergoing treatment. a specific glutamate receptor, mGluR5, reverses these [0006] The molecular basis of FXS is an abnormal ex- symptoms in the animal model (Dölen G. et al. Neuron pansion of a CGG triplet located at Xq27 in the 5’ un- 35 56, 955-962 (2007)). translated region of the FMR1 gene, which leads to a [0012] As a consequence of this work mGluR5 inhibi- decrease in transcription of the gene. There are three tors were developed, notably by Merck & Co Inc and sub- generally accepted states of the chromosome region in- sequently have been taken into clinical trials. volved in FXS which relate to the length of the repeated [0013] A second class of drug exemplified by arba- CGG sequence: Normal (29-31 CGG repeats) (not af- 40 clofen, has also been proposed which stimulates recep- fected by the syndrome), Premutation (55-200 CGG re- tors of gamma amino-butyric acid(B) or GABA(B) and peats) (not affected by the syndrome), Full Mutation thereby dampens glutamate signaling. Clinical trials are (more than 200 CGG repeats) (affected). also underway to test arbaclofen on children and adults [0007] The FMR protein (FMRP) acts as a suppressor with fragile X syndrome, as well as an open- label trial of of translational activity particularly in neuronal dendrites 45 children with autism. that control the localization and expression of a set of [0014] The Applicants have now discovered a further synaptic specific proteins. It has been proposed that the class of drugs which can be used to specifically treat the loss of negative feedback as a consequence of the drop symptoms of FXS and also may be generally applicable in FMRP production, results in abnormalities in the struc- to the treatment and alleviation of the symptoms of autism ture and functioning of the synapses which in turn cause 50 spectrum disorder and/or other classes of neuropsychi- the FXS phenotype. atric disorders. [0008] Aside from intellectual disability, prominent [0015] In particular the Applicants have investigated characteristics of FXS include an elongated face, large the effects of agents which act upon potassium channels or protruding ears, flat feet, larger testes (mac-as the means to treat the symptoms of specifically FXS roorchidism) and low muscle tone. Speech may include 55 and more generally those of autism. cluttered or nervous speech patterns. Behavioral char- [0016] Surprisingly the inventors have established that acteristics may include stereotypic movements (e.g., this class of compound can reverse characteristic symp- hand-flapping) and atypical social development, partic- toms associated with FXS and therefore in accordance 2 3 EP 2 540 295 A1 4 with a first aspect of the present invention therefore there 130015), indole carboxylates such as Indole-3-carboxy- is provided a composition comprising a maxi-potassium lic acid (CGS 7181, CGS 7184), Arylpyrrole (NS 8), Di- channel opener for use in the treatment of a neuropsy- hydrosoyasaponin-1 (DHS-1), Terpene, Cerebroside chiatric disorder. (Baifuzi), Mallotoxine (Rottlerin), Arylquinoline, Aryloxin- [0017] In accordance with this aspect of the present 5 dole, Pimaric acid (PiMa), Dichlorodehydroabietic (diCl- invention the neuropsychiatric disorder may in particular DHAA), Flavonoid (Naringenin, Phloretin), Benzofuroin- show symptoms/behaviors characteristic of autism spec- dole (LDD 175), Benzimidazolinone (1-EBIO), Fluoro trum disorders. propionamide [(S)-N-(4-benzoylphenyl)-3,3,3-trifluoro- [0018] The autism spectrum, also called autism spec- 2-hydroxy-2-methyl-propionamide], Unoprostone (and trum disorders (ASD) or autism spectrum conditions10 unoprostone isopropyl), Benzothiadiazolamine [6-(trif- (ASC), is a spectrum of neuropsychiatric conditions char- luoromethoxy) benzothiazol-2-amine], ethylbromide acterized by widespread abnormalities of social interac- tamoxifen, epoxyeicosatrienoic acid, estradiol-17 beta, tions and communication, as well as restricted interests Diphenylurea (NS 1608). and repetitive behavior. [0024] One class of potassium channel openers which [0019] Specifically in accordance with the present in- 15 selectively function on cells having high intracellular cal- vention there is provided a composition comprising a cium concentrations are 3- phenyl substituted oxindol de- maxi-K potassium channel opener for use in the treat- rivatives, as described in U. S. Patent Nos. 5,565,483 ment of fragile X syndrome. and 5,602,169. Halo-oxindoles such as fluoro-oxindole [0020] In accordance with the present invention a and chloro-oxindole compounds are within the above- Maxi-K channel also known as a BK channel (Big Potas- 20 described class and are capable of acting selectively as sium) or slol or BKCa (Big Potassium Calcium) channel, maxi-K channel openers on cells having high intracellular are ion channels characterized by their large conduct- calcium concentration. ance of potassium ions (K+) through cell membranes. [0025] This class of potassium channel opener has These channels are activated (opened) by changes in been characterized as being sensitive to the intracellular membrane electrical potential and/or by increases in con- 25 calcium concentration of cells and demonstrated to be centration of intracellular calcium ion (Ca 2+). Opening of most effective under conditions of increased intracellular maxi-K channels allows K + to passively flow through the calcium concentrations, e.g.