WO2019045121A1 – March 7, 2019 – TREATMENT OF CNS CONDITIONS

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Inventors :

NISHI, Toshiya - c/o Ovid Therapeutics Inc., 1460 Broadway, Suite 15021, New York, NY 10036; KONDO, Shinichi - c/o TAKEDA PHARMACEUTICAL COMPANY LIMITED, 26-1, Muraoka-Higashi 2-chome, Fujisawa-shi, Kanagawa, 2510012

Owner :

TAKEDA PHARMACEUTICAL COMPANY LIMITED

Application Number :

WOJP18032949

Document Number :

WO2019045121A1

Priority Date :

August 31, 2017

Filing Date :

August 30, 2018

Date of Grant/ Publication :

March 7, 2019

Class :

A61K31 / 444; A61P25 / 08

Abstract

Aspects of the present invention relate to a method of treating an epileptic encephalopathy in a mammal in need thereof, comprising administering a composition comprising an effective amount of (4-benzyl-4-hydroxypiperidin-l-yl) (2, 4′ – bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof to the mammal.

Claim(s)

1. A method of treating an epileptic encephalopathy in a mammal in need thereof, comprising administering a composition comprising an effective amount of (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4 ‘ -bipyridin-3-yl ) methanone or a pharmaceutically acceptable salt thereof to the mammal.;
2. The method of claim 1, wherein the epileptic encephalopathy is selected from the group of Dravet syndrome, Early myoclonic encephalopathy, Epilepsy with continuous spike-and-waves during slow-wave sleep other than Landau- Kleffner syndrome, epilepsy of infancy with migrating focal seizures, Hypothalamic epilepsy, Landau-Kieffner syndrome, Lennox-Gastaut syndrome, Doose syndrome, Myoclonic status in non-progressive encephalopathies, Ohtahara syndrome or early infantile epileptic encephalopathy, West syndrome, Glycine encephalopathy, 15q duplication syndrome and Tuberous Sclerosis Complex and seizures associated with mutations in CHD2, Cyclin-Dependent Kinase-Like 5, SCNlA, SCN2A, SCN8A, ARX, KCNA1, KCNA2, KCNTl, KCNQ2, HCNl, PCDH19, GRIN1, GRIN2A and GRIN2B.;
3. The method of claim 1, wherein the epileptic encephalopathy is selected from the group of Dravet syndrome, Lennox-Gastaut syndrome, Tuberous Sclerosis Complex and seizures associated with mutations in CHD2, Cyclin-Dependent Kinase-Like 5, SCNlA, SCN2A, SCN8A, ARX, KCNAl, KCNA2, KCNTl, KCNQ2, HCNl, PCDH19, GRINl, GRIN2A and GRIN2B .;
4. The method of claim 1, wherein administering the effective amount of (4-benzyl-4-hydroxypiperidin-l-yl) (2, 4 ‘ – bipyridin-3-yl) methanone or a pharmaceutically acceptable salt thereof results in (i) a reduction in the frequency of seizures in the mammal and/or (ii) a reduction in the plasma 24HC levels in the mammal.;
5. The method of claim 1, wherein the effective amount of (4-benzyl-4-hydroxypiperidin-l-yl) (2,4* -bipyridin-3- yl)methanone or a pharmaceutically acceptable salt thereof is administered orally.;
6. The method, of claim 1, wherein the effective amount of (4-benzyl-4-hydroxypiperidin-l-yl) (2,4’ -bipyridin-3- yl)methanone or a pharmaceutically acceptable salt thereof is administered as a single unit dose.;
7. The method of claim 6, wherein the single unit dose is at least about 0.8 mg/kg.;
8. The method of claim 6, wherein the single unit dose is between about 2 mg/kg and about 12 mg/kg.;
9. The method of claim 6, wherein the single unit dose is selected from the consisting of about 0.8mg/kg, about 2 mg/kg, about 3 mg/kg, about 3. 33 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 10 mg/kg, and about 12 mg/kg.;
10. The method of claim 1, wherein the effective amount of (4-benzyl-4-hydroxypiperidin-l-yl) ( 2 , 4 ‘ -bipyridin-3- yl)methanone or a pharmaceutically acceptable salt thereof is administered according to a dose regimen of either twice a day or once a day dosing.;
11. The method of claim 1, wherein the mammal is a human.;
12. The method of claim 11, wherein the human is an adult, a juvenile, a child, or an infant.;
13. The method of claim 11, wherein the effective amount of (4-benzyl-4-hydroxypiperidin-l-yl) (2,4′ -bipyridin-3- yl) methanone or a pharmaceutically acceptable salt thereof is administered as a single unit dose.;
14. The method of claim 13, wherein the single unit dose is less than about 1350 mg.;
15. The method of claim 13, wherein the single unit dose is between about 50 mg and about 800 mg.;
16. The method of claim 13, wherein the single unit dose is between about 100 mg and about 800 mg.;
17. The method of claim 13, wherein the single unit dose is selected from the group consisting of about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg and about 800 mg.;
18. The method of claim 11, wherein the effective amount of (4-benzyl-4-hydroxypiperidin-l-yl) (2,4’ -bipyridin-3- yl) methanone or a pharmaceutically acceptable salt thereof is administered twice a day.;
19. The method of claim 18, wherein (4-benzyl-4- hydroxypiperidin-l-yl) ( 2 , 4 ‘ -bipyridin-3-yl ) methanone is administered at the daily dose of between about 100 mg and about 800 mg.;
20. The method of claim 18, wherein (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4 ‘ -bipyridin-3-yl ) methanone is administered according to a dose regimen selected from the group consisting of about 50 mg twice a day, about 100 mg twice a day, about 200 mg twice a day, about 300 mg twice a day and about 400 mg twice a day.;
claim 21: 21. The method of claim 18, wherein (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4 ‘ -bipyridin-3-yl ) methanone ‘is administered according to a dose regimen of about 400 mg twice a day.;
claim 22: 22. The method of claim 1, further comprising administering an additional composition comprising an effective amount of an additional anti-epileptic drug.;
claim 23: 23. The method of claim 22, wherein the additional anti- epileptic drug is selected from the group of acetazolamide , brivaracetam, bromide, cannabidiol, carbamazepine, clobazam, clonazepam, diazepam, eslicarbazepine acetate, ethosuximide, felbamate, fosphenytoin sodium, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, mephenytoin, methlyphenobarbital, methosuximide, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital , phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, fenfluramine, vigabatrin, and zonisamide.;
claim 24: 24. The method of claim 1, wherein the composition further comprises one or more of an additional anti-epileptic drug and a pharmaceutically acceptable carrier.;
claim 25: 25. The method of claim 24, wherein the additional anti- epileptic drug is selected from the group of acetazolamide, brivaracetam, bromide, cannabidiol, carbamazepine, clobazam, clonazepam, diazepam, eslicarbazepine acetate, ethosuximide, felbamate, fosphenytoin sodium, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, mephenytoin, methlyphenobarbital, methosuximide, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.;
claim 26: 26. A pharmaceutical composition comprising (4-benzyl-4- hydroxypiperidin-l-yl) (2, 4 ‘ -bipyridin-3-yl ) methanone or a pharmaceutically acceptable salt thereof, which is for treating an epileptic encephalopathy.;
claim 27: 27. ( 4-Benzyl-4-hydroxypiperidin-l-yl ) ( 2 , 4 ‘ -bipyridin-3- yl)methanone or a pharmaceutically acceptable salt thereof for use in treatment of epileptic encephalopathy.

Summary

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