US 12,226,394 B2
Treatment of mitochondrial diseases
Julien David Beyrath, Nijmegen (NL); and Johannes Albertus Maria Smeitink, Beuningen (NL)
Assigned to Khondrion IP B.V., Beuningen (NL)
Filed by Khondrion IP B.V., Beuningen (NL)
Filed on Feb. 16, 2022, as Appl. No. 17/672,731.
Application 17/672,731 is a division of application No. 16/500,437, granted, now 11,285,130, previously published as PCT/EP2017/072172, filed on Sep. 5, 2017.
Claims priority of application No. 17165012 (EP), filed on Apr. 5, 2017.
Prior Publication US 2022/0265604 A1, Aug. 25, 2022
Int. Cl. A61K 31/355 (2006.01); A61K 9/00 (2006.01); A61K 45/06 (2006.01)
CPC A61K 31/355 (2013.01) [A61K 9/0053 (2013.01); A61K 9/0095 (2013.01); A61K 45/06 (2013.01)] 20 Claims
 
1. A method of treating or suppressing symptoms associated with a mitochondrial disorder or with a disease or condition associated with mitochondrial dysfunction by administration of a total daily dose in the range of about 10 to 1000 mg of a compound represented by general structure (I):

OG Complex Work Unit Chemistry
wherein,
T is represented by structure (IIIa) or (IIIb):

OG Complex Work Unit Chemistry
wherein each R7 is individually a C1-C6 alkyl moiety;
N* is represented by structure (IIa) or (IIb)

OG Complex Work Unit Chemistry
R1 and R2 are each independently selected from hydrogen (H), C1-C6 alkyl or C1-C6 alkenyl, or R1 and R2 are joined together and thus form a second linker between the amide nitrogen atom and the distal nitrogen atom, or R1 is joined with a backbone atom of the linker L in a cyclic structure and/or R2 is joined with a backbone atom of the linker L in a cyclic structure;
R3 is selected from hydrogen (H), C1-C6 alkyl or C1-C6 alkenyl, wherein the alkyl or alkenyl moiety may be substituted with one or more halogen atoms, hydroxyl moieties or (halo)alkoxy moieties, or R3 is absent when the distal nitrogen atom is part of an imine moiety; and
R4 is selected from hydrogen (H) or C1-C6 alkyl, wherein the alkyl moiety may be substituted with one or more halogen atoms or (halo)alkoxy moieties;
X is an anion;
wherein the mitochondrial disorder is a disorder selected from the group consisting of: Myoclonic epilepsy; Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Leber's Hereditary Optic Neuropathy (LHON); neuropathy ataxia and retinitis pigmentosa (NARP); Mitochondrial Myopathy, Encephalopathy, Lactic acidosis, Stroke-like episodes (MELAS); Leigh syndrome; Leigh-like syndrome; Dominant Optic atrophy (DOA); Kearns-Sayre Syndrome (KSS); Maternally Inherited Diabetes and Deafness (MIDD); Alpers-Huttenlocher syndrome; Ataxia Neuropathy spectrum: Chronic Progressive External Ophthalmoplegia (CPEO); Pearson syndrome; Mitochondrial Neuro-Gastro-Intestinal Encephalopathy (MNGIE); Sengers syndrome: 3-methylglutaconic aciduria, sensorineural deafness, encephalopathy and neuro-radiological findings of Leigh-like syndrome (MEGDEL); myopathy; mitochondrial myopathy; cardiomyopathy; and encephalomyopathy, SURF1 (COX deficient Leigh syndrome due to complex IV surfeit protein deficiency) and isolated or combined OXPHOS deficiencies with so far unsolved genetic defect including disturbed pyruvate oxidation and ATP plus PCr production rates; and
wherein the disease or condition associated with mitochondrial dysfunction is a disease or condition selected from the group consisting of: Friedreich's Ataxia (FRDA); renal tubular acidosis; Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis (ALS); Huntington's disease; developmental pervasive disorders: hearing loss; deafness; ageing; and adverse drug effects hampering mitochondrial function.