Compounds for the treatment of mitochondrial diseases

• US 10,639,287 B2
• Filed: 12/01/2015
• Issued: 05/05/2020
• Est. Priority Date: 12/02/2014
• Status: Active Grant

• Current Assignee: Centre Hospitalier Universitaire d'Angers, Centre National De La Recherche Scientifique, Universite Paris - Sud
• Original Assignee: Universite Paris - Sud
• Inventors: Delahodde, Agnes, Pitayu, Laras Ajeng, Baruffini, Enrico, Lodi, Tiziana, Rotig, Agnes, Procaccio, Vincent
• Primary Examiner(s): Lundgren, Jeffrey S
• Assistant Examiner(s): Strong, Tori
• Application Number:
  US15/532,011
• Publication Number:
  US 20170266136A1
• Time in Patent Office: 1,617 Days
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/14 Quaternary ammonium compounds, e.g. edrophonium, choline betaines A61K31/205
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Disclosed is a compound of formula (Ia) for the use thereof in the treatment or prevention of diseases relating to the instability of mitochondrial DNA.

Claims

1. Method for the treatment of diseases relating to the instability of mitochondrial DNA comprising administering to a patient having instability of mitochondrial DNA a compound of formula Ia:

2. Method according to claim 1 wherein the compound is of formula Ia:

3. Method according to claim 1, wherein the compound is of formula Iaa:

4. Method according to claim 1, wherein the compound is of formula (a):

5. Method according to claim 1, wherein the compound is of formula (a):

6. Method according to claim 1, wherein the compound is of formula (a):

7. Method according to claim 1, wherein the compound is of formula (a):

8. Method according to claim 1, wherein the compound is of formula (b):

9. Method according to claim 1, wherein the compound is of formula (c):

10. Method according to claim 1, for the treatment of diseases relating to at least one mutation, or at least one deletion or at least one insertion, or a combination thereof, in the POLG gene, or of diseases relating to the instability of mitochondrial DNA not associated with mutations of the POLG gene, or of diseases associated with a depletion or a deletion of mitochondrial DNA, or of diseases associated with a point mutation of mitochondrial DNA.

11. Method according to claim 1, for the treatment

of diseases associated with quantitative or qualitative abnormalities of mitochondrial DNA, such as Alpers disease (AHS), childhood myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), spinocerebellar ataxia with epilepsy (SCAE), ataxia with neuropathy syndromes including MIRAS and SANDO, autosomal recessive progressive external ophthalmoplegia (arPEO), autosomal dominant progressive external ophthalmoplegia (adPEO), mitochondrial neurogastrointestinal encephalopathy (MNGIE), Pearson syndrome, Kearns-Sayre syndrome, infantile myopathy and spinal muscular atrophy relating to TK2 mutations, liver failure with depletion of mtDNA, pathologies associated with mutations of the genes SUCLA2 and SUCLAG1, RRM2B, AIF1, MPV17, or

of diseases associated with point mutations of mitochondrial DNA, such as Leber hereditary optic neuropathy, MELAS syndrome, MERRF syndrome, and some forms of Leigh syndrome, chronic progressive external ophthalmoplegia, myopathy, cardiomyopathy, diabetes-deafness, encephalomyopathy, and deafness.

12. Method according to claim 1, for the treatment of MELAS syndrome.