Compounds for the treatment of mitochondrial diseases

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:

in which

R 1 represents a halogen atom, in particular Cl or Br, a C1-C4 alkoxy group, a C1-C3 alkyl group, or NHSO 2 R 6 ;

R 2 represents OH or H;

R 3 and R 4 independently of one another represent an alkyl group having 1 to 10 carbon atoms or

in which R 7 represents a hydrogen atom, a halogen atom, a C1-C4 alkoxy group, a C1-C3 alkyl group, or NHSO 2 R 8 ;

R 6 and R 8 independently of one another represent a C1-C4 alkyl group;

—X═—R 5 or the non-bonded electron pair of nitrogen, on the condition that i=+ when —X═—R 5 ;

R 5 represents a hydrogen atom or a C1-C4 alkyl group;

m=0 or 1, on the condition that m=1 when —X═—R 5 and m=0 when —X═ the non-bonded electron pair of nitrogen;

n=0, 1, 2 or 3;

Y − is a therapeutically acceptable anion, in particular Y − is selected from the tosylate ion, the carbonate ion, the phosphate ion, and the chloride ion.

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

in which

R 1 represents Cl, Br, or NHSO 2 R 6 ;

R 2 represents OH or H;

R 3 and R 4 independently of one another represent an alkyl group

having 1 to 10 carbon atoms or

where R 7 represents a halogen atom or NHSO 2 R 8 , on the condition that R 3 and R 4 cannot simultaneously be

R 6 and R 8 independently of one another represent a C1-C4 alkyl group;

—X═—R 5 or the non-bonded electron pair of nitrogen, on the condition that i=+ when —X═—R 5 ;

R 5 represents a C1-C4 alkyl group;

m=0 or 1, on the condition that m=1 when —X═—R 5 and m=0 when —X=the non-bonded electron pair of nitrogen;

n=0, 1, 2 or 3;

Y − is selected from the tosylate ion, the carbonate ion, the phosphate ion and the chloride ion.

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

or of formula Iab:

in which R2, R3, R4, —X, R5,

Y—, m and n have the meanings indicated in claim 1 .

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

or of formula (b):

or of formula (c):

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

or of formula (b):

or of formula (c):

and is present in the form of a unit dose of from 30 μg to 6000 mg.

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

or of formula (b):

or of formula (c):

and is present in the form of a unit dose of from 30 μg to 6000 mg, for oral administration,

or is present in the form of a unit dose of from 30 μg to 6000 mg, for intravenous administration.

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

and is present in the form of a unit dose of from 1.5 mg to 60 mg for oral administration,

or present in the form of a unit dose of from 0.5 mg to 30 mg, for intravenous administration.

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

and is present in the form of a unit dose of from 125 to 500 μg, for oral administration.

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

and is present in the form of a unit dose of from 150 to 2500 μg, for intravenous administration.

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.