THERAPEUTIC COMPOUNDS AND METHODS

• US 20200131119A1
• Filed: 04/20/2018
• Published: 04/30/2020
• Est. Priority Date: 04/21/2017
• Status: Active Grant

• Current Assignee: University of Tasmania
• Original Assignee: University of Tasmania
• Inventors: GUVEN, Nuri, SMITH, Jason, WOOLLEY, Krystel Lee, NADIKUDI, Monila
• Granted Patent: US 10,934,253 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: C07C 233/11 with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/22 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/47 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/51 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 323/52 the carbon skeleton being acyclic and saturated
• CPC Class Codes: C07C 46/00 Preparation of quinones
• CPC Class Codes: C07C 50/32 the quinoid structure being part of a condensed ring system having two rings
• CPC Class Codes: C07C 51/353 by isomerisation; by change of size of the carbon skeleton
• CPC Class Codes: C07C 57/50 containing condensed ring systems
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Abstract

The invention relates to compounds of Formula (I) and methods for their preparation. Also described are pharmaceutical compositions comprising a compound of Formula (I) and their use in the treatment or prevention of conditions associated with mitochondrial dysfunction. Formula (I)

Claims

1. A compound of Formula (Ib):

2. A compound according to claim 1 wherein R⁶ is optionally substituted C₆ aryl.

3. A compound according to claim 1, wherein R⁶ is dimethoxy phenyl, preferably 3,4-dimethoxy phenyl.

4. A compound according to claim 1 wherein R⁵ is H.

5. A compound according to claim 1 wherein R⁵ is methyl.

7. A pharmaceutical composition comprising a compound according to any one of the preceding claims.

8. A pharmaceutical composition according to claim 7 further comprising an additional active agent.

9. A pharmaceutical composition according to claim 8 wherein the additional active agent is an anti-diabetic agent.

10. A method of treating or preventing a disease or disorder associated with mitochondrial dysfunction, comprising administering to a person in need thereof, a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 7,

wherein the disease or disorder associated with mitochondrial dysfunction is selected from the group consisting of Leber'"'"'s hereditary optic neuropathy (LHON), dominant optic neuropathy (DOA), Leigh syndrome, Friedreich'"'"'s ataxia, mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), myoneurogenic gastrointestinal encephalomyopathy (MNGIE), Kearns-Sayre syndrome, CoQ.10 deficiency, mitochondrial complex deficiencies, Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP), spinocerebellar ataxias, ataxia telangiectasia, ataxia oculomotor apraxia 1 and 2 (AOA1 and 2), epileptic seizures, amyotrophic lateral sclerosis (ALS), motor neuron disease (MND), Parkinson'"'"'s disease, Alzheimer'"'"'s disease, Huntington'"'"'s disease, stroke/reperfusion injury, or dementia, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Limb-Girdle muscular dystrophy (LGMD), X-linked dilated cardiomyopathy (XLDCM), pantothenate kinase-associated neurodegeneration (PKAN,), spinal muscular atrophy (SMA), multiple sclerosis, primary progressive multiple sclerosis (PP-MS), Kugelberg-Welander disease, Werdnig-Hoffmann disease, diabetes mellitus and deafness (DAD), Wolfram syndrome, non-alcoholic liver disease, ageing-related physical decline, obesity, overweight, diabetes mellitus, type II diabetes, diabetic retinopathy, metabolic syndrome, schizophrenia, major depressive disorder, bipolar disorder, epilepsy, post-traumatic stress disorder (PTSD), circadian rhythm disorders, ulcerative colitis (UC), Crohn'"'"'s disease (CD), arthritis, psoriasis or rheumatoid arthritis, migraine, dry eye syndrome, uveitis, allergic conjunctivitis, post-operative inflammation and acute kidney injury.

11. A method of treating or preventing drug-induced or environmental-induced mitochondrial dysfunction, comprising administering to a person in need thereof, a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 7,

wherein the mitochondrial dysfunction is drug-induced mitochondrial dysfunction caused by the use of an antiviral;

an anti-cancer agent;

an antibiotic;

a CNS drug;

a hypertension drug;

an anthracyclines;

a non-steroidal anti-inflammatory drug (NSAID);

an anesthetic;

a beta-blocker;

an anti-arrhythmic;

an anti-diabetic;

an anti-inflammatory;

or another agent.

12. Use of a compound according to claim 1 in the manufacture of a cosmetic for the amelioration of the effects of aging.

14. A method for the treatment or prevention of drug-induced or environmental-induced mitochondrial dysfunction in a subject in need thereof, the method comprising administering an effective amount of a compound of claim 1 or a pharmaceutical salt thereof, or a pharmaceutical composition of claim 7, wherein the mitochondrial dysfunction is drug-induced mitochondrial dysfunction caused by the use of an antiviral;

an anti-cancer agent;

an antibiotic;

a CNS drug;

a hypertension drug;

an anthracyclines;

a non-steroidal anti-inflammatory drug (NSAID);

an anesthetic;

a beta-blocker;

an anti-arrhythmic;

an anti-diabetic;

an anti-inflammatory;

or another agent.

6. A compound selected from the group consisting of:

13. (canceled)