Pro-drugs of riluzole and their method of use for the treatment of amyotrophic lateral sclerosis
View Patent ↗Pharmaceutical compositions of the invention include substituted riluzole pro drugs useful for the treatment of amyotrophic lateral sclerosis (ALS) and related disorders through the release of riluzole, especially to avoid patient to patient variability in first pass, hepatic metabolism promoted by Cyp 1A2. Pro-drugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process. The invention further includes pro-drugs of riluzole useful for the treatment of disease states that can be treated with riluzole through the release of riluzole from a pro-drug agent.
1. A method for treating a non-proliferative disease in which riluzole is clinically relevant, said method comprising administering to a subject an effective amount of at least one compound of the formula (III):
including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R 12a , R 12b , R 12c , R 2d , and R 12e are each independently selected from the group consisting of hydrogen, deuterium, halogen, trifluoromethyl, triflouromethoxy, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy;
wherein the disease in which riluzole is clinically relevant is amyotrophic lateral sclerosis, bipolar disorder, treatment resistant and major depression, obsessive-compulsive disorder, spinal muscular atrophy, radiation therapy, multiple sclerosis, chronic cerebellar ataxia, cervical spondylotic myelopathy, spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome, autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson's Disease, or Huntington's disease.
2. A method for treating a non-proliferative disease in which riluzole is clinically relevant, said method comprising administering to a subject an effective amount of at least one at least one compound of:
2-Amino-N-(6-trifluoromethoxy-benzothiazol-2-yl)-acetamide;
(R)-2-Amino-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;
(R)-2-Amino-3-phenyl-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;
(R)-2-Amino-3-benzyloxy-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;
(S)-2-Amino-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;
(S)-2-Amino-3-methyl-N-(6-trifluoromethoxy-benzothiazol-2-yl)-butyramide;
(S)-2-Amino-3-phenyl-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;
(S)-2-Amino-3-benzyloxy-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;
(S)-2-amino-3-(4-fluorobenzyloxy)-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propanamide;
(S)-2-amino-3-(2,4-difluorobenzyloxy)-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propanamide;
(S)-2-amino-3-methoxy-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propanamide;
(S)-3-tert-butoxy-2-amino-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide;
(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid methyl ester;
(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid ethyl ester;
(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid propyl ester;
(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid butyl ester;
(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid isobutyl ester;
(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid hexyl ester;
(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid 2-dimethylamino-ethyl ester;
(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid 3-dimethylamino-propyl ester;
N-(6-Trifluoromethoxy-benzothiazol-2-yl)-succinamic acid;
N-(6-Trifluoromethoxy-benzothiazol-2-yl)-succinamic acid methyl ester;
N-(6-Trifluoromethoxy-benzothiazol-2-yl)-succinamic acid tert-butyl ester;
N-Pyridin-3-ylmethyl-N′-(6-trifluoromethoxy-benzothiazol-2-yl)-succinamide;
N-(2-Morpholin-4-yl-ethyl)-N′-(6-trifluoromethoxy-benzothiazol-2-yl)-succinamide;
5-Methylamino-pentanoic acid (6-trifluoromethoxy-benzothiazol-2-yl)-amide;
5-Amino-pentanoic acid (6-trifluoromethoxy-benzothiazol-2-yl)-amide;
4-Amino-N-(6-trifluoromethoxy-benzothiazol-2-yl)-benzamide;
2-(1-Aminomethyl-cyclohexyl)-N-(6-trifluoromethoxy-benzothiazol-2-yl)-acetamide;
or a pharmaceutically acceptable form thereof;
wherein the disease in which riluzole is clinically relevant is amyotrophic lateral sclerosis, bipolar disorder, treatment resistant and major depression, obsessive-compulsive disorder, spinal muscular atrophy, radiation therapy, multiple sclerosis, chronic cerebellar ataxia, cervical spondylotic myelopathy, spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome, autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson's Disease, or Huntington's disease.
3. The method of claim 1 , wherein the at least one compound of the formula (III) is administered in a composition further comprising at least one excipient.
4. The method of claim 2 , wherein the at least one compound is administered in a composition further comprising at least one excipient.