Novel thyromimetics
AssigneeAutobahn Therapeutics, Inc.
InventorsThomas Von Geldern, Jean-Christophe Poupon, Bradley Backes
Life of this patent
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Abstract
Compounds are provided having the structure of Formula (I): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X1, X2, and R1 are as defined herein. Such compounds function as thyromimetics and have utility for treating diseases such as neurodegenerative disorders and fibrotic diseases. Pharmaceutical compositions containing such compounds are also provided, as are methods of their use and preparation.
Claims55
A compound having the structure of Formula (I):
- or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
- X1 and X2 are halo, lower alkyl, lower alkenyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cycloalkyl, and cycloalkylalkyl;
- wherein
- X1 and X2 do not have the same molecular formula, or
- X1 and X2 have the same molecular formula, and X1 and X2 do not have the same connectivity or configuration;
- R1 is —NR1aR1b or —OR1c;
- R1a and R1b are each, independently, H, —ORa, —NRaRb, lower alkyl, lower alkenyl, lower alkynyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl, wherein Ra and Rb are each, independently, H or lower alkyl;
- and
- R1c is H, lower alkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;
- wherein R1a, R1b, R1c, Ra, and Rb are each, independently, optionally substituted with one or more halo, cyano, —OR′, —NR′R″, —S(O)2R′ or —S(O)2OR′, wherein R′ and R″ are each, independently, H or lower alkyl.
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A method of treating a subject having a neurodevelopmental disorder comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of claim L or a pharmaceutically salt or composition thereof.
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A method of treating a subject having a medical condition associated with over-expression of TGF-β comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of claim L or a pharmaceutically salt or composition thereof.
55-56. (canceled)
A method of treating a subject having adult Refsum disease, infantile Refsum disease, Alexander disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendineous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic's syndrome, diffuse myelinoclastic sclerosis, encephalomyelitis, idiopathic inflammatory demyelinating disease (HDD), Krabbe disease, Leber hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease (PMD), progressive multifocal leukoencephaalopathy (PML), tropical spastic paraparesis (TSP), X-linked adrenoleukodystrophy (X-ALD, ALO, or X-linked ALO), Zellweger syndrome, MCT8 deficiency, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, lacunar stroke, primary age-related tauopathy (PART), Pick's disease, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), adrenomyeloneuropathy (AMN), cerebral form of adrenoleukodystrophy (cALD), nonalcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF), systemic scleroderma, or Alport syndrome, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of claim L or a pharmaceutically acceptable salt or composition thereof.
A method of treating a subject having NASH, NAFLD, NAFLD with hyperlipidemia, alcoholic liver fisease/alcoholic steatohepatitis, liver fibrosis associated with viral infection (HBV, HCV), fibrosis associated with cholestatic diseases (primary biliary cholangitis, primary sclerosing cholangitis), (familial) hypercholesterolemia, dyslipidemia, genetic lipid disorders, cirrhosis, alcohol-induced fibrosis, hemochromatosis, glycogen storage diseases, alpha-1 antitrypsin deficiency, autoimmune hepatitis, Wilson's disease, Crigler-Najjar Syndrome, lysosomal acid lipase deficiency, liver disease in cystic fibrosis, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of compound of claim L or a pharmaceutically acceptable salt or composition thereof.
A method of treating a subject having Alport syndrome, diabetic nephropathy, FSGS, fibrosis associated with IgA nephropathy, chronic kidney diseases (CKD), post AKI, HIV associated CKD, chemotherapy induced CKD, CKD associated with nephrotoxic agents, nephrogenic systemic fibrosis, tubulointerstitial fibrosis, glomerulosclerosis, or polycystic kidney disease (PKD), the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of claim k or a pharmaceutically acceptable salt or composition thereof.
A method of treating a subject having IPF, ILD, pulmonary fibrosis, pulmonary fibrosis associated with autoimmune diseases like rheumatoid arthritis, scleroderma or Sjogren's syndrome, asthma-related pulmonary fibrosis, COPD, asbestos or silica induced PF, silicosis, respiratory bronchiolitis, Idiopathic interstitial pneumonias (IIP), Idiopathic nonspecific interstitial pneumonia, Respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia, acute interstitial pneumonia, Rare IIPs:
- Idiopathic lymphoid interstitial pneumonia, idiopathic pleuroparenchymal fibroelastosis, unclassifiable idiopathic interstitial pneumonias, hypersensitivity pneumonitis, radiation-induced lung injury, progressive massive fibrosis—pneumoconiosis, bronchiectasis, byssinosis, chronic respiratory disease, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary arterial hypertension (PAH), or Cystic fibrosis, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of claim F or a pharmaceutically acceptable salt or composition thereof.
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Dependencies are inferred from the claim text.