Thio compounds
Inventors
Grieg, Nigel H. • Luo, Weiming • Tweedie, David • Holloway, Harold W. • Yu, Qian-Sheng • Goetzl, Edward J.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9084783-B2
Publication Date
2015-07-21
Expiration Date
2031-12-02
Abstract
A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of: wherein A, B and D are each oxygen or sulfur, provided that least one of A, B and D is sulfur; and R1-R8 are each independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, or a thio-containing group.
Core Innovation
The invention disclosed relates to compounds, or pharmaceutically acceptable salts or esters thereof, that have structures where certain elements A, B, D (and in some embodiments E) can be oxygen or sulfur, with at least one being sulfur. The compounds have various possible substituents R1 to R8 chosen independently from a broad array of chemical groups including hydrogen, hydroxyl, acyl, alkyl, amino, halogen, heterocycloalkyl, heteroaryl, and thio-containing groups.
These compounds are designed to modulate tumor necrosis factor alpha (TNF-α) activity and/or angiogenesis. The background identifies the problem of diseases associated with excessive or abnormal TNF-α activity, such as inflammatory diseases, autoimmune disorders, neurodegenerative diseases, and certain cancers. Existing compounds like thalidomide have toxicity issues. Hence, new compounds that effectively modulate TNF-α with reduced toxicity are needed.
The disclosed compounds, particularly thiocarbonyl-substituted derivatives of lenalidomide or pomalidomide, provide a solution by retaining TNF-α inhibition while potentially reducing toxicity. They also inhibit proinflammatory cytokines and inducible nitric oxide synthase. These compounds have physicochemical properties suitable for passing the blood-brain barrier, making them useful in treating neuroinflammation linked to neurodegenerative disorders.
Claims Coverage
The patent includes two independent claims directed to methods of modulating TNF-α activity using compounds of specified structures.
Methods for modulating TNF-α activity using specified thio-substituted compounds
Methods involve contacting a cell or administering to a subject a therapeutically effective amount of a compound or its pharmaceutically acceptable salt, having a structure where atoms A, B, D and optionally E are oxygen or sulfur with at least one sulfur, and substituents R2-R4 and R6-R8 are independently various chemical groups, with preferred embodiments where these substituents are hydrogen.
TNF-α inhibition via structural variants of lenalidomide or pomalidomide
The modulation of TNF-α activity includes inhibitory activity. This inhibition leads to inhibition of activation of transcription factors AP-1 and NFκB, which are involved in inflammatory responses.
The independent claims cover methods of modulating, particularly inhibiting, TNF-α activity by using compounds bearing sulfur substitutions at key positions, and administering therapeutically effective amounts to cells or subjects to achieve TNF-α inhibition.
Stated Advantages
Compounds such as dithiolenalidomide are unexpectedly less toxic than dithiothalidomide while retaining TNF-α inhibitory effects.
The disclosed compounds can cross the blood-brain barrier due to their small molecular weight and lipophilic properties, enabling treatment of neuroinflammatory conditions.
They inhibit inducible nitric oxide synthase and proinflammatory cytokines including IFN-γ, IL-2, and IL-17, providing broad immunomodulatory effects.
Documented Applications
Treatment of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, head trauma, stroke, ALS, HIV dementia, Huntington's disease, multiple sclerosis, cerebral amyloid angiopathy, tauopathies, peripheral neuropathies, and macular degeneration by reducing neuroinflammation.
Treatment of autoimmune diseases such as rheumatoid arthritis, immune arthritis, and degenerative arthritis.
Modulating angiogenesis for diseases involving pathological angiogenesis like diabetic retinopathy, retinopathy of prematurity, neovascular glaucoma, macular degeneration, psoriasis, hemangiomas, atherosclerosis, Crohn's disease, scleroderma, hypertrophic scars, and cancer including primary and metastatic solid tumors.
Use as immunomodulatory agents to reduce chronic systemic and central nervous system inflammation.
Combination therapies with chemotherapeutic agents, radiation, surgery, and other TNF-α inhibitory agents for treatment of cancer and inflammatory diseases.
Interested in licensing this patent?