Radio-protective and chemo-protective substituted thiols
Inventors
Schein, Philip S. • Rideout, Darryl C.
Assignees
Schein Group Inc • Tonix Pharmaceuticals Holding Corp • Tonix Pharmaceuticals Inc
Publication Number
US-11566032-B2
Publication Date
2023-01-31
Expiration Date
2041-05-07
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Abstract
The present disclosure relates to prodrugs, double prodrugs, derivatives and analogues of 3-(methylamino)-2-((methylamino)methyl)propane-1-thiol. The compounds of this disclosure also relate to The use of these compounds as radio— and chemo—protectors is also described.
Core Innovation
The invention relates to prodrugs, double prodrugs, derivatives, and analogues of 3-(methylamino)-2-((methylamino)methyl)propane-1-thiol and their pharmaceutically acceptable salts or stereoisomers. These compounds are designed as radio-protective and chemo-protective agents and can be formulated in pharmaceutical compositions, optionally with antioxidants, for administration through various routes including oral, parenteral, transmucosal, transdermal, topical, and cutaneous means.
The problem being addressed is the lack of effective and orally bioavailable multi-organ radioprotectors and chemoprotectors for individuals exposed to ionizing radiation or chemotherapy, particularly with a focus on ease of administration, reduced side effects, and minimal interference with tumor response. Current FDA-approved agents, such as amifostine, are limited by their route of administration, restricted organ protection, and associated toxicities.
The disclosed compounds, such as PrC-210-PT and its derivatives and analogues, offer structural designs (including prodrugs and double prodrugs) that enhance stability, bioavailability, and selectivity for protecting healthy tissues over tumor tissues due to differential expression of metabolizing enzymes like alkaline phosphatase. These compounds are described for use in preventing or reducing toxicities and syndromes associated with ionizing radiation, chemotherapeutic exposure, and oxidative stress-related conditions.
Claims Coverage
The independent claims cover four main inventive features related to novel compounds, pharmaceutical compositions, and composition variants with specific administration routes and antioxidant inclusion.
Novel substituted thiol compounds of formula I
Claims cover compounds according to formula I, including their pharmaceutically acceptable salts and stereoisomers, with comprehensive definition of structural substituents. The central inventive features include: - Compounds based on 3-(methylamino)-2-((methylamino)methyl)propane-1-thiol with various substitutions. - Inclusion of analogues and derivatives where B can be specific heterocycles as explicitly defined. - The compounds may exist as prodrugs or double prodrugs, and include crystalline salt forms or polymorphs.
Pharmaceutical compositions containing the novel compounds
Claims are directed to pharmaceutical compositions comprising any of the novel compounds or their salts/stereoisomers, and a pharmaceutically acceptable carrier. The features include: - Possibility of formulation for oral or parenteral administration. - Further inclusion of antioxidants as an explicit inventive feature.
Compounds selected from explicitly listed group members
Coverage extends to compounds selected from explicit lists—such as PrC-210-PT, PrC-210-PT-BzOM, PrC-210-PT-POE, PrC-210-PT-PivTB, and others as identified in the claim text. The compounds can be used individually or as part of a composition. - The inventive feature includes the detailed structural diversity of the selected group.
Pharmaceutical compositions comprising specific compound lists
Includes pharmaceutical compositions comprising any of the explicitly listed compounds (as detailed above), a pharmaceutically acceptable carrier, and optionally an antioxidant. The inventive scope details: - Formulation for oral or parenteral administration, with parenteral methods including subcutaneous, intravenous, intramuscular, or intrathecal administration.
The claims establish inventive coverage for a broad range of structurally defined thiol-containing compounds, select compound lists, their pharmaceutical compositions (with flexible administration routes), and the optional inclusion of antioxidants, highlighting a strategic, multifaceted coverage of chemoprotective and radioprotective modalities.
Stated Advantages
The compounds are suitable for oral administration, providing ease of administration compared to approved intravenous-only radioprotectors.
Prodrugs and double prodrugs enhance bioavailability over parent compounds and offer improved stability and longer shelf life.
The compounds selectively protect normal tissues over tumor tissues by exploiting higher enzyme expression in healthy tissues.
The compounds exhibit fewer side effects when administered for radioprotection or chemoprotection.
Stable crystalline salt forms increase storage lifespan and resistance to degradation.
Pharmaceutical compositions with antioxidants can synergistically enhance radioprotective effects.
Documented Applications
Prevention or reduction of toxicities and syndromes associated with ionizing radiation or chemotherapy, including acute and chronic exposure scenarios.
Protection of normal tissues in subjects undergoing radiation therapy or chemotherapy, with minimal adverse effects on tumor response.
Reduction of the risk of secondary tumor induction in subjects treated with radiation therapy or chemotherapy.
Treatment or prevention of diseases and conditions associated with oxidative stress, such as ischemia injury, Alzheimer’s disease, Parkinson’s disease, rheumatoid arthritis, myocardial infarction, cardiovascular disease, and specific mitochondrial disorders.
Use in subjects at occupational risk of radiation exposure such as astronauts, pilots, flight attendants, first responders, nuclear power plant workers, and emergency personnel.
Applications in slowing the aging process and increasing health span.
Treatment for COVID-19-associated cytokine storm, multisystem inflammatory syndrome in children (MIS-C), and post-COVID-19 SARS-CoV-2-induced autoimmunity.
Stimulation of bone marrow production or recovery following chemotherapy or in diseases requiring bone marrow growth.
Animal and cell research models for assessment of radioprotective, chemoprotective, and antioxidant effects.
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