Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10745435-B2
Publication Date
2020-08-18
Expiration Date
Abstract
The invention relates to deoxynucleotide prodrugs and pharmaceutical preparations thereof. The deoxynucleotide prodrugs include, but are not limited to,The invention further relates to methods of treatment of a mitochondrial DNA (mtDNA) depletion syndrome (MDS) by administering a therapeutically-effective amount of a deoxynucleotide prodrug of the present invention.
Core Innovation
The invention relates to deoxynucleotide/nucleobase prodrugs having the structure of formula (I) and/or formula (Ia), including Compound 1017 and Compound 15, and multiple enumerated embodiments. These compounds are described as prodrugs of dNMPs and as deoxynucleotide prodrugs having a phosphonate/phosphoramidate linkage to a deoxyribose moiety bearing a nucleobase prodrug or a natural nucleobase.
The disclosure addresses the limitation that direct dNMP/dNTP supplementation is hindered by poor membrane diffusion and dephosphorylation, and presents prodrug delivery to mitochondria for mitochondrial DNA depletion syndrome. The treatment context includes deficiencies including DGUOK, TK2, MNGIE, POLG, MPV17, and RRM2B deficiencies, and it is also presented in the context of treating myelodysplastic syndromes (MDS) and other diseases.
The compounds are defined by variable substituents R1–R5 and nucleobase options (NT), with preferred embodiments including aryl or heteroaryl, alkyl or aralkyl, nucleobase prodrug moieties, and chirality constraints. The disclosure also includes pharmaceutically acceptable salts, pharmaceutical compositions, pharmaceutically acceptable excipients, and pharmaceutical formulations, and references calculated physicochemical properties including logP, logS, and TPSA for compounds 1–36.
Claims Coverage
The independent claim coverage centers on compounds of formula (I) or pharmaceutically acceptable salts thereof, defined by R1–R4 and NT, with dependent claims narrowing nucleobase substitution, R5, and R1 selections. A pharmaceutical composition with a pharmaceutically acceptable carrier is also claimed. In total, the consolidated claim set presents six inventive features.
Formula (I) prodrug compound with defined nucleobase and substituents
A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is aryl; R2 and R2′, each independently, are hydrogen, alkyl, or aralkyl; R3 is alkyl or aralkyl; R4 is hydrogen or alkyl; and NT is a nucleobase.
Pharmaceutical composition including the formula (I) compound
A pharmaceutical composition comprising the compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
Defined nucleobase for the formula (I) compound via OR5 and R5 limitation
The compound wherein the nucleobase includes an OR5 substituent and R5 is alkyl or aralkyl.
Restricted R5 substituent options for the nucleobase OR5 substituent
The compound wherein R5 is methyl, ethyl, isopropyl, or benzyl.
Restricted aryl options for R1
The compound wherein R1 is phenyl, naphthyl, or 4-fluorophenyl.
Specified nucleobase identities for NT with constrained R1–R4 definitions
A compound with the structure of formula (I) or a pharmaceutically acceptable salt thereof, where substituents R1–R4 and NT have specified meanings including NT being one of 9-adeninyl, 9-guaninyl, 1-cytosinyl, or 1-thyminyl.
The claim coverage is centered on formula (I) compounds defined by R1–R4 and NT, with dependent claims narrowing nucleobase substitution and R5, limiting R1 to specific aryl options, and including a pharmaceutical composition embodiment with a pharmaceutically acceptable carrier.
Stated Advantages
Calculated physicochemical properties support biological performance of the prodrug compounds, including cell membrane crossing and solvation in biological fluids.
The prodrug approach addresses poor membrane diffusion and dephosphorylation associated with direct dNMP/dNTP supplementation.
Documented Applications
Treatment of mitochondrial DNA depletion syndrome (MDS).
Treatment of deficiencies including DGUOK, TK2, MNGIE, POLG, MPV17, and RRM2B deficiencies.
Treatment of myelodysplastic syndromes (MDS) and other diseases.
Interested in licensing this patent?