Adenosine derivative and pharmaceutical composition comprising the same
Inventors
Assignees
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Publication Number
US-11793827-B2
Publication Date
2023-10-24
Expiration Date
Abstract
Disclosed herein are adenosine derivative prodrugs and compositions thereof that can be used for the treatment of HIV infection or RNA virus infection.
Core Innovation
The invention relates to adenosine derivatives having a structure of formula (I), formula (Ie), or related formula variants, and pharmaceutically acceptable salts thereof. The structures define variable linkage positions A, E, G, and J and substituent groups R1, R2, R3, R4, and in some embodiments R5 and R6, together with stereodefined scaffold features, tautomer, solvate, and isomeric forms. The disclosed compounds include fluoroaminopurinyl-ethynyl-tetrahydrofuran scaffold embodiments and specific compounds represented in multiple formula-based variants.
The descriptions specify that A and E are independently selected from bond, —(CO)—, —(CO)-G-, —(CO)-G-(C1-10 alkylene)-J-, —(CO)-G-(C2-10 alkenylene)-J-, and —(CO)-G-(C2-10 alkynylene)-J-, with G selected from bond, O, NH, and S, and J selected from bond, O, NH, S, and —(CO)-G-. R1 is selected from H, C1-5 alkyl, and adamantyl, and R3 and R4 are selected from H and enumerated carbonyl-linked and non-carbonyl alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups. Some embodiments further define formula (Ie) with E as a bond and q as an integer from 0-5, and another formula (I) embodiment requires R1 and R2 together to form a 6- to 15-membered heterocyclic ring.
The document describes adenosine-derivative prodrugs and carbonate derivatives, including carbonate, ester, acetate, propanoate, and isobutyrate derivatizing groups, adamantyl carbonates, hydroxymethyl and hydroxy variants, and larger cyclic tetraoxabicyclo dione derivatives. The patent also states that the adenosine derivatives are reverse transcriptase inhibitors and chain terminators, with DNA translocation inhibitor activity, and that some prodrugs metabolize in vivo to generate EFdA-like active species including T-1A/EFdA and (2R,3S,5R)-4′-ethynyl-2-fluoro-2′-deoxyadenosine.
Pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts are described, and therapeutic use is stated for treating HIV infection, HIV/AIDS, drug-resistant HIV variants, retroviral diseases, and RNA virus infections. The disclosure also refers to treatment/prophylaxis and prevention methods associated with HIV infection and AIDS, monitoring through specimen-based analytical approaches, and combination contexts with additional anti-HIV agents.
Claims Coverage
The consolidated claim coverage centers on adenosine derivatives defined by formula (I) and formula (Ie), plus a broader compound-of-formula claim, with four recurring inventive feature groups across the provided items. The claims repeatedly define linkage and substituent selections for A, E, G, J, R1, R2, R3, and R4, with one independent claim further requiring R1 and R2 to form a 6- to 15-membered heterocyclic ring and another fixing E as a bond with q from 0-5. Independent composition and HIV-treatment claim context is also present.
Formula (I) adenosine derivative with enumerated linkage and substituent options
An adenosine derivative having a structure of formula (I) or pharmaceutically acceptable salt thereof, wherein A and E are each independently selected from bond, —(CO)—, —(CO)-G-, —(CO)-G-(C1-10 alkylene)-J-, —(CO)-G-(C2-10 alkenylene)-J-, and —(CO)-G-(C2-10 alkynylene)-J-; G is selected from bond, O, NH, and S; J is selected from bond, O, NH, S, and —(CO)-G-; R1 is selected from H, C1-5 alkyl, and adamantyl; and R3 and R4 are selected from the enumerated substituent groups.
Formula (Ie) adenosine derivative with fixed E and q range
An adenosine derivative having a structure of formula (Ie) or pharmaceutically acceptable salt thereof, wherein E is a bond; R1 is H, C1-5 alkyl, or adamantyl; R3 is H, —(CO)-C1-5 alkyl, —(CO)-O-C1-5 alkyl, or C1-5 alkyl; R4 is H, C1-5 alkyl, C1-5 haloalkyl, or C1-5 alkoxy; and q is an integer from 0-5.
Formula (I) adenosine derivative with heterocyclic ring formed by R1 and R2
An adenosine derivative having a structure of formula (I) or pharmaceutically acceptable salt thereof, wherein A and E are each independently selected from bond, —(CO)—, —(CO)-G-, —(CO)-G-(C1-10 alkylene)-J-, —(CO)-G-(C2-10 alkenylene)-J-, and —(CO)-G-(C2-10 alkynylene)-J-; G is selected from bond, O, NH, and S; J is selected from bond, O, NH, S, and —(CO)-G-; R1 and R2 taken together with the atoms to which they are attached form a 6- to 15-membered heterocyclic ring; and R3 is selected from the enumerated substituent groups.
Compound of formula with pharmaceutical composition and HIV treatment context
A compound of the formula or a pharmaceutically acceptable salt thereof, with dependent coverage for a pharmaceutical composition comprising the compound or salt and a pharmaceutically acceptable carrier, and a method of treating an HIV infection by administering an effective dosage of the pharmaceutical composition to a subject in need.
The claim set covers formula-based adenosine derivatives with enumerated linkage elements and substituent selections, including a narrower formula (Ie) embodiment with E fixed as a bond and q limited to 0-5, and a formula (I) embodiment where R1 and R2 form a 6- to 15-membered heterocyclic ring. It also includes a broader compound-of-formula claim and dependent pharmaceutical composition and HIV-treatment coverage.
Stated Advantages
Reverse transcriptase inhibitor activity.
Reverse transcriptase chain terminator activity.
DNA translocation inhibitor activity.
Rapid conversion to the target drug in plasma, with stated conversion percentages within stated time windows.
Treat retroviral diseases including HIV/AIDS.
Treat RNA virus infections.
Reverse-transcriptase inhibitor activity in vivo.
Reverse-transcriptase chain termination activity in vivo.
DNA translocation inhibition activity in vivo.
Documented Applications
Treatment of HIV infection by administering an effective dosage of a pharmaceutical composition to a subject in need.
Treatment/prophylaxis and prevention methods associated with HIV infection and AIDS.
Treatment of HIV/AIDS and drug-resistant HIV variants.
Treating retroviral diseases including HIV/AIDS.
Treating RNA virus infections.
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