Cancer treatment with (2,2-bishydroxymethyl) methylenecyclopropane nucleotides
Inventors
Klasson, Björn • Öberg, Fredrik
Assignees
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Publication Number
US-12221459-B2
Publication Date
2025-02-11
Expiration Date
Abstract
The invention provides a compound of formula (I)whereinB is a nucleobase;U is O or S;Rx is —OC(═O)Ry, —OC(═O)CH(Ry)NH2, —OCH2OC(═O)Ry;Ry is optionally substituted alkyl or alkenyl or the side chain of a natural or unnatural amino acidR1 is H, or optionally substituted phenyl, benzyl, naphthyl, pyridyl or indolyl, orRx and R1 together define a bond thus forming a cyclic phosphate;R2 and R2′ together define the side chain of a natural or unnatural amino acid;R3 is optionally substituted alkyl, cycloalkyl, phenyl or benzyl;and pharmaceutically acceptable salts and compositions thereofwhich are useful in the treatment of cancer, especially leukemias.
Core Innovation
The disclosure describes phosphorus prodrug compounds of (2,2-bishydroxymethyl) methylenecyclopropane nucleoside analogues, including cyclopropavir (CPV), for cancer therapy. A broad scaffold is defined by formula I in which the nucleobase B is selected from specified nucleobase groups and U is O or S. The phosphorus-containing feature is introduced through linkage variables and substituent families including Rx/Ry, R1, R2/R2′, R3, and R4–R11, with extensive allowable variants and optional substitutions.
The structural definitions include Rx as —OC(═O)Ry, —OC(═O)CH(Ry)NH2, or —OCH2OC(═O)Ry, with Ry being C1–C20 alkyl or C2–C20 alkenyl optionally substituted by fluoro, hydroxy and amino, or the side chain of a natural amino acid in the D or L configuration. R1 is defined as H or a cyclic group selected from phenyl, benzyl, naphthyl, pyridyl or indolyl optionally substituted, and R1 and Rx together define a bond to form a cyclic phosphate.
The disclosure further allows R2 and R2′ to be selected independently from H, various alkyl and cycloalkyl groups, phenyl, benzyl, or indolyl, or alternatively for R2 and R2′ to form a C3–C7 cycloalkylene group with the carbon atom to which they are attached. The compounds are also described as including pharmaceutically acceptable salt and solvate forms, with multiple representative structures provided, including CPV and cyclopropavir.
Claims Coverage
The consolidated claim coverage centers on one broad independent Formula I phosphorus prodrug compound genus with extensive structural variability, including nucleobase selection, U being O or S, Rx/Ry, R1, R2/R2′, R3, and R4–R11, optional cyclic phosphate formation, and pharmaceutically acceptable salts. Dependent refinements further narrow substituent choices, stereochemical/natural-amino-acid side-chain options, and a therapeutic use in leukemia.
Phosphorus prodrug compound of formula I
A compound represented by formula I with nucleobase B selected from specified groups, U being O or S, and the phosphorus-related linkage and substituent families defined by Rx/Ry, R1, R2/R2′, R3, and R4–R11, including optional substitutions and stereochemical options; the compound includes pharmaceutically acceptable salt thereof.
Rx substituted phosphorus linkage options
Rx is defined as —OC(═O)Ry, —OC(═O)CH(Ry)NH2, or —OCH2OC(═O)Ry, and Ry is defined as C1–C20 alkyl or C2–C20 alkenyl optionally substituted with fluoro, hydroxy and amino, or as the side chain of a natural amino acid in D or L configuration.
Optional cyclic phosphate via R1 and Rx together
R1 and Rx together define a bond, thus forming a cyclic phosphate in the formula I scaffold.
R2/R2′ substitution or cycloalkylene formation
R2 and R2′ are each independently selected from H, alkyl, cycloalkyl, phenyl, benzyl, or indolyl, or alternatively R2 and R2′ together with the carbon atom form a C3–C7 cycloalkylene group, with additional substitution constraints as specified.
Pharmaceutically acceptable salt option
A compound represented by formula I wherein the compound is or includes a pharmaceutically acceptable salt.
Therapeutic use for leukemia
A method of treating cancer by administering an effective amount of a compound as defined in the formula I claim to a subject in need, wherein the cancer is leukemia.
Overall, the claim set centers on a formula I compound class featuring a nucleobase-selected scaffold, an O or S linkage, Rx/Ry substituent options including natural amino-acid side-chain stereochemical choices, optional cyclic phosphate formation via R1 and Rx, and extensive optional substitution scope for the remaining variables. The claims also include pharmaceutically acceptable salts and an oncology treatment method specifically directed to leukemia.
Stated Advantages
The invention compounds are more active than the prior-art cyclopropavir nucleoside model, as concluded from leukemia cell-line activity evaluation.
Documented Applications
Cancer treatment by administering an effective amount of a compound according to claim 1, where the cancer is leukemia.
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