Compounds for treatment of cancer
Inventors
Li, Wei • MILLER, Duane D • Arnst, Kinsie E. • Hwang, Dong-Jin
Assignees
University of Tennessee Research Foundation • Oncternal Therapeutics Inc
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Publication Number
US-12187720-B2
Publication Date
2025-01-07
Expiration Date
Abstract
The present invention relates to novel compounds having anti-cancer activity, methods of making these compounds, and their use for treating cancer and drug-resistant tumors, e.g. melanoma, metastatic melanoma, drug resistant melanoma, prostate cancer and drug resistant prostate cancer.
Core Innovation
The invention relates to compounds of Formula IX. The compounds include variable substituents R4 and R5 that are independently selected from hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CN, —CH2CN, NH2, hydroxyl, alkylamino, aminoalkyl, —OC(O)CF3, C1-C5 linear or branched alkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH2, and NO2, together with the broader set including —(CH2)iNHCH3, —(CH2)iNH2, and —(CH2)iN(CH3)2. The A′ ring is optionally substituted by 1-5 substituents independently chosen from the same set of groups.
The invention further defines structural variability through the integers i and n, where i is an integer between 1-5 and n is an integer between 1-3. The A′ ring is described as a substituted or unsubstituted single-, fused- or multiple-ring aryl or (hetero)cyclic ring system, including substituted or unsubstituted N-heterocycles, S-heterocycles, O-heterocycles, cyclic hydrocarbons, and mixed heterocycles. The compounds are also covered as pharmaceutically acceptable salt, hydrate, polymorph, or isomer.
The invention also describes anticancer compounds intended for treating cancer, including drug-resistant tumors, and links the disclosed invention to cancer treatment while targeting the colchicine-binding site and related microtubule/tubulin interactions. For cervical cancer, the text links disease biology to HPV E6 and HPV E7 effects, including disruption of p53 and related pathways such as pRb, p21, and JAK2/STAT3 signaling. It further describes Formula XI embodiments, broader Formula I and related Ia/II/III frameworks, and example compounds, but the supplied content does not explicitly state a separate technical problem for all of the described compound classes.
Claims Coverage
The provided claim set includes two independent claims. One independent claim covers Formula IX compounds with broad substituent variability at R4 and R5, an optionally substituted A′ ring, and integer ranges for i and n, together with pharmaceutically acceptable salt, hydrate, polymorph, or isomer forms. The other independent claim narrows the scope to an enumerated list of specific isoquinoline derivatives.
Formula IX with defined substituent sets for R4 and R5
A compound of Formula IX wherein R4 and R5 are independently selected from hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CN, —CH2CN, NH2, hydroxyl, —(CH2)iNHCH3, —(CH2)iNH2, —(CH2)iN(CH3)2, —OC(O)CF3, C1-C5 linear or branched alkyl, alkylamino, aminoalkyl, —OCH2Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, C(O)NH2, or NO2; and A′ ring optionally substituted by 1-5 substituents independently selected from the same broad substituent set.
A′ ring optional substitution and ring-system breadth
A′ is a substituted or unsubstituted single-, fused- or multiple-ring, aryl or (hetero)cyclic ring system, including substituted or unsubstituted N-heterocycles, S-heterocycles, O-heterocycles, cyclic hydrocarbons, and mixed heterocycles, and is optionally substituted by 1-5 substituents independently selected from the same broad substituent set.
Integer constraints on i and n
i is an integer between 1-5 and n is an integer between 1-3.
Pharmaceutically acceptable forms
The compound is also claimed as a pharmaceutically acceptable salt, hydrate, polymorph, or isomer.
Specific isoquinoline derivatives as embodiments
The compound is at least one selected from the listed isoquinoline derivatives, including 1-chloro-7-(4-fluorophenyl)isoquinoline, 7-(4-fluorophenyl)-1-(1H-indol-5-yl)isoquinoline, 7-(4-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)isoquinoline, 1,7-bis(4-fluorophenyl)isoquinoline, 1,7-bis(3,4,5-trimethoxyphenyl)isoquinoline, 1-(4-fluorophenyl)-7-(3,4,5-trimethoxyphenyl)isoquinoline, 1-(1H-indol-5-yl)-7-(3,4,5-trimethoxyphenyl)isoquinoline, or 1-chloro-7-(3,4,5-trimethoxyphenyl)isoquinoline.
A′ equals 5-indolyl with R4 and R5 hydrogen
A′ is 5-indolyl and R4 and R5 are hydrogen.
A′ indolyl with R4 and R5 hydrogen
A′ is indolyl and R4 and R5 are hydrogen.
A′ equals 4-fluorophenyl with R4 and R5 hydrogen
A′ is 4-fluorophenyl and R4 and R5 are hydrogen.
A′ equals 3,4,5-trimethoxyphenyl
A′ is 3,4,5-trimethoxyphenyl.
Overall claim coverage is anchored on a Formula IX scaffold with broad R4/R5 substituent selection, a broad optional substitution scheme for the A′ ring, and constrained integers i and n, with additional dependent refinements that specify particular A′ identities, fix R4 and R5 to hydrogen for those variants, and enumerate specific isoquinoline derivatives.
Stated Advantages
New low-toxicity therapies for cervical cancer.
Documented Applications
Treating cancer, including cervical cancer (HPV-associated cervical cancer).
Use in cancer contexts involving drug-resistant tumors and drug-resistant melanoma.
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