US 11,649,232 B2Granted

Synthetic dimeric cinchona alkaloids against cancer

AssigneeAres Pharmaceuticals, LLC

InventorsFatih M. Uckun, Taracad Venkatachalam

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Abstract

Synthetic, novel dimeric cinchona alkaloid compounds having potent cytotoxic activity against human cancer cells. The compounds are effective agents for inhibiting cellular proliferation, for example, in cancer cells. The compounds cause apoptotic cell death in and cause inhibition of clonogenic growth of human breast cancer, prostate cancer, leukemia, lymphoma cells at nanomolar concentrations. The chemical structure of the compound includes dimeric cinchona alkaloid and derivatives containing various groups attached in their structure. The compounds also possess hydroxy group functionality in the structure to enable the preparation of pharmaceutically applicable salts to enhance their solubility for ease of systemic administration in animals and in humans, for example, in cancer patients.

Claims10

Dependent claims

A pharmaceutical formulation comprising:

(a) a compound of Formula I, Compound A, Formula II, Compound B, or Formula III:
wherein
R is, independent of R′ and R″, selected from the group consisting of H, Me, Et, Pr, Bu, tBu, Ph,PhCH2, OH, OMe, OEt, OPr, OBu, OtBu, OPh, and OCH2Ph;
R′ is, independent of R and R″, selected from the group consisting of OH, OMe, OEt, OPr, OBu, OtBu, OPh, and OCH2Ph;
and R″ is, independent of R and R′, selected from the group consisting of OMe, OEt, OPh, F, Cl, Br, I, COOH, COOMe, and COOEt;
Compound A is (2-[6-({4-({5-ethyl-5-hydroxy-1-azabicyclo[2.2.2]octan-2yl}(6-methoxyquinolin-4yl)methoxy) phthalazine-1-yl}oxy}(6-methoxyquinolin-4yl) methyl)-3hydroxy-1-azabicyclo[2.2.2]octan-3yl]ethylidyne);
Compound B is (2-[6-({4-({5-ethyl-5-hydroxy-1-azabicyclo [2.2.2]octan-2yl}(6-methoxyquinolin-4yl)methoxy)phthalazine-1-yl }oxy}(6-methoxyquinolin-4yl)methyl)-1-azabicyclo[2.2.2]octan-3-yl]ethylidyne);
for the compound of Formula III, the linker moiety L is formed by condensation with 1,4-dichlorophthalazine, 1,4-dicholoroanthraquinone 3,6-dichloropyridazine, 1,4-dichlorophthalazine;
2,4-dichloropyrimidine;
4,6-dichloro-2,5-diphenyl pyrimidine;
2,6-dichloro pyrazine:
1,3-dichloro iso quinoline;
2,3,5,6-tetrafluoro pyridine;
2-chloro-3,6-dibromopyrimidine;
3,6-dichloro-4-methyl pyridazine;
2,6-difluoropyridine;
3,5-dichloro-2,4,6-trifluoro pyridine;
5-chloro-2,4,6-pyrimidine;
2,3,5,6-tetrafluoro-4-methyl pyridine;
3,6-dichloro pyridazine;
2,3-dichloro quinoxaline;
2,4-dichloropyrimidine;
or a substituted heterocyclic derivative of one of:
or a pharmaceutically acceptable salt of any of the foregoing:
and
(b) a pharmaceutically acceptable carrier.

23 more elements

Dependencies are inferred from the claim text.