Tricyclic compounds having cytostatic and/or cytotoxic activity and methods of use thereof
Inventors
Assignees
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Publication Number
US-9896455-B2
Publication Date
2018-02-20
Expiration Date
Abstract
The present invention provides tricyclic compounds having cytostatic and cytotoxic activity in a single molecule having receptor tyrosine kinase(s), dihydrofolate reductase, thymidylate synthase and/or dihydroorotate dehydrogenase inhibitory activity, which are useful as anti-angiogenic and anti-tumor agents. Also provided are methods of utilizing these inhibitors to treat tumor cells and other proliferative diseases and disorders.
Core Innovation
The invention relates to tricyclic heteroaromatic compounds and their use in inhibiting receptor tyrosine kinase(s), dihydrofolate reductase, thymidylate synthase and/or dihydroorotate dehydrogenase activity. The approach targets both receptor tyrosine kinases and folate-pathway enzymes to provide combined single-molecule cytostatic (anti-angiogenic) and cytotoxic activity. The compounds are described by formula I with extensive structural definitions for the B and C rings, ring saturation/unsaturation, and allowed heteroatoms and substituent patterns.
For formula I, the bond 4b-8a, 5-6 and 7-8 may be completely or partially saturated or unsaturated, and the C ring may include an N or substituted N depending on the saturation level. Substitution options are defined through X and/or Y, P, and Z, as well as substituent variables R1, R2, and R3. The definitions also include coverage of chirality and stereoisomers when the substituted Z or R3 creates chirality, and inclusion of stereoisomers separately and as racemic and/or diastereoisomeric mixtures.
The invention further frames a method of inhibiting the above enzymatic and receptor activities in an animal or human in need thereof by administering a therapeutically effective unit dosage amount of a compound of formula I. The document provides treatment/administration context in animals and humans for proliferative diseases and disorders, including cancers and ocular disorders. The described biological effect includes inhibition of targets associated with anti-angiogenic and cytotoxic outcomes, including reduction of tumor vascularity and reduced metastasis in mouse models.
Claims Coverage
The document contains one independent claim and dependent claims. The independent claim recites administering a therapeutically effective unit dosage form of a compound of formula I to inhibit receptor tyrosine kinase(s) together with dihydrofolate reductase, thymidylate synthase and/or dihydroorotate dehydrogenase activity in an animal or human in need thereof, with the formula I scaffold subject to extensive structural constraints; additionally, dependent claims refine substituent definitions, route/modalities of administration, and the treated disease/disorder categories.
Unit-dose inhibition of RTKs and folate-pathway enzymes with formula I
A method of inhibiting receptor tyrosine kinase(s), dihydrofolate reductase, thymidylate synthase and/or dihydroorotate dehydrogenase activity in an animal or human in need thereof by administering to said animal or human a therapeutically effective amount in unit dosage form of a compound of formula I with defined saturation/unsaturation of B and C rings, defined heteroatoms X and/or Y and P, and defined substituent variables R1, R2, R3, and Z including attachment positions and optional stereoisomer coverage.
Overall, claim coverage centers on administering unit dosage amounts of a compound of formula I to inhibit receptor tyrosine kinase(s) and simultaneously inhibit dihydrofolate reductase, thymidylate synthase and/or dihydroorotate dehydrogenase activity, with the formula I tricyclic scaffold constrained by detailed ring and substituent definitions, including inclusion of stereoisomers when chirality arises.
Stated Advantages
Provides single-molecule cytostatic (anti-angiogenic) and cytotoxic activity by simultaneously inhibiting receptor tyrosine kinases together with dihydrofolate reductase and/or thymidylate synthase, and optionally dihydroorotate dehydrogenase.
Anti-angiogenic effect is reported as reduced tumor vascularity.
In mouse models, reduced metastasis is reported.
Documented Applications
Treatment/administration context for inhibiting these targets in animals/humans with proliferative diseases, including multiple cancers.
Treatment/administration context for ocular disorders including macular degeneration and retinopathies.
The document reports biological support in mouse models, including outcomes described for tumor vascularity reduction and reduced metastasis.
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