Epoxyazulene derivatives useful for treating cancer and diabetes
Inventors
Beutler, John A. • ECHAVARREN, ANTONIO M. • LOPEZ, Laura • BRAVO, Fernando • RIESGO, Lorena • RANSOM, Tanya Tannaquil
Assignees
Institut Catala dInvestigacio Quimica ICIQ • Universitat Rovira i Virgili URV • US Department of Health and Human Services
Publication Number
US-10287297-B2
Publication Date
2019-05-14
Expiration Date
2036-04-13
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Abstract
Disclosed is a compound of formula (I) in which R1-R5 and X1 are as described herein. Also provided are methods of using a compound of formula (I), including a method of treating cancer and a method of treating diabetes.
Core Innovation
The invention provides compounds of formula (I), where the substituents R1-R5 and X1 vary as described, including pharmaceutically acceptable salts. These compounds include an additional double bond in the core structure, which twists the geometry of the core. Despite this expected distortion, it was surprisingly discovered that these compounds retain therapeutic activity, especially against certain cancers such as renal cancer.
Current therapies for cancer, notably renal cancer, suffer from incomplete therapeutic responses and possible adverse side effects, necessitating new treatments. Englerin compounds, derived from Phyllanthus engleri, have been studied for cancer therapy due to their ability to bind and activate protein kinase C theta (PKCθ) and potentially activate transient receptor potential canonical (TRPC) ion channels, resulting in cell cytotoxicity and selective viral replication in T cells.
The compounds of formula (I) provided by this invention also offer methods for treating diseases in mammals including cancer and diabetes by administering effective amounts of these compounds. The invention further includes pharmaceutical compositions comprising compounds of formula (I) with pharmaceutically acceptable carriers. The compounds can be administered via various routes including oral, intravenous, topical, and others. The invention addresses the unmet need for novel englerin derivatives useful for treating diseases related to PKCθ and calcium ion channel proteins.
Claims Coverage
The patent contains one independent claim directed to a compound of formula (I) and one independent claim directed to a method of treating cancer by administering said compounds. The main inventive features include the chemical structure of the compound, selection of substituents, stereochemistry, pharmaceutical compositions, and methods of treating specific cancers.
Compound of formula (I) with defined substituents and stereochemistry
A compound defined by formula (I), where R1, R2, R3, R4, R5, X1 and other substituents are selected as specified, including stereoisomers and pharmaceutically acceptable salts.
Selective substituent definitions for enhanced activity
Specific selections for R1 (e.g., isopropyl, tert-butyl, cycloalkyl, phenyl), R2 (e.g., hydroxy or specific radicals), R5 (e.g., alkyl or aryl substitutions with specified chain lengths and configurations), and methyl substitution at R3 and R4.
Pharmaceutical compositions with compounds of formula (I)
Pharmaceutical compositions comprising an effective amount of a compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier.
Method of treating cancer using compounds of formula (I)
Method of treating cancer by administering an effective amount of the compound of formula (I), including treatment of leukemia, non-small cell lung cancer, colon cancer, melanoma, prostate cancer, renal cancer, breast cancer, CNS cancer, ovarian cancer, and Ewing's sarcoma, with a particular emphasis on renal, prostate, and Ewing's sarcoma cancers.
Defined stereochemistry of compounds
Compounds of formula (I) having the stereochemistry of formula (I') as defined in the specification.
The claims cover novel epoxyazulene derivatives with specific substituent configurations and stereochemistry, pharmaceutical formulations containing these compounds, and methods of treating various cancers by administering these compounds, notably renal, prostate, and Ewing's sarcoma.
Stated Advantages
Compounds of formula (I) unexpectedly retain therapeutic activity despite modification of the core structure.
The compounds are therapeutically active against certain cancers, especially renal cancer, with potent inhibitory effects on cancer cell growth.
The compounds provide new treatment options for cancer and diabetes, addressing the unmet need for therapies associated with PKCθ and calcium ion channel-related diseases.
They can be formulated in various pharmaceutical compositions and administered by multiple routes, increasing their therapeutic versatility.
Documented Applications
Treatment of cancer, including renal cancer, prostate cancer, Ewing's sarcoma, leukemia, non-small cell lung cancer, colon cancer, melanoma, breast cancer, CNS cancer, ovarian cancer, and other specified cancers.
Treatment of diabetes, including type 1 and type 2 diabetes, specifically by preventing insulin resistance and activating heat shock proteins.
Treatment of human immunodeficiency virus (HIV) infection by activating protein kinase C theta (PKCθ) to sensitize HIV-infected patients to antiretroviral therapy, including use in combination with HAART and other antiviral agents.
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