Methods and compositions relating to steroid hormone receptor-dependent proliferative disorders
Inventors
Assignees
Publication Number
US-11938127-B2
Publication Date
2024-03-26
Expiration Date
2042-09-28
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Abstract
Pharmaceutical compositions are provided according to aspects of the present disclosure which include a compound having chemical structural formula I: where R1 is selected from the group consisting of: an alkyl group, a heteroalkyl group, an aryl group, a heteroaryl group, an alkenyl group, a heteroalkenyl group, an alkynyl group, a heteroalkynyl group, a cycloalkyl group, a hetercycloalkyl group, an alkylcycloalkyl group, a heteroalkyl cycloalkyl group, an aralkyl group, a heteroaralkyl group, an alkoxy group, a polar group, an ester and a charged group; a pharmaceutically acceptable hydrolysable, or enzymatically cleavable, prodrug form thereof; and/or a pharmaceutically acceptable salt thereof; where R4′ is H or an alkoxy group; where both R5 and R3′ are OH, or where one or both OH groups is optionally modified as a pharmaceutically acceptable hydrolysable, or enzymatically cleavable, prodrug form thereof; and/or a deuterated form thereof; and/or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
Core Innovation
The invention provides pharmaceutical compositions comprising compounds of specific chemical structural formulas (I and II), along with derivatives, prodrug forms, deuterated forms, and pharmaceutically acceptable salts. These compounds are designed for the treatment of steroid hormone receptor-dependent proliferative disorders. The invention also includes pharmaceutical compositions that combine these compounds with additional therapeutic agents and outlines methods for treating various disorders by administering therapeutically effective doses of these compositions.
The core problem addressed by this invention is the ongoing need for effective methods and compositions to treat steroid hormone receptor-dependent proliferative disorders, which include both cancerous and non-cancerous conditions characterized by abnormal cell proliferation. These disorders rely on receptors such as the androgen receptor or estrogen receptor for growth and survival. Current treatments have limitations, particularly with resistant cancers or those involving receptor variants.
The pharmaceutical compositions of the invention disrupt the association between the androgen receptor (AR) and the transcription factor ELK1, an interaction crucial for the growth of certain prostate cancers and other receptor-dependent proliferative disorders. This disruption selectively suppresses growth of tumors reliant on AR and ELK1, including those resistant to existing treatments or dependent on AR splice variants, without significantly affecting other AR or ELK1 functions.
Claims Coverage
The independent claims of the patent encompass three major inventive features set out in pharmaceutical compositions, a method of treatment, and a synthetic method.
Pharmaceutical composition containing compounds of formula I
A pharmaceutical composition comprising a compound having chemical structural formula I, where: - R1 is selected from various groups, including alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkyl cycloalkyl, aralkyl, heteroaralkyl, alkoxy, polar group, ester, or charged group; - Includes pharmaceutically acceptable hydrolysable or enzymatically cleavable prodrug forms, and/or pharmaceutically acceptable salts; - R4′ is H or an alkoxy group; - Both R5 and R3′ are OH, or one/both modified as pharmaceutically acceptable prodrug forms, and/or a deuterated form, and/or a pharmaceutically acceptable salt; - With a pharmaceutically acceptable carrier.
Method of treating steroid hormone receptor-dependent proliferative disorder
A method of treating a steroid hormone receptor-dependent proliferative disorder in a subject in need thereof, comprising: - Administering a therapeutically effective dose of a pharmaceutical composition as defined above (including any of compounds of formula I, suitable derivatives, prodrug forms, deuterated forms, or salts) to a subject in need of such treatment.
Synthesis method for 4-quinolone compounds
A method of synthesizing a 4-quinolone compound, comprising: 1. Contacting a flavone with a strong acid in a ratio of molar equivalents in the range of 1:2 to 1:100, in a closed system at a temperature of 0°C to 60°C for a period of 2 hours to 10 days, producing a precipitate containing a flavylium salt. 2. Reacting the flavylium salt with an amine, with a flavylium salt to amine molar equivalent ratio of 1:3 to 1:5, in an aprotic solvent for a second period of 2 hours to 2 days, producing a mixture comprising a 4-quinolone compound in the solvent. 3. Purifying the 4-quinolone compound from the mixture. The method does not require protecting hydroxyl groups on the flavone and can use strong acids other than perchloric acid.
In summary, the claims protect pharmaceutical compositions based on new compounds targeting steroid hormone receptor-dependent proliferative disorders, methods for their use in treatment, and efficient synthetic methods for producing key compounds.
Stated Advantages
The compounds selectively disrupt the interaction between AR and ELK1, effectively inhibiting growth of AR-dependent cancer cells, including those resistant to standard therapies.
The compositions are poor inducers and substrates for major human hepatic drug-metabolizing enzymes, reducing the potential for drug-drug interactions.
The compounds show limited activity in AR-negative cell lines, indicating target-selectivity and reduced off-target effects.
The synthetic methods described avoid the use of perchloric acid, improving safety during compound preparation.
The pharmaceutical compositions are effective against both wild-type and splice variant forms of the androgen receptor, including forms involved in treatment-resistant cancer.
Documented Applications
Treatment of steroid hormone receptor-dependent proliferative disorders, including both cancers and non-cancer disorders characterized by abnormal cell proliferation.
Treatment of androgen receptor-dependent cancers, such as androgen receptor-dependent prostate cancer and breast cancer.
Treatment of estrogen receptor-dependent cancers, including estrogen receptor-dependent breast cancer.
Treatment of steroid hormone receptor-dependent bladder cancer.
Treatment of benign prostate hyperplasia (BPH).
Combination therapies with additional therapeutic agents including anti-cancer drugs and immune checkpoint inhibitors.
Use in commercial pharmaceutical packages for treating proliferative disorders in subjects.
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