Piperazinone compounds as anti-tumor and anti-cancer agents and methods of treatment
Inventors
Hamilton, Andrew D. • Sebti, Said • Peng, Hairuo
Assignees
Yale University • University of South Florida • University of South Florida St Petersburg
Publication Number
US-7763620-B2
Publication Date
2010-07-27
Expiration Date
2022-08-23
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Abstract
The present invention relates to piperazinone compounds, pharmaceutical compositions containing those compounds and methods of treating tumors and cancer, among other disease states and conditions in mammalian patients, especially including humans.
Core Innovation
The present invention relates to piperazinone compounds, pharmaceutical compositions containing those compounds, and methods for treating tumors and cancer in mammalian patients, especially humans. The compounds are defined by specific structural features, with varied substituents including alkyl, aryl, heterocycle, and amino acid groups, and all geometric and optical isomers as well as pharmaceutically acceptable salts are contemplated. The compounds are formulated for administration with a pharmaceutically acceptable additive, carrier, or excipient, and are aimed at providing effective anticancer therapies.
The invention addresses the problem of current chemotherapeutic approaches, which are limited by inherent toxicity and tumor resistance. It is especially significant to find less toxic anti-tumor agents capable of inhibiting growth of resistant tumors. The focus is on inhibition of GGTase enzymes, particularly GGTase I, which are implicated in critical post-translational protein modifications required for tumorigenesis and metastasis. The development of highly selective GGTase-I inhibitors offers a promising approach for novel anticancer agents with reduced toxicity.
Methods are disclosed for administering these compounds to inhibit GGTase I enzyme in patients, thus providing a pharmacological effect consistent with GGTase inhibition. Additionally, methods for treating tumors and/or cancer, hyperproliferative cell growth, psoriasis, intimal hyperplasia, and chronic inflammatory diseases are described. The invention includes detailed synthesis procedures, compound characterizations, and experimental data demonstrating the compounds' capability to inhibit GGTase activity in vitro, along with in vivo efficacy in reducing tumor growth in animal models.
Claims Coverage
The patent contains several independent claims outlining key inventive features related to piperazinone compounds, their pharmaceutical compositions, methods of enzyme inhibition, and methods of treating disease.
Piperazinone compound with defined substituents
A compound defined by a specific structure wherein various substituents (R1, R2, R3, R4, R5) have particular identities such as C5-C15 alkyl or alkenyl group, aryl, heterocycle, alkylenearyl, alkenylenearyl, alkyleneheterocycle, alkenylene heterocycle, with certain preferences and structural restrictions, including their possible substitution, geometric, and optical isomers, or pharmaceutically acceptable salts.
Pharmaceutical composition containing defined compound
A pharmaceutical composition comprising an effective amount of at least one of the specified piperazinone compounds, in combination with a pharmaceutically acceptable additive, carrier, or excipient.
Method of inhibiting GGTase I enzyme
A method for inhibiting GGTase I enzyme in a mammal by administering an effective amount of the mentioned piperazinone compound to reduce the activity of GGTase I by at least about 100 fold.
Compound according to alternative specific structure
A compound having a formula as defined by another set of specific substituent identities (as per claim 11 and claim 12), with options for further substitution on R2 and R3 groups, covering different chemical variations within the piperazinone scaffold.
The independent claims cover the structural definition of new piperazinone compounds, their formulations as pharmaceutical compositions, methods for inhibiting GGTase I enzyme in mammals, and alternative specific chemical structures. These features extend to methods of treatment and cover a broad range of chemical variations within the piperazinone scaffold.
Stated Advantages
The compounds provide antitumor and anticancer activity with low toxicity to host cells.
Compounds are particularly useful for treating drug resistant cancers.
Highly selective inhibition of GGTase I is achieved, which is beneficial for targeting tumors with less toxicity.
The compounds have favorable water solubility, high potency, and exceptional selectivity for GGTase I inhibition.
The compositions may be administered prophylactically to help prevent tumor and/or cancer and delay onset of related diseases in patients at risk.
Documented Applications
Treatment of tumors and/or cancer in mammals, especially humans.
Treatment of benign and malignant neoplasia, including cancers such as stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, prostate, testis, bladder, renal, brain/cns, head and neck, throat, Hodgkins disease, non-Hodgkins leukemia, multiple myeloma leukemias, skin melanoma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms Tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx, oesophagus, larynx, melanoma, kidney, and lymphoma.
Treatment of hyperproliferative cell growth and psoriasis and related conditions.
Treatment of arthritis and chronic inflammatory diseases, including rheumatoid arthritis and osteoarthritis.
Prophylactic treatment to prevent or delay onset of tumors/cancer, psoriasis, arthritis, atherosclerosis, intimal hyperplasia, and chronic inflammatory diseases.
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