Rapamycin derivatives
Inventors
BONAZZI, Simone • Connolly, Michael • Glass, David Jonathan • Mihalic, Manuel • PATTERSON, Andrew William • Roggo, Silvio • SHAVLAKADZE, Tea
Assignees
Novartis AG • Novartis Pharma AG • Novartis Institutes for Biomedical Research Inc
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Publication Number
US-12091424-B2
Publication Date
2024-09-17
Expiration Date
Abstract
The disclosure relates to compounds of formula (I) and pharmaceutically acceptable salts, and compositions thereof, wherein the substituents are as defined herein. Also provided are methods of making compounds of formula (I), and methods involving the compounds or compositions for treating disorders and diseases described herein.
Core Innovation
The invention relates to compounds of formula (I) and pharmaceutically acceptable salts, including rapamycin-derived compounds and stereochemical variants at C16. The structure is defined by selections for R1, R2, R3, R4, R5, R6, and the variables m, n, o, p, q, r, s, and X, with ring heteroatom choices including O, S, NR6, or SO2.
The disclosed compounds are positioned as agents for treating disease or disorder mediated by an mTOR pathway in a subject in need thereof. The patent text associates the compounds with inhibition of the mTORC1 complex and pathway inhibition, including p-S6/S6 and S6K1 Thr389 readouts, and describes intracellular complex formation involving FKBP12.
The disclosure further includes named rapamycin analog embodiments such as C16-(1,1-dioxidoisothiazolidin-2-yl)-C32-deoxo-rapamycin and related C16 and C40-linked variants. Final compounds are tied to stereochemical assignments at C16 using FKBP12 co-crystallization and X-ray crystallography, and the therapeutic scope includes age-related diseases and a broad set of disorders including cancers, neurodegenerative diseases, liver disorders, and kidney disorders.
Claims Coverage
The independent claims are directed to treatment methods using therapeutically effective amounts of compounds of formula (I) or pharmaceutically acceptable salts, with the treated condition limited to mTOR-pathway-mediated disease or disorder, a selected therapeutic condition list, or an age-related disease or disorder. The claim set emphasizes structural variability within formula (I) and indication-based limitations; one independent claim also recites a disease/disorder list that includes transplant rejection, inflammatory and infectious disorders, proliferative disorders, neurodegenerative diseases, mitochondrial conditions, liver disorders, and kidney disorders.
mTOR-pathway-mediated treatment using formula (I) compound or salt
A method of treating a disease or a disorder mediated by an mTOR pathway in a subject in need thereof by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, with R1, R2, R3, R4, R5, R6, m, n, o, p, q, r, s, and X defined by specified structural selections.
Selected disease category treatment using formula (I) compound or salt
A method of treating a disease or a disorder in a subject in need thereof by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from acute or chronic organ or tissue transplant rejection; transplant vasculopathies; vessel intimal thickening, blood vessel obstruction, obstructive coronary atherosclerosis, restenosis; autoimmune diseases; inflammatory conditions; asthma; multi-drug resistance (MDR); fungal infections; infection; age-related diseases; neurodegenerative diseases; proliferative disorders; seizures and seizure related disorders; mitochondrial myopathy and mitochondrial stress; liver disorders; and kidney disorders.
Age-related disease treatment using formula (I) compound or salt
A method of treating an age-related disease or disorder in a subject in need thereof by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from an enumerated list including sarcopenia, skin atrophy, cherry angiomas, seborrheic keratoses, brain atrophy, atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, high blood pressure, erectile dysfunction, cataracts, macular degeneration, glaucoma, stroke, cerebrovascular disease, chronic kidney disease, diabetes-associated kidney disease, impaired hepatic function, liver fibrosis, autoimmune hepatitis, endometrial hyperplasia, metabolic dysfunction, renovascular disease, hearing loss, mobility disability, cognitive decline, tendon stiffness, heart dysfunction, immune senescence, Parkinson's disease, Alzheimer's disease, cancer, a decrease in immune-surveillance, a decline in immune-function, chronic obstructive pulmonary disease (COPD), obesity, loss of taste, loss of olfaction, arthritis, type II diabetes, diabetic blindness, and diabetic neuropathy.
Across the independent claims, the core commonality is treatment by administering formula (I) rapamycin-derived compounds or pharmaceutically acceptable salts with defined structural-variable constraints, for diseases mediated by an mTOR pathway or for selected therapeutic indication lists, including age-related diseases.
Stated Advantages
Inhibition of the mTORC1 complex/pathway is described, including p-S6/S6 and S6K1 Thr389 readouts.
Documented Applications
Therapeutic treatment of diseases or disorders mediated by an mTOR pathway in a subject, including age-related diseases.
Treatment indications explicitly enumerated include cancers, neurodegenerative diseases, transplant rejection and transplant vasculopathies, vessel intimal thickening and restenosis, autoimmune and inflammatory conditions including asthma, multi-drug resistance (MDR), fungal infections, infections, seizures and seizure related disorders, mitochondrial myopathy and mitochondrial stress, liver disorders including liver fibrosis and inflammation, and kidney disorders including kidney fibrosis and inflammation.
Combination concept for cancer treatment optionally includes PD-1/PD-L1 inhibitors.
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