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Publication Number
US-10131640-B2
Publication Date
2018-11-20
Expiration Date
Abstract
Disclosed are novel compounds that are useful in regulating the expression of interleukin-6 (IL-6) and/or vascular cell adhesion molecule-1 (VCAM-1), and their use in the treatment and/or prevention of cardiovascular and inflammatory diseases and related disease states, such as, for example, atherosclerosis, asthma, arthritis, cancer, multiple sclerosis, psoriasis, and inflammatory bowel diseases, and autoimmune disease(s). Also, disclosed are compositions comprising the novel compounds, as well as methods for their preparation.
Core Innovation
The invention relates to methods for reducing IL-6 and/or VCAM-1 in a subject by administering a therapeutically effective amount of at least one compound of Formula I, including stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates. Formula I is defined by extensive structural variables including Q, V, U, Rc, Ra1, Ra2, Ra3, Rb2, Rb3, Rb5, and Rb6, together with an optionally fused 3-8 membered ring system defined by W and Z selections. The scope is further limited by conditional requirements and explicit exclusions of specific quinazolin-4(3H)-one compounds.
The patent also includes methods for reducing IL-6 and/or VCAM-1 using selected quinazolin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives, including pharmaceutically acceptable salts and hydrates. The administered compounds are specifically enumerated and include substituted derivatives with groups such as piperazinyl, piperidinyl, pyrrolidinyl, diazepanyl, and carbonyl-containing groups. The therapeutic intent remains reduction of IL-6 and/or VCAM-1 in a subject.
Further embodiments tie the biomarker reduction to treating and/or reducing the risk of acquiring cardiovascular disorders, inflammatory diseases, and/or cancer characterized by altered expression of IL-6 and/or VCAM-1 proliferation. The claims also list specific inflammatory diseases and cancer types to which the methods apply. The patent additionally identifies pharmaceutically acceptable compositions including at least one pharmaceutically acceptable carrier.
Claims Coverage
The independent claims cover a broad method for reducing IL-6 and/or VCAM-1 using Formula I compounds, a method using a specified list of compounds, the Formula I compound definition itself, and a selected-compounds chemical entity claim. Across these independent claims, the inventive coverage centers on biomarker-targeted administration of defined quinazolin/pyridopyrimidinone derivatives with extensive structural constraints, optional salts and hydrates, and specified exclusions.
Reduce IL-6 and/or VCAM-1 by Formula I compound administration
A method for reducing IL-6 and/or VCAM-1 in a subject by administering a therapeutically effective amount of at least one compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, with defined selections for Q, V, U, Rc, Ra1, Ra2, Ra3, Rb2, Rb3, Rb5, and Rb6, together with an optionally fused 3-8 membered ring system and conditional exclusions of specific compounds.
Reduce IL-6 and/or VCAM-1 by administering selected listed compounds
A method for reducing IL-6 and/or VCAM-1 in a subject by administering a therapeutically effective amount of at least one compound selected from the enumerated quinazolin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives, including pharmaceutically acceptable salts and hydrates thereof.
Formula I compound definition
A compound of Formula I, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein Q is selected from CH and nitrogen, V is nitrogen, U is selected from C=O and SO2, Rc is selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl, and Ra/Rb substituent selections and the 3-8 membered ring system are defined by stated ranges, optional fusion, conditional constraints, and exclusions.
Specific selected compounds
A compound selected from the listed quinazolin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives, and pharmaceutically acceptable salts and hydrates thereof.
Overall claim coverage centers on reducing IL-6 and/or VCAM-1 in a subject by administering therapeutically effective amounts of either broadly defined Formula I compounds or explicitly enumerated quinazolin/pyridopyrimidinone derivatives, with direct claim coverage also given to the Formula I chemical entity and a selected list of compounds.
Stated Advantages
Reduces IL-6 and/or VCAM-1 in a subject.
Treats and/or reduces the risk of acquiring cardiovascular disorders, inflammatory diseases, and/or cancer characterized by altered expression of IL-6 and/or VCAM-1 proliferation.
Documented Applications
Treating and/or reducing the risk of acquiring cardiovascular disorders, inflammatory diseases, and/or cancer characterized by altered expression of IL-6 and/or VCAM-1 proliferation.
Treating inflammatory diseases including arthritis, rheumatoid arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, ocular inflammation, uveitis, rhinitis, ischemic-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Grave's disease, gastrointestinal allergies, and conjunctivitis.
Treating cancer including multiple myeloma, lymphoma, leukemia, solid tumors, prostate cancer, bladder cancer, cardiac myxoma, cerebral edema secondary to brain tumors, hormone-independent prostate cancer, B cell lymphoma, AIDS-associated lymphoma, and metastatic renal cell carcinoma.
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