Compounds for the prevention and treatment of cardiovascular diseases
Inventors
Assignees
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Publication Number
US-10532054-B2
Publication Date
2020-01-14
Expiration Date
Abstract
The present disclosure relates to compounds, which are useful for regulating the expression of apolipoprotein A-I (ApoA-I), and their use for treatment and prevention of cardiovascular disease and related disease states, including cholesterol- or lipid-related disorders, such as, for example, atherosclerosis.
Core Innovation
The invention provides compounds of Formula II and related Formula II derivatives, optionally as pharmaceutically acceptable salts and hydrates thereof. The compounds are characterized by a defined core scaffold having variable positions X and Y and multiple substituent groups with extensive selection ranges, together with conditional provisos that restrict how particular substituents may be combined, including relationships among R1, R3, R7, R2, R6, R8, W, and p.
The structural framework is further constrained by selections involving W and p and by bonding restrictions where Z1 is a double bond and Z2 and Z3 are each a single bond. Additional conditional statements specify which substituent groups are permitted under certain variable settings, including constraints on R10, R7, R2, and related substituents.
In particular embodiments, the invention identifies specific compound members within the general Formula II framework, including 1,6-naphthyridin-5(6H)-one derivatives and quinazolinone/phenol derivatives. The document also discloses compounds selected from 7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one and 4-(1,6-naphthyridin-7-yl)phenol, together with substitution patterns such as hydroxyl and dimethyl phenyl groups and other named heterocyclic structures.
Claims Coverage
The independent claims cover Formula II compounds with extensive substituent-variable selection and multiple conditional provisos, narrower Formula II instantiations, and a separate independent claim directed to specific naphthyridinone/phenol structures. Across the independent claims, the main inventive features are the Formula II structural definitions with conditional substituent restrictions and the inclusion of pharmaceutically acceptable salts and hydrates.
Formula II compound with conditional substituent selection and provisos
A compound of Formula II with variable X and Y positions, multiple substituent groups selected within defined ranges, R5 and R9 fixed as hydrogen, R7 selected from amino, amide, alkyl, hydroxyl, or alkoxy, constraints on R10, W and p, Z1/Z2/Z3 bonding restrictions, and conditional provisos restricting allowable combinations, including pharmaceutically acceptable salts and hydrates thereof.
Enumerated naphthyridinone/phenol compound selection
A compound selected from 7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one and 4-(1,6-naphthyridin-7-yl)phenol, including pharmaceutically acceptable salts and hydrates thereof.
Formula II compound with narrower substituent definitions and provisos
A compound of Formula II with X as CH and Y as CO, R1 and R3 independently selected from alkoxy and hydrogen, R2 selected from alkoxy, alkyl, or hydrogen, R6 and R8 independently selected from alkyl, alkoxy, halogen, or hydrogen, R5 and R9 fixed as hydrogen, R7 selected from amino, hydroxyl, substituted ethoxy, or alkyl substituted with a heterocyclyl, R10 fixed as hydrogen, plus variable W and p and Z1/Z2/Z3 bonding constraints and provisos restricting relationships among substituents, together with pharmaceutically acceptable salts and hydrates.
Formula II compound with specified R7 options and detailed R2, R6, R8, and R10 constraints
A compound of Formula II with X selected from CR11, Y selected from CO, R11 selected from hydrogen and unsubstituted alkyl, alkenyl, or alkynyl, R1 selected from alkoxy or amino, R3 as alkoxy, R2 selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, or hydrogen, R6 and R8 each independently selected from alkyl, alkoxy, amino, halogen, or hydrogen, R5 and R9 fixed as hydrogen, R7 selected from amino, amide, alkyl, or alkoxy, R10 selected from hydrogen and methyl, plus W and p and Z1/Z2/Z3 bonding constraints and a conditional proviso tied to R7 selection, and including pharmaceutically acceptable salts and hydrates.
Overall, the independent claims cover a family of Formula II compounds defined by variable substituent selection and multiple conditional provisos that restrict how substituents may co-occur, together with inclusion of pharmaceutically acceptable salts and hydrates. The claims also include an independent selection limited to specific named naphthyridinone/phenol members.
Stated Advantages
The document states that increasing ApoA-I expression can raise HDL-C and reduce cholesterol.
The document describes prevention and treatment of cardiovascular disease, including atherosclerosis, and treatment of cholesterol- or lipid-related disorders.
Documented Applications
ApoA-I mRNA quantification assay in HepG2 cells where compounds are identified as active when they increase ApoA-I mRNA by more than 15% at ≤100 μM.
ApoA-I mRNA and protein induction evaluations, and in vivo efficacy evaluations in hApoA-I transgenic mice and C57BL/6 wild-type mice using ELISA and HDL-C measurements.
Preventing and treating cardiovascular disease, including atherosclerosis.
Treating cholesterol- or lipid-related disorders.
Regulating ApoA-I expression, including via increasing ApoA-I expression to raise HDL-C and reduce cholesterol.
Regulating ApoA-II, as described in embodiments.
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