Tetrahydronaphthyridine and tetrahydropyrido[4,3-D]pyrimidine compounds and compositions thereof useful for the treatment of inflammatory and respiratory diseases
Inventors
Kelly, Michael G. • Kincaid, John • Kaub, Carl J.
Assignees
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Publication Number
US-8859545-B2
Publication Date
2014-10-14
Expiration Date
Abstract
Tetrahydronaphthyridine and tetrahydropyrido[4,3-d]pyrimidine compounds are disclosed that have formula 1: where A, B, L, N, R1, R3, R4′, Y and Z are as defined herein. The compounds and pharmaceutical compositions thereof are useful for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, respiratory conditions, and others.
Core Innovation
The invention relates to fused heterocyclic compounds defined by formula 1 and formula 1a, and related structural variants, together with a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound having formula 1. The compounds are specified by variable substituents including A, B, Y, W, Z, L, R1, R2, R2', R3, and R4', and the scope includes pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, tautomers, and isotopic variants.
A second set of compounds is defined by formula 2, in which W is N and Z is NH. In this formula, L is substituted or unsubstituted C1-C9 alkylene or substituted or unsubstituted C1-C9 heteroalkylene, R3 is selected from cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, bicycloalkyl, bicycloheteroalkyl, bicycloalkenyl, and bicycloheteroalkenyl ring types, and R1 is phenyl or pyridyl with specific substitution patterns.
The disclosure further describes tetrahydropyrido[4,3-d]pyrimidine amines and pyrido[4,3-d]pyrimidine derivatives, including substituted variants and specific example compounds, intermediates, and analytically characterized compounds. It also presents pharmacological assessment in a calcium influx assay for evaluation of antagonists at purinergic P2X2 and P2X3 receptors, including the P2X2/3 heteromer.
Claims Coverage
The consolidated content includes three independent claims: one to a formula 1 compound, one to a formula 2 compound, and one to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a formula 1 compound. The independent claims are primarily structural and define permitted substituent classes and bonding relationships.
Formula 1 compound defined by structural variables
A compound having formula 1 wherein A and B are independently selected from CR2'R2', CO, and CS; Y is CR2'R2'; W is N; Z is selected from O and NR2; L is substituted or unsubstituted C1-C9 alkylene or substituted or unsubstituted C1-C9 heteroalkylene; R1 is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; R2 is selected from hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; each R2' is independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, aryl and aralkyl; R3 is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group, provided that R3 is other than substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and R4' is H.
Formula 2 compound with constrained ring and substituent sets
A compound having formula 2 wherein W is N; Z is NH; L is substituted or unsubstituted C1-C9 alkylene or substituted or unsubstituted C1-C9 heteroalkylene; R3 is selected from cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, bicycloalkyl, bicycloheteroalkyl, bicycloalkenyl, and bicycloheteroalkenyl ring; R4' is H; R1 is phenyl substituted with 1, 2, 3, 4, or 5 R5 groups or pyridyl substituted with 1, 2, 3, or 4 R5 groups; and each R5 is independently selected from the enumerated substituent set.
Pharmaceutical composition with carrier and effective amount of formula 1 compound
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound having formula 1 wherein A and B are independently selected from CR2'R2', CO, and CS; Y is CR2'R2'; W is N; Z is selected from O and NR2; L is a bond; R1 is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; R2 is selected from hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; each R2' is independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, aryl and aralkyl; R3 is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group; and R4' is H.
Overall, the claim coverage is directed to structurally defined compound classes for formula 1 and formula 2, plus a pharmaceutical composition embodiment that includes a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a formula 1 compound.
Stated Advantages
Treatment, prevention, and amelioration of pain including inflammatory pain and neuropathic pain.
Reduction of hyperalgesia and allodynia.
Treatment, prevention, and amelioration of arthritis.
Treatment, prevention, and amelioration of asthma.
Treatment, prevention, and amelioration of Parkinson’s disease and Alzheimer’s disease.
Treatment, prevention, and amelioration of neurodegenerative disorders.
Treatment, prevention, and amelioration of inflammatory bowel disease.
Treatment, prevention, and amelioration of autoimmune disorders.
Documented Applications
Treatment, prevention, and amelioration of pain, including inflammatory pain and neuropathic pain, and related conditions such as hyperalgesia and allodynia.
Treatment, prevention, and amelioration of arthritis.
Treatment, prevention, and amelioration of asthma.
Treatment, prevention, and amelioration of Parkinson’s disease and Alzheimer’s disease.
Treatment, prevention, and amelioration of neurodegenerative disorders.
Treatment, prevention, and amelioration of inflammatory bowel disease.
Treatment, prevention, and amelioration of autoimmune disorders.
Pharmaceutical composition embodiments are described.
Oral, injectable, transdermal, and topical administration are described in the disclosed content.
Treatment-use statements cover neurodegenerative conditions, autoimmune disorders, and inflammatory conditions.
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