Bronchodilating alpha, beta-unsaturated isoquinoline amides
Inventors
Dalence, Maria • Johansson, Martin • Thornqvist Oltner, Viveca • TOFTERED JOERGEN, null • Toftered, Jörgen • Wensbo, David
Assignees
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Publication Number
US-8318768-B2
Publication Date
2012-11-27
Expiration Date
Abstract
The invention relates to novel compounds having the general formula (I), and which compounds are useful to manufacture a medicament to treat a disorder or disease characterized by bronchoconstriction, e.g. COPD and asthma, and vasoconstriction, e.g. hypertension.
Core Innovation
The invention relates to title compound(s) of formula I defined by a constrained, multi-variable chemical structure with specific substituent selections for R1, R2, R3, and R4, and with stereochemical constraints for the double-bond of G1 and for the double-bond of G2. The structural definition further constrains X1, X2, X3, X4, and X5, independently selected from N and C with at most two nitrogens, and it optionally defines additional substitution patterns on condensed rings W1 and W2 via R7 and R10 with maximum substitution numbers n and p of 0 to 2.
The invention additionally fixes stereochemistry in both olefinic segments by requiring that, in G1, the substituents R5 and R6 are oriented in a cis-fashion or a trans-fashion relative to each other, and likewise in G2 the substituents R8 and R9 are oriented in a cis-fashion or a trans-fashion relative to each other. It also defines that W1 and W2 together represent a bicyclic aromatic system with X6, X7 and X8 each selected from N and C and with none or one of X6, X7 and X8 being N.
The compounds are defined as a free base, an acid in its non-charged protonated form, or a pharmaceutically acceptable salt, and as a pure stereoisomer, a racemic-diastereomeric-or scalemic mixture. The compound definition further includes the proviso that not both of R1 and R2 is methyl.
Claims Coverage
The independent claim coverage is directed to a compound according to formula I with constrained substituent selections, cis/trans stereochemistry for the double-bonds in G1 and G2, ring heteroatom and optional bicyclic aromatic substitution constraints, and specified compound forms. One independent claim is supported, with multiple inventive features merged from the inputs.
Compound according to formula I
A compound according to formula I with R1, R2, R3, and R4 selections; G selected from G1 and G2; in G1 the stereochemistry of the double-bond specifies that R5 and R6 are oriented in a cis-fashion or in a trans-fashion relative to each other; in G2 the stereochemistry of the double-bond specifies that R8 and R9 are oriented in a cis-fashion or in a trans-fashion relative to each other; X1, X2, X3, X4, and X5 are independently selected from N and C with 0, 1 or 2 of X1-X5 being N; and the proviso that not both of R1 and R2 is methyl.
Optional substitution and bicyclic aromatic system constraints
Q is optionally substituted with a maximum of n independently selected substituent(s) R7, where n is 0 to 2; and W1 and W2 together represent a bicyclic aromatic system with X6, X7, and X8 selected from N and C such that none or one is N, optionally substituted with a maximum of p independently selected substituent(s) R10, where p is 0 to 2.
Defined solid-form and stereoisomer availability
The compound is provided as a free base, an acid in its non-charged protonated form, or a pharmaceutically acceptable salt, and as a pure stereoisomer, a racemic-diastereomeric-or scalemic mixture.
The claim coverage centers on a formula I compound defined by constrained substituent choices, cis/trans stereochemistry for G1 and G2, capped heteroatom counts in X1-X5, optional substitution limits on Q and the bicyclic aromatic system W1/W2, and defined free base, salt, and stereoisomer forms, with exclusion of the case where both R1 and R2 are methyl.
Stated Advantages
Reduces human bronchiol contraction after LTD4 induction, with tested compounds showing reduced remaining contraction as % remaining contraction at 10 μM.
Documented Applications
In vitro bronchiol contraction assay using human bronchiols after LTD4 induction to evaluate reduction of LTD4-induced contraction by the disclosed title compound(s) of formula I.
In vitro human PBMC model in which PBMCs are treated with compound examples and then stimulated with LPS to quantify MCP-1 and LTB4 levels under −LPS and +LPS conditions.
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